Revolutionising CKD Care: Novel Treatment Paradigms and Cutting-edge Strategies

Dinesh Khullar^1*, Narinder Pal Singh¹, Anish Kumar Gupta¹

¹Department of Nephrology and Renal Transplant Medicine, Max Super Speciality Hospital, Saket, New Delhi

Abstract: Chronic Kidney Disease (CKD) represents a public health crisis globally. New therapeutic horizons in CKD management encompass a diverse array of options for a more holistic and personalised approach. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors exhibit promising results in preserving kidney function and mitigating cardiovascular risks in patients with or without diabetes. Non-steroidal selective Mineralocorticoid Receptor Antagonists (MRA) present targeted strategies for CKD management. Glucagon-like peptide-1 (GLP-1) receptor agonists offer innovative approaches for glycaemic control and complication reduction. Endothelin Receptor Antagonists contribute to CKD care by modulating endothelial function and reducing kidney damage. Aldosterone synthase inhibitors offer a unique angle, targeting aldosterone production to manage CKD-related complications. Additionally, hypoxia-inducible factor (HIF) inhibitors represent a cutting-edge therapeutic class, addressing the hypoxic conditions associated with kidney damage. This diverse range of advancements underscores a transformative shift towards more personalised and effective CKD treatments, providing newfound optimism for improved patient outcomes. Beyond providing evidence-based insights into recent therapeutic advancements in CKD, this review also delineates contemporary treatment guidelines for CKD. It underscores the imperative for holistic strategies to enhance outcomes for individuals grappling with this complex condition.

Key words: Chronic kidney disease, Sodium-glucose cotransporter-2 inhibitors, Hypoxia-inducible factor inhibitors, Glucagon-like peptide-1 receptor agonists, Mineralocorticoid receptor antagonists

Introduction

Chronic Kidney Disease (CKD) is a significant global public health concern, impacting around 10% of the worldwide population and posing substantial challenges in terms of health and mortality.[1] Individuals with CKD face heightened risks of kidney failure, cardiovascular diseases, acute kidney injury, heart failure and re-hospitalisation. Despite its considerable impact, CKD often goes unrecognised by both patients and healthcare providers. It commonly coexists with hypertension and diabetes. The causes of CKD are diverse, involving genetic factors, drug related adverse effects, and autoimmune processes.[2] In specific regions, such as Central America, Sri Lanka, Egypt and Central India, clusters of CKD cases with unknown causes have been identified.[3] CKD is a progressive, long-term condition marked by a gradual decline in kidney function. Diagnosis relies on more than serum creatinine levels, as they lack sensitivity in assessing glomerular filtration rate (GFR). An accurate CKD diagnosis involves evaluating factors like estimated GFR, urinalysis and albuminuria quantification. CKD is indicated by an eGFR below 60 mL/min/1.73 m², even without apparent kidney damage and confirmation of kidney damage is necessary for those with an eGFR ≥60 mL/min/1.73 m². The condition requires persistence for over three months for an accurate diagnosis. [4]

The demand for innovative CKD therapies arises from the limitations of current treatments, the progressive nature of the disease and the desire for more effective, targeted drug delivery and patient-centred interventions. Innovations in medical science, offer promising avenues for developing therapies that can minimise side effects, improve cost-effectiveness and provide tailored solutions to individual patients. While angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are recognised as standard treatments in CKD management, their efficacy can be limited. These medications primarily target the Renin-angiotensin-aldosterone system (RAAS), reducing proteinuria and managing blood pressure. However, they may not provide comprehensive renoprotection, as CKD involves diverse pathophysiological pathways. Responses to ACEIs and ARBs vary and some patients experience a continued decline in kidney function despite treatment. Adverse effects, tolerability issues and controversies surrounding dual blockade further contribute to their limitations. This review describes novel treatment paradigms along with contemporary treatment guidelines for CKD.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors

Over the last decade, a significant breakthrough in managing CKD has emerged with the discovery of the robust protective effects of SGLT-2 inhibitors on both the heart and kidneys, irrespective of diabetes status. Recent trials, including CREDENCE, DAPA-CKD and EMPA-KIDNEY, revealed an approximately 30% reduction in the risk of various kidney outcomes, even in patients with baseline estimated GFR as low as 20 mL/min/1.73 m2.[5-8] Notably, these trials were concluded ahead of schedule due to meeting pre-defined efficacy criteria, demonstrating the compelling benefits of SGLT-2 inhibitors (Table 1).

