Diabetic Kidney Disease: Challenges, Progress, and Possibilities

Abstract

Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.

Keywords: altered renal hemodynamics; diabetic nephropathy; diagnosis; natural history; novel therapies; pathogenesis; structural changes.

Figure 1.

Electron microscope images of structural changes in diabetic kidney disease. Structural changes in diabetic glomerulopathy found with electron microscopy. A indicates marked expansion of the mesangium. B indicates marked diffuse thickening of capillary basement membranes (to three times the normal thickness in this case). C indicates segmental effacement of the visceral epithelial foot processes. Original magnification, ×3500.

Figure 2.

Normal kidney morphology and structural changes in diabetes mellitus. Diabetic kidney disease induces structural changes, including thickening of the glomerular basement membrane, fusion of foot processes, loss of podocytes with denuding of the glomerular basement membrane, and mesangial matrix expansion.

Figure 3.

Diabetic glomerulopathy. Changes in glomerular histology in diabetic glomerulopathy (A) Normal glomerulus. (B) Diffuse mesangial expansion with mesangial cell proliferation. (C) Prominent mesangial expansion with early nodularity and mesangiolysis. (D) Accumulation of mesangial matrix forming Kimmelstiel–Wilson nodules. (E) Dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic insudation). (F) Obsolescent glomerulus. A–D and F were stained with period acid–Schiff stain, and E was stained with Jones stain. Original magnification, ×400.

Figure 4.

Tubulointerstitial changes and arteriolar hyalinosis in diabetic kidney disease. Tubulointerstitial changes in diabetic kidney disease. (A) Normal renal cortex. (B) Thickened tubular basement membranes and interstitial widening. (C) Arteriole with an intimal accumulation of hyaline material with significant luminal compromise. (D) Renal tubules and interstitium in advancing diabetic kidney disease, with thickening and wrinkled tubular basement membranes (solid arrows), atrophic tubules (dashed arrow), some containing casts, and interstitial widening with fibrosis and inflammatory cells (dotted arrow). All sections were stained with period acid–Schiff stain. Original magnification, ×200.

Figure 5.

Conceptual model of the natural history of diabetic kidney disease. Duration of diabetes, in years, is presented on the horizontal axis. Timeline is well characterized for type 1 diabetes mellitus; for type 2 diabetes mellitus, timeline may depart from the illustration due to the variable timing of the onset of hyperglycemia. *Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy.

Figure 6.

Different pathways and networks involved in the initiation and progression of diabetic kidney disease. AGE, advanced glycation end product; CTGF, connective tissue growth factor; JAK-STAT, Janus kinase/signal transducer and activator of transcription; PKC, protein kinase C; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SAA, serum amyloid A; VEGF-A, vascular endothelial growth factor A. *JAK/STAT signaling can be unchanged (↔) or upregulated (↑) in early and later stages of diabetes, respectively.

Figure 7.

Normal and diabetic nephron with altered renal hemodynamics.