Making Prevention of Diabetic Kidney Disease a PRIORITY

Making Prevention of Diabetic Kidney Disease a PRIORITY
McKenzie Moore, Pharm.D., Saint Cloud VA

Background: Diabetic kidney disease, a leading cause of renal failure, is also associated with increased risk of cardiovascular disease. With the rate of diabetes increasing, the number of people being treated for end-stage kidney disease has more than doubled. Considering this, there is a need for improved treatment of diabetic kidney disease, potentially through prediction and prevention. Currently, diabetic kidney disease is diagnosed by albuminuria, a decrease in estimated glomerular filtration rate (eGFR), or both. Microalbuminuria (urine albumin-to-creatinine ratio [UACR] >30mg/g in at least two of three consecutive urine samples) and macroalbuminuria (UACR>300mg/g) is commonly treated with renin-angiotensin-aldosterone system (RAAS) blockers, however prognosis remains poor. There is consideration for more complete inhibition of RAAS with mineralocorticoid receptor antagonists (MRAs), such as spironolactone, for further renal effects. In studies using RAAS blockade for the prevention of microalbuminuria, results have been conflicting. If biomarkers could be utilized to identify those who would respond to preventive therapy, this intervention may prove more successful. A high-dimension urinary biomarker pattern of 273 peptides associated with overt kidney disease, CKD273, has been described and found to be robust across many causes of kidney disease, including diabetic kidney disease. In retrospective analyses, CKD273 identified those at risk of diabetic kidney disease and progression in albuminuria sooner than current clinical practice indices like eGFR and albuminuria.

Purpose: The goals of the PRIORITY study were to show association between CKD273 and progression to microalbuminuria in a prospective study setting and determine if increased RAAS inhibition (with addition of spironolactone) reduces the risk of microalbuminuria in those with high-risk CKD273 pattern. 

Study design: PRIORITY was a prospective, double-blind, randomized, placebo-controlled, international, multi-center clinical and observational study. Patients with type 2 diabetes, normoalbuminuria (UACR<30mg/g), and eGFR>45 ml/min aged 18-75 were recruited. Exclusion criteria included dual use of RAAS blockade or MRA, or heart failure. Proteomic analysis of urine samples were completed with CKD273 score used to stratify patients into high- or low-risk groups. Those in the high-risk group were randomized to receive spironolactone 25mg daily or matching placebo in addition to current therapies. Follow-up took place every 13 weeks to receive the study drug and complete UACR monitoring. Low-risk participants continued current treatments and were followed without further intervention beyond yearly UACR monitoring. The primary endpoint was development of microalbuminuria with >30% increase in UACR from the initial sample or more than 40mg/g over the study period. The secondary endpoint was comparing progression to microalbuminuria in high-risk patients prescribed spironolactone versus placebo. 

Results: Median follow-up was 2.5 years. The primary endpoint of microalbuminuria was increased in the high-risk group compared to low-risk (HR 3.92 [95% CI 2.90-5.30]). In those with baseline eGFR >60 ml/min, development of stage 3 chronic kidney disease was more frequent in the high-risk than low-risk group (HR 3.50 [95% CI 2.50-4.90]). Percentage decrease in eGFR from baseline by 30% and 40% was more frequent in the high-risk group (HR 16.70 [95% CI 4.31-64.67] and 5.15 [95% CI 3.41-7.76] respectively). Progression to albuminuria and decrease in eGFR was faster in those in the high-risk group.The secondary study endpoint evaluating use of spironolactone in the high-risk group resulted in no significant difference (HR 0.81 [95% CI 0.49-1.34]). However, the medication was generally well-tolerated with low rates of discontinuation due to gynecomastia (3%) and hypotension (3%), and few mild episodes of hyperkalemia (13%). 

Conclusions: Higher CKD273 classifier scores were associated with increased risk of progression to microalbuminuria and a decrease in renal function. Spironolactone did not delay the development of microalbuminuria or declining eGFR. This lack of difference could have been related to not meeting study power, the short duration of the study, or true absence of effect in this population. Although progression can be linked to CKD273 classifier scores, there is no evidence to suggest progression of microalbuminuria can be delayed with treatment, leaving use of CKD273 without a cost-effective place in clinical practice. It could however be used to enhance high-risk population identification in clinical trials for the time being.

Key point:  Microalbuminuria is the earliest clinical marker for renal damage, but at the time of detection, histological changes may already be advanced. The urinary proteomic biomarker CKD273 could be used to predict which individuals are at high-risk for progression to microalbuminuria and worsening renal function. 

Reference:

  1. Tofte N, Lindhardt M, Adamova K, et al. Early Detection Of Diabetic Kidney Disease By Urinary Proteomic Sand Subsequent Intervention With Spironolactone To Delay Progression (PRIORITY): A Prospective Observational Study And Embedded Randomized Placebo-controlled Trial. Lancet Diabetes Endocrinol. 2020;8(4):301-312. doi: 10.1016/S2213-8587(20)30026-7