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Connexins are membrane-spanning proteins that allow for the formation of cell-to-cell channels and cell-to–extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment.

Background:We conducted a pilot trial to compare the effectiveness and safety of 2 different treatments in patients with membranous nephropathy and nephrotic syndrome. Methods:To validate the hypothesis that the 2 treatments were equivalent, patients with biopsy-proven membranous nephropathy and nephrotic syndrome were randomly assigned to methylprednisolone alternated with a cytotoxic drug every other month for 6 months (group A) or to intramuscular synthetic adrenocorticotropic hormone administered twice a week for 1 year (group B). Results:The primary outcome measure is cumulative number of remissions as a first event. Fifteen of 16 patients in group A and 14 of 16 patients in group B entered complete or partial remission as a first event. After a median follow-up of 24 months (interquartile range, 15 to 25 months), there were 4 complete remissions and 8 partial remissions in group A versus 8 complete remissions and 6 partial remissions in group B. Median proteinuria decreased from protein of 5.1 g/d (interquartile range, 4.0 to 7.3 g/d) to 2.1 g/d (interquartile range, 0.4 to 3.8 g/d; P= 0.004) in group A and 6.0 g/d (interquartile range, 4.4 to 8.5 g/d) to 0.3 g/d (interquartile range, 0.2 to 1.9 g/d; P= 0.049) in group B. Two patients from each group interrupted treatment because of side effects or inefficacy. Conclusion:Most nephrotic patients with membranous nephropathy responded to either treatment. Proteinuria was significantly decreased with both methylprednisolone and cytotoxic agents or prolonged administration of synthetic adrenocorticotropic hormone, without significant differences between these 2 therapies.

Background:Few data are available about the long-term outcome of renal transplantation in patients with systemic lupus erythematosus (SLE). Methods:Between June 1982 and 2004, a total of 33 adults with lupus nephritis received 35 kidney allografts. Outcomes of these grafts and those of 70 controls matched for age, sex, and donor source who underwent transplantation during the same period were compared. Results:Mean follow-up after renal transplantation was 91 ± 59 months for patients with lupus and 90 ± 64 months for controls. Actuarial 15-year patient (80% versus 83%) and death-censored graft survival rates (69% versus 67%) were not significantly different between patients with lupus and controls. Risks for acute and chronic rejection, arterial hypertension, and infection were not different between the 2 groups. Mean serum creatinine levels also were similar in the 2 groups at the last follow-up visit. Intravascular thrombotic events occurred in 9 patients with SLE (26%) and 6 controls (8.6%; P= 0.038). In the SLE group, 6 of 7 antiphospholipid (aPL) antibody-positive versus 3 of 17 aPL antibody-negative patients experienced thrombotic events (P= 0.015). Recurrence of lupus nephritis was documented in 3 renal grafts (8.6%), but no graft was lost because of recurrent lupus nephritis. Conclusion:Long-term patient and graft survival probabilities were similar in patients with SLE and matched controls. The risk for thrombotic complications was greater in patients with SLE, particularly aPL-positive patients. Nephritis recurred in less than 10% of patients with SLE and did not influence graft survival.

Background:Previous studies have documented the high frequency of thrombosis and fetal loss in patients with lupus nephritis and antiphospholipid (aPL) antibodies, but there is little information on the impact of aPL antibodies on the outcome of lupus nephritis. The aims of this study are to evaluate the prevalence of aPL antibodies in patients with lupus nephritis and assess their prognostic value for thrombosis and pregnancy morbidity and impact on long-term renal outcome. Methods:One hundred eleven patients with lupus nephritis followed up for a mean of 173 ± 100 months were tested regularly for immunoglobulin G (IgG) and IgM anticardiolipin antibodies and lupus anticoagulant. Results:The overall prevalence of aPL antibodies was 26%. In follow-up, 79% of aPL antibody-positive patients experienced thrombotic events and/or fetal losses, and aPL antibodies were associated significantly with arterial or venous thrombosis (P= 0.00001), pregnancy morbidity (P= 0.045), thrombocytopenia (P= 0.0015), and persistent arterial hypertension (P= 0.028). aPL antibodies were significantly more frequent in patients with biopsy-proven membranous lupus nephritis (P= 0.01). A strong association between aPL antibodies and the development of chronic renal insufficiency in the long-term outcome also was found (P= 0.01). With multivariate analysis, aPL antibody positivity (P= 0.02), high plasma creatinine level at presentation (P= 0.01), and chronicity index (P= 0.00004) were independent predictors of chronic renal function deterioration. Conclusion:Detection of aPL antibodies in patients with lupus nephritis is useful not only to identify patients at risk for vascular and obstetric manifestations, but also for their potential deleterious impact on renal outcome.

