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 tumor in 2000 to 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 chronic kidney disease (CKD) was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy estimated glomerular filtration rate (eGFR). Cox models assessed risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for 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.

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies

“…One study found 21% of native kidney biopsy patients with >50% IFTA had not progressed to ESKD at 5 years after their biopsy. Among radical nephrectomy patients, those with smaller more scattered IFTA foci were older, had smaller cortical volumes on imaging, and were more likely to have progressive CKD than those with the same %IFTA but larger and fewer IFTA foci 18 . As seen in nephrectomy patients, 18 IFTA foci density also had an inverted U-shaped association with %IFTA in native kidney biopsy patients.…”

“…To calculate %IFTA, the total areas of all IFTA foci were divided by the total area of cortex 8 . The IFTA foci density was calculated by dividing the count of distinct IFTA foci by the traced cortical area (number of IFTA foci per square millimeter) 18 . The %luminal stenosis (morphometric measure of arteriosclerosis) was determined from the area of intima divided by the area of intima and lumen 27 .…”

“…The added prognostic value of other chronic changes on routine native kidney biopsies is less clear. Specifically, ischemic-appearing glomeruli or segmentally sclerosed glomeruli, larger glomerular volume, larger cortex per glomerulus (lower glomerular density), arteriolar hyalinosis (AH), interstitial inflammation, and the scattering (increased density) of interstitial fibrosis foci are common nonspecific chronic changes; many associate with lower eGFR in a variety of settings 9 , 11 , 15 – 18 …”

The incidence and risk factors of chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma

“…Some of them have an underlying chronic disease, which will cause worsening kidney function over time [ 5 ]. In addition, pathology examination of radical nephrectomy always shows some kidney disease in the “no-tumor part” [ 6 ], which may be associated with CKD after RN [ 7 ]. Therefore, the probability of CKD after radical nephrectomy is often higher than expected.…”

The Kidney in Normal Aging

“…While IF/TA appears to be less prominent when due to nephron loss from aging rather than from CKD, the pattern of IF/TA with aging is also informative. Analysis of large wedges of unaffected kidney tissue from patients undergoing radical nephrectomy for tumors reveals that older patients have a more scattered pattern of IF/TA at the same %IF/TA as younger patients (6). This suggests: ( 1 ) IF/TA foci atrophy into smaller IF/TA foci with contraction of the cortex, which increases their density; and ( 2 ) this atrophy helps explain the minimal extent of %IF/TA in older individuals despite significant loss of nephrons.…”