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February 2, 2023

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Scientists first in the world to regenerate diseased kidney cells

by Federico Graciano, Duke-NUS Medical School

In a world first, scientists at Duke-NUS Medical School, the National Heart Center Singapore (NHCS) and colleagues in Germany have shown that regenerative therapy to restore impaired kidney function may soon be a possibility.

In a preclinical study reported in Nature Communications , the team found that blocking a damaging and scar-regulating protein called interleukin-11 (IL-11) enables damaged kidney cells to regenerate, restoring impaired kidney function due to disease and acute injuries.

"Kidney failure is a global epidemic," said Assistant Professor Anissa Widjaja, a molecular biologist with Duke-NUS' Cardiovascular & Metabolic Disorders (CVMD) Signature Research Program. "Closer to home, Singapore ranks first in the world for diabetes-induced kidney failure and fourth in terms of kidney failure prevalence. The contribution of chronic kidney disease to mortality is rapidly increasing, suggesting there are shortcomings in current therapeutic approaches."

Searching for ways to restore the kidney's ability to regenerate damaged cells, Widjaja worked with Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine at the SingHealth Duke-NUS Academic Medical Center and the CVMD Program, and Clinician Scientist and Senior Consultant with the Department of Cardiology, NHCS, and Duke-NUS Dean Professor Thomas Coffman, a world-leading nephrologist. They teamed up with scientists in Germany to investigate the role of IL-11, which is known to trigger scarring in other organs, including the liver, lungs and heart, in acute and chronic kidney disease.

Their findings implicate the protein in triggering a cascade of molecular processes in response to kidney injury that leads to inflammation, fibrosis (scarring) and loss of function. They also discovered that inhibiting IL-11 with a neutralizing antibody can prevent and even reverse kidney damage in this setting.

"We found that IL-11 is detrimental to kidney function and triggers the development of chronic kidney disease," said Cook. "We also showed that anti-IL11 therapy can treat kidney failure, reverse established chronic kidney disease, and restore kidney function by promoting regeneration in mice, while being safe for long term use."

More specifically, the researchers showed that renal tubular cells, which line the tiny tubes inside kidneys, release IL-11 in response to kidney damage . This turns on a signaling cascade that ultimately leads to increased expression of a gene, called Snail Family Transcriptional Repressor 1 (SNAI1), which arrests cellular growth and promotes kidney dysfunction.

In a preclinical model of human diabetic kidney disease, turning off this process by administering an antibody that binds to IL-11 led to proliferation of the kidney tubule cells and reversal of fibrosis and inflammation, resulting in the regeneration of the injured kidney and the restoration of renal function.

While clinical trials of an antibody that binds to another pro-fibrotic molecule called transforming growth factor beta have been unsuccessful, this new approach brings hope of a new target.

"By boosting the kidney's intrinsic capability to regenerate, Prof. Cook and Asst. Prof. Widjaja have shown that we can restore function to a damaged kidney," said Coffman, who is also the principal investigator of the Diabetes Study in Nephropathy and other Microvascular Complications (DYNAMO), a large collaborative study that aims to find new solutions for the prevention and treatment of diabetic kidney disease.

"This discovery could be a real game-changer in the treatment of chronic kidney disease —which is a major public health concern in Singapore and globally—bringing us one step closer to delivering the benefits promised by regenerative medicine."

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Novartis receives FDA accelerated approval for Fabhalta® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN)

Ad hoc announcement pursuant to Art. 53 LR

• Fabhalta achieved a 44% proteinuria reduction from baseline in Phase III APPLAUSE-IgAN interim analysis, compared with 9% in placebo arm, demonstrating a clinically meaningful reduction of 38% vs. placebo (p<0.0001) 1
• Fabhalta is an inhibitor of the alternative complement pathway, activation of which is thought to contribute to the pathogenesis of IgAN 1-4
• Despite current standard of care, up to 50% of IgAN patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis 5-11
• This marks the first approval from Novartis’ renal pipeline, which also includes atrasentan and zigakibart

Basel, August 8, 2024 – Novartis today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Fabhalta ® (iptacopan), a first-in-class complement inhibitor for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. This is generally defined as a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g 1 . Fabhalta specifically targets the alternative complement pathway of the immune system. When overly activated in the kidneys, the complement system is thought to contribute to the pathogenesis of IgAN 1- 4 .

This indication is granted under accelerated approval based on the pre-specified interim analysis of the Phase III APPLAUSE-IgAN study measuring reduction in proteinuria at 9 months compared to placebo. It has not been established whether Fabhalta slows kidney function decline in patients with IgAN. The continued approval of Fabhalta may be contingent upon verification and description of clinical benefit from the ongoing Phase III APPLAUSE-IgAN study, evaluating whether Fabhalta slows disease progression as measured by estimated glomerular filtration rate (eGFR) decline over 24 months 1 . The eGFR data are expected at study completion in 2025 and are intended to support traditional FDA approval.

“The heterogeneous and progressive nature of IgA nephropathy has made it challenging to effectively treat this disease. Thankfully, the treatment landscape is rapidly evolving,” said Professor Dana Rizk, Investigator and APPLAUSE-IgAN Steering Committee Member and professor in the University of Alabama at Birmingham Division of Nephrology. “Mounting clinical evidence underscores the pivotal role of complement activation in IgA nephropathy. I am thrilled that this advancement is now available to help enable a targeted treatment approach for IgAN patients.”

IgAN is a progressive, rare disease in which the immune system attacks the kidneys, often causing glomerular inflammation and proteinuria 12 . Approximately 25 people per million worldwide are newly diagnosed with IgAN each year 13 . Each person’s disease journey is unique as IgAN progresses differently and treatment responses vary as well 12,14 .

Despite current standard of care, up to 50% of IgAN patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis. These patients often require maintenance dialysis and/or kidney transplantation 5 - 11 . Effective, targeted therapies with different mechanisms of action can help physicians select the most appropriate treatment for patients 12,14 .

Data supporting approval The ongoing Phase III APPLAUSE-IgAN study is evaluating the efficacy and safety of twice-daily oral Fabhalta (200 mg) versus placebo in adult IgAN patients on a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy with or without a stable dose of SGLT2i. The primary endpoint for the interim analysis was the percent reduction of proteinuria, a marker of kidney damage, measured by comparing UPCR at 9 months to baseline 1, 4 .

Fabhalta achieved a 44% reduction in proteinuria at 9 months relative to baseline, compared with a 9% reduction in the placebo arm, demonstrating a clinically meaningful and statistically significant 38% reduction vs. placebo (p<0.0001). The treatment effect on UPCR at 9 months was consistent across all subgroups, including age, sex, race and baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i 1 . Fabhalta demonstrated a favorable safety profile, consistent with previously reported data 1, 13 . In patients with IgAN, the most common adverse reactions (≥5%) with Fabhalta were upper respiratory tract infection, lipid disorder, and abdominal pain. Fabhalta may cause serious infections caused by encapsulated bacteria and is available only through a Risk Evaluation and Mitigation Strategy (REMS) that requires specific vaccinations 1 .

Expanding commitment in IgAN “Today’s approval of Fabhalta as a first-in-class medicine for IgA nephropathy is an important milestone in our journey to evolve rare renal disease care by bringing new treatments to people in urgent need of options,” said Victor Bultó, President US, Novartis. “We are deeply committed to those living with rare renal diseases and look forward to continued partnership with this community as we further advance our broad portfolio.”

Novartis is advancing the late-stage development of two additional IgAN therapies with highly differentiated mechanisms of action: atrasentan, an investigational oral endothelin A receptor antagonist that received FDA filing acceptance in Q2 2024, and zigakibart, an investigational subcutaneously administered anti-APRIL monoclonal antibody that is currently in Phase III development.

“As a parent of a son living with the disease for 20 years, I understand firsthand the fear and uncertainty that come with an IgAN diagnosis, and the devastating impact it can have on patients and their families,” said Bonnie Schneider, Director and Co-Founder, IgAN Foundation. “Today’s approval offers new hope for people living with IgA nephropathy as it represents a treatment innovation that provides us with a new way to fight this multifaceted disease.”

About APPLAUSE-IgAN APPLAUSE-IgAN ( NCT04578834 ) is a Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of twice-daily oral Fabhalta (200 mg) in 518 adult primary IgAN patients 1 ,15 .  

The two primary endpoints of the study for the interim and final analysis, respectively, are proteinuria reduction at 9 months as measured by 24 hour UPCR, and the annualized total eGFR slope over 24 months 1, 4 . At the time of final analysis, the following secondary endpoints will also be assessed: proportion of participants reaching UPCR <1 g/g without receiving corticosteroids/immunosuppressants or other newly approved drugs or initiating new background therapy for treatment of IgAN or initiating kidney replacement therapy (KRT), time from randomization to first occurrence of composite kidney failure endpoint event, and change from baseline to 9 months in the fatigue scale as measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire 1 5,16 .   

The main study population included 250 IgAN patients with an eGFR ≥30 mL/min/1.73 m 2 and UPCR ≥1 g/g at baseline 1 5 ,1 6 . In addition, a smaller cohort of patients with severe renal impairment (eGFR 20–30 mL/min/1.73 m 2 at baseline) was also enrolled to provide additional information but will not contribute to the main efficacy analyses 1 .

Novartis in rare kidney diseases At Novartis, our journey in nephrology began more than 40 years ago when the development and introduction of cyclosporine helped reimagine the field of transplantation and immunosuppression. We continue today with a broad renal R&D portfolio targeting the underlying causes of disease to preserve kidney function. We aim to help transform the lives of people living with kidney diseases enabling them to live longer without the need for dialysis or transplantation.

Discovered at Novartis, Fabhalta (iptacopan) is the first of our renal pipeline to receive FDA approval. Novartis is also studying the investigational agents atrasentan and zigakibart for IgAN.

Beyond IgAN, Fabhalta is in development for a range of additional rare diseases, including C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and lupus nephritis (LN). Studies are ongoing to evaluate the safety and efficacy profiles in these investigational indications and support potential regulatory submissions. Fabhalta submissions to the FDA and EMA for the treatment of C3G are planned by year-end.

Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” “progress,” “accelerated,” “targets,” “continued,” “contingent,” “progressive,” “evolving,” “enable,” “innovation,” “ongoing,” “evaluating,” “evolve,” “committed,” “advance,” “advancing,” “commitment,” “to developing,” “to provide, “development,” “to address,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Fabhalta or the other investigational or approved products described in this press release, or regarding potential future revenues from such product. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Fabhalta or the other investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. 

About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn , Facebook , X/Twitter and Instagram .

• FABHALTA prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2024.
• Lafayette RA, Kelepouris E. lmmunoglobulin A nephropathy: advances in understanding of pathogenesis and treatment. Am J Nephrol . 2018;47(suppl 1):43-52.
• Rizk DV, Maillard N, Julian BA, et al. The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol . 2019;10:504.
• Perkovic V, Kollins D, Renfurm R, et al. Efficacy and Safety of Iptacopan in Patients with IgA Nephropathy: Interim Results from the Phase 3 APPLAUSE-IgAN Study. Presented at the World Congress of Nephrology (WCN); April 15, 2024; Buenos Aires, Argentina.
• Xie J et al. PLoS One . 2012;7;e38904.
• Rodrigues J, et al. Clin J Am Soc Nephrol . 2017;12(4):677-686.
• Pitcher D et al. Clin J Am Soc Nephrol . 2023;18(6):727-738.
• Hastings MC et al. Kidney Int Rep . 2018;3(1):99-104.
• Sim JJ et al. Poster TH-PO615 presented at: ASN Kidney Week 2023; November 2-5, 2023; Philadelphia, PA.
• Bobart SA et al. Nephrol Dial Transplant . 2021;36(5):840-847.
• Saha MK et al. Poster TH-PO1016 presented at: ASN Kidney Week 2019; November 5-10, 2019; Washington, DC.
• Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int . 2021;100(4):S1-S276.
• Zhang H, Rizk DV, Perkovic V, et al. Results of a Randomized Double-Blind Placebo-Controlled Phase 2 Study Propose Iptacopan as an Alternative Complement Pathway Inhibitor for IgA Nephropathy. Kidney Int . 2024;105(1):189-199.
• Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An Update on the Pathogenesis and Treatment of IgA Nephropathy. Kidney Int . 2012;81(9):833-843.
• ClinicalTrials.gov. NCT04578834. A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase III Study to Evaluate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients. Available from: https://clinicaltrials.gov/ct2/show/NCT04578834 . Accessed June 2024.
• Rizk DV, Rovin BH, Zhang H, et al. Targeting the Alternative Complement Pathway with Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. Kidney Int Rep . 2023;8(5):968-979.

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FDA Approves Treatment for Chronic Kidney Disease

FDA News Release

Approval is First to Cover Many Causes of Disease

Today, the U.S. Food and Drug Administration approved Farxiga (dapagliflozin) oral tablets to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.  

“Chronic kidney disease is an important public health issue, and there is a significant unmet need for therapies that slow disease progression and improve outcomes,” said Aliza Thompson, M.D., M.S., deputy director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Farxiga for the treatment of chronic kidney disease is an important step forward in helping people living with kidney disease.” 

Chronic kidney disease occurs when the kidneys are damaged and cannot filter blood normally. Due to this defective filtering, patients can have complications related to fluid, electrolytes (minerals required for many bodily processes), and waste build-up in the body. Chronic kidney disease sometimes can progress to kidney failure. Patients also are at high risk of cardiovascular disease, including heart disease and stroke. 

The efficacy of Farxiga to improve kidney outcomes and reduce cardiovascular death in patients with chronic kidney disease was evaluated in a multicenter, double-blind study. In this study, 4,304 patients were randomly assigned to receive either Farxiga or a placebo. The study compared the two groups for the number of patients whose disease progressed to a composite (or combined) endpoint that included at least a 50% reduction in kidney function, progression to kidney failure, or cardiovascular or kidney death. Results showed that 197 of the 2,152 patients who received Farxiga had at least one of the composite endpoint events compared to 312 of the 2,152 patients who received a placebo. The study also compared the two groups for the number of patients who were hospitalized for heart failure or died from cardiovascular disease. A total of 100 patients who received Farxiga were hospitalized or died compared to 138 patients who received a placebo. 

Farxiga was not studied, nor is expected to be effective, in treating chronic kidney disease among patients with autosomal dominant or recessive polycystic (characterized by multiple cysts) kidney disease or among patients who require or have recently used immunosuppressive therapy to treat kidney disease. 

Patients should not use Farxiga if they have a history of serious hypersensitivity reactions to the medication or if they are on dialysis treatment. Serious, life-threatening cases of Fournier’s Gangrene have occurred in patients with diabetes taking Farxiga. Patients should consider a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia (low blood sugar) if they are also taking Farxiga. Farxiga can cause dehydration, serious urinary tract infections, genital yeast infections, and metabolic acidosis or ketoacidosis (acid build-up in the blood). Patients should be assessed for their volume status and kidney function before starting Farxiga. 

Farxiga was originally approved in 2014 to improve glycemic control in adults with type 2 diabetes in addition to diet and exercise.

Farxiga received Fast Track , Breakthrough Therapy and Priority Review designations for the indication being approved today. Fast track is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Breakthrough therapy designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). Priority review directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications.

The FDA granted the approval of Farxiga to AstraZeneca.

Related Information

• NIH: Chronic Kidney Disease

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Advances in the management of chronic kidney disease

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• Peer review
• Teresa K Chen , assistant professor 1 ,
• Melanie P Hoenig , associate professor 2 ,
• Dorothea Nitsch , professor 3 ,
• Morgan E Grams , professor 4
• 1 Kidney Health Research Collaborative and Division of Nephrology, Department of Medicine, University of California San Francisco; and San Francisco VA Health Care System, San Francisco, CA, USA
• 2 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
• 3 Department of Non-Communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
• 4 Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
• Correspondence to: M E Grams Morgan.Grams{at}nyulangone.org

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.

Introduction

Chronic kidney disease (CKD) affects approximately 10% of the world’s population and is associated with substantial morbidity and mortality. 1 Risks of kidney failure, acute kidney injury, heart failure, cardiovascular disease, and hospital admissions are all heightened in people with CKD. 2 The Global Burden of Disease Consortium projects that CKD will be in the top five conditions contributing to years of life lost by 2040. 3 However, CKD remains under-recognized by both patients and providers. 1 A diverse entity, CKD is most commonly attributed to diabetes or high blood pressure, but many other causes exist, from genetic causes to adverse effects of drugs to autoimmune processes. 2 In this review, we summarize the evidence for current paradigms of disease identification and classification, discuss new equations developed for estimating glomerular filtration rate (GFR) and harmonizing different measures of albuminuria, report major progress in individualized risk estimation of kidney failure and other adverse outcomes both for CKD in general and within specific disease entities, and describe longstanding and novel treatment strategies. Notable advances have been made in both general and cause specific therapies, including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists (MRA), and endothelin receptor antagonists. Finally, we describe major guidelines in CKD and highlight common themes as well as differences in their recommendations.

Sources and selection criteria

We searched PubMed for peer reviewed articles in the English language from 1 January 2010 to 14 July 2023 using the keywords listed in the web appendix. We additionally reviewed reference lists of selected articles, prioritizing randomized controlled trials, systematic reviews, and meta-analyses when possible but also including observational studies and reviews that were of high quality. We included older articles if we deemed them to be of high importance. Finally, we reviewed guidelines from websites of professional societies and advisory committees (for example, the National Institute for Health and Care Excellence (NICE), Kidney Disease: Improving Global Outcomes (KDIGO), US Centers for Disease Control and Prevention, US Department of Health and Human Services, and International Society of Hypertension).

Epidemiology

CKD is a global public health crisis. Recent estimates suggest that more than 700 million people have CKD, with greater burdens in low income and middle income countries. 1 4 Determining the global, regional, and national burden of disease is challenging owing to inconsistent use of estimating equations for GFR, laboratory assay standardization, and albuminuria testing. Despite this, some important observations can still be made. The prevalence of CKD increases with age and is greatest in people over 70 years. 2 In the US, compared with White people, Black people have substantially higher rates of kidney failure, followed by Native Americans, people of Hispanic ethnicity, and people of Asian descent. 5

The most commonly reported risk factors for CKD are diabetes mellitus and hypertension. 6 7 Social determinants of health are also important and likely contribute to racial disparities in kidney disease. Specific genetic variants increase risk of CKD, including variants in the APOL1 and HBB genes that are present in far greater proportions among people of African ancestry. 8 9 10 11 In Central America, Sri Lanka, Egypt, and Central India, defined geographic areas exist where many cases of CKD of unknown cause have been identified. 12 Some experts postulate that heat stress or pesticides may contribute.

