Narasimhan, Ramya

Significance Statement A higher percentage of the kidney cortex area that exhibits interstitial fibrosis/tubular atrophy (IF/TA) is a feature of poor prognosis on biopsy. This study describes IF/TA density (the number of IF/TA foci per area of cortex) and shows it predicts progressive CKD, independent of both percentage IF/TA and clinical characteristics among patients who have undergone nephrectomy. Other patterns of IF/TA and inflammation were not predictive for progressive CKD and mortality beyond percentage IF/TA and clinical characteristics. At the same percentage IF/TA, a higher IF/TA density suggests more scattered and widespread damage to the nephrons, with a worse kidney prognosis. This information may be helpful for accurate interpretation of the severity of “chronic changes” observed on a kidney biopsy. 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 mm 2 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 1.73m 2 ), 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.

Abstract Background Home enteral nutrition (HEN) use continues to increase in children unable to meet nutritional needs through oral intake. Some patients do not tolerate standard polymeric formula (SPF), which may lead to malnutrition. Use of peptide‐based diet (PBD) has demonstrated benefits in adults, however there remains a paucity of data in pediatric population. Methods Retrospective review of medical records of children receiving HEN between October 2015 and October 2019 was conducted. Nutrition, tolerance, and healthcare utilization was tracked through May 2020. Children receiving PBD as initial formula or transitioned to PBD from SPF were included. Our objective was to assess gastrointestinal tolerance and impact on healthcare utilization in children receiving PBD. Results During study period, 30 children (mean age, 9 ± 5.44 years; 20 of 30 [66.7%] male) utilized PBDs. Twenty‐one patients started PBD directly with malnutrition as primary indication. Nine patients transitioned from SPF to PBD, most often due to intolerance of SPF (66%). After transition to PBD, no symptoms were reported in 6 of 9 (66.7%) patients, and symptoms of SPF intolerance resolved in 4 of 9 (44.5%) patients. Healthcare utilization declined significantly after transition to PBD, including mean numbers of emergency room visits (0.78 ± 1.09 to 0.11 ± 0.33; P = .025), provider visits (1.67 ± 1.32 to 0.56 ± 0.73; P = .007), and phone calls (1.22 ± 1.39 to 0.33 ± 0.50; P = .026). Conclusions PBD is well tolerated and can result in significant reduction in healthcare utilization in children intolerant to SPF.

Significance Statement Predicting outcomes on the basis of renal histology after a radical nephrectomy has been limited to studies with small sample sizes, short follow-ups, and only a descriptive characterization of histology. In this study of 936 patients followed up for a median of 6.4 years after establishing a new baseline kidney function following radical nephrectomy, the authors used morphometric methods to quantitatively characterize microstructural features on large renal wedge sections. Findings of larger nephrons and more extensive glomerulosclerosis and interstitial fibrosis predicted progressive CKD; interstitial fibrosis also predicted mortality from causes other than cancer. These findings provide insight into the important microstructural features of “generic” CKD in patients without a specific kidney disease and support the use of quantitative methods to evaluate renal histology after a radical nephrectomy to determine patients’ long-term risks. 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 m 2 ), 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.

Significance Statement Research investigating glomerular morphology in different cortical regions has been limited to animal models and a small number of human autopsy kidneys. In this study, the authors used tissue from living patients who underwent a radical nephrectomy (for a renal tumor) to characterize glomerular morphology and glomerulosclerosis by cortical depth. They found that glomerular volume and glomerulosclerosis differed by depth across three cortical regions (superficial, middle, and deep). Although most clinical associations with glomerulosclerosis and glomerulomegaly did not differ by cortical depth, there were important exceptions. Age-related glomerulosclerosis appeared to be an ischemic process and was more evident in the superficial (subcapsular) region. Diabetes-related glomerulosclerosis was more evident in the deep (juxtamedullary) region. Obesity more strongly associated with larger glomeruli in the superficial region. Background Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. Methods To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions. Results The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µ m 3 , respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex. Conclusions Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.