It has been hypothesized that hemodialysis (HD) treatment per se can preserve patients from an aggressive course of hepatitis C virus (HCV) infection by reduction of viral load. The aim of the present study in HCV-positive (HCV+) HD patients is to determine whether HD induces the production of interferon-α (IFN-α) and if such production can contribute to viremia reduction.

Control of the spread of hepatitis B virus (HBV) infection in dialysis units has been one of major advances in the management of end-stage renal disease. However, the natural history of HBV in dialysis patients remains unclear. The aim of this study is to measure monthly HBV viral load (HBV DNA) in a large cohort (n = 29) of hepatitis B surface antigen (HBsAg)-positive chronic dialysis patients during 12 months.

Background:Fetal and maternal outcomes of 70 pregnancies in 48 women with lupus nephritis were retrospectively analyzed. Methods:In 13 women, lupus nephritis developed during pregnancy (group A). In 38 patients with known lupus nephritis (including 3 patients in group A who had another pregnancy), 57 pregnancies occurred. In 6 patients, a therapeutic abortion was performed. The remaining 51 pregnancies were considered pregnancies in lupus nephritis (group B). Results:Fetal loss was 36% (38%, group A; 35%, group B); it decreased from 46% in the 1970s to 30% in the last decade. Among 41 live births, there were 13 preterm deliveries and 28 full-term deliveries. At multivariate analysis, proteinuria (P= 0.025), arterial hypertension (P= 0.05), and antiphospholipid antibodies (P= 0.01) were independent predictors of fetal loss. In group A, 3 patients developed acute renal failure, irreversible in 1 patient (7.7%); all other patients recovered after steroid and immunosuppressive therapy. In group B, 12 renal flares and 1 extrarenal flare developed during pregnancy or the postpartum period. Two patients progressed to irreversible renal failure (3.9%), and 1 of the 2 patients died. All other patients recovered. The incidence of renal flares before or during pregnancy was not different (P= 0.51). Renal quiescence at the onset of pregnancy was the only predictor of favorable maternal outcome. Conclusion:Proteinuria, hypertension, and positivity of antiphospholipid antibodies are independent predictors of adverse fetal outcome. Quiescence of renal disease is the only predictor of favorable maternal outcome. © 2002 by the National Kidney Foundation, Inc.

Background:Results of peritoneal dialysis (PD) in cirrhotic patients with renal failure are debated. The aim of the present study is to assess the outcome of PD patients with liver cirrhosis. Methods:A retrospective study based on clinical records was performed in 21 cirrhotic and 41 PD patients without liver disease followed up at our PD unit. Results:Five-year patient and technique survival were similar in the two groups. Seven cirrhotic patients (33%) died of liver failure (5 patients), liver cancer (1 patient), and peritonitis (1 patient). Ten controls (24%) died of cardiovascular complications (6 patients), pneumonia (1 patient), cachexia (1 patient), and unknown reasons (2 patients). Six cirrhotic patients discontinued PD therapy after 44.3 ± 24.7 months because of inadequate dialysis (2 patients), sclerosing peritonitis (2 patients), dementia (1 patient), or patient choice (1 patient). Twelve controls discontinued PD therapy after 33 ± 25.9 months because of peritonitis (6 patients), exit-site infection (1 patient), inadequate peritoneal clearance (3 patients), catheter malfunction (1 patient), and patient request (1 patient). The peritonitis rate was 0.31 episodes/y in cirrhotic patients and 0.53 episodes/y in controls (P= not significant). The hospitalization rate was similar (16.5 d/y in cirrhotic patients, 15.4 d/y in controls). In cirrhotic patients, complications were leakage (3 patients), symptomatic hypotension (5 patients), anemia (5 patients), severe malnutrition (14 patients), sclerosing peritonitis (2 patients), and hepatic encephalopathy (3 patients). Conclusion:The outcome of PD and risk for bacterial peritonitis or other dialysis complications are not worsened by the presence of liver cirrhosis. © 2002 by the National Kidney Foundation, Inc.