Whereas the incidence of CKD is difficult to estimate, reliant as it is on testing for GFR and albuminuria, the incidence of kidney failure with the receipt of replacement therapy (KFRT) is more readily captured. Many countries have developed national registries of patients with kidney failure, allowing comparison of incidence across ages and countries. 13 For example, the countries with the highest incidence of treated kidney failure in 2020 were Taiwan, the US, and Singapore, whereas the countries with the highest prevalence were Taiwan, the Republic of Korea, and Japan. 5

Definition and classification of CKD: cause, GFR, and albuminuria staging

CKD is defined as persistent abnormalities in kidney structure or function for more than three months, manifest as either low GFR or presence of a marker of kidney damage. 2 Specifically, diagnosis requires one or more of the following: albuminuria, defined as an albumin-to-creatinine ratio (ACR) ≥30 mg per gram of creatinine (approximately ≥3 mg/mmol) or albumin excretion of ≥30 mg/day; GFR <60 mL/min/1.73 m 2 ; abnormalities on urine sediment, histology, or imaging; electrolyte or other abnormalities attributed to tubular disorders; or history of kidney transplantation. The KDIGO heat map helps with understanding of overall risk (low, moderately increased, high, and very high) of patients according to level of albuminuria (A category), level of GFR (G category), and cause of disease ( fig 1 ), such that people with normal estimated GFR but higher albuminuria have a similar risk to people with moderately reduced estimated GFR and no albuminuria.

Kidney Disease: Improving Global Outcomes heat map with guidance on monitoring. 2 Numbers in boxes indicate recommended frequency of monitoring (number of times per year). Colors denote risk as follows: green (low risk), yellow (moderately increased risk), orange (high risk), and red (very high risk). CKD=chronic kidney disease; GFR=glomerular filtration rate

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Clinical manifestations of CKD

Albuminuria.

Albuminuria is often the first sign of kidney damage, and its detection drives many treatment decisions. 2 The prevalence of albuminuria in people with diabetes or hypertension is estimated to be 32% and 22%, respectively. 14 However, only a minority of patients receive urine screening tests. 14 15 For example, the mean albuminuria screening rates across health systems in the US were 35% among adults with diabetes and 4% among adults with hypertension. 14

The gold standard for assessing albuminuria is either a sample collected mid-stream from an early morning urine void or a 24 hour urine collection; however, in situations where this is not possible, a spot collection is reasonable. 2 Quantification of albumin is preferred over that of total protein. 2 16 This preference is because the sensitivity of the total protein assay to different protein components can vary by laboratory, as well as the fact that proteinuria assessments do not easily discriminate A1 and A2 categories. Both urine albumin and urine protein are typically indexed to urine creatinine to account for differences in dilution, as urine ACR or urine protein-to-creatinine ratio (PCR). Dipstick protein assessment is generally more economical than both methods; however, like PCR, dipstick assessment can be insensitive in A1 and A2 categories. Although conversion calculators exist to aid in the harmonization of ACR and PCR measures; they do not work well at lower ranges of albuminuria. 17 18

The second axis for CKD classification focuses on GFR. 2 The gold standard for assessing GFR is direct measurement from clearance of an exogenous filtration marker such as iohexol or iothalamate; however, this is relatively cumbersome and rarely done in clinical practice. Instead, GFR is usually estimated by using plasma or serum concentrations of endogenous filtration markers, such as creatinine and cystatin C, and demographic variables. Early equations for adults, such as Modification of Diet in Renal Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) 2009 equations, used filtration markers along with age, sex, and race (Black versus non-Black) to estimate GFR. 19 20 21 The newer European Kidney Function Consortium equation, which allows for seamless GFR evaluation from infancy to old age, uses a population specific divisor to adjust creatinine values (for example, separate values for Black European and White European populations). 22 However, the use of race in GFR estimation has faced strong criticism and, in 2021, the US based American Society of Nephrology-National Kidney Foundation Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recommended immediate adoption of the race-free CKD-EPI 2021 estimating equations, which exist for creatinine alone (eGFRcr) as well as for creatinine and cystatin C (eGFRcr-cys). 23 24 25 Cystatin C has distinct confounders (non-GFR determinants) of its relation with GFR compared with creatinine ( fig 2 ). 2 26 Thus, eGFRcr-cys is a more accurate estimate of GFR than eGFRcr alone, irrespective of equation used, in most scenarios, including those in which large differences exist between eGFRcr and that estimated solely using cystatin C (eGFRcys). 25 27 28 However, the newest GFR estimating equations have not been tested extensively in Asian populations. 29 30

Common non-glomerular filtration rate (GFR) determinants of blood concentrations of creatinine and cystatin C. 2 26 eGFR=estimated glomerular filtration rate

The third axis for classification is cause of CKD, which is generally ascertained through imaging, assessment of extrarenal manifestations and biomarkers, or kidney biopsy. 2 Classification of cause typically hinges on the presence or absence of systemic disease (for example, obesity, diabetes, hypertension, systemic autoimmune disease) and the specific location of the kidney pathology (for example, glomeruli, tubulointerstitium, vasculature, or cystic/congenital abnormality). Unfortunately, the cause of CKD is often unknown, limiting its utility. Molecular phenotyping and genetic testing are increasingly being used to assign cause of disease. Targeted gene panels offered commercially may have high diagnostic yields in select populations, such as patients with glomerular disease, nephrotic syndrome, or congenital anomalies of the kidney and urinary tract. 31 One study suggested that for appropriately selected patients, 34% had disease either reclassified or assigned on the basis of genetic testing, thus changing clinical management. 32 The European Renal Association and the European Rare Kidney Disease Reference Network have issued a joint statement providing recommendations for how to provide genetic testing, including specific settings in which it may be considered ( box 1 ). 33

European Renal Association and European Rare Kidney Disease Reference Network recommendations for settings in which genetic testing might be considered 33

Most tubulopathies

Glomerulopathies:

Congenital nephrotic syndrome

Nephrotic syndrome refractory to standard steroid therapy

Multi-organ phenotypes suggestive of syndromic steroid resistant nephrotic syndrome

Complement disorders:

Immune complex mediated membranoproliferative glomerulonephritis

C3 glomerulopathy

Atypical hemolytic uremic syndrome

Renal ciliopathies

Congenital anomalies of the kidney and urinary tract

Patients aged <50 years with severe CKD of unknown cause

Patients aged >50 years with adult onset CKD and family history of CKD

CKD=chronic kidney disease

Individualized prognosis and treatment

Identifying the cause of CKD is critical as different causes of CKD carry different prognoses and can have distinct treatments. 2 For example, autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of CKD and is typically associated with faster progression than other disease entities. 32 34 Individualized prognosis is often determined by using disease specific risk classification or calculators (for example, the Mayo classification or the ADPKD Prognostic Tool), and screening and treatment recommendations such as increased fluid intake and tolvaptan are unique to this entity. 35 36 37 38 IgA nephropathy, the most common type of glomerulonephritis worldwide, particularly in East Asian and Pacific Asian countries, 39 has its own prognostic aids, such as the International IgA Nephropathy Prediction Tool, 40 41 and treatments specific to IgA nephropathy are in various stages of development. 42 The APOL1 high risk genotypes confer about twofold higher risk of kidney failure in the general population and are common in people of African ancestry. 8 43 44 45 A recently published phase 2A study of targeted therapy for APOL1 related disease showed promising reductions in albuminuria; the phase 3 study is ongoing. 46 Other disease specific therapies are increasingly available, such as belimumab in lupus nephritis and lumasiran for primary hyperoxaluria type 1. 47 48

Individualized risk prediction is also available for more general populations of patients with CKD. The most widely known and validated is the kidney failure risk equation (KFRE), which is used in patients with GFR <60 mL/min/1.73 m 2 . 49 Tested in more than 30 countries and 700 000 people, the tool provides probabilities of kidney failure at two years and five years based on age, sex, and estimated GFR and albuminuria levels. 50 Like all risk equations, the KFRE may perform better with recalibration to absolute risk levels of local populations, but the discriminatory ability (that is, distinguishing people at high risk from those at low risk) has been extremely consistent across all studies. The KFRE has also been validated in recipients of kidney transplants. 51 52 Although the KFRE does not explicitly take into account the competing risk of death, estimates are quite accurate except among the members of the oldest segments of the population at the highest risk. 53 One study suggested that the KFRE provides more accurate prediction of kidney failure than both patients and providers. 54 Even within categories of GFR and urine ACR, the KFRE provides a wide estimate of risk prediction, which can be helpful in the counseling and referral of patients ( fig 3 ). Some centers will refer patients with a two year risk of kidney failure greater than 20-40% for vascular access and kidney transplantation evaluation, on the basis that tools that incorporate albuminuria provide more accurate and unbiased time to kidney failure than does estimated GFR alone. 55 Studies suggest that the KFRE is robust to different GFR equations (specifically, CKD-EPI 2009 and CKD-EPI 2021) and that many patients value being counseled using this information. 53 56

Range of predicted risk of kidney failure using the kidney failure risk equation (KFRE) within G and A categories of chronic kidney disease (CKD). The KFRE ( ckdpcrisk.org/kidneyfailurerisk ) was used to estimate two year risk of kidney failure in 350 232 patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 from the Optum Laboratories Data Warehouse (OLDW). OLDW is a longitudinal, real world data asset with deidentified administrative claims and electronic health record data. Patients with eGFR and albuminuria (urine albumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, or dipstick protein) within a two year window were included in this analysis. Different measures of albuminuria were harmonized to ACR levels for A categories ( ckdpcrisk.org/pcr2acr )

Other risk equations exist to predict the risk of cardiovascular disease and death in CKD; some of these do consider the competing risk of death ( www.ckdpcrisk.org ). For example, the advanced CKD risk tool provides simultaneous estimates of kidney failure, cardiovascular disease, and death for patients with estimated GFR <30 mL/min/1.73 m 2 , which can inform decisions on access placement and reinforce the importance of cardiovascular risk reduction. 57 Estimating risks of cardiovascular disease is particularly relevant given that many more patients with CKD have cardiovascular disease events than need KFRT. 58 Other efforts incorporate estimated GFR and albuminuria into existing tools, such as SCORE2 and the pooled cohort equation for the prediction of cardiovascular disease. 59 60

Patient specific prognostic clues may stem from discrepant estimated GFR values between eGFRcr and eGFRcys. 61 62 63 When eGFRcys is substantially lower than eGFRcr, the risk for kidney related laboratory abnormalities (for example, anemia, hyperuricemia, and hyperphosphatemia) and subsequent adverse outcomes (for example, kidney failure, heart failure, and mortality) is higher. 61 64 65 By contrast, having a lower eGFRcr than eGFRcys is associated with lower risk of adverse outcomes. 66 Risk factors for having a discrepancy between eGFRcr and eGFRcys include older age, female sex, higher body mass index, recent weight loss, and smoking.

General principles of management

The mainstays of therapy for patients with CKD include treating the underlying cause if known, and correcting risk factors (for example, albuminuria) for CKD progression and other CKD related complications ( fig 4 ). 2

Comprehensive care of patients with chronic kidney disease (CKD), irrespective of cause

Blood pressure targets

The three major studies for evaluating the optimal blood pressure target in CKD were the Modification of Diet in Renal Disease Study (MDRD), African American Study of Kidney Disease and Hypertension (AASK), and Systolic Blood Pressure Intervention Trial (SPRINT). 67 68 69 In both MDRD and AASK, intensive blood pressure control did not slow GFR decline overall. 67 68 However, in MDRD, participants with baseline proteinuria of ≥3 g/day seemed to benefit from intensive blood pressure control, with slower mean rates of GFR decline compared with their counterparts in the usual blood pressure control group. 67 Among SPRINT participants with baseline CKD (n=2646), aiming for a systolic blood pressure goal of <120 mm Hg versus <140 mm Hg did not significantly reduce the risk for a composite kidney outcome that included a ≥50% reduction in estimated GFR, long term dialysis, or kidney transplant. 69 70 However, benefits of intensive blood pressure control were seen with respect to prevention of the composite cardiovascular outcome (defined as myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes—hazard ratio 0.75, 95% confidence interval 0.64 to 0.89) and all cause mortality (hazard ratio 0.73, 0.60 to 0.90), regardless of CKD status. 69 Blood pressure control can also reduce albuminuria, as shown in the Chlorthalidone in Chronic Kidney Disease (CLICK) trial of chlorthalidone in advanced CKD. 71

Glycemic targets

Among patients with diabetes and CKD, glycemic control is an important component of comprehensive care. 72 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was the largest trial of intensive glucose control to enroll patients with CKD. 73 Among the 11 140 trial participants, 19% had an estimated GFR <60 mL/min/1.73 m 2 and 31% had albuminuria at baseline. 74 Compared with standard glucose control, intensive glucose control was associated with 9% (hazard ratio 0.91, 0.85 to 0.98), 30% (0.70, 0.57 to 0.85), and 65% (0.35, 0.15 to 0.83) lower risks of developing new onset ACR 30-300 mg/g, ACR >300 mg/g, and end stage kidney disease (ESKD), respectively.

Specific classes of therapy

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

When choosing antihypertensive agents, those that act by inhibiting the renin-angiotensin-aldosterone system (RAAS) have particular relevance in CKD. A 2001 meta-analysis of 11 studies suggested that, for non-diabetic CKD, the use of angiotensin converting enzyme (ACE) inhibitors resulted in a 30% reduction in risk of KFRT or doubling of serum creatinine. 75 Clinical trials in populations with CKD and diabetes (for example, IDNT, RENAAL) have also shown benefit of angiotensin receptor blockers (ARB) in preventing CKD progression ( table 1 ). 77 78 RAAS inhibition also plays a role in prevention of cardiovascular disease. The Heart Outcomes Prevention Evaluation (HOPE) study showed that ACE inhibitors reduced the risks of myocardial infarction, stroke, and cardiovascular death in populations at high risk for cardiovascular disease, including those with diabetes and albuminuria. 80 The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) showed that ACE inhibitors and ARB were generally equivalent in the prevention of cardiovascular events. 81 Because of the increased risk of hyperkalemia and acute kidney injury, dual therapy with both an ACE inhibitor and an ARB is typically avoided. 82

Landmark randomized clinical trials on angiotensin converting enzyme inhibitors or angiotensin receptor blockers in chronic kidney disease

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When GFR declines, providers often grapple with whether RAAS inhibitors should be continued. The Benazepril in Advanced CKD study showed that benazepril reduced the risk of the primary composite kidney endpoint by 43% compared with placebo, thus suggesting that RAAS inhibitors are beneficial even in advanced CKD (baseline serum creatinine 3.1-5.0 mg/dL). 79 Three recent reports further explored this question, also examining the benefits in prevention of death and cardiovascular events associated with continuation of RAAS inhibitors. 83 84 85 A retrospective, propensity score matched study of patients with estimated GFR <30 mL/min/1.73 m 2 showed higher risk of all cause mortality and major adverse cardiovascular events in those who stopped RAAS inhibitors compared with those who continued them, 83 as did a Swedish trial emulation study. 84 The risk of kidney replacement therapy associated with cessation of RAAS inhibitors was not statistically significant in the first study and lower in the second study. 83 84 In an open label randomized trial, cessation of RAAS inhibitors did not show significant between group differences in long term decline in estimated GFR or initiation of kidney replacement therapy, providing reassurance that RAAS inhibitors can be safely continued as GFR declines. 85

SGLT-2 inhibitors

One of the biggest advancements in CKD management over the past decade was the discovery that SGLT-2 inhibitors have robust protective effects on the heart and kidneys in patients with and without diabetes. Recent trials showed an approximate 30% reduction in risk for diverse kidney outcomes among patients with baseline estimated GFR values as low as 20 mL/min/1.73 m 2 ( table 2 ). 86 88 89 91 Importantly, the three trials designed with primary kidney outcomes (Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE), Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD), and Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY)) were terminated early because pre-specified efficacy criteria were met, with median follow-up times ranging from 2.0 to 2.6 years. 88 89 91 The overwhelming majority of trial participants were taking an ACE inhibitor or ARB before randomization, showing that the benefits of SGLT-2 inhibitors on slowing CKD progression are additive to those of RAAS inhibitors. One simulation study estimated that a 50 year old adult with non-diabetic albuminuric CKD would have seven extra years free from doubling of serum creatinine, kidney failure, or all cause mortality if treated with an SGLT-2 inhibitor and RAAS inhibitor. 92

Landmark randomized clinical trials on sodium-glucose co-transporter 2 inhibitors in chronic kidney disease (CKD)

Subgroup analyses of the DAPA-CKD and EMPA-KIDNEY trials have provided additional insights on the wide range of patients who are likely to benefit from SGLT-2 inhibitors. 89 91 In DAPA-CKD, dapagliflozin was favored over placebo in all pre-specified subgroups by baseline age, sex, race, diabetes status, systolic blood pressure, estimated GFR (<45 v ≥45 mL/min/1.73 m 2 ), and ACR (≤1000 v >1000 mg/g or ≤113 v >113 mg/mmol). 89 Similarly, in EMPA-KIDNEY, empagliflozin was associated with lower risk of the primary composite outcome compared with placebo regardless of baseline diabetes status or estimated GFR (<30 v ≥30 mL/min/1.73 m 2 to <45 v ≥45 mL/min/1.73 m 2 ). 91 The risk of the primary outcome was not lower among patients with ACR ≤300 mg/g (approximately ≤30 mg/mmol). In exploratory analyses, however, empagliflozin was associated with slower annual rates of decline in estimated GFR compared with placebo among participants with ACR between 30 and 300 mg/g (approximately 3-30 mg/mmol) and slower chronic slope (from two months to the final follow-up visit) among all ACR subgroups.

