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      Understanding the Mechanisms of Proteinuria: Therapeutic Implications

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          Abstract

          A large body of evidence indicates that proteinuria is a strong predictor of morbidity, a cause of inflammation, oxidative stress and progression of chronic kidney disease, and development of cardiovascular disease. The processes that lead to proteinuria are complex and involve factors such as glomerular hemodynamic, tubular absorption, and diffusion gradients. Alterations in various different molecular pathways and interactions may lead to the identical clinical end points of proteinuria and chronic kidney disease. Glomerular diseases include a wide range of immune and nonimmune insults that may target and thus damage some components of the glomerular filtration barrier. In many of these conditions, the renal visceral epithelial cell (podocyte) responds to injury along defined pathways, which may explain the resultant clinical and histological changes. The recent discovery of the molecular components of the slit diaphragm, specialized structure of podocyte-podocyte interaction, has been a major breakthrough in understanding the crucial role of the epithelial layer of the glomerular barrier and the pathogenesis of proteinuria. This paper provides an overview and update on the structure and function of the glomerular filtration barrier and the pathogenesis of proteinuria, highlighting the role of the podocyte in this setting. In addition, current antiproteinuric therapeutic approaches are briefly commented.

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          Most cited references112

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          Relation between kidney function, proteinuria, and adverse outcomes.

          The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse outcomes, it is not used to refine risk estimates of adverse events in this current system. To determine the association between reduced GFR, proteinuria, and adverse clinical outcomes. Community-based cohort study with participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920 985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). All-cause mortality, myocardial infarction, and progression to kidney failure. The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m(2) or greater. Over median follow-up of 35 months (range, 0-59 months), 27 959 participants (3.0%) died. The fully adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed when proteinuria was measured by ACR (15.9 [95% CI, 14.0-18.1] and 7.0 [95% CI, 6.4-7.6] per 1000 person-years for heavy and absent proteinuria, respectively; rate ratio, 2.3 [95% CI, 2.0-2.6]) and for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.
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            Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.

            For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P=0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.
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              Aliskiren combined with losartan in type 2 diabetes and nephropathy.

              Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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                Author and article information

                Journal
                Int J Nephrol
                Int J Nephrol
                IJN
                International Journal of Nephrology
                Hindawi Publishing Corporation
                2090-214X
                2090-2158
                2012
                4 July 2012
                : 2012
                : 546039
                Affiliations
                1Laboratorio de Medicina Experimental, Hospital Alemán, Facultad de Medicina, University of Buenos Aires, Avenida Pueyrredon 1640, 1118 Buenos Aires, Argentina
                2Servicio de Nefrología, Hospital Alemán, 1118 Buenos Aires, Argentina
                3Departamento de Medicina Interna, Hospital Alemán, 1118 Buenos Aires, Argentina
                4Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
                5Hospital de Clinicas “José de San Martín”, Universidad de Buenos Aires, 1120 Buenos Aires, Argentina
                Author notes

                Academic Editor: Claudio Bazzi

                Article
                10.1155/2012/546039
                3398673
                22844592
                cee3feca-f1e1-423c-9580-06a48fec196a
                Copyright © 2012 Jorge E. Toblli et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 February 2012
                : 30 April 2012
                Categories
                Review Article

                Nephrology
                Nephrology

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