With the success of organ transplantation, liver disease has emerged as an important cause of morbidity and mortality of renal transplant (RT) recipients. Numerous studies performed during the 1990s have shown that hepatitis C virus (HCV) infection is the leading cause of chronic liver disease among RT recipients. The transmission of HCV by renal transplantation of a kidney from an HCV-infected organ donor has been shown unequivocally. Liver biopsy is essential in the evaluation of liver disease of RT recipients, and histological studies have shown that HCV-related liver disease after renal transplantation is progressive. The outcome of HCV-related liver disease is probably more aggressive in RT recipients than immunocompetent individuals. Various factors can affect the progression of HCV in the RT population: coinfection with hepatitis B virus, time of HCV acquisition, type of immunosuppressive treatment, and concomitant alcohol abuse. The role of virological features of HCV remains unclear. The natural history of HCV infection after renal transplantation is under evaluation; however, recent surveys with long follow-ups have documented adverse effects of HCV infection on patient and graft survival in RT recipients. Use of renal grafts from HCV-infected donors in recipients with HCV infection does not appear to result in a greater burden of liver disease, at least for a short period. The association between HCV and de novo or recurrent glomerulonephritis after RT has been hypothesized and is an area of avid research. Reported studies do not support interferon (IFN) treatment for RT recipients with chronic hepatitis C because of the frequent occurrence of graft failure, and information on the use of other types of IFN or combined therapy (IFN plus ribavirin or amantadine) is not yet available in the RT population. © 2001 by the National Kidney Foundation, Inc.

Hepatitis C virus (HCV) infection is common in the dialysis population and patients with chronic renal failure (CRF) not requiring dialysis. HCV is the most important cause of chronic liver disease in dialysis patients; however, its role has been underestimated by the lower aminotransferase activity in the dialysis population. Aminotransferase activity in patients with CRF not requiring dialysis has not been adequately addressed to date. The aim of this study is to investigate whether serum aminotransferase levels in predialysis patients with CRF are less than those obtained in healthy individuals and dialysis patients. We also analyzed the potential association between serum aminotransferase activity and demographic, clinical, and biochemical parameters. Aspartate (AST) and alanine aminotransferase (ALT) activity was greater in antibody to hepatitis C (anti-HCV)-positive than anti-HCV-negative patients with CRF not requiring dialysis (AST, 32.3 ± 19 versus 18.1 ± 8 IU/L [P= 0.0001]; ALT, 32.9 ± 28 versus 17.7 ± 11 IU/L [P= 0.00001], respectively). Predialysis patients with CRF had lower AST and ALT activity in comparison to healthy individuals (AST, 19.7 ± 11.2 versus 20.4 ± 6.8 IU/L [P= 0.00001]; ALT, 19.5 ± 15.1 versus 21.7 ± 11.3 IU/L [P= 0.00001], respectively). The difference was much greater after correction for viral markers: AST and ALT levels in hepatitis B surface antigen (HBsAg)-negative anti-HCV-negative predialysis patients with CRF were less than those in the healthy population (AST, 17.9 ± 8 versus 20.4 ± 6.8 IU/L [P= 0.00001]; ALT, 17.5 ± 10 versus 21.7 ± 11.3 IU/L [P= 0.00001], respectively). Comparison of AST and ALT activity between age-matched healthy and predialysis seronegative CRF groups showed lower AST and ALT values in the study population. HBsAg-negative anti-HCV-negative dialysis patients had lower AST and ALT activity than seronegative predialysis patients with CRF (AST, 16.6 ± 11.6 versus 17.9 ± 8 IU/L [P= 0.01]; ALT, 16.3 ± 9.4 versus 17.5 ± 10 [P= 0.041], respectively). Multivariate analysis in the predialysis CRF population showed an independent association between AST (P= 0.00001) and ALT (P= 0.00001) activity and anti-HCV positivity, and age was negatively linked to AST (P= 0.011) and ALT levels (P= 0.001). AST level was negatively related to serum creatinine level (P= 0.0001). In conclusion, HCV infection causes significant liver injury in predialysis patients with CRF. These patients have decreased aminotransferase activity compared with the general population. Dialysis patients show lower aminotransferase activity than predialysis patients with CRF. Because serum aminotransferase levels are commonly used to screen for liver disease in the dialysis and predialysis CRF population, recognition of liver damage may be hampered by the reduction in aminotransferase values in these patients. Studies aimed to clarify the pathogenesis of this phenomenon are in progress. © 2001 by the National Kidney Foundation, Inc.