The DAPA-CKD trial also showed that the kidney protective effects of SGLT-2 inhibitors extend to patients with IgA nephropathy and perhaps also those with focal segmental glomerulosclerosis (FSGS). 93 94 Among 270 participants with IgA nephropathy (mean estimated GFR 44 mL/min/1.73 m 2 ; median ACR 900 mg/g (102 mg/mmol)), dapagliflozin was associated with a 71% lower risk of developing the primary outcome and a 70% lower risk of ESKD compared with placebo. 93 Among the 104 participants with FSGS (mean estimated GFR 42 mL/min/1.73 m 2 ; median ACR 1248 mg/g (141 mg/mmol)), dapagliflozin was not associated with a lower risk of the primary composite outcome, although this analysis was limited in power (only 11 events). 94 In exploratory analyses, dapagliflozin was associated with slower chronic decline in estimated GFR in the FSGS population. Investigations on the use of SGLT-2 inhibitors in other patient populations, such as those with polycystic kidney disease and kidney transplant recipients, are ongoing (clinicaltrials.gov).

SGLT-2 inhibitors, which act at the level of the proximal tubule to block the reabsorption of glucose and sodium, 95 are generally safe to use in patients with CKD. Early signals of heightened risks of volume depletion, serious genital infections, bone fractures, and need for limb amputation in the Canagliflozin Cardiovascular Assessment Study (CANVAS) were not observed in subsequent studies—CREDENCE, DAPA-CKD, and EMPA-KIDNEY—thus assuaging these concerns ( table 3 ). 86 88 89 91 A pooled analysis of 15 081 participants with type 2 diabetes and CKD G3-4 showed similar rates of serious adverse events for empagliflozin versus placebo, with a higher rate only of mild genital infections with the SGLT-2 inhibitor. 96 A real world study of patients receiving SGLT-2 inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors found no increased risk of outpatient urinary tract infections or severe urinary tract infection events requiring hospital admission. 97

Adverse effects of SGLT-2 inhibitors * in CANVAS, CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials

GLP-1 receptor agonists

GLP-1 receptor agonists have also been shown to improve kidney outcomes among patients with type 2 diabetes, albeit in trials that were designed for primary cardiac outcomes ( table 4 ). 98 99 100 101 102 103 104 105 106 107 108 109 The reduction in risk of kidney outcomes, which included albuminuria, ranged from 15% to 36%. A large meta-analysis of approximately 44 000 participants from the six trials in table 4 reported that use of GLP-1 receptor agonists was associated with a 21% lower risk of developing the composite kidney outcome, defined as new onset albuminuria >300 mg/g, doubling of serum creatinine, ≥40% decline in estimated GFR, kidney replacement therapy, or death due to kidney causes, compared with placebo. 100 This risk reduction seemed to be driven by the reduction in incident albuminuria >300 mg/g; associations between GLP-1 receptor agonists and CKD progression and kidney failure were not statistically significant. However, results were more promising in A Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease (AWARD-7), a clinical trial designed to evaluate change in glycated hemoglobin. 110 Among 577 adults with type 2 diabetes and CKD G3-4 randomized to open label dulaglutide 1.5 mg once weekly, dulaglutide 0.75 mg once weekly, or insulin glargine daily, both dulaglutide groups had slower estimated GFR declines compared with the insulin glargine group; among participants with baseline albuminuria >300 mg/g, dulaglutide was associated with greater ACR reductions in a dose dependent manner over the one year follow-up.

Landmark randomized clinical trials on associations of glucagon-like peptide-1 (GLP-1) receptor agonists with secondary kidney outcomes among patients with type 2 diabetes mellitus

Exact mechanisms by which the GLP-1 receptor agonists slow decline in estimated GFR and/or reduce albuminuria are not entirely clear, but proposed mechanisms include improved glycemic control, weight loss, increased natriuresis, and reduced inflammation and oxidative stress. 111 112 113 Adverse effects observed with this class of drugs have included diarrhea, nausea, and vomiting. 103 104 107 109 110

Mineralocorticoid receptor antagonists

Several MRAs are available and can be useful adjuncts to RAAS inhibitors, particularly among populations with albuminuria and/or diabetes. Two common steroidal non-selective MRAs, spironolactone and eplerenone, both lower albuminuria. 72 In a meta-analysis of 372 participants from seven trials, combination therapy with a non-selective MRA and an ACE inhibitor and/or ARB was associated with a significant reduction in proteinuria, albeit with a higher risk of hyperkalemia. 114 Finerenone, a non-steroidal selective MRA, was also recently approved. 115 Compared with the steroidal non-selective MRAs, finerenone has a stronger selectivity for the mineralocorticoid receptor, a shorter half life, less of a blood pressure lowering effect, and a more favorable side effect profile, as well as potentially greater anti-inflammatory and antifibrotic effects. 115 116 117 The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial were two complementary phase 3 clinical trials designed to investigate the kidney and cardiovascular benefits of finerenone, respectively, in people with albuminuria levels ≥30 mg/g and type 2 diabetes ( table 5 ). 116 118 Both trials included patients taking maximally tolerated ACE inhibitor or ARB, with participants in FIDELIO-DKD generally having more severe baseline CKD. In a pooled analysis of the two trials, finerenone was associated with a 15-23% lower risk of developing the kidney composite outcomes and a 32% lower mean change in ACR from baseline to four months. 119 Hyperkalemia was more frequent among patients randomized to finerenone (14%) compared with placebo (7%). In pre-specified analyses, baseline SGLT-2 inhibitor use (n=877) or GLP-1 receptor agonist use (n=944) did not modify the beneficial effect of finerenone on the kidney composite outcome, thus suggesting a potential role for dual therapy (for example, finerenone plus SGLT-2 inhibitor or GLP-1 receptor agonist) among patients with type 2 diabetes and CKD.

Landmark randomized clinical trials on finerenone in chronic kidney disease

Endothelin receptor antagonists

Endothelin receptor antagonists have emerged as novel treatments for a variety of kidney diseases. The Study of Diabetic Nephropathy with Atrasentan (SONAR) evaluated the effect of atrasentan on a composite kidney outcome (defined as a doubling of serum creatinine or ESKD) among adults with type 2 diabetes, estimated GFR 25-75 mL/min/1.73 m 2 , and urine ACR 300-5000 mg/g taking a stable dose of ACE inhibitor or ARB. 120 After a six week enrichment period during which all participants received atrasentan 0.75 mg daily (n=5517), those who responded (defined as a ≥30% reduction in urine ACR without the development of substantial fluid retention or increase in serum creatinine by >0.5 mg/dL and 20% from baseline; n=2648) were randomized to receive atrasentan or placebo. Over a median follow-up of 2.2 years, the atrasentan group had a 35% lower risk of developing the composite kidney outcome compared with the placebo group, although fluid retention and anemia were more frequent in the former. Of note, the frequency of hyperkalemia was low (1%) in both treatment groups. Sparsentan, a dual endothelin and angiotensin II receptor antagonist, is also being investigated as a treatment for FSGS and IgA nephropathy. 121 122 In a phase 2, randomized, double blind, active control trial, 109 adults with biopsy proven FSGS (estimated GFR >30 mL/min/1.73 m 2 and urine PCR ≥1 g/g) received varying doses of sparsentan (200, 400, or 800 mg daily) or irbesartan 300 mg daily. 121 At eight weeks, participants receiving sparsentan had greater reductions in urine PCR compared with those receiving irbesartan. In an interim analysis of the PROTECT phase 3 trial, adults with biopsy proven IgA nephropathy (urine PCR ≥1 g/day) randomized to sparsentan 400 mg daily had a 41% greater reduction in urine PCR over 36 weeks and threefold higher odds of achieving complete remission of proteinuria at any point compared with their counterparts who were randomized to irbesartan 300 mg daily. 122 Based in part on the results of this study, the US Food and Drug Administration (FDA) granted accelerated approval for the use of this drug in adults with primary IgA nephropathy considered to be at risk of rapid disease progression. 123

Endothelin 1 has been implicated in the pathogenesis of kidney disease via various mechanisms including vasoconstriction, vascular hypertrophy, endothelial and podocyte injury, inflammation, cell proliferation, extracellular matrix accumulation, and fibrosis. 124 Systemic and local kidney production of endothelin 1 is augmented in CKD.

Other nephroprotective and cardiovascular risk reduction strategies

A bidirectional association exists between CKD and cardiovascular disease: cardiovascular disease is both a risk factor for CKD and a common outcome in patients with CKD. 125 126 Thus, patients with CKD are likely to benefit from efforts at cardiovascular risk reduction including administration of a statin as well as the gamut of lifestyle changes. 2 127

Lipid management

The Study of Heart and Renal Protection (SHARP) trial evaluated the efficacy of ezetimibe and simvastatin combination therapy in patients with moderate to severe CKD (33% on dialysis; 67% not on dialysis with mean estimated GFR of 27 mL/min/1.73 m 2 ). 128 Treatment with these low density lipoprotein (LDL) cholesterol lowering agents led to a 17% risk reduction for development of a first major atherosclerotic event compared with placebo, although this benefit was seen only in the patients not requiring maintenance dialysis. Those at very high risk (for example, with previous major atherosclerotic cardiovascular disease events) may benefit from additional therapies to lower LDL cholesterol, including evolocumab. 129 Evolocumab is a monoclonal antibody for proprotein convertase subtilisin/kexin type 9, which increases LDL cholesterol receptors and hence clearance of LDL; this novel therapy also seems to be safe and efficacious in patients with CKD. 129 130

Physical activity

Exercise has been shown to benefit patients with CKD. Several small, randomized trials have reported that exercise training programs in patients with moderate to severe CKD are safe, feasible, and effective in improving physical activity levels, cardiorespiratory fitness, and quality of life. 131 132 133 134 135 Whether these interventions also slow CKD progression remains to be determined, as many of these studies were underpowered for this outcome.

For patients with obesity, weight loss may reduce the risk of CKD progression, whether it comes from intensive lifestyle intervention such as in the Look AHEAD (Action for Health in Diabetes) trial or, as in observational studies, from bariatric surgery. 136 137 138 Micronutrient and macronutrient composition of diets may also matter. 139

Traditional recommendations about diet in the setting of CKD have focused on limiting protein and dietary acid intake. Experimental evidence suggests that protein intake can increase intraglomerular pressure and cause glomerular hyperfiltration. 140 141 142 Observational data from large cohort studies suggest that the type of protein may be important; a diet high in animal protein may increase risk, whereas protein from plant sources may be better tolerated. 143 144 For example, an observational study in Singapore found a strong correlation between red meat intake and risk of ESKD. 145 Little clinical trial evidence for protein restriction exists. The MDRD study randomized patients to different levels of protein restriction but found no statistically significant difference in the rate of GFR decline. 67

A second line of investigation has been into the benefits of increasing nutritional alkali intake, with a body of open label trials suggesting benefits on kidney function and prevention of starting dialysis. 146 A phase 3 double blinded, placebo controlled trial reported that veverimer (a potent acid binder that acts in the intestine) was effective in raising or normalizing serum bicarbonate among patients with CKD and chronic metabolic acidosis. 147 Other double blinded studies using veverimer suggested that treating acidosis in CKD improves quality of life and overall physical function. 148 However, a recent trial evaluating veverimer in slowing progression of CKD was negative. 149

Although patients with CKD are prone to hyperkalemia, potassium intake has a beneficial effect on blood pressure, cardiovascular disease, and death independent of and opposite to that of sodium intake. 150 151 152 153 One large randomized controlled trial suggested that substituting 25% of sodium chloride intake with potassium chloride reduced the risk of major adverse cardiovascular events by 13% in the general population. 154 Similarly, small studies suggest that diets rich in potassium may be beneficial in CKD. A feeding trial in people with CKD G3 observed that 100 mmol compared with 40 mmol of dietary potassium per day increased serum potassium by 0.21 mmol/L, 155 similar to the increase seen with finerenone. 156 Many dietary studies have evaluated patterns of diet rather than potassium alone: for example, plant based diets tend to be rich in not only potassium but also alkali and fiber. Observational data from prospective cohorts suggest that plant based diets are associated with less CKD progression. 143 157 158 Evidence is also emerging to suggest that increasing fiber intake benefits the gut microbiome, decreases inflammation, and possibly slows CKD progression. 159

Appropriate drug dosing and nephrotoxin avoidance

An important component of care for patients with CKD is avoidance of additional insults. Many drugs are cleared by glomerular filtration or tubular secretion by the kidney, and reduced GFR can lead to accumulation of the drug or its metabolites resulting in adverse effects. 160 Careful estimation of GFR is generally a first step in determining dosage for renally excreted drugs. 161 The US FDA guidance to industry suggests that estimated GFR based on serum creatinine may be used in pharmacokinetic studies. 162 If drugs are dosed on the basis of estimated GFR (rather than estimated creatinine clearance from the Cockcroft-Gault equation, an equation that is known to be flawed), estimated GFR must be “de-indexed” by multiplying the standardized estimated GFR by the individual’s calculated body surface area and dividing by 1.73 m 2 . 163 164 165 This is because drug clearance is thought to be proportional to a person’s GFR and not the GFR standardized to body surface area. Antibiotics and antiviral agents, direct oral anticoagulants, drugs for diabetes mellitus, and chemotherapeutic agents are the most common drugs that require attention to dosing in CKD. 2 160 164

Some drugs should be avoided or minimized in CKD because of their potential to worsen kidney function. For example, non-steroidal anti-inflammatory drugs (NSAIDs) can exacerbate hypertension, cause fluid retention, and contribute to the risk of acute kidney injury. 166 Particularly when used with RAAS inhibitors and diuretics, NSAIDs are ideally avoided. 167 In select patients with CKD, however, some clinicians will prescribe an abbreviated course of NSAIDs given that the most common alternative, opioids, also have significant adverse effects. 168 Proton pump inhibitors can lead to acute or chronic interstitial nephritis and have been associated with incident CKD, progression of CKD, and ESKD. 169 170 Although the mechanism by which proton pump inhibitors contribute to CKD remains unclear, most experts agree that these agents should be used judiciously.

Emerging treatments

Many phase 3-4 clinical trials are ongoing to evaluate emerging treatments for kidney disease (clinicaltrials.gov). These include, but are not limited to, investigations on the use of dapagliflozin in advanced CKD (for example, estimated GFR <25 mL/min/1.73 m 2 , on maintenance dialysis with residual daily urine output of >500 mL, and kidney transplant recipients with estimated GFR ≤45 mL/min/1.73 m 2 ; NCT05374291 ); finerenone in non-diabetic CKD ( NCT05047263 ); and monteluklast ( NCT05362474 ) and pentoxyifylline ( NCT03625648 ) in diabetic CKD. Several therapies are also being tested for rarer causes of kidney disease: obinutuzumab ( NCT04629248 ), zanubrutinib ( NCT05707377 ), and SNP-ACTH (1-39) gel ( NCT05696613 ) in membranous nephropathy; voclosporin ( NCT05288855 ), atacicept ( NCT05609812 ), anifrolumab ( NCT05138133 ), inanalumab ( NCT05126277 ), secukinumab ( NCT04181762 ), obinutuzumab ( NCT04221477 ), and ACTHar gel ( NCT02226341 ) in lupus nephritis; VX-147 in APOL1 related kidney disease ( NCT05312879 ); imlifidase in antiglomerular basement membrane disease ( NCT05679401 ); sparsentan in focal segmental glomerulosclerosis ( NCT03493685 ); and pegcetacoplan ( NCT05067127 ) in immune complex glomerulonephritis. IgA nephropathy, in particular, is an area of high interest, as recent work suggests that disease activity may be driven by the overproduction of galactose deficient IgA antibodies that are recognized as autoantigens, triggering glomerular deposition of immune complexes. 171 Monoclonal antibodies to signaling molecules that enhance IgA production are in phase 3 trials, as are immunosuppressive and non-immunosuppressive agents (for example, those acting on the endothelin-1 and angiotensin II pathways): budesonide ( NCT03643965 ), sparsentan ( NCT03762850 ), atrasentan ( NCT04573478 ), LNP023 ( NCT04578834 ), RO7434656 ( NCT05797610 ), atacicept ( NCT04716231 ), and sibeprenlimab ( NCT05248646 ; NCT05248659 ).