Parameters	CREDENCE[5]	DAPA-CKD[6,7]	EMPA-KIDNEY[8]
N	4464	4304	6609
eGFR related Inclusion criteria	eGFR 30 to <90 ml/min and ACR>300 to 5000 mg/g	eGFR 25 to 75 ml/min and ACR 200 to 5000 mg/g	eGFR >20 to <45 ml/min OR eGFR >45 to <90 ml/min and ACR >200 mg/g
Investigational agent	Canagliflozin 100 mg OD	Dapagliflozin 100 mg OD	Empagliflozin 10 mg OD
Median follow-up duration (in years)	2.6	2.4	2.0
Diabetes (in %)	100	68	46
CKD cause	100% diabetes	diabetes (58%); hypertension (16%), IgA nephropathy (6%), FSGS (3%), Pyelonephritis (2%), interstitial nephritis (1%), unknown (5%), other (9%)	Diabetes: 31%, Hyperetnsion: 22% Glomerural: 25% other: 12%, unknown: 10%
Mean eGFR at baseline	56 ml/min	43 ml/min	37 ml/min
Median ACR	927 mg/g	949 mg/g	329 mg/g
Primary outcome	Composite of doubling of SCr, ESKD, or death from CV/renal cause: 0.70 (0.59-0.82)	A composite outcome involving a significant and reduction in eGFR >50%, ESKD, or CV/renal related death 0.61 (0.51-0.72)	A composite of a decline in eGFR to <10 mL/min or a reduction of at least 40% from the initial level, along with the outcomes of ESKD or CV/ kidney related death 0.72 (0.64 – 0.82)
CKD progression	0.66 (0.53 - 0.81)	0.56 (0.45 - 0.68)	0.71 (0.62 - 0.81)
ESKD	0.68 (0.54 - 0.86)	0.64 (0.50 - 0.82)	0.73 (0.59 - 0.89)

Table 1: Landmark randomised clinical trials on SGLT2 in CKD

Criteria for CKD progression

CANVAS: 40% decline in eGFR, dialysis or transplantation requirement, or kidney-related death

CREDENCE: doubling of serum creatinine, ESKD, or kidney-related death

DAPA-CKD: ≥50% reduction in eGFR, ESKD, or kidney-related death

EMPA-KIDNEY: reduction in eGFR to <10 mL/min/1.73 m² or by ≥40% from baseline, ESKD, or kidney-related death

Crucially, the majority of participants in these trials were already on ACE inhibitors or ARBs before randomisation, underscoring the additive benefits of SGLT-2 inhibitors in slowing CKD progression alongside RAAS inhibitors. A simulation study estimated that a non-diabetic adult with albuminuric CKD could potentially gain an additional seven years free from adverse outcomes by combining SGLT-2 inhibitors and RAAS inhibitors.[9]

Analyses of subgroups in the DAPA-CKD and EMPA-KIDNEY trials have revealed that both dapagliflozin and empagliflozin exhibited effectiveness across diverse subpopulations. These include variations in age, gender, race, diabetes status, blood pressure levels and baseline kidney function. In particular, the protective effects were consistent regardless of diabetes status or baseline GFR, with exploratory analyses suggesting benefits even in patients with ACR between 30 and 300 mg/g.

The DAPA-CKD trial extended the evidence by showing kidney protective effects in patients with IgA nephropathy, with dapagliflozin associated with a substantial reduction in the risk of adverse outcomes. However, the evidence in patients with focal segmental glomerulosclerosis (FSGS) was limited due to low power, with only exploratory analyses indicating a potential benefit in slowing chronic decline in estimated GFR.

Ongoing investigations are exploring the use of SGLT-2 inhibitors in other patient populations, such as those with polycystic kidney disease and kidney transplant recipients.

