Critical timing of ACEi initiation prevents compensatory glomerular hypertrophy in the remaining single kidney.

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy "compensatory" glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.

Urine marker analysis identifies evidence for persistent glomerular podocyte injury across allograft lifespan.

Long-term kidney transplant (KT) survival has remained relatively stagnant. Protocol biopsy studies suggest that glomerulosclerosis is a significant contributor to long-term graft failure. We previously demonstrated that podocyte loss in the first year post-transplantation predicted long-term allograft survival. However, whether increased podocyte loss continues over the lifespan of a KT remains unclear. We performed a cross-sectional analysis of 1182 urine samples from 260 KT recipients up to 19-years after transplantation. Urine pellet (UP) mRNAs were assayed for podocyte (NPHS2/podocin and nephrin/NPHS1), distal tubule (aquaporin2), and profibrotic cytokine (TGFbeta1). Multivariable generalized estimating equations were used to obtain "population-averaged" effects for these markers over time post-KT. Consistent with early stresses both podocyte and tubular markers increased immediately post-KT. However, only podocyte markers continued to increase long-term. A role for hypertrophic stresses in driving podocyte loss over time is implied by their association with donor BMI, recipient BMI, and donor-recipient BMI mismatch at transplantation. Furthermore, UP podocin mRNA was associated with urine TGFbeta1, proteinuria, and reduced estimated glomerular filtration rate, thereby linking podocyte injury to allograft fibrosis and survival. In conclusion we observed that podocyte loss continues long-term post-KT suggesting an important role in driving late graft loss.

Podocyte stress and detachment measured in urine are related to mean arterial pressure in healthy humans.

Hypertension-associated progressive glomerulosclerosis is a significant driver of both de novo and all-cause chronic kidney disease leading to end-stage kidney failure. The progression of glomerular disease proceeds via continuing depletion of podocytes from the glomeruli into the ultrafiltrate. To non-invasively assess injury patterns associated with mean arterial pressure (MAP), we conducted an observational study of 87 healthy normotensive individuals who were cleared for living kidney donation. Urine pellet podocin and aquaporin2 mRNAs normalized to the urine creatinine concentration (UPod:Creat ratio and UAqp2:Creat ratio) were used as markers of podocyte detachment and tubular injury, respectively. The ratio of two podocyte mRNA markers, podocin to nephrin (UPod:Neph) as well as the ratio of podocin to the tubular marker aquaporin2 (UPod:Aqp2) estimated the relative rates of podocyte stress and glomerular vs. tubular injury. The MAP was positively correlated with the UPod:Neph and UPod:Aqp2, thereby confirming the relationship of MAP with podocyte stress and the preferential targeting of the glomerulus by higher MAP. In multivariable linear regression analysis, both UPod:Neph and UPod:Creat, but not UAqp2:Creat or proteinuria, were both significantly related to a range of normal MAP (70 to 110 mm Hg). Systolic, as opposed to diastolic or pulse pressure was associated with UPod:Creat. Thus, higher podocyte stress and detachment into the urine are associated with MAP even in a relatively "normal" range of MAP. Hence, urine pellet mRNA monitoring can potentially identify progression risk before the onset of overt hypertension, proteinuria or chronic kidney disease.

Accelerated podocyte detachment early after kidney transplantation is related to long-term allograft loss of function.

BACKGROUND: Kidney allograft half-life has not improved despite excellent short-term survival. Recent long-term surveillance biopsy studies identify accumulating glomerulosclerosis (GS) to be associated with late allograft loss. While podocyte depletion is well known to drive proteinuria and GS in animal models and human glomerular diseases, its role in renal allograft loss of function is generally not recognized. METHODS: To address these questions, we collected urine from 125 kidney allograft recipients in the first posttransplant year for urine pellet messenger RNA (mRNA) and protein analysis, with a median follow up of 4.5 years. RESULTS: Using multivariable linear models adjusted for proteinuria, transplant, recipient and donor factors, we observed that the average urine pellet podocin mRNA normalized to urine creatinine (UPodCR) in the first posttransplant year was significantly associated with an estimated glomerular filtration rate (eGFR) decline (P = 0.001). The relationship between UPodCR and eGFR decline persisted even among recipients who were nonproteinuric and who had no recurrent or de novo glomerular disease identified on 1-year protocol biopsy. Finally, we identified recipient, donor and recipient:donor body surface area mismatch ratio to be independently associated with UPodCR early after transplantation. A larger donor was protective, while a larger recipient and increased recipient:donor size mismatch ratio were associated with increased UPodCR. CONCLUSIONS: These findings support the concept that in kidney allografts, accelerated podocyte loss precedes proteinuria and is associated with inferior long-term allograft outcomes as measured by eGFR decline and may be initiated by recipient:donor size mismatch. Modulating factors driving early podocyte detachment after kidney transplantation may help improve long-term outcomes.