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HCV & Kidney Disease, Extra-hepatic Manifestations of HCV
  from Jules: HCV has been associated with many what is called extra-hepatic manifestations, meaning patients with HCV appear to be at risk for numerous other other diseases including but not limited to kidney disease, diabetes....read on from these studies......
HCV Extrahepatic Mortality-kidney/heart/cancers
Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study - (R.E.V.E.A.L.)-HCV study......http://www.natap.org/2012/HCV/071912_01.htm
"anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for [kidney] nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA."
Hepatitis C virus viremia increases the incidence of chronic kidney disease in HIV-infected patients.....In conclusion, in the EuroSIDA observational HIV cohort, we have shown that chronic, but not resolved HCV infection, was associated with an increased risk of CKD compared with HIV-monoinfected patients......http://www.natap.org/2012/HIV/092112_01.htm
Hepatitis C Co-infection and the Risk of Chronic Kidney Disease in HIV-infected Individuals: Does Hepatitis C Viremia Matter?
HCV Drives Down Kidney
Renal disease associated with hepatitis C virus
There is a strong and likely causal association between chronic hepatitis C virus (HCV) infection and glomerular disease
Hypertension, proteinuria, and progressive renal failure are the main clinical manifestations of HCV-associated
HCV infection is both a cause and complication of chronic kidney disease. It may cause glomerular disease, occurring largely in the context of mixed cryoglobulinemia. This infection also represents a major medical and epidemiologic challenge both in patients on renal replacement therapy and those undergoing kidney transplantation. The presence of HCV correlated with higher rates of mortality in patients on dialysis and transplantation than HCV-negative ones. The major concern is the lack of safe and effective drugs to treat HCV-infected patients with chronic kidney disease. Unfortunately, there are no large-scale clinical trials performed in this population, so that the evidence for treatment recommendations is scant (Table 4). The recently published Kidney Disease: Improving Global Outcomes (KDIGO) statements on screening, prevention, and therapy of HCV patients in kidney disease could be, however, an additional useful tool (127).
"Another possible mechanism underlying HCV-related kidney injury is nonimmunologically mediated. HCV-positive patients with and without cirrhosis have elevated levels of fasting serum insulin and insulin resistance, and higher prevalence of diabetes (reviewed in (23)"
"Hemodialysis patients are at particular high risk for bloodborne infections because of prolonged vascular access and potential for exposure to contaminated equipment."
"HCV infection is also a major health care issue in renal transplantation. Among kidney recipients, the prevalence of HCV infection before transplantation is reported as high as 40% (46)."
Treatment of HCV-Related Glomerulonephritis
Hypertension, proteinuria, and progressive renal failure are the main clinical manifestations of HCV-associated CKD. Thus, renoprotection with blood pressure-lowering and antiproteinuric agents-shown effective in other proteinuric chronic nephropathies (33,34)-must be applied. Diuretics, renin-angiotensin system inhibitors (either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), and eventually lipid-lowering agents, have been proven to be beneficial in HCV patients with CKD (35).
Nevertheless, given the link between HCV infection and immune response targeting the glomerulus, antiviral and immunosuppressive therapies have also been used in these patients (36). The antiviral therapy in HCV-positive patients with CKD is aimed at eliminating the virus and reducing the generation of HCV-related antibodies and immune complexes. Current treatment options for HCV infection are reported in Table 1. Several indicators of therapy efficacy have been proposed. The most reliable for long-term prognosis is sustained virologic response (SVR)-HCV RNA clearance from serum at least 6 mo after cessation of therapy.
Mechanisms of HCV-Induced Kidney Injury
Renal parenchyma expresses CD81 and SR-B1 receptors that allow HCV binding to the cell surface and endocytosis (14). Indeed, HCV RNA and related proteins have been found in mesangial cells, tubular epithelial cells, and endothelial cells of glomerular and tubular capillaries (15,16). The presence of HCV-related proteins in the mesangium was associated with higher proteinuria (16), possibly reflecting direct mesangial injury by HCV infection.
A role in HCV-associated renal injury has been recently suggested for toll-like receptors (TLRs), primary proteins expressed on immune and nonimmune cells as key components of the innate immune system
(17). TLRs recognize molecular patterns associated with microbial pathogens and induce an immune response (17). Renal biopsy findings of increased expression of TLR3 specifically in microdissected glomeruli of patients with HCV-related membranoproliferative glomerulonephritis (MPGN), but not non-HCV MPGN (18), suggest a link between TLR3 and HCV-related glomerular disease. TLR3 is expressed preferentially in the mesangial cell target of HCV-related MPGN. However, while HCV is a single strain RNA virus, TLR3 recognizes double-strand RNA, and the implications of these findings in disease pathophysiology remain to be established.
Much more is known about kidney injury due to systemic immune response to HCV infection that is mediated by cryoglobulins (a group of globulins with the common property of precipitating from cooled serum), HCV-antibody immune complexes, or amyloid deposition (14). Persistence of HCV leads to chronic overstimulation of B-lymphocytes and production of mixed cryoglobulins mainly composed of a polyclonal immunoglobulin (Ig), either IgG or IgM, bound to another Ig that acts as an anti-rheumatoid factor (RF) (19-22).
Cryoglobulins are deposited in the mesangium during their trafficking in the glomerulus. Their nephrotoxicity is attributed to particular affinity of the IgM-κ-RF for cellular fibronectin in the mesangial matrix. Cryoglobulins can also be deposited in the glomerular capillaries as eosinophilic material that stains densely with antisera to IgM, C3, and fibrin by immunofluorescence (14). This is usually associated with histologic signs of vasculitis and downstream fibrinoid necrosis of the glomeruli. Cryoglobulins may also induce endothelitis via anti-endothelial antibody activity and complement activation leading to overexpression of VCAM-1 and subsequent platelet aggregation (14).
Another possible mechanism underlying HCV-related kidney injury is nonimmunologically mediated. HCV-positive patients with and without cirrhosis have elevated levels of fasting serum insulin and insulin resistance, and higher prevalence of diabetes (reviewed in (23)). HCV core protein directly reduces expression of insulin receptor substrate proteins (IRS) 1 and 2 (24), responsible for metabolic effects of insulin, and promotes activation of IRS-1 and high expression of TNF-α at least in hepatic cells (25). Insulin resistance and hyperinsulinemia cause excess intrarenal production of IGF-1 and TGFβ, thus promoting proliferation of renal cells, and upregulate the expression of angiotensin II type 1 receptors in mesangial cells, thus enhancing the deleterious effects of angiotensin II in the kidney. This setting also leads to excess local production of endothelin-1, reduced endothelial synthesis of nitric oxide, and increased oxidative stress (26).
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