SGLT2 inhibitors exhibit a favourable safety profile in patients with CKD. A combined analysis of individuals with diabetes and CKD stages G3-4 indicated comparable rates of serious adverse events between empagliflozin and a placebo. However, the use of SGLT2 inhibitors is linked to a heightened occurrence of mild genital infections.[10]

Glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RA), initially studied for cardiac outcomes in type 2 diabetes, have demonstrated notable effectiveness in improving kidney outcomes. A comprehensive meta-analysis involving approximately 44,000 participants across 6 trials showed a 21% reduced risk of composite kidney outcomes, such as new-onset albuminuria, doubling of serum creatinine, significant decline in estimated GFR, kidney replacement therapy, or kidney-related death. The risk reduction for albuminuria and other kidney-related issues ranged from 15% to 36%[11] Landmark randomised clinical trials on GLP-1 receptor agonists in CKD have been described in Table 2.

Parameters	EXSCEL[12]	REWIND[13]	AMPLITUDE-O[14]	FLOW[15]
N	14752	9901	4076	3534
Inclusion criteria related to kidney (eGFR)	eGFR ≥30	eGFR ≥15 mL/ min	Individuals at least 18 years old with a medical history of CVD or age ≥50( for men) or ≥55 (for women) years with eGFR between 25 to 60 ml/min	eGFR ≥50 to ≤75 ml/ min/1.73 m2 and UACR >300 to <5000 mg/g or eGFR ≥25 to <50 ml/min and UAR >100 to <5000 mg/g
Drug	Exenatide 2 mg weekly	Dulaglutide 1.5 mg weekly	Efpeglenatide 4 mg or 6 mg weekly	Semaglutide 1.0 mg
Median follow-up	3.2	5.4	1.8	On-going trial
Baseline eGFR	Median eGFR 76 ml/min	Mean eGFR 78 ml/min	Mean eGFR 72 ml/min	Mean eGFR 47 ml/min
Baseline median ACR -	-	1.94 mg/mmo	28 mg/g	ACR 568 mg/g
Kidney outcome	ACR level >300 mg/g, ≥40% reduction in eGFR, initiation of KRT, or kidney-related death	ACR: >300 mg/g, eGFR: ≥30% decline from baseline, or maintenance KRT	ACR: >300 mg/g ACR: ≥30% increase from baseline, eGFR: ≥40% decline from baseline	Composite primary endpoint: time to first kidney failure (initiation of KRT or persistent eGFR <15 ml/min), eGFR: persistently ≥50% reduction from baseline or death from CV or kidney causess
Hazard ratio (HR)	0.85 (0.74 to 0.98)	0.85 (0.77 to 0.93)	0.68 (0.57 to 0.79)	Ongoing trial

Table 2: Landmark randomised clinical trials on SGLT2 in CKD

The precise mechanism by which GLP-1 RA contributes to the slowdown of eGFR decline and/or the reduction of albuminuria is not fully understood. Proposed mechanisms involve enhancements in glycaemic control, weight loss, heightened natriuresis and a decrease in inflammation and oxidative stress. Common adverse effects linked to GLP-1 RA include diarrhoea, vomiting and nausea.[12-14]

The recent FLOW trial is set to evaluate the impact of semaglutide on kidney outcomes in individuals with both CKD and T2D, addressing a critical research gap.[15] FLOW aims to determine whether once-weekly subcutaneous semaglutide can effectively delay CKD progression, mitigate the risk of kidney failure and reduce rates of kidney and cardiovascular disease mortality compared to a placebo. Enrolled participants, identified as high or very high risk for CKD progression based on established guidelines, will provide valuable data to inform clinical decision-making and potentially broaden treatment options for patients dealing with both T2D and CKD. The trial’s anticipated completion in late 2024 underscores its significance in providing timely insights into the potential benefits of semaglutide on kidney outcomes in this high-risk population.

Mineralocorticoid receptor antagonists (MRA)

Several MRAs are beneficial supplements to RAAS inhibitors, particularly in individuals experiencing albuminuria and/or diabetes. Steroidal non-selective MRAs, including both spironolactone and eplerenone, have demonstrated efficacy in decreasing albuminuria. Findings from a meta-analysis encompassing seven trials having 372 participants indicated that the combination of a non-selective MRA with an ACEI and/or ARB led to a notable decrease in proteinuria.[16] The study population commonly experienced Hyperkalemia.

The recent approval of finerenone, a non-steroidal selective MRA, provides a promising alternative.

