Introduction
The glomerulus is a specialized network of capillaries designed for blood filtration and the regulation of body homeostasis (Figure 1). Podocytes are distinct epithelial cells, both morphologically and functionally characterized by foot processes that envelop the glomerular capillaries (1). Together with the fenestrated endothelium and basement membrane, the foot processes of the podocytes form the glomerular filtration barrier (2). The disruption of the glomerular filtration barrier leads to protein leakage from the plasma into the urine (proteinuria), which is linked to the loss of normal kidney function and is a significant risk factor for disease progression toward organ failure (3). Glomerular diseases encompass a broad range of etiologies and clinical manifestations, yet they nearly always result from disruptions in the glomerular filtration barrier (4).
Case
A 45-year-old male with a history of uncontrolled diabetes and biopsy-proven diabetic nephropathy diagnosed 3 years ago presents with worsening kidney function and proteinuria (Table). Vital signs are normal, except for a blood pressure measurement of 153/92 mm Hg. His physical examination is significant for decreased sensation and 2+ pitting edema in lower extremities. The patient inquires why his kidney function is worsening. He is currently being treated with empagliflozin, finerenone, and losartan.
Laboratory results from the initial diagnosis 3 years prior and 3 years later before current treatment initiation
Discussion
Each kidney comprises approximately 500,000 glomeruli, which are multicellular structures composed of capillaries designed for blood filtration and the regulation of body homeostasis found in the outer rim of the kidney (cortex) (4). The kidneys receive about 20%–25% of cardiac output, which equals 1–1.2 L/min. The calculated plasma renal flow rate using renal blood flow (RBF)×1-HCT (hematocrit) is approximately 600–720 mL/min, and a glomerular filtration rate (GFR) is approximately 120 mL/min (180 L/day) (5).
In the diabetic kidney, the initial phase consists of a supraphysiologic increase in the whole-kidney GFR (sum of all functional nephrons), known as glomerular hyperfiltration secondary to diabetes-induced structural changes (6). This is followed by subsequent nephron damage due to increased glomerular hydraulic pressure and transcapillary convective flux of the ultrafiltrate. Furthermore, single nephrons increase filtration to compensate for reduced functional nephrons, leading to more damaged glomeruli (6). This phenomenon is thought to precede albuminuria and the decline in kidney function. Therefore, whole-kidney GFR may be normal despite significant loss of nephrons (Figure 2) (6).
Classic progression of GFR and UAE in the proteinuric course of diabetic nephropathy
Citation: Kidney News 16, 12
Teaching points
Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduce proteinuria by promoting efferent arteriolar vasodilation, which lowers intraglomerular pressure and mitigates hyperfiltration. They also reduce cytokine-induced glomerulosclerosis and fibrosis, preserving kidney function (6).
Sodium-glucose cotransporter-2 inhibitors reduce proteinuria by enhancing tubulo-glomerular feedback with increased sodium passing along the nephron, leading to afferent arteriolar constriction and reduced intraglomerular pressure and hyperfiltration (7). Additionally, improving tubular oxygenation and metabolism reduces kidney inflammation and fibrosis, offering further protection against kidney damage. In combination with these medications, strict glycemic control is critical to preventing further kidney damage and disease progression (8).
Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, is used due to its anti-inflammatory and antifibrotic effects on the kidney; studies show a reduction in the urinary albumin-to-creatinine ratio with use, leading to a delay in kidney disease progression and cardiovascular dysfunction (9).
Footnotes
References
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Lassén E, Daehn IS. Insights into glomerular function and disease pathogenesis. Nat Rev Nephrol 2023; 19:85–86. doi: 10.1038/s41581-022-00667-9
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Bronstein R, et al. Podocyte-parietal epithelial cell interdependence in glomerular development and disease. J Am Soc Nephrol 2023; 34:737–750. doi: 10.1681/ASN.0000000000000104
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Daehn IS, Duffield JS. The glomerular filtration barrier: A structural target for novel kidney therapies. Nat Rev Drug Discov 2021; 20:770–788. doi: 10.1038/s41573-021-00242-0
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Murray I, Paolini MA. Histology, kidney and glomerulus. In: StatPearls [Internet]. StatPearls Publishing; 2024.
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Kaufman DP, et al. Physiology, glomerular filtration rate. In: StatPearls [Internet]. StatPearls Publishing; 2024.
- 6.↑
Tonneijck L, et al. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and treatment. J Am Soc Nephrol 2017; 28:1023–1039. doi: 10.1681/ASN.2016060666
- 7.↑
Athavale A, Roberts DM. Management of proteinuria: Blockade of the renin-angiotensin-aldosterone system. Aust Prescr 2020; 43:121–125. doi: 10.18773/austprescr.2020.021
- 8.↑
Bailey CJ, et al. Renal protection with SGLT2 inhibitors: Effects in acute and chronic kidney disease. Curr Diab Rep 2022; 22:39–52. doi: 10.1007/s11892-021-01442-z
- 9.↑
Bakris GL, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383:2219–2229. doi: 10.1056/NEJMoa2025845
