Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases

Abstract

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P,0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P,0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimalchange disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.

Relationships among injury, fibrosis, and time in human kidney transplants

“…It is critical to understand these issues in human kidneys: mouse and rat models are potentially misleading because they have a strong tendency to develop progressive glomerular pathology after injury. Nevertheless, rodent models and human kidneys may share some elements that limit nephron survival, such as podocyte loss (20).…”

“…The decision to commit to irreversible nephron shutdown and atrophy fibrosis is probably regulated by nephron homeostatic and cybernetic mechanisms and reflects limiting factors such as extent of injury, biological aging, and podocyte numbers. Podocyte loss is a feature of all glomerular diseases in proportion to the rate of progression and is a feature of kidney transplantation (20,79,80). Active control of function of each nephron is implicit in the intact nephron hypothesis, which states that even in CKD with the majority of function lost, only intact nephrons are permitted to function and, by implication, severely damaged nephrons are functionally silenced (81).…”

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

“…The urine pellet podocin mRNA/creatinine ratio (UPodCR) assay therefore provides an estimate of the amount of podocyte detachment from glomerular tufts measured in spot urine samples analogous to the urine protein/creatinine ratio, as previously described. 17 Data are shown as a fold comparison with 2K age-matched control values (n=174). We previously reported that the UPodCR is detectable in normal urine and does not vary significantly with age, sex, or race.…”

“…16 We recently adapted methodologies for quantitating podocytes in urine and kidney biopsies for use in humans. 17,18 Therefore, tools are available to begin to understand what happens to podocytes in the transition from a two-kidney (2K) state to a 1K state as well as in glomerulopathies. Human kidney transplantation offers a scenario in which these questions can be examined.…”

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

“…In light of emerging evidence that epigenetic mechanisms play homeostatic roles in terminally differentiated cells, 13 especially under diabetic conditions, 3,6,14 we focused our experiments on the effects of this pathway in podocytes, the final barriers to protein leakage into the urinary filtrate, in which early injury may contribute to the subsequent development of diabetic glomerulosclerosis. 15 …”