Major guidelines in CKD are issued by the international KDIGO group ( https://kdigo.org/ ), and locally in the UK by NICE ( www.nice.org.uk/guidance/ng28/chapter/Recommendations#chronic-kidney-disease ), with the most recent issuances primarily from 2023 (currently in public review) and 2021, respectively. KDIGO publishes guidelines on the evaluation and management of patients with CKD in general, as well as myriad other aspects (for example, diabetes, blood pressure, lipids, anemia, mineral and bone disease, hepatitis C, ADPKD, glomerular diseases). With the expansion of therapeutic options, both organizations are updating recommendations frequently. Other guideline producing organizations such as the American College of Cardiology, the American Heart Association, the European Society of Cardiology, the European Society of Hypertension, the International Society of Hypertension, and the American Diabetes Association (ADA) provide more limited statements of recommendation for the specific aspects of the management of patients with CKD. 172 173 174 175

Annual screening for CKD (including testing for albuminuria) is widely recommended in people with diabetes. 72 174 175 176 177 Guidelines in hypertension are less clear. 178 The 2020 Global Hypertension Practice Guideline from the International Society of Hypertension is a notable exception and now recommends routine assessment of albuminuria in addition to estimated GFR in people with hypertension. 173 KDIGO and NICE also recommend testing anyone who is at risk for CKD, which includes those with hypertension, cardiovascular disease, diabetes, and previous acute kidney injury, along with multiple other, less common conditions. 179 For CKD, the KDIGO guidelines recommend at least annual albuminuria testing with greater frequency in higher risk categories ( fig 1 ). 2 The NICE guidelines, on the other hand, recommend annual ACR testing with individualization based on clinical characteristics, risk of progression, and whether a change in ACR would lead to a change in management. 16

KDIGO guidelines and those from NICE differ slightly on staging CKD. KDIGO recommends using a validated equation for GFR estimation and suggests that using “race as a distinct variable in the computation of GFR” is not appropriate. 179 NICE recommends using the CKD-EPI 2009 equation, which did include race, but using the computed value for non-Black people for everyone, a position that is also endorsed by other European groups. 16 180 181 The KDIGO guidelines recommend staging CKD by eGFRcr-cys when cystatin C is available, as well as when precise estimates of GFR are needed for clinical decision making. 2 179 The NICE guidelines recommend direct measurement of GFR rather than the use of cystatin C in clinical situations requiring additional precision. 16

Both KDIGO and NICE emphasize the importance of risk assessment in patients with CKD. The NICE guidelines suggest that primary care providers should counsel patients using the KFRE five year risk estimate, with referral to a specialist if risk is greater than 5%. 16 KDIGO 2023 additionally suggests that the two year risk estimate can drive referral for multidisciplinary care (>10%) and preparation for kidney replacement therapy, including vascular access planning and referral for transplantation (>40%). 179 The KDIGO 2023 guidelines also emphasize the importance of cardiovascular risk assessment using equations developed in people with CKD or that encompasses estimated GFR and albuminuria and the use of disease specific tools in IgA nephropathy and ADPKD. 179

Multiple guidelines comment on target blood pressures in the setting of CKD. The NICE guidelines recommend a target of <140/90 mm Hg, or <130/80 mm Hg if ACR is ≥70 mg/mmol (approximately 700 mg/g). 16 Guidelines from the American College of Cardiology, American Heart Association, European Society of Cardiology, and European Society of Hypertension recommend a systolic blood pressure target of <130 mm Hg as a best practice target, with the European Society of Cardiology and European Society of Hypertension specifically advising against lower targets. 172 The KDIGO guidelines on hypertension in CKD advocate for a systolic blood pressure goal of <120 mm Hg, as assessed using standardized office measurements. 182 This recommendation is based largely on data from SPRINT and the observed benefits in cardiovascular endpoints and survival rather than benefits in kidney endpoints. 70

Of note, disparate guideline recommendations may reflect different emphasis on standardized blood pressure measurement techniques, which can result in measured blood pressure that is substantially lower than measurement in an uncontrolled setting. 183 Joint statements from several international groups including KDIGO stress the importance of proper technique when assessing blood pressure. 184 Both NICE and KDIGO recommend RAAS inhibitors (either ACE inhibitor or ARB) as first line antihypertensive treatment for people without diabetes but with albuminuria (NICE: urine ACR >70 mg/mmol; KDIGO: A3) as well as those with diabetes and CKD G1-G4, A2-A3. 16 182 KDIGO 2023 suggests continuation of RAAS inhibitors even when estimated GFR is <30 mL/min/1.73 m 2 . 179

For patients with diabetes and CKD not treated with dialysis, KDIGO recommends a hemoglobin A 1c target ranging from <6.5% to <8%. 72 NICE does not provide specific recommendations for people with CKD, instead emphasizing shared decision making but a general goal of hemoglobin A 1c <7% for people with diabetes treated with drugs associated with hypoglycemia and <6.5% for people with diabetes managed by lifestyle or a single drug not associated with hypoglycemia. 185

KDIGO and ADA guidelines recommend SGLT-2 inhibitors as first line drug therapy for all people with type 2 diabetes, CKD, and an estimated GFR ≥20 mL/min/1.73 m 2 ( fig 5 ). 72 174 175 179 The NICE guidelines recommend that an SGLT-2 inhibitor should be offered when ACR is >30 mg/mmol (approximately >300 mg/g) and considered when ACR is between 3 and 30 mg/mmol (approximately 30 to 300 mg/g) in patients with type 2 diabetes and CKD who are already taking an ACE inhibitor or ARB and meet estimated GFR thresholds. 185 The NICE guidelines further specify that dapagliflozin should also be considered in people with estimated GFR 25-75 mL/min/1.73 m 2 and ACR ≥22.6 mg/mmol (approximately 200 mg/g) regardless of diabetes status 186 ; KDIGO is broader and recommends SGLT-2 inhibitors in general in people with ACR ≥200 mg/g and estimated GFR ≥20 mL/min/1.73 m 2 , as well as in those with CKD and heart failure. 179 KDIGO further specifies that once started, a SGLT-2 inhibitor can be continued even if the estimated GFR drops below 20 mL/min/1.73 m 2 , as long as it is tolerated and kidney replacement therapy has not yet been started. 72 179 The KDIGO and ADA guidelines recommend the use of GLP-1 receptor agonists in patients with type 2 diabetes and CKD who are unable to tolerate metformin or an SGLT-2 inhibitor or do not meet their individualized glycemic target with these drugs. 72 174 175 179

Kidney Disease: Improving Global Outcomes/American Diabetes Association recommendations on the management of diabetes in populations with chronic kidney disease. 72 174 ACR=albumin-to-creatinine ratio; ASCVD=atherosclerotic cardiovascular disease; BP=blood pressure; CCB=calcium channel blocker; CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; GLP-1 RA=glucagon-like peptide-1 receptor agonist; HTN=hypertension; MRA=mineralocorticoid receptor antagonist; PCSK9i=proprotein convertase subtilisin/kexin type 9 inhibitor; RAS=renin-angiotensin system; SGLT2i=sodium-glucose cotransporter-2 inhibitor

In patients with diabetes and CKD, the KDIGO and ADA guidelines recommend that finerenone should be used as add-on therapy to maximally tolerated ACE inhibitor or ARB if ACR is ≥30 mg/g (approximately ≥3 mg/mmol) and potassium is within normal limits (that is, ≤4.8 mmol/L based on trial and ≤5.0 mmol/L as per FDA). 72 174 175 179 More specifically, the starting dose should be 10 mg daily when estimated GFR is 25-59 mL/min/1.73 m 2 and 20 mg daily when it is ≥60 mL/min/1.73 m 2 . The guidelines also recommend that potassium concentration should be checked at four weeks after starting treatment, with each dose change, and routinely during treatment. If potassium is >5.5 mmol/L, the drug should be stopped and restarted at the lower dose of 10 mg daily when potassium is ≤5.0 mmol/L. Additionally, finerenone need not be stopped when estimated GFR falls below 25 mL/min/1.73 m 2 as long as the patient is normokalemic. 174 175

With respect to cardiovascular risk reduction, the KDIGO guidelines suggest that all patients aged over 50 with CKD G3-G5 but not treated with chronic dialysis or kidney transplantation should be treated with a statin, irrespective of cholesterol concentrations or a statin/ezetimide combination. 179 187 The NICE recommendation is broader, recommending starting atorvastatin 20 mg for all people with CKD. 188 KDIGO recommends regular physical activity for people with CKD, for at least 150 minutes a week of moderate intensity exercise. 179 NICE simply suggests providing lifestyle advice, including encouragement of exercise, maintenance of healthy weight, and smoking cessation, and specifically recommends against offering low protein diets (defined as dietary protein intake <0.8 g/kg/day). 16 KDIGO recommends maintaining sodium intake <2 g/day and a protein intake of 0.8 g/kg/day but no higher than 1.3 g/kg/day. 179

People with CKD face high risks of many adverse outcomes, including requirement for kidney replacement therapy, cardiovascular events, and death. Fortunately, major advances have been made in the field of CKD over the past decade. Estimating equations for GFR and ACR have evolved for more precise classification of disease. Individualized risk prediction tools exist to assist in the counseling, referral, and treatment of patients. Novel therapies build on the fundamentals—a healthy lifestyle, blood pressure and glucose control, and statin therapy and RAAS blockade—to provide effective preventive strategies for CKD progression and cardiovascular events.

Glossary of abbreviations

ACE—angiotensin converting enzyme

ACR—albumin-to-creatinine ratio

ADA—American Diabetes Association

ADPKD—autosomal dominant polycystic kidney disease

ARB—angiotensin receptor blockers

CKD—chronic kidney disease

CKD-EPI—CKD Epidemiology Collaboration

DPP-4—dipeptidyl peptidase-4

eGFRcr—estimated glomerular filtration rate using creatinine

eGFRcr-cys—estimated glomerular filtration rate using creatinine and cystatin C

eGFRcys—estimated glomerular filtration rate using cystatin C

ESKD—end stage kidney disease

FDA—Food and Drug Administration

FSGS—focal segmental glomerulosclerosis

GFR—glomerular filtration rate

GLP-1—glucagon-like peptide-1

KDIGO—Kidney Disease: Improving Global Outcomes

KFRE—kidney failure risk equation

KFRT—kidney failure with replacement therapy

LDL—low density lipoprotein

MDRD—Modification of Diet in Renal Disease

MRA—mineralocorticoid receptor antagonists

NICE—National Institute for Health and Care Excellence

NSAID—non-steroidal anti-inflammatory drug

PCR—protein-to-creatinine ratio

RAAS—renin-angiotensin-aldosterone system

SGLT-2—sodium-glucose cotransporter-2

Questions for future research

How do the race-free estimating equations perform in global populations?

Where can genetic testing add value in patient care?

Can cause of chronic kidney disease be incorporated into risk prediction tools?

How can medical therapy be best tailored for the individual patient with chronic kidney disease?

Patient perspective

Increasing awareness of chronic kidney disease is key to empowering patients to make lifestyle changes and seek treatments to improve their health outcomes. We are pleased to offer our perspective as husband and wife, and as physicians, who have been affected by kidney disease. Roberta M Falke is a patient with autosomal dominant polycystic kidney disease (ADPKD), a kidney transplant recipient, and a retired hematologist-oncologist. Andrew S Levey is a kidney donor and a nephrologist. Our knowledge of Roberta’s family history enabled early diagnosis and treatment. 189 Although we have benefited from our training and positions in the healthcare system, all patients can benefit from early diagnosis.

RMF —My ADPKD was diagnosed when I developed pyelonephritis at age 22 years. Thereafter, I had prophylaxis and prompt treatment of recurrent urinary tract infections and, as the disease progressed, complications of kidney and liver cysts, hypertension, hyperparathyroidism, vitamin D deficiency, acidosis, hyperkalemia, and ultimately kidney failure, with fatigue, dietary restrictions, and a long list of medications to take every day. I had always known that living donor kidney transplantation would be the best treatment for my kidney failure. Over time, family members without ADPKD donated to others, and when I was ready at age 60 years no family members were available. Fortunately, Andy stepped up. I felt better immediately after the transplant, and in the 13 years since then I have continued to take medications daily but have had few complications. I am grateful to all those who have cared for me for many years and enabled me to make the best choices I could to help myself, and I’m especially grateful to Andy who gave me the gift of life.

ASL —I knew that Roberta would develop kidney failure and hoped that a living kidney donor would be available for her. I wanted to donate, but our blood group incompatibility was an obstacle, so it was exciting when paired donor exchange was conceived and implemented in our region. I believe that kidney donors benefit from donation, not only by fulfilling their spirit of altruism but by improving their own lives. In my case, donating has been life changing. Roberta and I have been able to have an active, fulfilling life for more than a decade after the transplant, without the demands and complications of kidney failure or dialysis. I hope that we will have many more years together. I am also grateful to all those who enabled me to achieve my goal and to Roberta, who always takes full responsibility for caring for her kidney disease.

Acknowledgments

We thank Andrew S Levey and Roberta M Falke for providing both their perspective as patients affected by kidney disease and their input on the manuscript itself. We also acknowledge Alix Rosenberg and Yingying Sang for their help with the boxes and figures.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: All authors were involved in the conception, writing, and revision of the manuscript. MEG is the guarantor.

Funding: TKC is supported by NIH/NIDDK K08DK117068; MEG is supported by NIH/NIDDK R01DK108803, R01DK100446, R01DK115534, R01DK124399, and NIH/NHLBI K24HL155861.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: TKC and MEG received an honorarium from the American Society of Nephrology (nephSAP).

Patient involvement: We invited a husband and wife, Andrew S Levey and Roberta M Falke, who are affected by chronic kidney disease, to write a patient perspective together. They also reviewed and provided input on the penultimate draft of the paper.

Provenance and peer review: Commissioned; externally peer reviewed.

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• v.9(3); 2021 Sep

Advances in Clinical Research in Chronic Kidney Disease

1 Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China

Mark E. Cooper

2 Department of Diabetes, Central Clinical School, Monash University, Melbourne 3800, Australia

Dr. Zhonglin Chai

Introduction.

Current international guidelines define chronic kidney disease (CKD) as an abnormality of kidney function or structure that is present for at least 3 months, regardless of underlying causes, with implications for health. [ 1 ] The prevalence of CKD varies worldwide due to differences in socioeconomic conditions and ethnicity. Indeed, about 1 in 10 people have CKD in high- and middle-income countries, and this is even higher in low-income countries. CKD occurs primarily as a result of diabetes, hypertension, obesity, or glomerulonephritis. [ 2 , 3 ] Although current treatment strategies can improve the renal function to some extent, patients are still at high risk of progression to end-stage renal disease (ESRD) or all-cause death in the long term. Since the prevalence of CKD is an increasing public health issue and poses a significant social as well as medical and economic burden, effective drugs to preserve kidney function are urgently needed.

As recently known, correction of glomerular hyperfiltration, management of metabolic abnormalities, and addressing the risk factors associated with kidney injury, such as diabetes, hypertension, hyperlipidemia, obesity, and smoking, are effective in slowing down the progression of CKD. [ 4 ] Furthermore, a number of recent clinical studies have demonstrated promising specific renoprotection conferred by several classes of new agents, which can be used to optimize the management of patients with CKD.

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been demonstrated as renoprotective agents. These effects are attributed to their actions as anti-hypertensive and anti-proteinuric agents. [ 5 ] Moreover, the agents that interrupt the renin–angiotensin system have also been shown to attenuate renal damage via a range of mechanisms including reversal of chronic tubulointerstitial hypoxia, reducing the interstitial infiltration of inflammatory cells, decreasing iron deposition, inhibiting intrarenal activity of the plasminogen activator inhibitor (PAI-1), and acting as antifibrotic agents by inhibiting prosclerotic growth factors such as transforming growth factor beta (TGF-β) in various forms of CKD. [ 6 , 7 ] Despite the widespread use of ACEI/ARB, patients with CKD still have a high residual risk of progressing to ESRD.

To further interrupt the renin– angiotensin–aldosterone system (RAAS), mineralocorticoid receptor antagonists (MRAs), which block the action of aldosterone, can reduce fibrosis in many target organs, including blood vessels, kidneys, and heart. [ 8 ] The recently developed new generation of nonsteroidal MRAs such as finerenone appear to have less side effects such as hyperkalemia, thus making these drugs suitable for use in patients with CKD. [ 9 ] Phase III randomized clinical trials confirmed that finerenone therapy resulted in a lower risk of CKD progression and cardiovascular morbidity than placebo in patients with type 2 diabetes (T2D) and CKD. [ 10 ] Confirmation of the positive results of the initial finerenone therapy in reducing kidney failure and disease progression in diabetic kidney disease (FIDELIO-DKD) has been reported, albeit not yet fully published in the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease (FIGARO-DKD) study, where less-advanced CKD in T2D subjects was studied. In that study, finerenone reduced a composite of cardiovascular death and events. [ 11 ] Renal findings are pending for that study.

Notably, a series of recent studies have confirmed that a recently developed oral antidiabetic class of drugs, the sodium–glucose cotransporter-2 (SGLT2) inhibitors, can retard the decline in renal function beyond their hypoglycemic effect by acting in a hemodynamic manner, including reducing hyperfiltration in patients with diabetic kidney disease (DKD), a form of CKD, which is characterized by glomerular and systemic hemodynamic dysregulation. [ 12 ] Moreover, according to the results of various cardiovascular outcome trials (CVOTs), including empagliflozin cardiovascular outcomes (EMPA-RE), canagliflozin cardiovascular assessment study (CANVAS), and dapagliflozin effect on cardiovascular events (DECLARE-TIMI) studies, SGLT2 inhibitors have demonstrated not only cardiovascular, but also renoprotective properties. These agents not only reduce cardiovascular events and all-cause mortality in patients with T2D and CKD, but also reduce proteinuria and improve the prognosis, reducing the development of ESRD. [ 13 , 14 ] Indeed, building on these CVOTs, renally dedicated trials have been completed, including canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), and have demonstrated renoprotection in T2D subjects. [ 15 ] Furthermore, in the DAPA-CKD trial, non-diabetic subjects with other forms of CKD were also reported to have renoprotection to a similar degree to that seen in T2D. SGLT2 inhibitors reduce proximal tubule sodium chloride reabsorption and increase the delivery of these ions to the macula densa, thereby modulating tubuloglomerular feedback, leading to an increase in the resistance in the afferent arteriole and a reduction in intraglomerular pressure. [ 16 ] Furthermore, SGLT2 inhibitors inhibit fluid reabsorption in the proximal tubule, thus increasing the hydrostatic pressure in the tubule. By contrast, ACE inhibitors and ARBs decrease the resistance in the efferent arteriole and can be administered together with SGLT2 inhibitors, complementarily reducing intraglomerular pressure.

Other relatively new hypoglycemic drugs, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, also have shown renoprotective effects in improving albuminuria and/or retarding glomerular filtration rate (GFR); [ 17 , 18 ] but these effects are not as potent as those seen with SGLT2 inhibitors and the mechanism of action of these agents remains difficult to delineate.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of T2D. These drugs are often used in subjects with or at risk of CKD. Numerous CVOTs have evaluated these agents and, indeed, modest effects on reducing urinary albumin excretion have been observed. [ 19 ] However, whether this relates to the associated glucose-lowering effects or represents a specific renoprotective effect of these drugs has not been fully elucidated. One of the DPP-4 inhibitors, linagliptin, can be used safely without any dose change at any level of renal function, including in dialysis patients. This has led to several renally oriented trials such as MARLINA in type 2 diabetic subjects with albuminuria [ 20 ] and in a large CVOT known as CARMELINA which included a renal primary endpoint. [ 21 ] Modest reductions in albuminuria were observed with linagliptin, but no reduction in any hard renal endpoints, as has been seen with other glucose-lowering agents such as SGLT2 inhibitors, was observed. [ 21 ]

For the treatment of renal anemia in CKD, hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors have received much attention as a new drug class stabilizing the HIF-PH axis, stimulating endogenous erythropoietin production, upregulating the expression of transferrin receptor, increasing iron uptake by proerythrocytes, and promoting erythrocyte maturation. [ 22 ] Although a recent clinical trial showed increased levels of hemoglobin with one of these inhibitors, roxadustat, [ 23 ] further studies are still needed to investigate the effect of such therapies on long-term cardiovascular and renal outcomes. Interestingly, another agent of this class, enarodustat, showed beneficial effects on cardiovascular complications caused by CKD in a rat model. [ 24 ]

The use of selective endothelin receptor antagonists is another effective and safe approach to reduce albuminuria and blood pressure. [ 25 ] The study of diabetic nephropathy with atrasentan (SONAR) has reported that atrasentan decreased the risk of renal events in participants with T2D and CKD, demonstrating its potential benefits in preserving renal function in diabetic patients who otherwise would have a high risk of ESRD. [ 26 ]

The kidney can be damaged as a result of aberrant activity of the immune system. Approaches to target immune cells have been explored in the clinical setting using biological agents to treat certain kidney diseases. For example, rituximab, a monoclonal antibody that depletes B cells, is increasingly used “off-label” for certain renal conditions such as in renal transplantation and membranous nephropathy, [ 27 ] minimal change disease, focal segmental glomerulosclerosis, [ 28 ] and lupus nephritis. [ 29 ] Furthermore, using biological agents to target the innate inflammatory response, complement and T-cell activation, as well as to block systemic inflammation is also being considered as a new frontier of immunosuppressive therapy for CKD. For example, C-C chemokine receptor type 2 inhibition with CCX140-B has been observed to have a renoprotective effect in patients with DKD. [ 30 ]

Stem cell therapies have been considered to be a promising therapeutic strategy to treat CKD through stimulating kidney regeneration. Indeed, there is growing evidence that stem cells, including induced pluripotent stem cells, [ 31 ] mesenchymal stem/stromal cells, [ 32 ] and renal stem/ progenitor cells, [ 33 ] exert their therapeutic effects on CKD by replacing damaged tissues as well as influencing key paracrine pathways. However, further studies are needed to understand the risks of fibrosis, maldifferentiation, or tumor formation and adverse events of immunosuppression, as well as for further validation of the long-term safety and tolerability of these therapies.

