A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive CKD after a Radical Nephrectomy for Tumor

Abstract

Background: Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear.

Methods: We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000-2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm² cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics.

Results: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m²), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume.

Conclusions: Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

Keywords: chronic kidney disease; interstitial fibrosis; radical nephrectomy; tubular atrophy.

Figure 1.

Example of wedge biopsy sections from two patients with similar %IF/TA, but different IF/TA density. The green line outlines the cortical area. Black lines outline foci of IF/TA. (A) This patient had %IF/TA of 5.3% and IF/TA density of 16 IF/TA foci per cm² cortex. (B) This patient had %IF/TA of 5.6% and IF/TA density of 100 IF/TA foci per cm² cortex.

Figure 2.

Schematic example of how %subcapsular IF/TA, striped IF/TA, and inflammation measures were calculated. (A) Percent subcapsular IF/TA was obtained by dividing the length of cortex affected by IF/TA (two segments labeled by arrows) by total subcapsular cortex length (dashed black line). (B) All IF/TA foci that extend at more than 50% of mean cortical depth were counted and indexed to the length of capsule. This example shows six distinct foci, but only two were counted as striped IF/TA foci. (C) The percent of total interstitial inflammation was calculated by dividing the sum of all areas of inflammation (dark gray foci) by cortex area. The area of inflammation within the fibrotic areas (three black foci within light gray foci) was divided by the total IF/TA area (all gray shaded areas) to calculate %inflammation–IF/TA. The area of inflammation in the non-fibrotic (normal) cortex (two black foci outside of IF/TA) was divided by nonfibrotic cortex area (total cortex minus area of all IF/TA foci) to calculate %inflammation-outside–IF/TA.

Figure 3.

Correlation of Morphometry %IFTA, pathologist's %IFTA score, and IFTA foci density. (A) Morphometric measure of %IF/TA shows significant but modest correlation with pathologist’s visually estimated IF/TA score (r_s=0.38, P<0.0001). Gray shaded area and dotted lines represent the ranges for pathologic scores. (B) Morphometric measure of IF/TA density increase with morphometric %IF/TA until %IF/TA >20% (r_s=0.76, P<0.0001).

Figure 4.

The probability of developing progressive CKD (40% decline in eGFR from postnephrectomy baseline, dialysis, transplantation, or eGFR <10 ml/min per 1.73 m²) increased with a higher IF/TA density (foci per cm² cortex).