Molecular Signatures of Diabetic Kidney Disease Hiding in a Patient with Hypertension-Related Kidney Disease: A Clinical Pathologic Molecular Correlation

Abstract

The Kidney Precision Medicine Project (KPMP) seeks to establish a molecular atlas of the kidney in health and disease and improve our understanding of the molecular drivers of CKD and AKI. Herein, we describe the case of a 66-year-old woman with CKD who underwent a protocol KPMP kidney biopsy. Her clinical history included well-controlled diabetes mellitus, hypertension, and proteinuria. The patient's histopathology was consistent with modest hypertension-related kidney injury, without overt diabetic kidney disease. Transcriptomic signatures of the glomerulus, interstitium, and tubular subsegments were obtained from laser microdissected tissue. The molecular signatures that were uncovered revealed evidence of early diabetic kidney disease adaptation and ongoing active tubular injury with enriched pathways related to mesangial cell hypertrophy, glycosaminoglycan biosynthesis, and apoptosis. Molecular evidence of diabetic kidney disease was found across the nephron. Novel molecular assays can supplement and enrich the histopathologic diagnosis obtained from a kidney biopsy.

Keywords: clinical nephrology; molecular biology; pathology.

Figure 1.

Clinical trajectory of creatinine and proteinuria. The patient’s serum creatinine (Cr; milligrams per deciliter) is plotted in relation to urine protein-Cr ratio (grams per gram), albumin-Cr ratio (grams per gram), and total calcium (milligrams per deciliter) over time.

Figure 2.

Pathology assessment of the kidney biopsy specimen. (A) A hematoxylin and eosin-stained section (×100) reveals kidney cortex with glomeruli with normal cellularity (arrows) and focal interstitial fibrosis and tubular atrophy (IF/TA; arrows). An intralobar artery (A) shows mild fibrous thickening. G, global sclerosis. (B) On a periodic acid–Schiff-stained level (×100), there are three nonsclerotic glomeruli, and none have global sclerosis (G). There is focal IF/TA and mild chronic interstitial inflammation. Two arteries (A) within normal limits and proteinaceous casts (C) are also identified. (C) Silver–Jones (×200) shows an artery (A), several arterioles (a) with mild fibrous thickening, and likely afferent arterioles (aa). (D) Electron microscopy (×2550) reveals glomerular capillary loops (L) with mild segmental ischemic wrinkling (W) of the glomerular basement membrane and a vacuolated podocyte (P).

Figure 3.

Pathologic evidence of chronic active kidney cell injury. (A) A hematoxylin and eosin-stained section (×200) shows two normal glomeruli (G) and one glomerulus with global sclerosis (GS). Tubules (T) show several mild changes of acute tubular injury, such as apical blebbing, cytoplasmic vacuoles, and epithelial simplification. Epithelial simplification refers to the loss of columnar architecture and brush borders of the proximal tubular cells and their transition to a flat, squamoid undifferentiated appearance with loss of columnar and brush border. (B) Electron microscopy (×1050) depicts proximal tubule (PT) with normal apical brush border as well as focal epithelial cytoplasmic vacuoles (arrows) and mild thickening of the basement membrane (TBM). Two peritubular capillaries (PTC) are within normal limits.

Figure 4.

Pathways and differentially expressed genes identified through regional transcriptomics. Key enriched pathways and related significant genes are depicted for each segment of the nephron and the kidney interstitium. Genes upregulated in our participant as compared with the reference nephrectomies are depicted in red. Genes downregulated are depicted in blue. Each gene depicted passed an arbitrary significance threshold of P<0.05 (except claudin-10 [CLDN10], which is depicted as a comparison). Genes labeled with a white dot passed a false discovery rate–corrected significance threshold of P<1.98 x 10^-6. Immunofluorescence inset images are provided from laser microdissection microscopy. In all images, blue is DAPI (4′,6-diamidino-2-phenylindole), and green is FITC (fluorescein)-phalloidin, which labels F-actin. In the glomerulus, proximal tubule, and interstitium insets, the red channel is megalin (LDL receptor-related protein 2 [LRP2]) labeling proximal tubules. In the loop of Henle and collecting duct insets, the red channel is Tamm–Horsfall protein (uromodulin [UMOD]), which labels the loop of Henle.