Gene editing is also being explored for the treatment of CKD. In contrast to traditional gene therapy approaches, clustered, regularly interspaced short palindromic repeats (CRISPR) gene editing, a state-of-the-art technology that is not only a promising tool for research, but also has great potential to be used for gene therapy, can precisely edit or repair specific disease-causing mutations. [ 34 ] Specifically, CRISPR has been explored as a promising approach to treat immune-mediated kidney diseases such as lupus nephritis or immunoglobulin A nephropathy, where T lymphocyte receptors are engineered to recognize specific antigens. [ 35 ] Furthermore, CRISPR-Cas gene editing is being explored to alter key relevant genes in large domestic species in order to produce more suitable donor kidneys for transplantation in humans, thereby alleviating the shortage of donor organs. [ 35 ]

In summary, CKD is a major burden in human health globally, with a major treatment gap to efficiently deal with this devastating condition. Optimal management of risk factors such as diabetes and hypertension and the use of certain antidiabetic agents such as SGLT2 inhibitors and GLP-1R agonists as well as agents such as ACEI, ARBs, and, more recently, nonsteroidal MRAs appear to retard the progression of CKD as well as show associated cardiovascular benefits. However, despite all these treatments, CKD continues to progress, and therefore, safe and more efficacious treatment strategies are urgently needed. Fortunately, recent advances in basic and clinical research in this area, such as immunotherapy, newly identified drug targets, gene therapy, and CRISPR technology, have shown great potential to provide additional novel technologies and strategies in the near future to more successfully combat CKD.

Conflict of Interest

None declared.

Hemodialysis: New research could vastly improve this life-sustaining treatment for kidney failure patients

Assistant Professor, Chemical and Biomedical Engineering, University of Saskatchewan

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Dr. Amira Abdelrasoul receives funding from Social Sciences and Humanities Research Council, Natural Sciences and Engineering Research Council of Canada, and Saskatchewan Health Research Foundation.

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Around one in 10 Canadians has kidney disease and millions more are at risk. According to the Kidney Foundation of Canada, the number of people living with end-stage kidney disease or kidney failure has grown 35 per cent since 2009, with 46 per cent of new patients under the age of 65 .

Hemodialysis is a life-sustaining treatment for kidney failure patients to clean and filter their blood of waste products, salts and excess fluid. However, this membrane-based therapy is not perfect, and hemodialysis patients experience acute side-effects, life-threatening chronic conditions and unacceptably high morbidity and mortality rates.

While hemodialysis treatment can be efficient at replacing some lost kidney function, patients experience some complications such as blood clots, heart conditions, cardiac arrest , blood poisoning , anemia, high/low blood pressure, bone diseases, itching, sleep problems, heart inflammation, fluid overload, infections and muscle cramps .

As a membrane science researcher, I am working on creating hemodialysis membranes that are more compatible with the human body than current membranes. My short-term aim is to achieve reduced patient side-effects and increase quality of life.

My long-term goal is to design an artificial wearable kidney based on a membrane with greatly improved performance compared to those in use in hospitals today. This is the only research program in Canada to address key problems associated with dialysis membranes.

Problems and challenges with hemodialysis

First, dialysis treatment is expensive, costing the Canadian health-care system more than $100,000 per patient per year . And while it does prolong life, it presents a number of challenges.

In a hemodialysis session, a patient’s blood is diverted to a machine to remove waste products and excess fluid. A typical patient requires three dialysis sessions per week, each taking four to five hours, so even mild interactions between a patient’s blood and the dialysis membrane may lead to big problems over time.

Because the membranes in use today cannot perfectly mimic the function of a healthy kidney, some toxins can be poorly filtered from the blood, new ones can arise from blood-membrane interactions and blood clotting can occur.

The five-year survival rate for hemodialysis patients is 35 per cent, and only 25 per cent for hemodialysis patients with diabetes ; both values are considerably worse than the five-year survival rate for cancer patients of approximately 64 per cent .

Additional kidney failure patients are now requiring treatment as more than 30 per cent of patients hospitalized with COVID-19 develop kidney injury . Some studies in Canada showed that around 54 per cent of the Canadian patients who were hospitalized with COVID-19 developed acute kidney injury . Although the rates of acute kidney injury have fallen from the early months of the pandemic, high-risk patients should have their kidney function and fluid status monitored closely .

Research program progress

My research group is working on creating hemodialysis membranes that are more compatible with the human body than current membranes. The first step was to conduct in-depth investigations of the membranes available in Canadian hospitals to determine how patient side-effects are related to the characteristics of the membranes and the clinical practices employed. We are getting answers to several key questions and taking steps towards new designs and new membrane materials.

Innovative imaging techniques available at the Canadian Light Source (CLS) synchrotron at the University of Saskatchewan have allowed my team to visualize and track the behaviour and deposits of blood proteins inside the membrane channels . This is important because these protein deposits can bring about severe inflammation and are undesirable. Imaging at the CLS allows real-time 3D visualization at high speeds.

We are currently using customized gold nanoparticles to label and track specific blood proteins, which have different shapes and sizes, through the filtration process. This is a huge advance over other imaging techniques that only allow us to see the top layer of the membrane.

We can now monitor the flow at every layer of both new and existing hemodialysis membranes, which means we can assess protein deposits on the dialysis membrane surface, accumulation and blockage of the membrane pores at all points in the process.

Using advanced software, the 3D images we obtain are being converted into valuable models that can predict how these blood proteins behave when they interact with different types of membranes. These models also enable us to understand when, how and why proteins accumulate and block the membranes for different clinical conditions.

Impact for patients

We are using this information to provide doctors with tools to optimize clinical practice and minimize the patients’ side-effects. For example, one recent study was the first to be able to predict the inflammation that patients may experience after a dialysis session .

Importantly, we are using all of this information to develop new membranes that better mimic the filtration ability of a healthy kidney. Again using gold nanoparticles to track blood proteins, imaging techniques at the CLS show the amount of attachment on current clinical membranes (Photo A) is greater than on membranes we developed with our new coating (Photo B) .

The information from all of our studies is being integrated to allow us to tune membrane characteristics for individual patient characteristics, which directly works towards our goal of improving patient quality of life.

The results of our work will reduce acute side-effects and life-threatening chronic conditions, and increase the quality of life and survival of the millions of people who suffer from kidney failure.

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Kidney articles from across Nature Portfolio

The kidney is the organ that filters blood and removes excess fluid and waste products, which are excreted in the urine. The kidney also has a role in the regulation of ion concentrations and blood pressure.

CD38 — a new target in renal immune disease

Targeting of CD38 has been posited as a potential therapeutic avenue for the treatment of immune-mediated conditions. A phase 2 study now reports promising safety, tolerability and intermediate endpoint of efficacy outcomes with the anti-CD38 monoclonal antibody felzartamab in kidney transplant recipients with antibody-mediated rejection.

• Ton J. Rabelink
• Aiko P. J. de Vries

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This study identifies shared immune-related gene signatures across kidney cell types in three distinct mouse models of renal disease and examines the role of glycosphingolipid metabolism in renal dysfunction.

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Healthy ageing and the kidney — lessons from centenarians

Centenarians — who are a putative model of healthy longevity — often have a low risk of cardiovascular disease, despite an age-associated decline in kidney function. An understanding of the molecular and cellular underpinnings of health kidney ageing in centenarians may provide clues for the prevention or alleviation of the burden of kidney disease in older populations.

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Cystatin C and the misdiagnosis of CKD in older adults

The use of cystatin C-inclusive equations will continue to propagate the unnecessary overdiagnosis of chronic kidney disease (CKD) in older people. Cystatin C is less biologically specific for CKD than is serum creatinine, inflates the risks of adverse outcomes compared to measured glomerular filtration rate, and does not establish chronicity at a single time point.

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Kidney disease ends here .

Research team in Manchester discover that kidney genes may lead to high blood pressure and that cells found in the urine could help to diagnose kidney disease early on

In new results , published in Nature Communications , r esearchers at the University of Manchester , led by Professor Maciej Tomaszewski and part funded by Kidney Research UK, have found 399 kidney genes that are linked to high blood pressure and that kidney cells in urine are an importan t non-invasive source of information about these genes .  

Studying genetic information from urine samples

Genes are sections of inherited instructions (DNA) that determine an individual's traits, such as hair colour and risk of certain medical conditions. The team at the University of Manchester measured the levels of 20,000 different genes in both human kidneys and cells harvested from urine, using a technique called transcriptomics. This approach is used by scientists to recognise which genes are turned on or off in different situations.

The project found that 399 kidney genes could be linked to increased blood pressure. Most of these genes were present in cells collected from urine and were expressed in similar ways in these cells and ones from inside the kidney.

Maciej commented: “ One of the exciting findings is that cells harvested from urine have the potential to provide a non-invasive insight into activity of genes in the kidney. This could be important in identifying and diagnosing kidney diseases non-invasively."

The link between blood pressure and kidney disease   

The relationship between the kidneys and blood pressur e is a complex one. Not only do the kidneys play a role in controlling blood pressure, but high blood pressure increases the risk of chronic kidney disease (CKD).  

The ENPEP gene

The team found that low levels of one of the kidney genes, called ENPEP, may be one of the causes of high blood pressure. This gene is responsible for production of a protein called aminopeptidase A in the kidneys, that has a role in blood pressure control and water balance.

Maciej added “Our results also show that ENPEP is a new promising target for development of new blood pressure lowering medications; this could be of importance not only for preventing kidney disease but also other conditions including heart disease and strokes”.

Dr Aisling McMahon, executive director of research at Kidney Research UK said: “Preventing progression of kidney disease is a high priority, so finding new non-invasive ways to detect it early are crucial. As we know from our 2023 Health Economics report , there are growing numbers of people who are at risk of kidney disease due to increased cases of other associated diseases such as high blood pressure. Further research into this area may lead to exciting new drug targets for lowering blood pressure which could protect people from developing chronic kidney disease in the future.”

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Diabetes technology in people with diabetes and advanced chronic kidney disease

Affiliations.

• 1 University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
• 2 University of Miami Miller School of Medicine, Miami, FL, USA.
• 3 University of Virginia Center for Diabetes Technology, Charlottesville, VA, USA.
• 4 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
• 5 Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
• PMID: 39112642
• DOI: 10.1007/s00125-024-06244-y

Diabetes is the leading cause and a common comorbidity of advanced chronic kidney disease. Glycaemic management in this population is challenging and characterised by frequent excursions of hypoglycaemia and hyperglycaemia. Current glucose monitoring tools, such as HbA 1c , fructosamine and glycated albumin, have biases in this population and provide information only on mean glucose exposure. Revolutionary developments in glucose sensing and insulin delivery technology have occurred in the last decade. Newer factory-calibrated continuous glucose monitors provide real-time glucose data, with predictive alarms, allowing improved assessment of glucose excursions and preventive measures, particularly during and between dialysis sessions. Furthermore, integration of continuous glucose monitors and their predictive alerts with automated insulin delivery systems enables insulin administration to be decreased or stopped proactively, leading to improved glycaemic management and diminishing glycaemic fluctuations. While awaiting regulatory approval, emerging studies, expert real-world experience and clinical guidelines support the use of diabetes technology devices in people with diabetes and advanced chronic kidney disease.

Keywords: Chronic kidney disease; Continuous glucose monitor; Diabetes; Diabetes technology; Review.

© 2024. The Author(s).

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• Diabetes technology and treatments in the paediatric age group. Shalitin S, Peter Chase H. Shalitin S, et al. Int J Clin Pract Suppl. 2011 Feb;(170):76-82. doi: 10.1111/j.1742-1241.2010.02582.x. Int J Clin Pract Suppl. 2011. PMID: 21323816 Review.
• Assessment of markers of glycaemic control in diabetic patients with chronic kidney disease using continuous glucose monitoring. Vos FE, Schollum JB, Coulter CV, Manning PJ, Duffull SB, Walker RJ. Vos FE, et al. Nephrology (Carlton). 2012 Feb;17(2):182-8. doi: 10.1111/j.1440-1797.2011.01517.x. Nephrology (Carlton). 2012. PMID: 21883672
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• Continuous glucose monitoring systems for type 1 diabetes mellitus. Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJ. Langendam M, et al. Cochrane Database Syst Rev. 2012 Jan 18;1(1):CD008101. doi: 10.1002/14651858.CD008101.pub2. Cochrane Database Syst Rev. 2012. PMID: 22258980 Free PMC article. Review.
• Galindo RJ, Beck RW, Scioscia MF, Umpierrez GE, Tuttle KR (2020) Glycemic monitoring and management in advanced chronic kidney disease. Endocr Rev 41(5):756–774. https://doi.org/10.1210/endrev/bnaa017 - DOI - PubMed - PMC
• United States Renal Data System (2023) USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
• Galindo RJ, Ali MK, Funni SA et al (2022) Hypoglycemic and hyperglycemic crises among U.S. adults with diabetes and end-stage kidney disease: population-based study, 2013–2017. Diabetes Care 45(1):100–107. https://doi.org/10.2337/dc21-1579 - DOI - PubMed
• Galindo RJ, Moazzami B, Tuttle KR, Bergenstal RM, Peng L, Umpierrez GE (2024) Continuous glucose monitoring metrics and hemoglobin A1c relationship in patients with type 2 diabetes treated by hemodialysis. Diabetes Technol Ther. https://doi.org/10.1089/dia.2024.0145 - DOI - PubMed
• Kaminski CY, Galindo RJ, Navarrete JE et al (2024) Assessment of glycemic control by continuous glucose monitoring, hemoglobin A1c, fructosamine, and glycated albumin in patients with end-stage kidney disease and burnt-out diabetes. Diabetes Care 47(2):267–271. https://doi.org/10.2337/dc23-1276 - DOI - PubMed

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Normal, healthy kidneys filter about 200 quarts of blood each day, generating about 2 quarts of excess fluid, salts, and waste products that are excreted as urine. Loss of function of these organs, even for a short period of time or due to gradual deterioration, can result in life-threatening complications. Loss of kidney function is an important health challenge whether it occurs suddenly or over a long period of time.

The NIDDK supports basic and clinical research on kidney development; the causes of kidney disease; improving kidney health equity and reducing kidney health disparities; the underlying mechanisms leading to progression of kidney disease; and the development and testing of possible treatments to prevent or slow progression of kidney disease. Also of interest are studies of inherited diseases such as polycystic kidney disease, congenital kidney disorders, and immune-related kidney diseases such as IgA nephropathy and hemolytic uremic syndrome.

It has been estimated that 35.5 million American adults have chronic kidney disease (CKD). CKD has two main causes: high blood pressure and diabetes. CKD, especially if undetected, can progress to irreversible kidney failure. People with kidney failure require dialysis or a kidney transplant to live. Minority populations, particularly African Americans, Hispanic and Latino Americans, and American Indians and Alaska Natives, bear a disproportionate burden of CKD and kidney failure.

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Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats

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• Yang Wang 1 ,
• Yinghao Wang 1 ,
• Zhenquan Sun 1 ,
• Xiaoxing Yin 1 &
• Xueyan Zhou   ORCID: orcid.org/0000-0003-2821-1013 1  

Stem Cell Research & Therapy volume  15 , Article number:  239 ( 2024 ) Cite this article

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The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN.

A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 10 6 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging.

The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys.

Conclusions

Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Introduction

Diabetes mellitus (DM) is an intractable global health challenge, and the number of people suffering from this disease reached 451 million worldwide as of 2017 and is projected to increase to 552 million by 2030 [ 1 ]. Approximately 20–40% of people with diabetes suffer from diabetic nephropathy, particularly those with type 2 diabetes mellitus (T2DM) [ 2 ].

Diabetic nephropathy (DN) is a type of kidney disease caused by chronic high blood glucose and is one of the most common and serious complications of diabetes. In the early stages of diabetic nephropathy, the glomeruli are damaged, and microalbumin is present in the urine, which is often one of the first signs. If not controlled in time, the patient's condition will rapidly deteriorate, and the patient will eventually develop end-stage renal disease (ESRD) and require hemodialysis or even kidney transplantation [ 3 ].

The pathogenesis of DN has not been fully elucidated, but the role of chronic inflammation induced by prolonged hyperglycemia in podocyte injury has received increasing attention. Podocytes are major components of the glomerular filtration barrier (GFB) [ 4 ], thus, podocyte injury impairs GFB integrity and is strongly associated with diffuse glomerulosclerosis and ESRD [ 5 ].

A hyperglycemic environment can increase the release of many cytokines, such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). Increased levels of these cytokines can promote the development of kidney inflammation, which can disrupt podocyte structure and reduce the number of podocytes. In turn, changes in podocyte structure and a reduction in podocyte numbers can lead to proteinuria [ 6 ]. To better understand the relationship between inflammation and DN, we used Rat Cytokine arrays (Catalog #: GSR-CYT-3-1, RayBiotech Inc) to confirm the expression of 27 cytokines in the renal cortex of rats. The advantages of antibiotic microarrays include low sample consumption, high sensitivity, and fast output of experimental results.