When compared to non-selective steroidal MRAs, finerenone exhibits increased specificity for the mineralocorticoid receptor, a shorter duration of action, milder blood pressure reduction effects and a more favourable profile of side effects. It may also offer greater anti-inflammatory and antifibrotic effects.[17]

The FIGARO-DKD and FIDELIO-DKD clinical trials were conducted to assess cardio-renal advantages of finerenone in individuals with type 2 diabetes exhibiting albuminuria (ACR≥30 mg/g), demonstrating its effectiveness[18,19] (table 3). A comprehensive analysis of the data indicated that finerenone significantly reduces the risk of composite kidney-related outcomes by 15-23%, along with a 32% decrease in the average change in ACR levels from the start to 4 months. Although hyperkalemia was prevalent in the finerenone group, pre-specified analyses revealed that use of SGLT2 inhibitors/GLP1-RA at baseline did not alter the positive impact of finerenone on kidney outcomes. This suggests the potential for dual therapy in patients with type 2 diabetes and CKD.

Parameters	FIDELIO-DKD[19]	FIGARO-DKD[18]
Inclusion criteria (renal related)	UACR of ≥30 mg/g but <300 mg/g along with an eGFR of ≥25 but <60 mL/min, and a history of diabetic retinopathy OR UACR of ≥ 300 mg/g and eGFR ≥ 25 but < 75 mL/min	UACR of ≥30 mg/g but <300 mg/g along with an eGFR of ≥25 but <90 mL/min UACR of ≥ 300 mg/g and eGFR ≥60 mL/min
Median follow-up	2.6 years	3.4 years
Mean eGFR at baseline	44 ml/min	68 ml/min
Median ACR at baseline	852 mg/g	308 mg/g
Hazard ratio: finerenone vs placebo
Primary composite outcome: renal failure, a decrease in eGFR by at least 40% from the baseline eGFR, or death resulting from kidneyrelated reasons	0.82 (0.73 to 0.93)	0.87 (0.76 to 1.01)
Secondary composite outcome: kidney failure, a decrease in eGFR by at least 57% from the baseline eGFR, or death resulted from kidney related causes	0.76 (0.65 to 0.90)	0.77 (0.60 to 0.99)
Secondary composite outcome: kidney failure, a decrease in eGFR by at least 57% from the baseline eGFR, or death resulted from kidney related causes	0.76 (0.65 to 0.90)	0.77 (0.60 to 0.99)
ESKD: initiation of kidney replacement therapy	0.86 (0.67 to 1.10)	0.64 (0.41 to 0.995
ACR change (baseline to month 4)	0.69 (0.66 to 0.71)	0.68 (0.65 to 0.70)

Table 3: Landmark randomized clinical trials on finerenone in CKD

A significant ongoing clinical trial, identified as FIND-CKD is currently investigating the impact of finerenone in nondiabetic kidney disease (ClinicalTrials.gov: NCT05047263). The trial aims to assess the effects of finerenone in conjunction with guideline-directed therapy on the progression of CKD. Another ongoing clinical trial, identified as CONFIDENCE “combination effect of FInerenone and EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR endpoint” is a multicentric, phase 2, double-blind, parallel-group, randomised study enrolling 807 diabetic patients with CKD (stage 2-3) and UACR of 300-5000 mg/g. The primary outcome of the study is to investigate change in UACR from baseline to 9 months.[20]

Hypoxia-inducible factor prolyl hydroxylase inhibitors

Recently, a novel class of medications known as HIF-PHIs has emerged as a promising addition to the armamentarium against anemia in CKD (Table 4). These medications work by stabilising HIF, a key player in EPO regulation. HIF-PHIs have demonstrated non-inferiority to traditional ESAs in terms of their ability to increase and sustain hemoglobin (Hb) concentrations in CKD patients, both those not on dialysis and those receiving dialysis therapy. Moreover, HIF-PHIs have shown a favourable impact on reducing transfusion requirements when compared to a placebo. However, an essential consideration in the evaluation of HIF-PHIs is their cardiovascular safety profile. In this regard, the data suggest that HIF-PHIs may be inferior to conventional ESAs or, at best, demonstrate similar cardiovascular outcomes. This aspect raises important questions and prompts further research into the long-term safety and efficacy of these agents, particularly in the context of CKD patients who often have a heightened cardiovascular risk.

