Francesco Paolo Schena

Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial.

Background. The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated. Methods. Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20–40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm. Results. Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort. Conclusions. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Pathogenetic Mechanisms of Diabetic Nephropathy

Diabetes is the leading cause of ESRD because diabetic nephropathy develops in 30 to 40% of patients. Diabetic nephropathy does not develop in the absence of hyperglycemia, even in the presence of a genetic predisposition. Multigenetic predisposition contributes in the development of diabetic nephropathy, thus supporting that many factors are involved in the pathogenesis of the disease. Hyperglycemia induces renal damage directly or through hemodynamic modifications. It induces activation of protein kinase C, increased production of advanced glycosylation end products, and diacylglycerol synthesis. In addition, it is responsible for hemodynamic alterations such as glomerular hyperfiltration, shear stress, and microalbuminuria. These alterations contribute to an abnormal stimulation of resident renal cells that produce more TGF-beta1. This growth factor upregulates GLUT-1, which induces an increased intracellular glucose transport and D-glucose uptake. TGF-beta1 causes augmented extracellular matrix protein deposition (collagen types I, IV, V, and VI; fibronectin, and laminin) at the glomerular level, thus inducing mesangial expansion and glomerular basement membrane thickening. However, low enzymatic degradation of extracellular matrix contributes to an excessive accumulation. Because hyperglycemia is the principal factor responsible for structural alterations at the renal level, glycemic control remains the main target of the therapy, whereas pancreas transplantation is the best approach for reducing the renal lesions.

Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review

Abstract Objective To evaluate the effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (AIIRAs) on renal outcomes and all cause mortality in patients with diabetic nephropathy. Data sources Medline, Embase, the Cochrane controlled trials register, conference proceedings, and contact with investigators. Study selection Trials comparing ACE inhibitors or AIIRAs with placebo or with each other in patients with diabetic nephropathy. Data extraction Mortality, renal outcomes (end stage renal disease, doubling of serum creatinine concentration, prevention of progression of microalbuminuria to macroalbuminuria, remission of microalbuminuria), and quality of trials. Data synthesis 36 of 43 identified trials compared ACE inhibitors with placebo (4008 patients), four compared AIIRAs with placebo (3331 patients), and three compared ACE inhibitors with AIIRAs (206 patients). We obtained unpublished data for 11 trials. ACE inhibitors significantly reduced all cause mortality (relative risk 0.79, 95% confidence interval 0.63 to 0.99) compared with placebo but AIIRAs did not (0.99, 0.85 to 1.17), although baseline mortality was similar in the trials. Both agents had similar effects on renal outcomes. Reliable estimates of the unconfounded relative effects of ACE inhibitors compared with AIIRAs could not be obtained owing to small sample sizes. Conclusion Although the survival benefits of ACE inhibitors for patients with diabetic nephropathy are known, the relative effects of ACE inhibitors and AIIRAs on survival are unknown owing to the lack of adequate head to head trials.

Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB10401+ Patients With Renal Cell Carcinoma or Melanoma

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit.

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22–23

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22–23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients

In a randomized, open‐label, multicenter study, de novo renal transplant patients received no steroids (n = 112), steroids to day 7 (n = 115), or standard steroids (n = 109) with cyclosporine microemulsion (CsA‐ME), enteric‐coated mycophenolate sodium (EC‐MPS) and basiliximab. The primary objective, to demonstrate noninferiority of 12‐month GFR in the steroid‐free or steroid‐withdrawal groups versus standard steroids, was not met in the intent‐to‐treat population. However, investigational groups were not inferior to standard steroids in the observed‐case analysis. Median 12‐month GFR was not significantly different in the steroid‐free or steroid‐withdrawal groups (58.6 mL/min/1.73 m2 and 59.1 mL/min/1.73 m2) versus standard steroids (60.8 mL/min/1.73 m2). The 12‐month incidence of biopsy‐proven acute rejection (BPAR), graft loss or death was 36.0% in the steroid‐free group (p = 0.007 vs. standard steroids), 29.6% with steroid withdrawal (N.S.) and 19.3% with standard steroids. BPAR was significantly less frequent with standard steroids than either of the other two regimens. Reduced de novo use of antidiabetic and lipid‐lowering medication, triglycerides and weight gain were observed in one or both steroid‐minimization group versus standard steroids. For standard‐risk renal transplant patients receiving CsA‐ME, EC‐MPS and basiliximab, steroid withdrawal by the end of week 1 achieves similar 1‐year renal function to a standard‐steroids regimen, and may be more desirable than complete steroid avoidance.

