Spatial Heterogeneity of Glomerular Phenotypes Affects Kidney Biopsy Findings

KEY POINTS: Glomeruli with pathologic changes are not homogeneously distributed throughout the kidney cortex. Biopsies that do not include the kidney capsule may underdetect glomeruli with pathologic changes. Location of glomeruli with pathologic changes may be related to underlying clinical characteristics. BACKGROUND: Detection of rare glomerular phenotypes can affect diagnosis in indication kidney biopsies and in kidney tissue used for research studies. Nephropathologists are aware of potential sampling error when assessing needle biopsy cores, but quantitative data are lacking. METHODS: Kidney tissue from patients undergoing total nephrectomy enrolled in an observational, cross-sectional cohort study was used to characterize glomeruli as typical or atypical, which included globally sclerotic glomeruli (GSGs), segmentally sclerotic glomeruli, ischemic-like, and imploding. A 2D map of the glomerular annotations was generated. Spatial centrality of atypical glomeruli using the L2 metric and differences in pairwise distances between typical or atypical glomeruli were calculated. To determine how the yield of capturing atypical glomerular phenotype was affected by biopsy depth (i.e., not including the renal capsule), simulated kidney biopsies were generated from the 2D map. RESULTS: The mean number of glomeruli in a nephrectomy specimen was 209 (SD 143), and GSGs were the most common type of atypical glomeruli (median: 13% [interquartile range: 5,31]). Typical glomeruli were more likely to be surrounded by other glomeruli (i.e., centrally located in the kidney cortex) than GSGs, segmentally sclerosed glomeruli, ischemic-like glomeruli, and imploding glomeruli. Atypical glomeruli were 7.3% (95% confidence interval, 4.1 to 10.4) closer together than typical glomeruli and were more likely to be closer together in older patients or those with hypertension. In simulated kidney biopsies, failure to capture the capsule was associated with underdetection of GSGs, ischemic-like glomeruli, and imploding glomeruli. CONCLUSIONS: Spatial analysis of large sections of kidney tissue provided quantitative evidence of spatial heterogeneity of glomerular phenotypes including clustering of atypical glomeruli in individuals with hypertension or older age. Most importantly, deep kidney biopsies that lack subcapsular area underdetect atypical glomerular phenotypes, suggesting that capturing the renal capsule is an important quality control measure for kidney biopsies.