Study	N	Treatment	Study duration (in weeks)	Primary efficacy outcomes
CKD-Non dialysis
DREAM-ND [21] (Desidustat)	588	Desidustat 100 mg TIW vs. Darbepoetin	24	ΔHb, at wk 16–24, Desidustat: 1.95 g/dl vs Darbepoetin: 1.83 g/dl
ASCEND-ND[22] (Daprodustat)	3872	Daprodustat 2 mg and 4 mg QD (ESA naïve) and 1-4 mg QD (ESA-users) vs. Darbepoetin	148	ΔHb, at wk 16–24, Desidustat: 1.95 g/dl vs Darbepoetin: 1.83 g/dl
OLYMPUS[23] (Roxadustat)	2781	Roxadustat 70 mg TIW vs. Placebo	164	FDA endpoint, wk 28–52: Roxadustat: 1.75 g/dl vs PBO: 0.4 g/dl
PRO2TECT[24] (Vadadustat)	1751	Vadadustat 300 mg QD, then adjusted to 150, 450, or 600 mg QD vs. Darbepoetin	168	ΔHb, at wk 24–36 Vadadustat: 0.41 g/dl DPO: 0.42 g/dl, ΔHb, at wk 40–52, Vadadustat: 0.43 g/dl DPO: 0.44 g/dl
CKD-Dialysis
DREAM-D[25] (Desidustat)	ESA naïve (n=50), ESA treated (n=392)	Desidustat 100 mg TIW (ESA naïve); 100, 125, or 150 mg TIW (ESA-treated) vs. epoetin alfa	24	ΔHb, at wk 16–24, Desidustat: 0.95 g/dl Epoetin alfa: 0.80 g/dl
ASCEND-D[26]	2964	Daprodustat 4–12 mg QD vs. epoetin alfa (for HD)/ darbepoetin (for PD)	52	ΔHb, at wk 28–52 Daprodustat: 0.28 g/dl ESA: 0.10 g/dl
ROCKIES[27]	2133	Roxadustat 70–200 mg TIW (in ESA-treated) and 70 or 100 mg TIW (in ESA-naïve) vs. epoetin alfa	52–164	ΔHb, at wk 28–52 Roxadustat: 0.77 g/dl Epoetin alfa: 0.68 g/dl
INNO2VATE[28]	369	Vadadustat 300 mg QD, (adjusted to 150, 450, or 600 mg) vs. Darbepoetin	116	ΔHb, wk 24–36: Vadadustat: 0.19 g/dl vs Darbepoetin: 0.36 g/dl ΔHb, wk 40–52: Vadadustat: 0.23 g/dl vs Darbepoetin: 0.41 g/dl

Table 4 Landmark randomized clinical trials on HIF-PHI in CKD

Δ, difference in mean Hb

Emerging treatments

Aldosterone synthase inhibitors

The acceleration of chronic kidney disease progression is linked to an excess of aldosterone. An appealing strategy to mitigate various pathologies associated with aldosterone involves inhibiting aldosterone synthase. A recently conducted randomised, controlled Phase 2 clinical trial evaluated the efficacy, safety and optimal dosage of BI 690517, an aldosterone synthase inhibitor (ASI).[29] The findings demonstrated that BI 690517 exhibited a dose-dependent reduction in albuminuria when combined with RAAS inhibition and empagliflozin. This suggests an additional therapeutic benefit for CKD treatment without any unexpected safety concerns. The investigation into aldosterone synthase inhibition is still ongoing.

Baxdrostat, an innovative ASI, demonstrates encouraging outcomes concerning safety and tolerability in reducing systolic BP among individuals with treatment-resistant hypertension.[30] Nevertheless, additional RCTs are required to explore their long-term effectiveness and to evaluate their potential role in CKD, uncontrolled hypertension and primary aldosteronism.

Endothelin receptor antagonists

Elevated levels of endothelin (ET) in kidney disease, triggered by factors like diabetes, hypertension, proinflammatory cytokines and acidosis, lead to the activation of endothelin receptor type A (ETA). This activation results in persistent vasoconstriction of afferent arterioles, causing hyperfiltration, proteinuria, podocyte damage and a decline in eGFR. To reduce proteinuria and slow the progression of kidney disease, the use of endothelin receptor antagonists (ERAs) has been suggested.

