Renal Histologic Analysis Provides Complementary Information to Kidney Function Measurement for Patients with Early Diabetic or Hypertensive Disease

Abstract

Background: Patients with diabetic or hypertensive kidney disease rarely undergo kidney biopsy because nephrologists commonly believe that biopsy-related risk outweighs the potential benefits of obtaining histologic information to guide clinical decisions. Although kidney function is acutely regulated, histologic changes such as interstitial fibrosis, tubular atrophy, and glomerulosclerosis may represent chronic kidney damage, and thus might provide additional information about disease severity. However, whether histologic analysis provides information complementary to clinically used kidney function measurements, such as eGFR and proteinuria, is unclear.

Methods: We performed a standardized semiquantitative histologic analysis of 859 nephrectomies obtained from individuals with or without diabetes mellitus or hypertension and varying degrees of kidney dysfunction. Changes in glomeruli, tubules, interstitium, and the vasculature were scored using 17 descriptive parameters in a standardized manner. We used multivariable linear and logistic regression analyses and unbiased, hierarchical clustering to assess associations between histologic alterations and clinical variables.

Results: At CKD stages 3-5, eGFR correlates reasonably well with the degree of glomerulosclerosis and interstitial fibrosis and tubular atrophy (IFTA). In patients with CKD stages 1-2, the degree of histologic damage was highly variable and eGFR poorly estimated the degree of damage. Individuals with diabetes mellitus, hypertension, or Black race had significantly more glomerulosclerosis and IFTA, at the same eGFR level. Inclusion of glomerulosclerosis improved the kidney function decline estimation, even at early disease stages.

Conclusions: Histologic analysis is an important complementary method for kidney disease evaluation, especially at early disease stages. Some individuals present with relatively severe structural damage despite preserved eGFR.

Keywords: chronic kidney disease; fibrosis; glomerular filtration rate; glomerulosclerosis; histopathology.

Figure 1.

IF, TA, and GS have a nonlinear relationship with eGFR. (A) Local two-degree polynomial smoothing for IF, TA, and GS (black line) overlay on scatterplots of IF, TA, or GS versus eGFR (open circles). (B) Beta-coefficients (with 95% confidence intervals [95% CI]) of six eGFR quantiles in regression models normalized to the highest eGFR sextile (eGFR 91–135 ml/min per 1.73 m²). Models were adjusted for age, sex, race, diabetes, HTN, BMI, and systolic BP.

Figure 2.

The relationship of histologic alterations and kidney function stratified by HTN and diabetes. (A–C) Adjusted means for percent IF, TA, and GS stratified by absence of HTN and DM (n=193, navy lines±shaded 95% CI and navy bars), HTN alone (n=290, light blue lines±shaded 95% CI and light blue bars), and presence of HTN and DM (n=238, orange lines±shaded 95% CI shaded and orange bars). Percentages of IF, TA, and GS modeled using linear regression as a cubic function of eGFR adjusted for age, sex, race, HTN, diabetes, and BMI. Asterisk denotes P<0.05 compared with the “No HTN or DM” group, **P<0.01, * <0.05.

Figure 3.

The relationship of histologic alterations and kidney function is altered by race. (A–C) Adjusted means for percent IF, TA, and GS stratified by non-Black race (n=590, gray lines±shaded 95% CI and light gray bars) and Black race (n=160, black lines±shaded 95% CI and black bars). Percentages of IF, TA, and GS modeled using linear regression as a cubic function of eGFR adjusted for age, sex, race, HTN, diabetes, and BMI. *P<0.05 compared with the non-Black race group.

Figure 4.

Histopathology-based clustering of subjects with eGFR≥60 ml/min per 1.73 m². (A) Hierarchical clustering dendrogram shows three distinct clusters. (B) Radar plot of histopathologic characteristics in cluster 1 (red), cluster 2 (orange), and cluster 3 (blue). (C) Clinical and select histopathologic characteristics of histopathology-based clusters. Clusters with follow-up data are indicated, and associations with longitudinal eGFR are assessed using linear mixed model. Complete fixed effects used in the model include: cluster, age, sex, race (as Black or non-Black), presence of diabetes or HTN, BMI (kg/m²), nephrectomy status (total versus partial), tumor size (cm), and length of follow-up (years). Random effects include subject-specific eGFR slopes obtained by regressing an average of three eGFR values on the time variable. SBP, systolic BP; DBP, diastolic BP.