Sharma, Vidit

Significance Statement Glomerular size differs by cortex depth. Larger nephrons are prognostic of progressive kidney disease, but it is unknown whether this risk differs by cortex depth or by glomeruli versus proximal or distal tubule size. We studied the average minor axis diameter in oval proximal and distal tubules separately and by cortex depth in patients who had radical nephrectomy to remove a tumor from 2019 to 2020. In adjusted analyses, larger glomerular volume in the middle and deep cortex predicted progressive kidney disease. Wider proximal tubular diameter did not predict progressive kidney disease independent of glomerular volume. Wider distal tubular diameter showed a gradient of strength of prediction of progressive kidney disease in the more superficial cortex than in the deep cortex. Background Larger nephrons are prognostic of progressive kidney disease, but whether this risk differs by nephron segments or by depth in the cortex is unclear. Methods We studied patients who underwent radical nephrectomy for a tumor between 2000 and 2019. Large wedge kidney sections were scanned into digital images. We estimated the diameters of proximal and distal tubules by the minor axis of oval tubular profiles and estimated glomerular volume with the Weibel–Gomez stereological model. Analyses were performed separately in the superficial, middle, and deep cortex. Cox proportional hazard models assessed the risk of progressive CKD (dialysis, kidney transplantation, sustained eGFR <10 ml/min per 1.73 m 2 , or a sustained 40% decline from the postnephrectomy baseline eGFR) with glomerular volume or tubule diameters. At each cortical depth, models were unadjusted, adjusted for glomerular volume or tubular diameter, and further adjusted for clinical characteristics (age, sex, body mass index, hypertension, diabetes, postnephrectomy baseline eGFR, and proteinuria). Results Among 1367 patients were 62 progressive CKD events during a median follow-up of 4.5 years. Glomerular volume predicted CKD outcomes at all depths, but only in the middle and deep cortex after adjusted analyses. Proximal tubular diameter also predicted progressive CKD at any depth but not after adjusted analyses. Distal tubular diameter showed a gradient of more strongly predicting progressive CKD in the superficial than deep cortex, even in adjusted analysis. Conclusions Larger glomeruli are independent predictors of progressive CKD in the deeper cortex, whereas in the superficial cortex, wider distal tubular diameters are an independent predictor of progressive CKD.

Abstract The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as “cytotoxic lymphocytes,” or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Significance Statement Nephron number currently can be estimated only from glomerular density on a kidney biopsy combined with cortical volume from kidney imaging. Because of measurement biases, refinement of this approach and validation across different patient populations have been needed. The prognostic importance of nephron number also has been unclear. The authors present an improved method of estimating nephron number that corrects for several biases, resulting in a 27% higher nephron number estimate for donor kidneys compared with a prior method. After accounting for comorbidities, the new nephron number estimate does not differ between kidney donors and kidney patients with tumor and shows consistent associations with clinical characteristics across these two populations. The findings also indicate that low nephron number predicts CKD independent of biopsy and clinical characteristics in both populations. Background Nephron number can be estimated from glomerular density and cortical volume. However, because of measurement biases, this approach needs refinement, comparison between disparate populations, and evaluation as a predictor of CKD outcomes. Methods We studied 3020 living kidney donors and 1354 patients who underwent radical nephrectomy for tumor. We determined cortex volume of the retained kidney from presurgical imaging and glomerular density by morphometric analysis of needle core biopsy of the donated kidney and wedge sections of the removed kidney. Glomerular density was corrected for missing glomerular tufts, absence of the kidney capsule, and then tissue shrinkage on the basis of analysis of 30 autopsy kidneys. We used logistic regression (in donors) and Cox proportional hazard models (in patients with tumor) to assess the risk of CKD outcomes associated with nephron number. Results Donors had 1.17 million nephrons per kidney; patients with tumor had 0.99 million nephrons per kidney. A lower nephron number was associated with older age, female sex, shorter height, hypertension, family history of ESKD, lower GFR, and proteinuria. After adjusting for these characteristics, nephron number did not differ between donors and patients with tumor. Low nephron number (defined by <5th or <10th percentile by age and sex in a healthy subset) in both populations predicted future risk of CKD outcomes independent of biopsy and clinical characteristics. Conclusions Compared with an older method for estimating nephron number, a new method that addresses several sources of bias results in nephron number estimates that are 27% higher in donors and 1% higher in patients with tumor and shows consistency between two populations. Low nephron number independently predicts CKD in both populations. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_06_22_JASN0000000000000124.mp3

674 Background: Metastasis directed therapy (MDT) is associated with improved cancer-specific survival and delay in use of systemic therapy for metastatic clear cell RCC (mccRCC). Although the benefits of MDT may differ based on organ site of metastasis due to differences in disease biology, survival based on site of metastasis remain underexplored. We aim to evaluate survival outcomes of patients who underwent MDT for solitary sites of mccRCC. Methods: The Mayo Clinic Nephrectomy Registry was queried to identify adults undergoing radical or partial nephrectomy for unilateral, sporadic ccRCC from 2000 to 2019 with a single site of metastasis treated with MDT including complete metastasectomy or radiation, in lieu of systemic therapy. Overall and cancer-specific survival were estimated using the Kaplan-Meier method, with the duration of follow-up calculated from the date of metastasis to the date of death or last follow-up. Associations with time to death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals (CIs). Results: In this cohort of 207 mccRCC patients, 152 underwent complete metastasectomy and 55 underwent radiation. 133 died at a median of 2.7 years (IQR 1.2-4.7) following metastasis, including 105 who died from RCC at a median of 2.2 years (IQR 1.0-3.9). The median duration of follow-up for the 74 patients who were still alive at last follow-up was 8.1 years (IQR 3.7-12.1). Overall survival rates (95% CI) at 2, 4, 6, 8, and 10 years following metastasis were 73% (69-79), 54% (48-62), 45% (38-52), 37% (30-44), and 32% (26-40), respectively; cancer-specific survival rates were 75% (69-81), 56% (50-64), 47% (41-55), 44% (37-52), and 42% (35-50), respectively. Age, poor performance status, presence of synchronous metastasis and asynchronous metastasis <1 year from nephrectomy, tumor size, and bone metastasis were associated with death from RCC (table). Conclusions: These findings provide useful survival benchmarks to patients who are considering MDT as a therapeutic option. In addition, synchronous and asynchronous metastasis <1 year from nephrectomy, poor performance status, and bone metastasis are significantly associated with worse survival from mccRCC. [Table: see text]