Recent findings indicate that ERAs can reduce kidney fibrosis, inflammatory cytokines and proteinuria. Nevertheless, the effectiveness of many ERAs in treating kidney disease is still under investigation. The limited utilisation of ERAs in clinical practice is attributed to setbacks in phase III trials and side effects like edema. To overcome these challenges, ongoing research explores combination therapies involving ERAs with SGLT2 inhibitors and dual angiotensin-II type 1/ET receptor blockers.[31]

Promising research, exemplified by ongoing trials like ZENITHCKD, which assesses the effectiveness of zibotentan and dapagliflozin in treating CKD, holds potential in determining the future role of ERAs in the treatment of CKD.[32]

Recent guidelines

The KDIGO[33] and NICE guidelines[34] recommend ACE inhibitors or ARBs as the primary antihypertensive treatment for individuals with albuminuria (defined as urine ACR >70 mg/mmol by NICE and KDIGO A3), without diabetes and for those with diabetes and CKD stage G1-G4, with albuminuria A2-A3. RAAS inhibitors may be continued even if eGFR is <30 mL/min/1.73 m².

Both KDIGO and ADA guidelines[35] advocate for the use of SGLT-2 inhibitors as first-line pharmacotherapy in patients with diabetes, CKD and in those with eGFR ≥20 mL/min/1.73 m². NICE guidelines also recommend SGLT2 inhibitors when ACR is >30 mg/mmol and possibly when ACR is 3-30 mg/mmol in diabetes patients with CKD on RAAS inhibitors and meeting eGFR thresholds. Dapagliflozin is recommended in patients with eGFR 25-75 mL/min/1.73 m² and ACR ≥22.6 mg/mmol, irrespective of diabetes status. According to KDIGO, SGLT2 inhibitors are recommended for those with ACR ≥200 mg/g and eGFR ≥20 mL/min/1.73 m² as well as for those with CKD and heart failure. Once initiated, SGLT2 inhibitors may be continued even if eGFR drops below 20 mL/min/1.73 m², given well tolerability and absence of kidney replacement therapy (KRT). KDIGO and ADA guidelines support GLP-1 receptor agonists in type 2 diabetes patients with CKD who cannot tolerate metformin or an SGLT-2 inhibitor. KDIGO and ADA guidelines recommend the use of Finerenone as add-on therapy in patients with diabetes and CKD, maximally tolerated with ACEI/ARBs if ACR is ≥30 mg/g and potassium level is within normal limits. The recommended starting dose varies based on estimated GFR, with emphasis on regular potassium monitoring. It is also noted that finerenone need not be discontinued if eGFR falls below 25 mL/min/1.73 m², as long as the patient maintains normokalemia.

CONCLUSION:

Emerging management strategies for CKD involve the utilisation of various pharmacological agents. Among these, SGLT2 inhibitors, GLP-1 receptor agonists and MRAs have shown promise in improving renal outcomes. Additionally, HIF-PHIs have emerged as a potential therapeutic avenue. Recent developments also include the exploration of Endothelin receptor antagonists and aldosterone synthase inhibitors in CKD management, offering novel approaches to address renal complications.

The updated guidelines from KDIGO and ADA provide comprehensive insights into the contemporary management of CKD. These guidelines emphasise the integration of newer therapies, particularly highlighting the role of SGLT2 inhibitors and GLP-1 receptor agonists in patients with diabetes and CKD. These advancements mark a significant stride in the pursuit of more effective and targeted approaches to address the complexities of CKD.

