Glomerular hyperfiltration as a therapeutic target for CKD

Abstract

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions.

Keywords: angiotensin; chronic kidney disease; glomerular haemodynamics; glomerular hyperfiltration; sodium–glucose co-transporter 2 inhibitors.

Figure 1:

Tubular and vascular mechanisms of glomerular hyperfiltration. The net effect of vascular mediators generates increased glomerular filtration. Diminished sodium chloride delivery to the macula densa results in deactivation of tubuloglomerular feedback and vasodilation of efferent arterioles. Shear stress results from increased blood and ultrafiltrate flow and is parallel to the surface. Tensile stress arises from increased hydrostatic pressure perpendicular to the capillary wall. FFSS: fluid flow shear stress; PGC: glomerular capillary pressure; RA: resistance of the afferent arteriole; RE: resistance of the efferent arteriole; TS: tensile stress.

Figure 2:

The pathological effects of mechanical stress on nephrons simplified in a schema. Mechanical stress induces a direct injury in podocytes, GBM, mesangial cells and proximal tubule cells. Simultaneously, mechanical stress induces glomerular hypertrophy and causes disproportionate hypertrophy in podocytes and the GBM. Direct injury and disproportionate hypertrophy result in irreversible podocyte loss and glomerulosclerosis. This structural damage, coupled with glomerulosclerosis and increased metabolic demand due to hyperfiltration, gives rise to observable clinical manifestations such as albuminuria, contributing to their heightened toxicity. Increased metabolic demand, toxicity and direct injury result in pro-inflammatory and profibrotic response coupled with decreased klotho, an anti-aging protein crucial for renal health, and causes nephron loss and CKD progression.