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Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease.

ABSTRACT: Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to end stage kidney disease (ESKD). In order to determine mechanisms contributing to persistent podocyte loss, we used a human diphtheria toxin transgenic rat model. After initial diphtheria toxin-induced podocyte injury (over 30% loss in 4 weeks), glomeruli became destabilized, resulting in continued autonomous podocyte loss causing global podocyte depletion (ESKD) by 13 weeks. This was monitored by urine mRNA analysis and by quantitating podocytes in glomeruli. Similar patterns of podocyte depletion were found in the puromycin aminonucleoside and 5/6 nephrectomy rat models of progressive end-stage disease. Angiotensin II blockade (combined enalapril and losartan) restabilized the glomeruli, and prevented continuous podocyte loss and progression to ESKD. Discontinuing angiotensin II blockade resulted in recurrent glomerular destabilization, podocyte loss, and progression to ESKD. Reduction in blood pressure alone did not reduce proteinuria or prevent podocyte loss from destabilized glomeruli. The protective effect of angiotensin II blockade was entirely accounted for by reduced podocyte loss. Thus, an initiating event resulting in a critical degree of podocyte depletion can destabilize glomeruli and initiate a superimposed angiotensin II-dependent podocyte loss process that accelerates progression resulting in eventual global podocyte depletion and ESKD. These events can be monitored noninvasively in real-time through urine mRNA assays.

SUBMITTER: Fukuda A

PROVIDER: S-EPMC3739490 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease.

Fukuda Akihiro A Wickman Larysa T LT Venkatareddy Madhusudan P MP Sato Yuji Y Chowdhury Mahboob A MA Wang Su Q SQ Shedden Kerby A KA Dysko Robert C RC Wiggins Jocelyn E JE Wiggins Roger C RC

Kidney international 20110921 1

Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to end stage kidney disease (ESKD). In order to determine mechanisms contributing to persistent podocyte loss, we used a human diphtheria toxin transgenic rat model. After initial diphtheria toxin-induced podocyte injury (over 30% loss in 4 weeks), glomeruli became destabilized, resulting in continued autonomous podocyte loss causing global podocyte depleti ...[more]

PMID: 21937979

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Project description:Patients with end-stage kidney disease (ESKD) have a greater risk of comorbidities, including diabetes and anemia, and have higher hospital admission rates than patients with other diseases. The cause of hospital admissions is associated with ESKD prognosis. This retrospective cohort study involved patients with ESKD who received hemodialysis and investigated whether the cause of hospital admission changed before versus after they started hemodialysis. This study recruited 592 patients with ESKD who received hemodialysis at any period between January 2005 and November 2017 and had been assigned the International Classification of Diseases Ninth Revision Clinical Modification (ICD-9-CM) code for ESKD. The patients' demographic data and hospitalization status one year before and two years after they received hemodialysis were analyzed. A McNemar test was conducted to analyze the diagnostic changes from before to after hemodialysis in patients with ESKD. The study's sample of patients with ESKD comprised more women (51.86%) than men and had an average age of 67.15 years. The numbers of patients admitted to the hospital for the following conditions all decreased significantly after they received hemodialysis: type 2 (non-insulin-dependent and adult-onset) diabetes; native atherosclerosis; urinary tract infection; gastric ulcer without mention of hemorrhage, perforation, or obstruction; pneumonia; reflux esophagitis; duodenal ulcer without mention of hemorrhage, perforation, or obstruction; and bacteremia. Most patients exhibited one or more of the following comorbidities: diabetes (n = 407, 68.75%), hypertension (n = 491, 82.94%), congestive heart failure (n = 161, 27.20%), ischemic heart disease (n = 125, 21.11%), cerebrovascular accident (n = 93, 15.71%), and gout (n = 96, 16.22%). An analysis of variance (ANOVA) indicated that changes in the ICD-9-CM codes for native atherosclerosis, urinary tract infection, pneumonia, and hyperkalemia were associated with age. Patients who developed pneumonia before or after they received hemodialysis tended to be older (range: 69-70 years old). This study investigated the causes of hospital admission among patients with ESKD one year before and two years after they received hemodialysis. This study's results revealed hypertension to be the most common comorbidity. Regarding the cause of admission, pneumonia was more prevalent in older than in younger patients. Moreover, changes in the ICD-9-CM codes of native atherosclerosis, urinary tract infection, pneumonia, and hyperkalemia were significantly correlated with age. Therefore, when administering comprehensive nursing care and treatment for ESKD, clinicians should not only focus on comorbidities but also consider factors (e.g., age) that can affect patient prognosis.

Dataset Information

Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease.

Publications

Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease.

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