Larger Nephron Size and Nephrosclerosis Predict Progressive CKD and Mortality after Radical Nephrectomy for Tumor and Independent of Kidney Function

Abstract

Background: Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease.

Methods: To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6-12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria.

Results: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m²), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence.

Conclusions: After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

Keywords: Nephrectomy; glomerulosclerosis; glomerulus; interstitial fibrosis; kidney biopsy; mortality risk; nephron; progression of chronic renal failure.

Figure 1.

Patients were followed from the time of their nephrectomy. Baseline for serum creatinine and urine protein was defined during the first 4 months postnephrectomy in order to study the nonsurgical changes in kidney function during follow-up. Thus, follow-up for outcomes started after 4 months postnephrectomy. Baseline for other characteristics was defined at or just prior to the nephrectomy.

Figure 2.

Morphometry was performed on wedge sections. (A) An example of a periodic acid–Schiff-stained wedge section, with cortex outline in green trace. (B) Nonsclerotic glomeruli (red trace) and GSG were traced manually. (C) An example of an artery with labeled media to intima boundary (red trace) and intima to lumen (yellow trace) to quantify percentage luminal stenosis. (D) Percentage interstitial fibrosis (black trace) was assessed in the whole cortex.

Figure 3.

Selection of study sample. Patients had to survive cancer-free and without kidney failure for the first 4 months after the nephrectomy. M0, no metastasis.

Figure 4.

Risk of progressive CKD with microstructural predictors. Cumulative incidence of progressive CKD increased with (A) larger glomerular volume, (B) larger cortex per glomerulus, (C) higher percentage IF/TA, and (D) higher percentage GSG.

Figure 5.

More severe percentage fibrosis is a predictor of noncancer mortality. (A) In unadjusted analysis, cumulative incidence of noncancer mortality is worse with increasing percentage fibrosis. (B) After adjusting for all clinical characteristics, fibrosis >5% associated with increased risk of noncancer mortality. Curves represent hazard ratios relative to 1% fibrosis, and dashed curves represent 95% confidence intervals.