Recently, stem cell therapy, as a potential regenerative treatment [ 7 ], has been widely applied in the research of diabetes and its complications, especially DN [ 8 ]. Mesenchymal stem cells (MSCs) were initially isolated and characterized from bone marrow but were subsequently isolated from other tissues, such as adipose tissue, placenta, and umbilical cord blood. Among these, umbilical cord-derived mesenchymal stem cells (UC-MSCs) are used as an alternative source of stem cells to bone marrow due to their advantages such as easy accessibility, low immunogenicity, and lack of ethical concerns [ 9 ]. Besides, MSCs can also migrate to damaged sites, regenerate tissue [ 10 , 11 ] and secrete paracrine mediators [ 12 ]. They also have excellent anti-inflammatory [ 13 ] and immunosuppressive [ 14 ] properties, making them safe for allogeneic and xenogeneic infusion. Recent studies [ 15 , 16 ] have proved that cell-based therapy endured a dose-dependent effect (a single dose was inferior to two doses) on improving the outcomes in damaged organs.

Since angiotensin II is the primary regulator of glomerular filtration, current guidelines recommend the use of renin-angiotensin-aldosterone system (RAAS) inhibitors as the primary treatment for DN to reduce glomerular pressure and increase the filtration rate [ 17 ]. Among these agents, the angiotensin II receptor antagonist irbesartan can effectively prevent the progression of type 2 diabetic nephropathy (T2DN), and this protective effect is independent of its ability to reduce blood pressure. In a clinical trial [ 18 ], compared with amlodipine, a placebo, and other antihypertensive drugs, irbesartan was associated with better renal outcomes and lower rates of other adverse effects, including cardiovascular mortality, than the placebo.

Previous studies showed that combined treatment with mesenchymal stem cells and the GLP-1 receptor agonist exenatide could protect against premature nephropathy in diabetic rats [ 19 ]. Xian et al. [ 20 ] validated the protective effect of umbilical cord mesenchymal stem cells combined with resveratrol on podocyte injury in NOD mice. The proposal of combined drug administration provides a new strategy for the treatment of DN. In addition, a clinical trial has shown that although improvements in the condition of patients with lupus nephritis were observed after injection of MSCs, some immunosuppressive drugs are still required for maintenance treatment [ 21 ]. Therefore, considering the future clinical applications of MSCs, combined therapy is also regarded as a worthwhile research topic. However, whether the combination of Irbesartan with MSCs can improve the treatment of DN through their respective therapeutic mechanisms remains to be further investigated.

MSCs, as "living" drugs, have pharmacokinetic parameters that are difficult to evaluate through conventional analytical methods, once they enter the body, these cells are akin to entering a black box. In recent years, radiolabeling and nuclear imaging tracking of adoptively transferred cells offer a promising noninvasive approach to studying their PK profile in vivo. Among them, it mainly includes positron emission tomography (PET) and single photon emission computed tomography (SPECT). In contrast, PET imaging has greater advantages, such as higher resolution, higher detection sensitivity, and less radioactivity [ 22 ]. However, a significant drawback of using nuclide labeling methods is the possibility of intracellular radioactive isotopes leaking out during cellular metabolism and cell death [ 23 , 24 ]. This creates difficulties in distinguishing between live cells, damaged cells, radioactive cell fragments, or leaked nuclides, thereby impacting the precision of tracer results [ 25 ]. Recently, Yang et al. [ 26 ] proposed that radiolabeled cells can be tracked in vivo through positron emission tomography (PET) imaging to trace the trajectory of cell migration. They found that the use of the iron chelators deferoxamine (DFO) can enhance the accuracy of PET imaging, reduce bone uptake, preserve uptake in major organs, and avoid interference from free isotopes released by dead cells. Hence, we employ this method to investigate the in vivo trajectory of MSCs and confirm their ability to home to damaged kidney tissue, consequently exerting a protective effect on renal function.

Materials and methods

Isolation, culture and identification of umbilical cord-derived mesenchymal stem cells.

UC-MSCs were obtained from Xuzhou Regional Cell Preparation Center Co., Ltd. Fresh umbilical cord tissue was collected and washed with phosphate-buffered saline (PBS), after which the Wharton's jelly was separated from the umbilical cord tissue using sterile scissors and forceps. The Wharton's jelly was then cut into small pieces approximately 1 mm 3 in size. These pieces were cultured in 15 mL of serum-free medium in T75 flasks. Upon reaching approximately 80% confluence, the cells were passaged. We used fifth passage cells for subsequent experiments. Cells expressed CD73, CD90, and CD105 but did not express CD19, CD34, CD45, CD79a, CD11b, or HLA-DR. These cells met the current international standards for defining mesenchymal stem cells derived from bone marrow [ 27 ]. Flow cytometry results were provided by Nanjing Kingmed for Clinical Laboratory.

PET imaging of 89 Zr labeled MSCs in DN model

To prepare the 89 Zr-oxine complex, we obtained a certain volume of oxalic acid 89 Zr solution, added 9 times the volume of HEPES buffer solution (0.1 mol/L) and added 0.375 times the volume of Na 2 CO 3 solution (1 mol/L) to adjust the pH to 7. Then, we labeled mesenchymal stem cells with 89 Zr-oxine. The cells were centrifuged and distributed into 15 mL sterile centrifuge tubes. Then, 10 μCi of labeled 89 Zr-oxine was added to each 1 × 10 6 stem cell sample and incubated for 15 min at room temperature. The cells were intermittently agitated to ensure that the cells were suspended. Then, the mixture was centrifuged at 300× g for 5 min at room temperature and washed 3 times with DPBS to remove unbound 89 Zr-oxine and free 89 Zr ions to obtain 89 Zr-stem cells ( 89 Zr-MSCs). Finally, we intravenously injected 89 Zr-labeled mesenchymal stem cells into the rats. To eliminate free Zirconium from the body, 200 μL of 50 mg/mL DFO was injected into the muscle of each rat 30 min before the injection of 89 Zr-MSCs. At 1 h, 3 h, 6 h, 24 h, 48 h, 72 h, 5 d, 10 d, or 12 d after 89 Zr-MSCs administration, an Inveon MicroPET scanner (Siemens Medical Solutions) was used for static PET scanning. PET images were quantitatively analyzed using a previously reported method [ 28 ].

Antibody arrays

Rat Cytokine arrays (GSR-CYT-3-1, RayBiotech, Norcross, GA, USA) were used according to the manufacturer’s instructions to measure the expression levels of 27 cytokines in in the renal cortex of rats. The slide scanning was performed using InnoSan 300 Microarray Scanner (Innopsys, Parc d'Activités Activestre; 31 390 Carbonne-France). Differentially expressed proteins were arranged using hierarchical clustering and represented as a heat map. Data analysis was conducted using the GSR-CYT-3 data analysis software.

Drugs and chemicals

Irbesartan (Sanofi-Aventis, France, 30 mg/kg/day, IG) and streptozotocin (STZ) (Sigma Chemical Co., St. Louis, MO, USA, 35 mg/kg, IP) were used. A Rat Cytokine Array GS3 was used (RayBiotech, USA). Nephrin (Santa Cruz, sc-376522), WT-1 (Abcam, ab267377), and NPHS2 (Proteintech, 20384-1-AP) were used. Serum creatinine (Scr) and blood urea nitrogen (BUN) levels were measured by a Hitachi automatic analyzer (Hitachi Co. Ltd., Tokyo, Japan). Urinary albumin was measured by standard methods using commercial ELISA kits (Wuhan Newqidi Biological Technology Co., Ltd.).

Animal experiments were approved by the Experimental Animal Ethics Committee of Xuzhou Medical University (202207s017). Forty male Sprague-Dawley (SD) rats weighing 160–180 g were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., and raised in the Animal Center of Xuzhou Medical University. The sample size of the experimental and control groups was determined based on previous studies regarding the treatment of DN using MSCs transplantation combined with other drugs [ 27 , 29 ] and our pilot trial. The laboratory temperature was 22 °C, and an alternative 12-h light/dark cycle was used. There were 4–5 rats per cage. Ear tags were used for labeling. These rats had free access to food and water and could freely move in their cages.

Animal experiments

After the animals were acclimatized and fed for one week, they were randomly divided into the following five groups using a random number generator: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). In order to control experimental bias, we requested a researcher unfamiliar with the animal modeling situation to perform blind grouping, with the number of rats that contributed data for analysis in each experiment indicated in figure legends. Rats in the control group were fed normal chow, and the remaining rats were fed high-fat chow (Research Diets, Shanghai Synergy; XTHF45 rodent diet with 45 kcal% fat) for 6 weeks. Except for control rats the rats were intraperitoneally injected with streptozotocin (35 mg/kg; Sigma-Aldrich, St. Louis, MO, USA) dissolved in 0.1 M sodium citrate (pH 4.5), and control rats were injected with 0.1 M sodium citrate [ 6 ]. Three days after STZ injection, blood glucose levels were measured by tail vein blood sampling for three consecutive days, and blood glucose levels above 16.7 mmol/L were considered to indicate diabetes [ 30 ]. Body weight was monitored weekly, and blood glucose levels were tested every two weeks. After 4 weeks of streptozotocin injection, the diabetic rats exhibited significant increases in urine output, and urine protein levels greater than 20 mg/24 h indicated successful modeling [ 17 ]. During the experiment, we tried to minimize the pain of the animals and did not experience any adverse events related to the experimental drug. After animal modeling, we closely observe the state of the experimental animals. Due to the serious progression of some animal diseases that meet humanitarian priorities and end of experiment indicators, such as anorexia and weakness, they should be removed from the experiment and euthanasia should be implemented in a timely manner. The rats in the MSCs group and the MSC + Irb group were injected with 5th generation UC-MSCs (2 × 10 6 cells, 1 mL) via the tail vein 3 times every 10 days [ 31 ]. The remaining groups were injected with an equal amount of PBS via the tail vein. Rats in the Irb group and MSC + Irb group were administered irbesartan (30 mg/kg/d) by gavage. The remaining groups received the same amount of saline by gavage. Ensure that each group has at least 6 rats.

For the pharmacokinetic experiment, animal breeding and modeling were similar to the pharmacological experiments, and the animals were divided into two groups. (1) the 89 Zr-MSCs-CON (C + M) group (n = 5); (2) the 89 Zr-MSCs-DN (D + M) group (n = 5). The meaning is respectively the injection of 89 Zr-labeled mesenchymal stem cells in control group and diabetic nephropathy group. 10 SD rats in total.

Before dissection, rats were euthanized with an overdose of pentobarbital sodium. Our animal studies were reported in accordance with the ARRIVE guidelines 2.0. (Additional file 1 ).

Assessment of glucose tolerance

After 3 weeks of drug treatment, the rats were fasted for 12 h, and glucose solution (1 g/kg) was injected intraperitoneally. Blood glucose was measured by collecting blood from the tail vein at 0, 25, 30, 60, and 120 min after injection. Insulin resistance was assessed by the steady-state test (HOMA-IR) and was calculated using the following formula: HOMA-IR = glucose concentration (mmol/L) × insulin (μU/L)/22.5.

Renal histopathological evaluation

Kidney tissues were fixed in 10% formalin for 24 h, embedded in paraffin, sectioned at a thickness of 3 μm, stained with hematoxylin-eosin (HE) and periodic acid-Schiff (PAS), and examined under a microscope. To prepare ultrathin sections, 1 mm 3 of kidney tissue was fixed with 2.5% glutaraldehyde (pH 7.4) for 24 h at 4 °C. The tissue was then fixed in 1% osmium tetroxide for 2–3 h, dehydrated in acetone and ethanol, and embedded in epoxy resin. Sections were cut to a thickness of 50 nm with an ultramicrotome and then stained with 3% uranyl acetate and lead citrate. The sections were examined by transmission electron microscopy.

Urine and blood samples and tissue specimens

Urine samples were collected from the rats before the end of the experiment, and to prevent the effects of feces and food on urinary proteins, the rats were placed in metabolic cages (Shanghai, China) and were fasted but watered. Urine was collected and centrifuged at 1500 rpm for 5 min, and the supernatant was collected and stored at −80 °C. These samples were used to measure urinary microalbumin and creatinine. The urine microalbumin/creatinine ratio (UACR) was subsequently calculated. Before the end of the experiment, the rats were fasted for 12 h and anesthetized with sodium pentobarbital for blood sampling. The collected blood was centrifuged at 3000× g for 15 min, and the supernatant was stored at −80 °C. These samples were used to measure blood creatinine, blood urea nitrogen, and inflammatory factor levels. Left kidney tissue was fixed in 10% formalin for histological examination. The other part of the renal cortex was cut into 1 mm × 1 mm × 1 mm cubes and placed in electron microscopy fluid for storage (stored at 4 ℃ in the dark). The right cortex was quickly frozen in liquid nitrogen and stored at −80 °C for biochemical and immunoblot analyses.

Western blotting

Kidney tissue was added to lysis buffer (Bi Biotechnology, Shanghai, China), cut into pieces with scissors and processed with a grinder. Total protein was separated by SDS-PAGE and transferred to an NC membrane (Millipore, MA, USA). The membranes were blocked with protein-free rapid blocking solution for 15 min and rapidly washed with 1× PBS for 2 min. The NC membranes were incubated overnight at 4 ℃ with the following antibodies: anti-nephrin (1:1000; Santa Cruz; sc-376522), anti-NPHS2 (1:1000; Proteintech; 20384-1-AP), anti-WT-1 (1:1000; Abcam; ab267377), and β-actin (1:10000; Bioworld; AP0060). Then, the membranes were incubated with secondary antibodies at room temperature. After 1 h, the protein bands were examined using near-infrared fluorescence imaging technology. The band intensity was analyzed using ImageJ software (NIH, Bethesda, MD, USA).

Quantitative reverse transcription PCR (real-time PCR)

Total RNA was extracted from approximately 30 mg of kidney tissue using TRIzol® reagent. The RNA concentration was measured by a super-trace ultraviolet spectrophotometer (Thermo). Total RNA (1 μg) was reverse transcribed. The following primer pairs were used: GAPDH forward 5′-CTGGAGAAACCTGCCAAGTATG-3′, reverse 5′-GGTGGAAGAATGGGAGTTGCT-3′; β-NGF forward 5′-GAGACTCTGTCCCTGAAGCCCA-3′, reverse 5′-CCACAGTGATGTTGCGGGTCT-3′; GM-CSF forward 5′-TACAGTTTCTCAGCACCCACC-3′, reverse 5′-TCTTCGTTCTTTTCGTTCTCCAG-3′; TNF-α forward 5′-CCAGGTTCTCTTCAAGGGACAA-3′, reverse 5′-GGTATGAAATGGCAAATCGGCT-3′; and IL-1β forward 5′-TGTGACTCGTGGGATGATGAC-3′, reverse 5′-CCACTTGTTGGCTTATGTTCTGTC-3′. Relative mRNA expression was normalized to the GAPDH level and calculated by the 2 −ΔΔCT method.

Statistical analysis

Statistical analysis was performed using SPSS statistics 20.0 software and GraphPad Prism 9.0 (GraphPad Software, Inc., San Diego, CA, USA). All data are presented as the mean ± SEM. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Differences between two groups were assessed with Student’s t test. P  < 0.05 indicated statistical significance.

Expression of cell surface markers to identify UC-MSCs

P1 UC-MSCs were analyzed using flow cytometry to identify cell surface markers. Results showed positive expression of CD105 (99.94%), CD90 (99.97%), and CD73 (100.00%) (Fig.  1 A–C). However, CD34, CD45, CD11b, CD19, CD79a, and HLA-DR were all negatively expressed, with respective negative rates of 0.31%, 0.2%, 0.19%, 0.12%, 0.59%, and 0.00% (Fig.  1 D–H). These findings indicate that UC-MSCs exhibit high expression of mesenchymal stem cell markers while lacking expression of hematopoietic stem cell markers, consistent with the international definition of MSCs.

The surface markers of UC-MSCs. A–I The surface markers were identified by flow cytometry. CD105, CD90 and CD73 were expressed, and the positive rates were 94%, 99.97% and 100.00%, respectively. CD34, CD45, CD11b, CD19 and CD79a were not expressed, and the expression rates were 0.31%, 0.2%, 0.19%, 0.12% and 0.59%, respectively. HLA-DR was not expressed, and the expression rate was 0.00%

Effects of UC-MSCs and irbesartan alone or in combination on the basic parameters of type 2 diabetic nephropathy

The control group had normal diet and water intake, were in good mental condition and were active. T2DN rats exhibited obvious polydipsia, polyphagia, polyuria and weight loss. The hair was yellow, the mental state was poor, and the movements were slow.

We measured body weight (Fig.  2 A), fasting blood glucose (Fig.  2 B), the HOMA-IR (Fig.  2 C) and IPGTT (Fig.  2 D–E). The body weights of DN rats were significantly lower than those of the control group. There was no notable change in body weight in any of the treatment groups. Compared to those in the control group, fasting blood glucose levels in the DN groups were significantly increased. However, UC-MSCs significantly decreased these levels; and combination treatment also induced decreases, but the difference was not significant. In addition, we examined glucose tolerance and insulin resistance indices in the rats. DN rats had impaired glucose metabolism and insulin resistance, and these conditions were significantly improved in the MSC + Irb group.

Effects of UC-MSC, irbesartan or the combination treatment on the biochemical indices of DN rats. A Body weight. B Fasting blood glucose. C HOMA-IR index. D IPGTT. E The AUC of the IPGTT. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Data were shown as mean ± SEM, n  = 6. * P  < 0.01 and **** P  < 0.0001 versus the CON group, # P  < 0.05 versus the DN group. IPGTT: Intraperitoneal glucose tolerance test, AUC: area under the curve, HOMA-IR: homeostasis model assessment index for insulin resistance, CON: control group, DN: diabetes nephropathy group, MSCs: mesenchymal stem cells treatment group, Irb: irbesartan treatment group, MSC + Irb: combined administration group

Effects of UC-MSCs and irbesartan alone or in combination on the renal function parameters of type 2 diabetic nephropathy

To evaluate the reno-protective effects of UC-MSCs and irbesartan alone or in combination on diabetic rats, we measured the urinary microalbumin/creatinine ratio (UACR), kidney index, and serum creatinine (Scr) and blood urea nitrogen (BUN) levels in each group. After treatment, the UACR was significantly lower in all the groups than in the DN group, and the effect was most significant in the combination administration group (Fig.  3 A). The kidney indices in the DN group were significantly higher than those in the control group. The kidney indices were decreased in all the treatment groups but were only significantly different in the combined administration group (Fig.  3 B). Serum creatinine and blood urea nitrogen (Fig.  3 C–D) levels were higher in DN rats than in control rats. Serum creatinine levels were significantly lower in all the groups after treatment, but this difference was significant only in the combined administration group. Blood urea nitrogen was significantly reduced in the UC-MSC treatment group and combined administration treatment group, but in the irbesartan group, there was a reduction but not a significant difference. More importantly, the effects were most significant in the combined administration group.

