Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats

Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2′-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state

Discontinuation of Hemodialysis in a Patient with Anti-GBM Disease by the Treatment with Corticosteroids and Plasmapheresis despite Several Predictors for Dialysis-Dependence

A 26-year-old man highly suspected of having antiglomerular basement membrane (GBM) disease was treated with corticosteroid pulse therapy 9 days after initial infection-like symptoms with high procalcitonin value. The patient required hemodialysis the next day of the treatment due to oliguria. In addition to corticosteroid therapy, plasmapheresis was introduced and the patient could discontinue hemodialysis 43 days after the treatment. Kidney biopsy after initiation of hemodialysis confirmed anti-GBM disease with 86.3% crescent formation. Physician should keep in mind that active anti-GBM disease shows even high procalcitonin value in the absence of infection. To pursue recovery of renal function, the challenge of the immediate and persistent treatment with high-dose corticosteroids plus plasmapheresis for highly suspected anti-GBM disease is vitally important despite the presence of reported predictors for dialysis-dependence including oliguria and requiring hemodialysis at presentation

Hazard ratio of subsequent ESRD by time-averaged values over 2 years.

<p>Hazard ratios of several predictors for subsequent risk of ESRD are depicted by sectioning the time-averaged values over 2 years with the respective normal range as references. Hazard ratios are adjusted for six basic covariates such as sex, age, diabetic nephropathy, baseline estimated GFR and time-averaged systolic blood pressure and proteinuria over 2 years. <b>a</b>) Proteinuria with reference of < 0.5 g/g creatinine (adjustment for time-averaged proteinuria over 2 years was not done), <b>b)</b> Hemoglobin with reference of 10–12 g/dL, <b>c)</b> Serum albumin with reference of 3.5–4.0 g/dL, <b>d</b>) LDL-cholesterol with reference of 100–120 mg/dL.</p

Flow chart of constructing the retrospective CKD cohort.

<p>Flow chart of constructing the retrospective CKD cohort.</p

Cox regression for ESRD using baseline dataset (n = 701).

<p>“0” following the parameter denotes the baseline value.</p><p>A univariate Cox regression was performed and the parameter showing <i>p</i> < 0.1 underwent a multivariate Cox regression analysis in a stepwise manner.</p><p>Model 1: Baseline dataset (Sex, Age, DMN, Baseline eGFR, SBP_0, Hb_0, Alb_0, UA_0, Na_0, K_0, Na-Cl_0, P_0, LDL-C_0, TPU/CrU_0, UB_score_0, RASi_0).</p><p>Cox regression for ESRD using baseline dataset (n = 701).</p

Hazard ratios of ESRD with every 10% decline in estimated GFR over 2 years.

<p>Hazard ratio reaching ESRD was determined by a Cox regression analysis by adjusting for age, sex, diabetic nephropathy and baseline estimated GFR as the baseline characteristics and 2-year time-averaged systolic blood pressure and proteinuria (total six confounders). Hazard ratios for subsequent risk of ESRD increase with every 10% decline in estimated GFR over 2 years in an exponential manner.</p

Distribution of percentage change in estimated GFR over 2 years.

<p>Percentage changes in estimated GFR were calculated with two measurements of serum creatinine at entry and after 2 years. The data show near normal distribution. The patients showing “rapid progression” defined as 50% decline over 2 years are observed in 7% of the total patients.</p

Hazard ratio of subsequent ESRD by time-averaged values over 2 years.

<p>Hazard ratios of several predictors for subsequent risk of ESRD are depicted by sectioning the time-averaged values over 2 years with the respective normal range as references. Hazard ratios are adjusted for six basic covariates such as sex, age, diabetic nephropathy, baseline estimated GFR and time-averaged systolic blood pressure and proteinuria over 2 years. <b>a</b>) Proteinuria with reference of < 0.5 g/g creatinine (adjustment for time-averaged proteinuria over 2 years was not done), <b>b)</b> Hemoglobin with reference of 10–12 g/dL, <b>c)</b> Serum albumin with reference of 3.5–4.0 g/dL, <b>d</b>) LDL-cholesterol with reference of 100–120 mg/dL.</p

Baseline characteristics and the time-averaged values over 2 years of the CKD cohort (n = 701).

<p>The difference of means between two groups was analyzed by paired t test if the data showed normal distribution; otherwise, Wilcoxon singed rank test was employed for CRP, TPU/CrU, UB_score and Drug use.</p><p>^¶ Paired t test or Wilcoxon signed rank test.</p><p>eGFR, estimated glomerular filtration rate; DMN, diabetic nephropathy; HTN, hypertensive nephropathy; CGN, chronic glomerulonephritis; PKD, polycystic kidney disease; BMI, Body Mass Index; SBP, systolic blood pressure; Hb, hemoglobin; WBC, white blood cell; Plt, platelet; Alb, albumin; UA, uric acid; Na, sodium; K, potassium; Cl, chloride; cCa, albumin-corrected calcium; P, phosphorus; CRP, C reactive protein; LDL-C, low-density lipoprotein cholesterol; UB_score, urine blood score; TPU/CrU, urine total protein divided by urine creatinine; RASi, RAS inhibitor; CCB, calcium channel blocker; other AHD, other antihypertensive drugs.</p><p>Baseline characteristics and the time-averaged values over 2 years of the CKD cohort (n = 701).</p