References

GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020;395:709-33. doi:10.1016/S0140- 6736(20)30045- 3
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:1-
Singh NP, Gupta AK, Kaur G, et al. Chronic Kidney Disease of Unknown Origin – What do we know?. Journal of The Association of Physicians of India 2020;68:76-79
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2022;102(5S):S1-127. doi:10.1016/j. kint.2022.06.008
Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380:2295- 306. doi:10.1056/ NEJMoa1811744
Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. DAPACKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383:1436-46. doi:10.1056/ NEJMoa2024816
Margaret K. Yu, Priya Vart, Niels Jongs, et al. Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex. J GEN INTERN MED (2023). https://doi.org/10.1007/s11606-023-08397-9
Herrington WG, Staplin N, Wanner C, et al, The EMPAKIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2023;388:117-27. doi:10.1056/ NEJMoa2204233
Vart P, Vaduganathan M, Jongs N, et al. Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes. Clin J Am Soc Nephrol 2022;17:1754-62. doi:10.2215/CJN.08900722
Tuttle KR, Levin A, Nangaku M, et al. Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care 2022;45:1445-52. doi:10.2337/dc21- 2034
Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653-62. doi:10.1016/S2213- 8587(21)00203-5
Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2018;6:859-69. doi:10.1016/S2213- 8587(18)30268-7
Gerstein HC, Colhoun HM, Dagenais GR, et al. REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30. doi:10.1016/ S0140-6736(19) 31149-3
Gerstein HC, Sattar N, Rosenstock J, et al. AMPLITUDE-O Trial Investigators. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med 2021;385:896-907. doi:10.1056/ NEJMoa2108269
Rossing P, Baeres FMM, Bakris G, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease [published correction appears in Nephrol Dial Transplant. 2023 Nov 30;:]. Nephrol Dial Transplant. 2023;38(9):2041-2051. doi:10.1093/ndt/gfad009
Navaneethan SD, Nigwekar SU, Sehgal AR, et al. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and metaanalysis. Clin J Am Soc Nephrol 2009;4:542-51. doi:10.2215/ CJN.04750908
Epstein M, Kovesdy CP, Clase CM, et al. Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A Review of Evolving Treatment Paradigms. Am J Kidney Dis 2022;80:658-66. doi:10.1053/j.ajkd.2022.04.016
Pitt B, Filippatos G, Agarwal R, et al; FIGARO-DKD Investigators. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med 2021;385:2252-63. doi:10.1056/ NEJMoa2110956
Bakris GL, Agarwal R, Anker SD, et al, FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med 2020;383:2219-29. doi:10.1056/ NEJMoa2025845
Green JB, Mottl AK, Bakris G et al. Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint study (CONFIDENCE). Nephrol Dial Transplant 2023;38:894–903. https://doi.org/10.1093/ndt/ gfac198
Agrawal D, Varade D, Shah H, et al. Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND). Am J Nephrol. 2022;53(5):352- 360. doi:10.1159/000523961
Singh AK, Carroll K, McMurray JJV, et al. ASCEND-ND Study Group: Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med 385: 2313–2324, 2021 10.1056/NEJMoa2113380
Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: Results from a randomized phase 3 study. J Am Soc Nephrol 32: 737–755, 2021 10.1681/ASN.2020081150
Chertow GM, Pergola PE, Farag YMK, et al. PRO2TECT Study Group: Vadadustat in patients with anemia and nondialysisdependent CKD. N Engl J Med 384: 1589–1600, 2021 10.1056/NEJMoa2035938
Gang S, Khetan P, Varade D, et al. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D). Am J Nephrol. 2022;53(5):343-351. doi:10.1159/000523949
Singh AK, Carroll K, Perkovic V, et al. ASCEND-D Study Group: Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med 385: 2325–2335, 2021 10.1056/ NEJMoa2113379
Fishbane S, Pollock CA, El-Shahawy M, et al. Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study. J Am Soc Nephrol. 2022;33(4):850-866. doi:10.1681/ASN.2020111638
Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med 384: 1601–1612, 2021 10.1056/NEJMoa2025956
Tuttle KR, Hauske SJ, Canziani ME, et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial. Lancet. 2024;403(10424):379-390. doi:10.1016/S0140-6736(23)02408-X
Freeman MW, Halvorsen YD, Marshall W, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023;388(5):395-405. doi:10.1056/NEJMoa2213169
Martínez-Díaz I, Martos N, Llorens-Cebrià C, et al. Endothelin Receptor Antagonists in Kidney Disease. Int J Mol Sci. 2023;24(4):3427. Published 2023 Feb 8. doi:10.3390/ ijms24043427
Heerspink HJL, Kiyosue A, Wheeler DC, et al. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet. 2023;402(10416):2004-2017. doi:10.1016/ S0140-6736(23)02230-4
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2022;102(5S):S1-127. doi:10.1016/j. kint.2022.06.008
National Institute for Health and Care Excellence. NICE guideline [NG28]: Type 2 diabetes in adults: management. 2022. https://www.nice.org.uk/guidance/ng28/chapter/ Recommendations#chronickidney-disease.
de Boer IH, Khunti K, Sadusky T, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the ADA and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022;45:3075-90. doi:10.2337/ dci22-0027