Effects of UC-MSC, irbesartan or the combination treatment on renal parameters in DN rats. A Urine albumin creatine ratio. B Kidney indices. C Serum creatine levels. D Blood urea nitrogen levels. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Data were shown as mean ± SEM, n  = 6. ** P  < 0.001, *** P  < 0.001 and **** P  < 0.0001 versus the CON group, # P  < 0.05, ## P  < 0.01 and ### P  < 0.001 versus the DN group. CON: control group, DN: diabetes nephropathy group, MSCs: mesenchymal stem cells treatment group, Irb: irbesartan treatment group. MSC + Irb: combined administration group

Effects of UC-MSCs and irbesartan alone or in combination on the renal histopathology

We performed HE (Fig.  4 A) and PAS (Fig.  4 B) staining and found that, compared with those in the control group, renal pathological changes in diabetic rats were obvious and mainly characterized by increased glomerular volume, mesangial cell proliferation, an increase in the extracellular matrix, and thickening of the glomerular basement membrane. After treatment in each group, these pathological changes were eliminated.

TEM (Fig.  4 C) showed that DN rats had significant fusion of foot processes and thickening of the glomerular basement membrane, and these effects were improved after the treatment of each group.

Histopathological analysis of the tissues of DN rats. A Representative images of H&E-stained kidney tissues in the different groups (scale bars = 100 μm). B Representative images of periodic acid–Schiff staining of kidney tissues in the different groups (scale bars = 100 μm), arrowhead indicate expansion of the mesangial matrix. C Representative transmission electron microscopy images of kidney tissues in the different groups (scale bar = 500 nm), arrowhead represents foot processes of the podocytes; asterisk represents GBM. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Data were shown as mean ± SEM, n = 6. **** P  < 0.0001 versus the CON group, # P  < 0.05, ## P  < 0.01 and #### P  < 0.0001 versus the DN group. CON: control group, DN: diabetes nephropathy group, MSCs: mesenchymal stem cells treatment group, Irb: irbesartan treatment group, MSC + Irb: combined administration group

Effects of UC-MSCs and irbesartan alone or in combination against podocyte injury in rats

WB experiments showed that the expression of the podocyte injury marker proteins podocin and nephrin was significantly lower in the DN group than in the control group (Fig.  5 A–B). The three groups showed significant improvements after treatment. However, the improvement in the combined administration group was the most evident. In addition, the expression of the podocyte nuclear protein WT-1 (Fig.  5 C) was significantly reduced in the DN group, indicating that rats in the DN group experienced significant podocyte loss. Podocyte loss in DN rats in each group improved after treatment, and the therapeutic effect in the combined administration group was the most significant. Uncropped images can be found in Figures S2 – 4 .

The effects of UC-MSCs, irbesartan, and the combination treatment on podocyte injury. A–C Representative Western blots showing podocin, nephrin and WT-1 in the renal cortex. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Data were shown as mean ± SEM, n  = 6. *** P  < 0.001 and **** P  < 0.0001 versus the CON group, # P  < 0.05, ## P  < 0.01, ### P  < 0.001 and #### P  < 0.0001 versus the DN group. CON: control group, DN: diabetes nephropathy group, MSCs: mesenchymal stem cells treatment group, Irb: irbesartan treatment group, MSC + Irb: combined administration group. The immunoblot has been cropped, full-length blots are presented in Supplementary Figs. 2–4

Safety and homing effect of UC-MSCs

In our study, 89 Zr-labeled mesenchymal stem cells were injected into rats through the tail vein, and a microPET device was used for imaging.

Using microPET imaging technology, we examined the distribution of mesenchymal stem cells in the body at the start of the experiment (Fig.  6 D). The results showed that within a short period of time, the injected clinical-grade mesenchymal stem cells were concentrated mainly in the lungs. PET imaging revealed no obvious signs of pulmonary embolism, which provided preliminary evidence of the safety of our mesenchymal stem cell therapy.

Consistent with the findings of previous studies, most bone marrow MSCs were distributed in the lungs and liver and had limited engraftment capacity [ 32 ]. The uptake in the lung, liver and kidney is shown in Fig.  6 A–C . In addition, PET imaging showed that UC-MSCs underwent renal homing at 3 h after injection (Fig.  6 D). This effect suggested that these cells could migrate to the damaged area, which is important for the treatment of various diseases.

These observations provide important insights into the safety and efficacy of mesenchymal stem cell therapy in rat models of normal and diabetic nephropathy, providing a basis for further research and potential clinical applications.

Quantitative analysis of UC-MSCs in different tissues and PET imaging. A–C Quantitative analysis of radiolabeled MSCs in the lungs, liver, and kidneys of the different groups of rats. D Representative PET images of each treatment group from Day 0 to Day 12. C + M: Injection of 89 Zr-MSCs in the control group. D + M: Injection of 89 Zr-MSCs in the diabetic nephropathy group

Effects of UC-MSCs and irbesartan alone or in combination on the expression of renal inflammatory factors in rats

We used an inflammatory factor antibody chip to examine inflammatory factors in the kidney cortex. A total of 27 inflammatory factors were identified on the chip. Cluster analysis (Fig.  7 A) showed that the enrichment of TNF-α, IL-1β, β-NGF, GM-CSF and IL-6 in the kidney tissues of the DN group was higher than that in the CON group. The concentrations of TNF-α, IL-1β, β-NGF and GM-CSF were decreased after treatment with UC-MSCs alone or combined with irbesartan, but irbesartan alone had no significant effects on these inflammatory factors (Fig.  7 B–D). In addition, the results of qPCR also confirm the above conclusion (Fig.  7 E–H). The enrichment of IL-2 in the kidney tissues of the DN group was lower than that in the CON group, and it decreased further after treatment with irbesartan alone or in combination (Fig.  7 B, D). These results suggest that UC-MSCs and irbesartan may synergistically enhance the anti-inflammatory effect of the combined treatment group by regulating different inflammatory factors.

The effects of UC-MSC, irbesartan, and the combination treatment on the expression of inflammatory factors. A–D Cytokines that were differentially expressed are shown as a heat map (red represents high content, and blue represents low content). D–G The expression of TNF-α, IL-1β, β-NGF, and GM-CSF was determined by qPCR. Comparisons among groups were performed using one-way analysis of variance (ANOVA). Data were shown as mean ± SEM, n  = 6. * P  < 0.05, ** P  < 0.01 and **** P  < 0.0001 versus the CON group, # P  < 0.05, ## P  < 0.01 and #### P  < 0.0001 versus the DN group. CON: control group, DN: diabetes nephropathy group, MSCs: mesenchymal stem cells treatment group, Irb: irbesartan treatment group, MSC + Irb: combined administration group

This study is the first to demonstrate the reno-protective effects of irbesartan combined with UC-MSCs. These effects may be attributed to the modulation of various inflammatory factors within the rat kidneys by MSCs and irbesartan, synergistically ameliorating podocyte injury and thereby improving diabetic nephropathy. Moreover, this paper was the first to demonstrate the homing of MSCs to the kidneys of rats with diabetic nephropathy using micro-PET.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus and a leading cause of end-stage renal disease [ 33 ]. Although its pathogenesis is unclear, diabetes induces adaptive pathological changes in the glomerulus, such as thickening of the glomerular basement membrane (GBM), the tethered matrix, and glomerular capillaries [ 34 ]. Moreover, with the development of DN, the structure and function of glomerular podocytes are markedly altered; for example, there is skeletal rearrangement in podocytes, podocyte fusion or even disappearance, an increase in the formation of intercellular tight junctions, a decrease in the length of slit septa, and a decrease in the number of podocytes [ 35 ]. This dysfunction leads to changes in intraglomerular capillary permeability, damage to the glomerular filtration barrier (GFB) and ultimately proteinuria [ 36 ]. These pathological changes can be monitored by measuring changes in the levels of nephrin, podocin and WT-1. Specifically, nephrin and podocin play key roles in regulating and stabilizing the integrity of the glomerular filtration barrier and renal function; WT-1 is expressed in the nucleus of podocytes, and its expression indirectly reflects the number of podocytes in the glomerulus [ 37 ]. Nephrin, podocin and WT-1 play important roles in maintaining the integrity of GFB, and decreases in their expression can result in podocyte apoptosis, detachment and fusion, ultimately leading to symptoms of renal insufficiency, such as proteinuria. Overall, glomerular podocyte injury is a key step in the progression of DN, and ameliorating podocyte loss and increasing the expression of podocyte-associated proteins, such as nephrin and podocin, can significantly slow the progression of proteinuria and protect the kidney. In addition, inflammation is a crucial pathological characteristic observed in chronic kidney diseases [ 38 ], including DN.

At present, there are various treatment methods for DN, including anti hyperglycemic drugs, lipid-lowering drugs, and renin angiotensin aldosterone system inhibitors (RAASi) [ 39 ]. The most widely used among them is RAASi, which includes angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) [ 40 ]. Among them, irbesartan has been shown to exhibit dose-dependent renoprotective effects on diabetic patients [ 41 ], as well as superior renal prognostic effects than the other drugs used in the study (amlodipine, placebos and antihypertensive drugs) [ 42 ]. In addition, compared with losartan and valsartan, irbesartan has higher bioavailability, lower plasma protein binding and a longer half-life. It has also been proven to reduce oxidative stress in diabetic kidneys [ 43 ]. Tunçdemir et al. [ 44 ] found that irbesartan can regulate kidney hemodynamics and reduce podocyte injury, thus exhibiting renoprotective effects on animal kidneys. Additionally, irbesartan can also reduce the production of proteinuria [ 45 ] and possesses a certain anti-inflammatory effect [ 46 ].

Recently, an increasing number of animal studies and clinical trials have highlighted the significant therapeutic potential of MSCs for DN [ 12 , 47 , 48 , 49 ]. Previous studies have reported that MSCs have the potential to promote renal regeneration through their anti-inflammatory and anti-fibrotic effects [ 50 , 51 ]. Li et al. [ 52 ] revealed that early administration of MSCs could maintain the balance of the immune microenvironment through an immunoregulatory mechanism, which prevented the occurrence of kidney injury, renal dysfunction, and glomerulosclerosis. Moreover, MSCs significantly reduce the expression of proinflammatory factors, including IL-1β, IL-6, and TNF-α, in the kidneys of DN rats [ 53 ]. The regulation of inflammation and tissue repair is related to the ability of MSCs to home to the site of inflammation to repair damaged tissue and maintain tissue homeostasis [ 54 ]. Because UC-MSCs contain younger stem cell populations, it has been suggested that they have greater regenerative potential. UC-MSCs also have the advantages of increased culture stability, increased replication potential, decreased immunogenicity, and increased accessibility; thus, many studies have focused on UC-MSCs [ 55 ].

In addition, a previous study showed that the combination of MSCs with the GLP-1 receptor agonist exenatide exerted significant protective effects against early-onset nephropathy in diabetic rats [ 27 ]. Other researchers have shown that the combination of UC-MSCs with the plant compound resveratrol protected against inflammation-induced glomerular podocyte injury in NOD mice [ 56 ]. The combination of cellular drugs with traditional therapeutic agents provides new ideas for the treatment of DN.

The FBG and UACR of the rats demonstrated the successful establishment of the DN model. We confirmed that the combination of MSCs and irbesartan led to a significant reduction in UACR, kidney index, BUN levels, serum creatinine levels, IPGTT and other relevant renal function parameters in rats with diabetic nephropathy. Furthermore, the combination therapy group showed significant improvements in parameters such as IPGTT, kidney index, and serum creatinine levels in T2DN rats, which were not observed in either the mesenchymal stem cell treatment group or the irbesartan treatment group. Interestingly, during the experiments, fasting blood glucose levels were greatly reduced in DN rats that were treated with UC-MSCs but were reduced but not significantly different in the rats that received the combination treatment. We believe that this effect is mainly due to interindividual differences. Differences in the dose and number of injections notably affected the hypoglycemic effect [ 20 ]. Previous studies have suggested that this hypoglycemic effect occurs because MSCs stimulate pancreatic β-cell regeneration [ 57 ].

Given the clear mechanism by which irbesartan treats diabetic nephropathy, primarily involving the regulation of the renin-angiotensin-aldosterone system (RAAS), our study focused on UC-MSCs. As living cell therapeutics, the pharmacological effects and pharmacokinetic characteristics of UC-MSCs are closely linked. Therefore, we believe that monitoring the in vivo biological distribution and behavior of injected cells is crucial. To validate the distribution of UC-MSCs in the bodies of DN rats, we administered 89 Zr-labeled UC-MSCs and utilized PET imaging technology for visualization. Consistent with prior studies, our observations indicate that MSCs survive in the bodies of rats for approximately 10 days, primarily homing to the lungs and liver initially, followed by migration to other organs, including the kidneys [ 33 , 58 , 59 ]. Additionally, we enhanced the accuracy and reliability of our imaging results by administering intramuscular DFO injections to eliminate false-positive results caused by free nuclides.

In addition, we examined the expression of inflammatory factors in rat kidney tissues by using an inflammatory factor antibody chip. We found that the enrichment of TNF-α, IL-1β, β-NGF, GM-CSF and IL-6 in the kidney tissues of the DN group was higher than that in the CON group. The expression levels of TNF-α, IL-1β, β-NGF and GM-CSF were significantly decreased in the MSC alone and combination groups, but no significant difference was observed in the irbesartan group. Compared with the CON group, the expression of IL-2 in the renal cortex of DN decreased, while it increased after treatment with irbesartan and combination therapy, with no significant difference observed in the MSCs treatment group. Among them, β-NGF is a member of the nerve growth factor family that regulates the development and function of the nervous system in combination with other nerve growth factors. An increase in NGF expression under high glucose conditions can lead to renal diseases such as diabetic nephropathy [ 29 ]. Neuroprotective growth factors such as NGF, GDNF and BDNF play important roles in podocyte differentiation, apoptotic resistance and cytoskeletal protection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) [ 60 ] plays an important role in regulating and promoting the growth, differentiation and function of white blood cells in the hematopoietic system. These results suggest that UC-MSCs and irbesartan may have a synergistic anti-inflammatory effect through the regulation of different cytokines when administered in combination.However, there are certain limitations in the research process of this article, previous research only explored the pharmacological effects of combined administration without investigating issues such as different drug dosages or treatment durations. Combining our pharmacokinetic experimental results, we will explore and validate these issues in subsequent experiments, aiming to further elucidate the mechanism of combined administration. Furthermore, it is essential to consider the influence of animal gender factors in future design of animal experiments.

In conclusion, the combination of umbilical cord-derived mesenchymal stem cells and irbesartan may be a promising therapeutic strategy for diabetic nephropathy and provides a new idea for the clinical translation of MSCs. Due to the complexity of DN pathogenesis, we will focus on the specific pathways in future studies.

In summary, we found that the combined application of umbilical cord-derived mesenchymal stem cells and irbesartan significantly improved glomerular podocyte damage in rats with diabetic nephropathy. Additionally, we observed that mesenchymal stem cells homed to the injured kidneys and regulated the expression of inflammatory factors. This may the potential mechanism by which mesenchymal stem cells exert their therapeutic effects. Therefore, these two treatments, which act through different mechanisms, synergistically protect the kidneys of rats with diabetic nephropathy. These findings provide new insights for the clinical application of mesenchymal stem cells.

Availability of data and materials

All remaining data and materials are available from the authors upon reasonable request. This protocol was not registered.

Abbreviations

Blood urea nitrogen

Diabetes mellitus

• Diabetic nephropathy

Enzyme Linked immunosorbent assay

End-stage renal disease

Fasting blood glucose

Glomerular basement membrane

Glomerular filtration barrier

Hematoxylin and eosin staining

Immunohistochemical

Mesenchymal stem cell

Periodic acid-Schiff stain

Phosphate buffer saline

Positron emission tomography

Quantificational real-time chain polymerase chain reaction

Renin-angiotensin-aldosterone system

Serum creatinine

Standard error of mean

Transmission electron microscope

Triglyceride

Urine albumin-to-creatinine ratio

Western Bolt

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Acknowledgements

We thank the Xuzhou Regional Cell Preparation Center Co., Ltd, for providing an ample supply of umbilical cord-derived mesenchymal stem cells for our experiments.

This work was supported by the Natural Science Foundation of China [No. 82173883]; the Traditional Chinese Medicine Technology Development Plan Project of Jiangsu Province [No. MS2023175]; the Science and Technology Foundation of Xuzhou [No. KC22469]; the National College Students Innovation and Entrepteneurship Training Program; and the Science and Technology Planning Project of Jiangsu Province [No. BE2019636].

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Jing Meng and Xiao Gao contributed equally to this work.

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Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China

Jing Meng, Xiao Gao, Xiaojuan Liu, Wen Zheng, Yang Wang, Yinghao Wang, Zhenquan Sun, Xiaoxing Yin & Xueyan Zhou

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Before conducting the experiment, we carefully designed the experimental plan and strictly followed it. XYZ, and XXY conceived and designed the study. JM, and XG collected and analyzed the data. JM, XG, XJL, ZW, YW, YHW, and ZQS performed the experiments. XYZ, and JM wrote the manuscript. All the authors read and approved the final manuscript. A protocol was prepared before the study.

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Correspondence to Xiaoxing Yin or Xueyan Zhou .

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The animal study was conducted with the approval of and in accordance with the rules and regulations of the Institutional Animal Care and Use Committee of Xuzhou Medical University, Xuzhou, China (Title of the approved project: To explore the therapeutic effect of mesenchymal stem cells derived from human umbilical cord on diabetes nephropathy; approval number: 202207s017; date: 15 July 2022).