It is still uncertain which, if any, immunologic parameters may help diagnose a renal flare of lupus nephritis. Anti-C1q antibody (Ab) titers have been elevated in patients with lupus with renal involvement, but little information is available on whether the titers are different in quiescent and active phases of lupus nephritis. In this study, we compared anti-C1q Ab titers with other serological test results in 48 patients with biopsy-proven lupus nephritis to assess which parameter could offer the best reliability for differentiating between quiescent and active phases of lupus nephritis. Serum C3 and C4 levels, as well as anti–double-stranded DNA, antiendothelial cell, anti-C1q, and antiphospholipid Ab titers, were evaluated in patients with quiescent renal disease (38 samples) and those with clinical evidence of renal activity (23 samples). Only anti-C1q Ab titers correlated with active renal disease in both univariate (P< 0.0001) and multivariate analysis (P< 0.0001), with a sensitivity of 87% and a specificity of 92%. In six patients, immunologic parameters were measured serially. In all patients, the high anti-C1q Ab titers returned to normal values after treatment-induced remission. The other serological parameters did not show a significant association with renal disease activity. In patients with biopsy-proven lupus nephritis, anti-C1q Ab titers appear to be strongly related to renal disease activity. Their measurement may be useful for confirming the diagnosis of renal flares of lupus nephritis.

There is little information on the long-term outcome of patients initially assigned to cyclosporine (CsA) monotherapy and requiring the addition of steroid therapy during follow-up. The aim of this report is to describe our experience with 143 first renal transplant recipients (120 cadaver transplants, 23 living donor transplants) randomized to receive CsA monotherapy as a treatment arm of three consecutive controlled clinical trials. Median follow-up was 86 months. Thirty-four percent of the patients remained on the original CsA monotherapy, whereas the remaining 66% required the addition of steroid therapy. Cumulative patient and graft survivals at 11 years were 0.89 (95% confidence interval [CI], 0.83 to 0.95) and 0.62 (95% CI, 0.52 to 0.72), respectively. The 11-year graft survival for converted patients was 0.53 (95% CI, 0.39 to 0.67). Cumulative graft half-life was 19.9 ± 3.47 (SE) years. According to the Cox model, variables at transplantation that correlated with a lower 11-year graft survival were yearly increases in age (relative risk [RR], 1.04; P= 0.039), monthly increases in hemodialysis duration (RR, 1.01; P= 0.029), no blood transfusion before transplantation (RR, 1.99; P= 0.043), CsA administration in a double daily dose (RR, 2.35; P= 0.008), and a cadaver donor transplant (RR, 4.76; P= 0.039). Multivariate analysis of time-dependent variables showed that delayed graft function recovery (RR, 2.20; P= 0.019) and the need to add steroid and/or azathioprine therapy (RR, 5.28; P= 0.000) were also correlated with a lower graft survival. Patients who added steroid therapy developed infections (P< 0.001), cataracts (P< 0.001), cardiovascular complications (P= 0.004), and arterial hypertension (P= 0.024) more frequently than patients remaining on CsA monotherapy. Patients administered CsA in a single daily dose received significantly less CsA over the years (P= 0.0042) than patients administered CsA in two divided doses. They also showed a trend toward greater creatinine clearance levels, although not statistically significant. In conclusion, this analysis showed that in patients assigned to CsA therapy alone, good long-term patient and graft survival probabilities can be obtained. In approximately one third of the patients, the use of steroids could be avoided for up to 11 years, and these patients had a better long-term outcome than those who required the addition of steroid therapy. Finally, in patients administered CsA in a single daily dose, the possibility of reducing CsA dosage probably led to better intrarenal hemodynamics with improving creatinine clearances.

Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P= 0.0001; RR, 3.93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P= 0.0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P= 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P= 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P= 0.0231; RR, 4.44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P= 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P= 0.0069; RR, 4.59; 95% CI, 1.52 to 13.88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.

