Diabetic Proteinuria Revisited: Updated Physiologic Perspectives

Abstract

Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin–angiotensin axis or of sodium–glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.

Efficacy of Huangkui Capsules in the Treatment of Diabetic Kidney Disease: A Systematic Review and Using Network Pharmacology

“…Generally speaking, the pathogenesis of metabolic-mediated proteinuria is complicated, including but not limited to glomerular hyperfiltration, highly increased trans-glomerular pressure, and the consequent glomerular and tubulointerstitial damage. [36] Notably, the reduction in trans-glomerular pressure and hyperfiltration benefits the attenuation of proteinuria, which has been found in clinical trials with the administration of ACEI, ARB, SGLT2 inhibitors, and finerenone. [37–40] The underlying mechanism of glomerular hyperfiltration at the early stage of DKD might be the excess glucose reabsorbed by the proximal tubules via SGLT2 and the reduction in distal sodium delivery, which decreases tubulo-glomerular feedback with consequent dilation of afferent arterioles and constriction of angiotensin-induced efferent arterioles.…”

Management of Hyperkalemia in Renin-Angiotensin-Aldosterone System Inhibitor: Strategies to Maintain Chronic Kidney Disease Patients with Type II Diabetes on Therapy

“…Activation of the RAAS results in vasoconstriction, increased sodium reabsorption, and enhanced release of noradrenaline, aldosterone, and antidiuretic hormones (Fig. 2) [10,21]. RAASis counteract the improper activation of the RAAS, thereby mitigating hypertension and other harmful effects on the CV and renal systems.…”

“…The principal cause is stemming from the unopposed RAAS as the underlying cause of high mortality risk [12,16]. The KDIGO 2021 clinical practice guidelines for managing BP in CKD patients and KDIGO 2022 guidelines for diabetes management in CKD patients recommend RAASi be used at the highest approved doses that are tolerated, given the CV and kidney benefits [17,[21][22][23]. A clear understanding of potassium homeostasis is crucial in mitigating the risk of hyperkalemia while maximizing the extended outcome benefits of RAASi.…”

Unveiling the pathogenesis and therapeutic approaches for diabetic nephropathy: insights from panvascular diseases

“…Activated endothelial cells exhibit disturbances in barrier function, increasing vascular permeability at the glomerular ( 43 ) and tubular ( 44 ) vascular beds. This allows plasma proteins such as albumin to leak into the urine, presenting clinically as proteinuria - a hallmark of DN ( 45 ). At the molecular level, hyperglycemia enhances endothelial expression of adhesion molecules that recruit leukocytes ( 46 ), decreasing the synthesis of antiproteinuric factors ( 47 ).…”