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13287_2024_3844_moesm1_esm.pptx.

Additional file 1. Figure S1. Animal allocation situation. Figure S2. Full-length blots of podocin. Figure S3. Full-length blots of nephrin. Figure S4. Full-length blots of WT-1. Figure S5. The effect of Irbesartam on the cell viability, proliferation, aging, and apoptosis rate of UC-MSCs. CCK-8 assay; Cells were plated at equal density before challenged with Irbesartan (1 μM), the OD450 values of the CCK-8 test assay were detected after Irbesartan incubation for 0, 24, 48, 72 h respectively. (B) EdU labeling; Cells were exposed to EdU and then fixed and stained. Images were taken using fluorescence microscope (Olympus BX53), and cells labeled with EdU were Red. Scale bar = 100 μm. (C) Senesence associated β-galactosidase staining; The SA-β-gal-positive cells exhibited blue color (indicated by arrows) under phase-contact microscope. Scale bar = 50 μm. (D) Detection of apoptosis in MSCs by flow cytometry. Differences between two groups were assessed with Student’s t test. Data were shown as mean ± SEM, n = 6. MSCs: MSCs without irbesartan incubation, MSCs + Irb: MSCs incubated with Irbesartan. (PPTX 15962 kb)

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Meng, J., Gao, X., Liu, X. et al. Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats. Stem Cell Res Ther 15 , 239 (2024). https://doi.org/10.1186/s13287-024-03844-8

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Coping with losing a transplant

Everyone loves to talk about kidney transplant success stories but rarely do we talk about what happens if a transplant fails. On today's episode Dori Muench, a post transplant social worker, and Sue George, a kidney warrior with experience losing a transplant, are here to discuss the impact of losing a kidney and how to cope.

Artificial Kidneys

When will the artificial kidney be ready for human use? Learn more about the progress of the artificial kidney and how it will affect someone's quality of life from expert Shuvo Roy, Ph.D.

What is a high KDPI kidney?

When a kidney from a deceased donor becomes available, it is scored on a system called the Kidney Donor Profile Index (KDPI). How accurate is it at predicting possible transplant survival? On this episode, we speak with experts to get the facts

Fad diets and kidney diets

It’s hard to keep up with all the new fad diets out there. Do you know which ones are right for you and your kidney health? On this episode, you will hear from experts on finding the diet that's right for you and how to stick to it.

Superfoods for people with kidney disease

You may have heard the buzzword superfoods but what are they and do they have special qualities? Board-certified renal dietitian, Jen Hernadez is here to break it down. 

What do clinical end points and trials mean for CKD research?

Clinical trials exist to help prevent, screen for, diagnose, or treat diseases and other health problems. Without them, we would not have new treatments or other advances in health and medicine. But how are the clinical trial endpoints, or the preferred outcomes of these trials determined? Today, Anthony Gucciardo NKF’s Senior Vice President of Strategic Partnerships, Dr. Joseph Vassalotti, NKF’s Chief Medical Officer, and Kent Bressler, a Patient advocate and FSGS patient, discuss this and more.

Mindfulness meditation for kidney patients

You may have heard the term mindfulness before but what does it mean, what are the benefits, and how can you integrate mindfulness into your life? On today’s episode Gary Petingola a Social Worker certified to teach Mindfulness-Based Stress Reductionexplains all this and more.

Transplants for All

At the National Kidney Foundation, we believe that everyone who needs a kidney should get a kidney. To make this dream a reality, we’ve launched the Transplants for All Initiative. What is this initiative and how will it make a difference in the lives of people with kidney disease? In today’s episode special guests Morgan Reid, NKF’s Transplant Policy & Strategy Director and Haley Jenson, NKF’s Transplant Programs Director explain this and more.

BONUS: Sexuality and kidney disease

Sexual dysfunction is incredibly common in patients with kidney disease. In today's bonus episode, you'll learn about why it is so prevalent, the different treatment options, and how to improve communication around this important but often neglected aspect of health.

LGBTQ+ advocacy in healthcare

Over 50% of LGBTQIA-plus people have experienced some form of healthcare discrimination and over 25% of transgender people reported being denied care due to their transgender status. Not having proper health care or avoiding health care due to discrimination, can result in dire consequences, including an increased risk of health problems like kidney disease. What is this discrimination, and how can you advocate for yourself and LGBTQIA+ rights? In today’s episode Dr. Joshua Wilder, a podiatrist, and Representative Jeff Currey, two kidney transplant recipients and members of the LGBTQIA+ community, discuss this and more.

NKF Innovation Fund: developing new treatments for kidney patients

For far too long treatments for CKD haven’t changed. Launched in 2021, the NKF Innovation Fund works to accelerate funding, and development of therapies that kidney patients deserve. On this episode, you will hear from NKF CEO Kevin Longino interviews Kathleen St. Jean, Chief Commercial Officer of 34 Lives, one of the first recipients of a significant investment from NKF’s Innovation Fund to help further develop a new technology to rehabilitate donated kidneys for transplantation.

Living donors and mental health

Donating a kidney is one of the most selfless gifts one person can give to another. But what is that experience like for the donor before and after the transplant surgery? Today, we'll hear from Jessica Kolansky, a living kidney donor, and Alexandra Catalyst, a transplant coordinator, about the post transplant experience and what resources are available to donors after the surgery.

Laughter therapy for kidney patients

Is laughter really the best medicine? On today’s episode we’ll discuss an exciting new coping strategy for dialysis patients called guided group laughing therapy. What is it and how does it help? Dr. Paul Bennet who ran a study on the benefits of laughing therapy and Kimberly Super-Harrigan, a dialysis patient, are here to break it down.

BMI and weight management for kidney patients and living donors

Obesity is one of the major risk factors for developing kidney disease, which is measured through the body mass index or BMI. This measurement factors into the process for both living donors and transplant recipients. On today’s episode, you’ll learn how to measure your BMI and hear from both kidney patients on how managing their weight affected their kidney health.

Access to reproductive care for kidney patients

In 2022, the US Supreme Court overturned precedent established by Roe v Wade, eliminating the constitutional right to abortion. Family planning decisions can be difficult and complex for kidney patients. On today’s episode, we’ll discuss how this impacts kidney patients and disadvantaged patients with limited access to healthcare.

Game Changers: Treating CKD earlier

Did you know that 40% of chronic kidney disease progression may be preventable with earlier diagnosis and treatment? On this episode, you will hear the facts around treating CKD earlier from Dr. Joe Vassalotti, NKF’s Chief Medical Officer. You will also hear from Jane DeMeis on her journey with kidney disease.

Exercise and bone health: what CKD patients should know

Keeping your body and bones strong are important when you have kidney disease. Do you know what types of exercise are good for kidney patients? What about for transplant recipients or people on dialysis? In this episode, we sat down with experts to discuss the benefits and recommendations of managing an exercise routine.

Managing fluid intake as a CKD patient

It is important that certain individuals with CKD limit their fluid intake, but many don’t understand why or where to begin. On today’s episode, we sat down with experts to discuss fluid restriction, such as why it’s important, the negative effects of consuming too much, and ways to manage a fluid-restricted diet.

Treatment options for undocumented people with kidney disease

Undocumented people face increased barriers to accessing health coverage and care, including treatment for kidney disease. In this episode, our guest experts discuss what treatment options are currently available for undocumented people and what kind of advocacy efforts are being made to improve their access to health care. 

Breaking Down New Medicare Coverage for Immunosuppressant Drugs

The Medicare coverage for immunosuppressive drugs for kidney transplant patients has recently been expanded. But what does this new benefit cover and who is eligible? in this podcast, Cynthia Nichols-Jackson, a registered nurse and a program coordinator for the National Kidney Foundation, and Troy Zimmerman, a special projects director for the National Kidney Foundation, discuss how this new policy will affect the future for kidney transplants.

Should You Follow A Special Diet After Transplant?

How potassium affects kidney patients

One of the jobs your kidneys is to manage your body’s levels of potassium, which keeps your heartbeat regular and your muscles working right. Many kidney patients need to watch what they eat to ensure that their potassium levels don’t become too high and cause dangerous health risks. On today’s episode, you’ll hear how to best manage your potassium levels to protect yourself.

How kidney patients should protect themselves from COVID-19 in 2022

While many people feel like the world is headed back to normal, many kidney patients can feel left behind. COVID-19 is still top of mind for those who are immunocompromised and we're here to offer resources and support. On today's episode, our guests will answer your questions about how COVID-19 affects transplant, dialysis, and early stage CKD patients.

What is basic science research and why is it important?

When we hear the word research, most of us think of innovative breakthrough treatments and technologies. But applied clinical research could not be possible without another type of research called basic science research in which scientists study the fundamental processes of the human body. In this episode, we’ll learn what basic science research is and how it applies to the area of kidneys and kidney disease.

Working with your clinician to make shared decisions for your care

Shared decision making can play a vital role in the treatment of kidney disease. When physicians involve patients in their care, they may be able to help slow progression and improve outcomes. In this episode, we discussed how patients and their physicians can achieve this and hear stories from patients who have been there.

How kidney disease affects your mental health

People with chronic conditions like kidney disease face mental health struggles such as depression or anxiety. In many kidney patients those challenges often go overlooked or undertreated. In this episode, we sat down with a mentor and mentee from NKF Peers to discuss their experiences and the importance of talking to someone who knows what you've been through.

Tips for finding a living donor

If you are in need of a kidney transplant, finding a living donor can sound scary and overwhelming. Where should you start and what’s the best way to share your story with the world? In this episode, you will hear from transplant recipients who once stood in your shoes.

Pig kidneys in humans? Xenotransplantation explained.

From the invention of the dialysis machine to the first successful kidney transplant, science has come a long way in extending life for kidney patients. Is transplantation between humans and animals the next step? In this episode, you will hear from a doctor behind the first successful transplant of a human receiving a pig kidney and where the science can take us from here.

Deciding to become a living donor

Pregnancy and kidney disease

Pregnancy can be an exciting time for most people, but what does it look like if you are a kidney patient? What does pregnancy look like if they have kidney disease, are on dialysis, or have received a transplant? In this episode, we’ll hear useful facts and tips from transplant nephrologist Dr. Mariana Markell, as well as personal stories from Cari Maxwell and Katie Reed, two mothers living with kidney disease.

What are SGLT2 Inhibitors and are they the right drug for you?

You might have heard about drugs called SGLT2 inhibitors used in treatment of kidney disease, but, just like many other kidney patients, you might not know if they’re right for you. On this episode, we explain how different SGLT2 inhibitors are from other kidney disease medications, discuss side effects, cost, and the ongoing research around this category of drugs.

How much sodium is safe for kidney patients?

Most patients on dialysis need to limit the amount of sodium in their diets. But how much sodium is safe and what are some ways to add flavor to your diet? On today‘s episode, our experts cover examples of high sodium foods, recommendations for low sodium substitutes, and how much sodium people with kidney disease should have as a part of a healthy diet.

What do changes to eGFR calculation mean for patients?

Tips for overcoming financial hardship for kidney patients

Many kidney disease patients often face financial hardships, such as having to leave a job or struggling to pay for medications. We sat down with physician and a postdoctoral research fellow Dr. Issac Acquah to talk about his recent research into the financial impact on people with chronic kidney disease.

How to become an advocate for kidney health

Over the past year, NKF advocates have won a number of policy campaigns both in Congress and state capitals across the country - but we're not done yet. In this episode, we discussed some recent wins and our upcoming challenges for the kidney advocate community with Jeff Currey, a Connecticut State Representative and kidney transplant recipient, and Armand Halter, an NKF patient advocate who helped lead NKF’s efforts to pass the Connecticut version of the Living Donor Protection Act.

A major worry for many people right now is the Delta variant, a highly contagious strain of COVID-19 which is making headlines across the United States. The FDA has just authorized a third dose of the COVID-19 vaccine so that immune compromised patients can better protecting themselves from the virus. What does this mean for CKD, dialysis, and transplant patients? We spoke with Dr. Joseph Vassalotti, NKF Chief Medical Officer, in a recent Facebook Live to share the facts about the Delta variant, COVID-19 booster shots, and other concerns facing kidney patients.

Coping with depression & anxiety during a global pandemic

What You Need to Know About Ozempic and Chronic Kidney Disease

Research has found a connection between semaglutide, Ozempic’s main active ingredient, and the condition. Here’s what’s behind it.

Can Ozempic help with chronic kidney disease?

Why might ozempic help with chronic kidney disease, who could benefit from ozempic for kidney health.

Type 2 diabetes medication Ozempic has been linked to a host of potential benefits outside of blood sugar management, including weight loss and helping to break addictions . Ozempic side effects tend to have a negative connotation (as is the case for just about any drug). But the latest one may actually have a positive outcome: Ozempic may help with chronic kidney disease.

Meet the experts : Dina Peralta-Reich, M.D., director of New York Weight Wellness Medicine ; Kunal Shah, M.D ., an assistant professor in the division of endocrinology at the Rutgers Robert Wood Johnson Medical Center; Dusty Price, A.P.R.N.-C.N.P ., a certified nurse practitioner with the weight management program at The Ohio State University Wexner Medical Center

Research into this—and Ozempic in general—is ongoing, making it hard to make definitive conclusions on this. But experts say there is something to the link. Here’s what we know about Ozempic and chronic kidney disease right now.

What is Ozempic?

Ozempic is a brand name for semaglutide. It’s an injectable medication that’s approved by the U.S. Food and Drug Administration (FDA) to help with blood sugar management in patients with type 2 diabetes. Semaglutide is also FDA-approved for weight management in people with overweight or obesity under the name Wegovy. As a result, Ozempic may be used off-label for weight management, too.

Ozempic works on the body in a few ways, according to Kunal Shah, M.D ., an assistant professor in the division of endocrinology at the Rutgers Robert Wood Johnson Medical Center. It mimics a protein in your body called glucagon-like peptide 1 (GLP-1), he explains.

“Semaglutide activates GLP-1 receptors in your body, and that causes an increase in the production of insulin,” he says. ( Insulin is a hormone that helps escort glucose into your body’s cells, where it’s used for energy.)

But Ozempic also has an impact on your gut and your brain. “Semaglutide slows down the movement of food from the stomach to the gut,” Dr. Shah says. At the same time, it signals to your brain to feel less hungry. So, you may wind up eating less and feeling fuller longer on the medication than you would without it.

People on Ozempic usually start at a low dose of 0.25 milligrams before working their way up to 0.5 milligrams or more, Dr. Shah says. “Most patients start to see weight loss after 0.5 milligrams,” he adds.

Ozempic is a medication that’s typically designed to be taken “indefinitely,” Dr. Shah says.

What is chronic kidney disease?

Chronic kidney disease is a condition that happens when your kidneys are damaged and can’t filter blood the way they should, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The disease progresses slowly over a long period of time. People with diabetes, high blood pressure, heart disease, and a family history of kidney failure are at a higher risk of developing chronic kidney disease.

The disease may have no symptoms at first, but as it becomes advanced, the NIDDK says you may notice the following symptoms:

• itching or numbness
• feeling tired
• increased or decreased urination
• loss of appetite
• muscle cramps
• shortness of breath
• sleep problems
• trouble concentrating
• weight loss

It seems so. “There are studies that have been done in patients with type 2 diabetes that found that semaglutide reduces the risk of clinically important outcomes and death in patients with chronic kidney disease,” says Dina Peralta-Reich, M.D., director of New York Weight Wellness Medicine .

One clinical trial published in the New England Journal of Medicine in May followed 3,533 people with kidney disease and Type 2 diabetes. Half of the participants were given a weekly shot of semaglutide; The other half got a weekly placebo shot.

During a follow-up period of about 3.5 years, the researchers found that people in the semaglutide group had a 24% lower chance of having a major kidney disease event, like losing half of their kidney function, needing a transplant, or going on dialysis. According to the findings, 331 people had these kidney events in the semaglutide group, while 410 had them in the placebo group. They also had slower rates of kidney decline. (Worth noting: The participants who received semaglutide were less likely to die from cardiovascular disease.)

The trial was so successful that it was stopped early .

It’s important to point out that research has just found a link, but experts say it makes sense that semaglutide can help with chronic kidney disease management.

Ozempic “can help those with co-conditions that have led to chronic kidney disease such as diabetes or other cardiovascular diseases,” says Dusty Price, A.P.R.N.-C.N.P ., a certified nurse practitioner with the weight management program at The Ohio State University Wexner Medical Center. Both conditions raise the risk of developing chronic kidney disease and by managing them, it’s possible that semaglutide can also help lower the risk of severe complications from chronic kidney disease, she explains.

“By doing this, [Ozempic] can potentially help to stop or slow down further kidney disease,” Price says.

But Ozempic can also lead to weight loss and lowered inflammation, Dr. Peralta-Reich says. “This is all related to renal health,” she says. “Semaglutide can ultimately can improve kidney health.”

Again, Ozempic is technically only FDA-approved for blood sugar management in people with type 2 diabetes. However, it’s also used off-label for weight loss in people with overweight or obesity.

Price says people with a range of conditions may have a boost in kidney health on Ozempic. Those include:

• Hypertension
• Elevated cholesterol levels
• Type 2 diabetes
• Existing chronic kidney disease

“Having chronic kidney disease is not a contraindication when looking at using semaglutide injections which, for those with chronic kidney disease, is often a barrier when trying to use new medications for other co-conditions,” Price says.

If you have chronic kidney disease or are at risk of developing the condition, Peralta-Reich says it’s best to speak with your doctor about your treatment options. Keep in mind that Ozempic is not currently FDA-approved to treat chronic kidney disease, although it may be a good fit if you have another condition that is approved, like type 2 diabetes. Ultimately, it’s best to connect with a medical professional about next steps.

Ozempic Alternatives to Know About

Ozempic May Lower Your Risk of Cognitive Decline

Study Links Ozempic to Vision Loss

Doctors Share 5 Foods to Avoid When Taking Ozempic

Rybelsus Vs. Ozempic: What to Know

9 in 10 Adults in U.S. Have CKM Syndrome

What a Hormone Specialist Wants You to Know

Kelly Clarkson Discusses Prediabetes Diagnosis

Why Walking May Lower Your Type 2 Diabetes Risk

Nick Jonas Opens Up About Type 1 Diabetes

Does Red Meat Increase Type 2 Diabetes Risk?