Long-Term Benefits with Sirolimus-Based Therapy after Early Cyclosporine Withdrawal

Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n = 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group). At 36 mo, the calculated GFR was significantly better with SRL-ST (47.3 versus 59.4 ml/min; P < 0.001) as was the slope of the GFR (-3.6 versus 0.8 ml/min; P < 0.001). This was accompanied by growing trend for improved graft survival in the SRL-ST group (85.1% versus 91.2%, P = 0.052 at 36 mo; 81.4% versus 91.2%, P = 0.015 in a cumulative data analysis up to 54 mo), despite numerically more biopsy-proven acute rejections after randomization (5.6% versus 10.2%; P = 0.107). Lipid parameters were similar between groups, whereas both systolic and diastolic BP were significantly lower in the SRL-ST group. Investigator-reported hypertension, abnormal kidney function, edema, hyperuricemia, hyperkalemia, gingival hyperplasia, and Herpes zoster occurred significantly more often in SRL-CsA-ST patients. Abnormal liver function test results, hypokalemia, thrombocytopenia, and abnormal healing were reported significantly more often with SRL-ST. The discontinuation rate was significantly higher for SRL-CsA-ST (48% versus 38%; P = 0.041). In conclusion, withdrawing CsA from a SRL-CsA-ST regimen at 3 mo after transplantation resulted in long-term benefits for renal transplant recipients.

Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy

BACKGROUND Immunoglobulin A nephropathy (IgAN) is the most common cause of chronic renal failure among primary glomerulonephritis patients. The best treatment for IgAN remains poorly defined. We planned a long-term, prospective, open-label, multicentre, centrally randomized controlled trial to assess whether the combination of prednisone and ramipril was more effective than ramipril alone in patients with proteinuric IgAN. METHODS Ninety-seven biopsy-proven IgAN patients with moderate histologic lesions, 24-h proteinuria > or =1.0 g and estimated glomerular filtration rate (eGFR) > or = 50 ml/min/ 1.73 m(2) were randomly allocated to receive a 6-month course of oral prednisone plus ramipril (combination therapy group) or ramipril alone (monotherapy group) for the total duration of follow-up. The primary outcome was the progression of renal disease defined as the combination of doubling of baseline serum creatinine or end-stage kidney disease (ESKD). The secondary outcomes were the rate of renal function decline defined as the eGFR slope over time, and the reduction of 24-h proteinuria. RESULTS After a follow-up of up to 96 months, 13/49 (26.5%) patients in the monotherapy group reached the primary outcome compared with 2/48 (4.2%) in the combination therapy group. The Kaplan-Meier analysis showed a significantly higher probability of not reaching the combined outcome in the combination therapy group than in the monotherapy group (85.2% versus 52.1%; log-rank test P = 0.003). In the multivariate analysis, baseline serum creatinine and 24-h proteinuria were independent predictors of the risk of primary outcome; treatment with prednisone plus ramipril significantly reduced the risk of renal disease progression (hazard ratio 0.13; 95% confidence interval 0.03-0.61; P = 0.01). The mean rate of eGFR decline was higher in the monotherapy group than in the combination therapy group (-6.17 +/- 13.3 versus -0.56 +/- 7.62 ml/min/ 1.73 m(2)/year; P = 0.013). Moreover, the combined treatment reduced 24-h proteinuria more than ramipril alone during the first 2 years. CONCLUSIONS Our results suggest that the combination of corticosteroids and ramipril may provide additional benefits compared with ramipril alone in preventing the progression of renal disease in proteinuric IgAN patients in the long-term follow-up.

Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.

Background. Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen. Methods. This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person-years of follow-up). Results. At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). Conclusion. In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.

Catheter-Related Interventions to Prevent Peritonitis in Peritoneal Dialysis: A Systematic Review of Randomized, Controlled Trials

As many as 15 to 50% of end-stage kidney disease patients are on peritoneal dialysis (PD), but peritonitis limits its more widespread use. Several PD catheter-related interventions (catheter designs, surgical insertion approaches, and connection methods) have been purported to reduce the risk of peritonitis in PD. The goal was to assess the trial evidence supporting their use. The Cochrane CENTRAL Registry, MEDLINE, EMBASE, and reference lists were searched for randomized trials of catheter types and related interventions in PD. Two reviewers extracted data on the rates of peritonitis and exit-site/tunnel infection, catheter removal/replacement, technique failure, and all-cause mortality. Analysis was by a random effects model, and results are expressed as relative risk and 95% confidence intervals. Thirty-seven eligible trials (2822 patients) were identified: eight of surgical strategies of catheter insertion, eight of straight versus coiled catheters, 10 of Y-set versus conventional spike systems, four of Y-set versus double-bag systems, and seven of other interventions. Despite the large total number of patients, few trials covered the same interventions, small numbers of patients were enrolled in each trial, and the methodologic quality was suboptimal. Y-set and twin-bag systems were superior to conventional spike systems (seven trials, 485 patients; relative risk, 0.64; 95% confidence intervals 0.53 to 0.77), and no other catheter-related intervention was demonstrated to prevent peritonitis in PD. This systematic review demonstrates that of all catheter-related interventions designed to prevent peritonitis in PD, only disconnect (twin-bag and Y-set) systems have been proved to be effective (compared with conventional spike systems). Despite the importance of PD as a renal replacement therapy modality and the large number of patients who receive it, it is still not known whether any particular PD catheter designs, implantation techniques, or modalities are effective, given the limitations of available trials.