Nonproteinuric Versus Proteinuric Phenotypes in Diabetic Kidney Disease: A Propensity Score–Matched Analysis of a Nationwide, Biopsy-Based Cohort Study

Abstract

OBJECTIVEClinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce. RESEARCH DESIGN AND METHODSWe retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived oneto-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ‡50%, or doubling of serum creatinine. The secondary end point was all-cause mortality. RESULTS Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR]<300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ‡300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P 5 0.005). CONCLUSIONSPatients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.

Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

“…In regard to the latter, tubular markers (e.g., increased plasma kidney injury molecule 1, and decreased plasma uromodulin, urine EGF, and EGF-to-MCP-1 ratio) were evaluated in well-designed cohorts of diabetes patients, and showed promise as independent predictors of early renal decline 24,41,42,65,67 . In line with this, data provided by recent analysis of Japan's nationwide renal biopsy registry have shown the extent of interstitial fibrosis and tubular atrophy as the strongest histological predictor of renal decline in non-albuminuric DKD 66 . Additionally, markers implicated in kidney fibrosis (e.g., markers of collagen formation and degradation, N-acetylseryl-aspartyl-lysyl-proline, and matrix metalloproteinase-7-to-WAP four-disulfide core domain 2 ratio) were associated with the eGFR trajectory in several pilot studies in normoalbuminuria [68][69][70][71][72] .…”

“…One important clinical problem that emerged from epidemiological studies is the importance of accurate tests of renal decline in non-albuminuric diabetes patients, for both clinical settings and drug trials [62][63][64][65] . Very recently, it was documented that although the presence of albuminuria influences the rate of eGFR decline 63,66 , with macroalbuminuric patients presenting the most pronounced loss in eGFR 63,66 , as many as 48% patients progress to CKD stage 3 remaining normoabuminuric 63 . Previously, studies of Joslin Clinic patients identified 9% of patients with type 1 diabetes and 20% of patients with type 2 diabetes (with normal eGFR at study entry) whose renal function had significantly and persistently declined without any increase in the albumin-to-creatinine ratio 13,64 , realizing the need for new tests to identify people at risk for eGFR loss earlier than albuminuria.…”

Effects of ipragliflozin on the development and progression of kidney disease in patients with type 2 diabetes: An analysis from a multicenter prospective intervention study

“…The UACR ≥300 group showed a significant decrease in eGFR, whereas the UACR <300 group showed a significant increase. Yamanouchi et al 23 reported that patients with non- proteinuric DKD had a lower risk of CKD progression and all-cause mortality than patients with proteinuric DKD . The present results here were similar, and proteinuric DKD patients required careful observation.…”

Introduction to clinical research based on modern epidemiology

“…Additionally, although diabetic nephropathy is a common disease, its pathophysiology is largely unclear. Therefore, we examined the association between pathological changes in diabetic nephropathy and clinical outcomes [55][56][57][58][59][60][61][62]. Other examples can be found in many areas, such as in the areas of treatment of polycystic liver disease [63,64], amyloidosis [65][66][67][68], and severe ischemic limb treatment [69][70][71][72].…”