Little information is available about the role of repeated renal biopsies in lupus nephritis. We analyzed retrospectively the prognostic significance of serial renal biopsies in patients with lupus nephritis. Thirty-one patients with lupus nephritis underwent two or more renal biopsies during follow-up. The indications for repeated biopsy were as follows: improvement of renal disease but persistence of nonnephrotic proteinuria (group A, 7 patients); persistent or relapsing nephrotic syndrome (group B, 12 patients); and worsening of renal function (group C, 19 patients). After a median follow-up of 10.5 years, 17 patients reached the end point (persistent doubling of plasma creatinine level). At repeated renal biopsy, there was a correlation between improved clinical and histological features for group A. In these patients, treatment was reduced or stopped successfully. Histological features remained almost unchanged in group B. All patients showed an improvement of proteinuria after reinforcement of therapy. In group C, the worsening of renal function was associated with a variable and clinically unpredictable combination of active and chronic lesions. Only the few patients with an elevated activity index and moderate chronicity index showed a favorable and persistent improvement of renal disease after reinforcement of therapy. At multivariate analysis of clinical and histological data at presentation, only male sex was predictive of an adverse outcome (P= 0.015). At repeated renal biopsy, crescents in more than 30% of glomeruli (P= 0.0009) and chronicity index of 5 or greater (P= 0.00006) were associated with the probability of reaching the end point at multivariate analysis. Repeated renal biopsy may be helpful for establishing the prognosis in patients with lupus nephritis, particularly in the presence of worsening of renal function.

In this study, we retrospectively analyzed the effects of treatment in 19 patients with membranous lupus nephritis (MLN) and nephrotic syndrome. Eight patients were treated with corticosteroids alone, and the other 11 patients received methylprednisolone and chlorambucil alternated every other month for 6 months. At presentation, sex, age, duration of renal disease before renal biopsy, plasma creatinine, and arterial hypertension were similar in the two study groups. Of the eight patients treated with corticosteroids alone, three showed complete remission and one partial remission of the nephrotic syndrome. During the follow-up (mean, 114+/-63 months), seven of these eight patients developed one or more renal flare-ups. Of the 11 patients treated with methylprednisolone and chlorambucil, seven had complete remission, and the other four had partial remission of the nephrotic syndrome. During the follow-up (mean, 83+/-59 months), only one patient had renal flare-up. At the end of the follow-up, all patients were alive, but three patients in the group treated with corticosteroids alone had developed a doubling of plasma creatinine, and another patient had persistent nephrotic syndrome. Two other patients were in complete remission, one patient was in partial remission, and the last patient had nonnephrotic proteinuria. In the group of patients treated with methylprednisolone and chlorambucil, one patient developed extracapillary glomerulonephritis and eventually entered end-stage renal failure 24 years after the clinical onset of renal disease. Seven patients were in complete remission, and three patients were in partial remission at the last follow-up visit. This retrospective study suggests that methylprednisolone and chlorambucil may induce a more stable remission of nephrotic syndrome and may better protect renal function in the long term in comparison with corticosteroids alone. However, these results must be confirmed by a prospective controlled trial. (Am J Kidney Dis 1998 Apr;31(4):681-6)

In all industrial countries, the number of elderly patients who need dialysis has increased in recent years. In the present study, we retrospectively analyzed two different age groups of nondiabetic peritoneal dialysis patients treated at the same unit by the same team of physicians and nurses with the same protocols. However, our purpose was to study possible differences in technique and survival rates, causes of dropout, complications, hospitalization rate, and everyday needs between the two groups. The results of 63 consecutive nondiabetic patients older than 70 years treated with continuous ambulatory peritoneal dialysis (CAPD) were compared with those of 86 nondiabetic patients aged 40 to 60 years treated during the same period. Patient survival was significantly worse in the elderly patients, but the observed to expected survival ratio with respect to age was similar. Technique survival was comparable in the two groups. Total hospitalization was 5,501 days (32 d/yr) in the elderly patients and 4,511 days (18 d/yr; P < 0.05) in the younger group. The peritonitis rate was 0.52 episodes/patient-year in the elderly patients and 0.37 episodes/patient-year in the younger patients (P < 0.002). The exit site infection rate was similar in the two groups (0.30 episodes/yr v0.29 episodes/yr). Other complications related to CAPD did not differ between the elderly and younger patients. Rehabilitation and biochemical data after 1 year of CAPD were similar in the two groups of patients. After 1 year of treatment, 12% of the younger patients and 43% of the elderly patients (P < 0.005) needed a partner for dialysis. Twenty-nine of 39 (74%) of the elderly patients and 30 of 53 (57%) of the younger patients considered their lifestyle acceptable after 1 year of dialysis. Thirty-four of 39 (87%) of the elderly patients and 32 of 53 (60%) of the younger patients (P < 0.02) rated their physical and social state after rehabilitation as better or comparable to that they had before terminal uremia. (Am J Kidney Dis 1998 Mar;31(3):479-90)