Albuminuria

Albuminuria is a manifestation of diseases that affect glomerular capillariy wall by altering its selective permeability and is associated with increased cardiovascular morbidity and mortality and even at levels of urine albumin not generally regarded as pathologic, and even in the absence of hypertension and diabetes.

All three layers of glomerular filtration barrier are required for selective glomerular ultrafiltration: podocyte, glomerular basement membrane and glomerular endothelium.

Podocyte injury underlies most, if not all proteinuric kidney diseases.

Damage to the glomerular endothelium can cause albuminuria has seen with preeclampsia were interference in vascular endothelial growth factor (VEGF) signaling to the glomerular endothelium cells causes a albuminuria and the nephrotic syndrome.

Anti-VEGF therapy with Bevacizumab can cause albuminuria, hypertension and glomerular disease.

Albuminuria in the presence of type II diabetes can predict for coronary artery disease.

Microalbuminuria these were the earliest clinical findings for diabetic nephropathy.

Increased urinary albumin excretion as an albumin-to- creatinine ratio of 30 mg per/gram or greater.

Increased urinary albumin is a important marker of kidney injury.

Guidelines recommend the use of urine ACR to stage chronic kidney disease rather than urine protein-to-creatinine ratio because assays for the former more likely to be standardized and have better precision at lower values of albuminuria.

Most precise measurements of urine albumin come from the first morning sample or 24 hour collection.

There is biological variability in urine albumin over the course of a day.

Black individuals have a higher level of urinary albumin excretion than whites, and may contribute to racial disparities in cardiovascular outcomes.

The glomerular basement membrane has less an important role in retaining albumin and other proteins in plasma while allowing free filtration of water and solute.

In proteinuric kidney disease the GFR may decline but permeability of albumin is increased.

The interdigitating podocyte foot processes serve as buttresses against physical forces of hydrostatic pressure in the glomerular capillaries, compressing GBM‘s gel like structure.

 

The altered GBM acts as selective filter and restricts the permeability to macromolecules transported by diffusion and bulk flow.

 

The podocyte foot process architecture maximizes the area available for filtration of water and small solutes and provides mechanical resistance against blood pressure that compresses the GBM, preserving selectivity and preventing loss of albumin and other macromolecules.

 

Podocyte injury is associated with a more simplified architecture and the slit-diaphragm length is reduced, resulting in a reduction in the filtration slit area and a decline in glomerular filtration rate of water and small solutes.

 

Podocyte injury concurrently loses buttressing force and compressive force of the GBM is also reduced, which increases the permeability to albumin.

In the Heart Outcomes Prevention Evaluation trial the presence of micro or macro albuminuria was associated with increased risk of cardiovascular events in patients with or without diabetes.

During a median followup of 56 months patient’s with albuminuria at a 21% increase odds of cognitive decline compared with those with no albuminuria, and participants who developed new onset albuminuria during followup at a 30-77% increased odds of developing cognitive decline compared with those who remained without albuminuria (Barzilav JI et al): Suggests a relationship between and cognitive impairment is related to microvascular disease.

The width of the filtration slit his thought to be fixed and determined by the interacting molecules that bridge the distance between the adjacent foot processes, shortening the filtration slit results in a reduction of the filtration area.

The filtration rate can be partially maintained by angiotensin II-mediated contraction of the efferent arteriole.

Preventing angiotensin II mediated constriction of the efferent arteriole by blockade of the renin-angiotensin system is the cornerstones of anti-proteinuric therapy to limit progressive podocyte  injury and loss in diabetic and nondiabetic kidney disease.

Hyperfiltration can occur through loss of regulation of the afferent arteriole.

SGLT2 inhibitors can mitigate renal damage such as progression to end-stage kidney disease, doubling of the serum creatinine level, or death from renal causes in patients with diabetic,  and those with nondiabetic kidney disease,  by an effect thought to be primarily mediated to constriction of the afferent arteriole and prevention of hyper filtration.

SGLT2 inhibition reduces reabsorption of glucose and sodium within the proximal tubule, reestablishing sodium delivery to the macular densa  and leads to a correction of hyperfiltration through tubuloglomerular feedback and afferent vasoconstriction.