Treatments for Chronic Kidney Disease: A Systematic Literature Review of Randomized Controlled Trials

Abstract

Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment renin-angiotensin-aldosterone system (RAAS) inhibitors as the standard of care have scarcely met their primary endpoints until recently. This systematic literature review explored treatments evaluated in patients with CKD since 1990 to understand what contemporary data add to the treatment landscape. Eighty-nine clinical trials were identified that had enrolled patients with estimated glomerular filtration rate 13.9-102.8 mL/ min/1.73 m 2 and urinary albumin-to-creatinine ratio (UACR) 29.9-2911.0 mg/g, with (75.5%) and without (20.6%) type 2 diabetes (T2D). Clinically objective outcomes of kidney failure and all-cause mortality (ACM) were reported in 32 and 64 trials, respectively. Significant reductions (P \ 0.05) in the risk of kidney failure were observed in seven trials: five small trials published before 2008 had evaluated the RAAS inhibitors losartan, benazepril, or ramipril in patients with (n = 751) or without (n = 84-436) T2D; two larger trials (n = 2152-2202) published onwards of 2019 had evaluated the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (in patients with T2D and UACR [ 300-5000 mg/g) and dapagliflozin (in patients with or without T2D and UACR 200-5000 mg/g) added to a background of RAAS inhibition. Significant reductions in ACM were observed with dapagliflozin in the DAPA-CKD trial. Contemporary data therefore suggest that augmenting RAAS inhibitors with new drug classes has the potential to improve clinical outcomes in a broad range of patients with CKD.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

“…Therapeutic options to decelerate kidney function decline are limited. In addition to pharmacological inhibitors of the RAAS-system 9 , the recent introduction SGLT2 inhibitors show promising reno-protective effects 10 , 11 . An understanding of the mechanisms of kidney function decline and the developing of new therapeutic options is thus of high clinical and public health relevance 7 , 12 .…”

Glucose‐lowering treatment pathways of individuals with chronic kidney disease and type 2 diabetes according to the Kidney Disease: Improving Global Outcomes 2012 risk classification

“…Data from recent clinical studies have suggested potential benefits of SGLT2i on kidney outcomes in individuals with CKD, 11,12 and current ADA guidelines recommend the use of SGLT2i in those with eGFR ≥25 mL/min/1.73 m 2 or UACR ≥300 mg/g 15 . Our data did not reveal any notable trends in SGLT2i prescriptions according to UACR level, but this may reflect the infrequent prescription of SGLT2i in the analysis period and the timeframe of our dataset, most of which was prior to the completion of clinical trials evaluating SGLT2i in CKD and the recommendation for these agents as part of first‐line therapy regimens in individuals with CKD and T2D 15 .…”

“…26 Insulin use is also associated with significant burden in terms of administration, side effects and cost, and does not confer the documented benefits seen across various cardiovascular and kidney outcomes with some oral medications, such as SGLT2i, finerenone and GLP-1 receptor antagonists. 15,[27][28][29][30] Data from recent clinical studies have suggested potential benefits of SGLT2i on kidney outcomes in individuals with CKD, 11,12 and current ADA guidelines recommend the use of SGLT2i in those with eGFR ≥25 mL/min/1.73 m 2 or UACR ≥300 mg/g. 15 Our data did not reveal any notable trends in SGLT2i prescriptions according to UACR level, but this may reflect the infrequent prescription of SGLT2i in the analysis period and the timeframe of our dataset, most of which was prior to the completion of clinical trials evaluating SGLT2i in CKD and the recommendation for these agents as part of first-line therapy regimens in individuals with CKD and T2D.…”

“…9 Renin-angiotensin-aldosterone system inhibitors are the mainstay of treatment to delay or prevent CKD progression 10 ; however, more recent data from randomised trials and observational studies have suggested benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and finerenone (a non-steroidal mineralocorticoid receptor antagonist) in improving a range of kidney and cardiovascular outcomes in individuals with CKD. 11,12 In addition, glucagon-like peptide-1 (GLP-1) receptor antagonists have been reported to improve kidney outcomes compared with placebo, mainly driven by a reduction in albuminuria. 13,14 Current guideline recommendations for the treatment of individuals with CKD and T2D differ.…”

“…Optimal management of individuals with CKD and T2D is multifaceted, aiming to attain glycaemic control as well as reduce the risks of CKD progression and cardiovascular disease/mortality 9 . Renin–angiotensin–aldosterone system inhibitors are the mainstay of treatment to delay or prevent CKD progression 10 ; however, more recent data from randomised trials and observational studies have suggested benefits of sodium–glucose co‐transporter‐2 inhibitors (SGLT2i) and finerenone (a non‐steroidal mineralocorticoid receptor antagonist) in improving a range of kidney and cardiovascular outcomes in individuals with CKD 11,12 . In addition, glucagon‐like peptide‐1 (GLP‐1) receptor antagonists have been reported to improve kidney outcomes compared with placebo, mainly driven by a reduction in albuminuria 13,14 …”