Piergiorgio Messa

The OPTIMA Study: Assessing a New Cinacalcet (Sensipar/Mimpara) Treatment Algorithm for Secondary Hyperparathyroidism

BACKGROUND AND OBJECTIVES Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower parathyroid hormone (PTH), calcium, and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients. STUDY DESIGN In this multicenter, open-label study, hemodialysis patients with poorly controlled SHPT were randomized to receive conventional care (n = 184) or a cinacalcet-based regimen (n = 368). Doses of cinacalcet, vitamin D sterols, and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH < or =300 pg/ml during a 7-wk efficacy assessment phase. RESULTS A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH (71% versus 22%, respectively; P < 0.001), Ca x P (77% versus 58%, respectively; P < 0.001), calcium (76% versus 33%, respectively; P < 0.001), phosphorus (63% versus 50%, respectively; P = 0.002), and PTH and Ca x P (59% versus 16%, respectively, P < 0.001), and allowed a 22% reduction in vitamin D dosage in patients receiving vitamin D at baseline. Achievement of targets was greatest in patients with less severe disease (intact PTH range, 300 to 500 pg/ml) and the cinacalcet dose required was lower in these patients (median = 30 mg/d). CONCLUSIONS Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial

BACKGROUND Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING Polycystic Kidney Disease Foundation.

Hepatitis B virus infection and the dialysis patient.

Prevention of nosocomial transmission of hepatitis B virus (HBV) has been a signal achievement in the management of chronic kidney disease. The rate of serum hepatitis B surface antigen (HBsAg) seropositivity in patients on maintenance hemodialysis in the developed world is currently low (0–10%) but outbreaks of acute HBV infection continue to occur in this setting. The prevalence of HBV infection within dialysis units in developing countries appears higher (2–20%) based on relatively few reports. Although data are limited, HBV infection in dialysis population diminishes survival; HBV viral load in HBsAg‐positive dialysis patients is reportedly low and stable over time. Updated recommendations for the management of HBsAg chronic carriers on maintenance dialysis have been issued. No rigorously controlled treatment trials for treatment of hepatitis B with either interferon or lamivudine therapy in dialysis patients are currently available.

Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis

Objectives: To evaluate the role of immunological tests for monitoring lupus nephritis (LN) activity. Methods: C3, C4, anti-dsDNA and anti-C1q antibodies were prospectively performed over 6 years in 228 patients with LN. Results: In membranous LN only anti-C1q antibodies differentiated proteinuric flares from quiescent disease (p = 0.02). However, in this group 46% of flares occurred with a normal value of anti-C1q antibodies versus 20% in proliferative LN (p = 0.02). In patients with antiphospholipid antibodies (APL), 33% of flares occurred with normal levels of anti-C1q antibodies versus 14.5% in patients that were APL-negative (p = 0.02). In proliferative LN, anti-C1q antibodies showed a slightly better sensitivity and specificity (80.5 and 71% respectively) than other tests for the diagnosis of renal flares. All four tests had good negative predictive value (NPV). At univariate analysis anti-C1q was the best renal flare predictor (p<0.0005). At multivariate analysis, the association of anti-C1q with C3 and C4 provided the best performance (p<0.0005, p<0.005, p<0.005 respectively). Conclusions: Anti-C1q is slightly better than the other tests to confirm the clinical activity of LN, particularly in patients with proliferative LN and in the absence of APL. All four “specific” tests had a good NPV, suggesting that, in the presence of normal values of each, active LN is unlikely.

Cinacalcet in Patients with Chronic Kidney Disease: A Cumulative Meta-Analysis of Randomized Controlled Trials

Giovanni Strippoli and colleagues report findings of a systematic review and meta-analysis examining the benefits and harms of calcimimetic therapy in adults with chronic kidney disease.

Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

BACKGROUND AND OBJECTIVES The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Serum IgG(1), IgG(3), and IgG(4) against aldose reductase (AR), SOD2, and α-enolase (αENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG(4) were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients. RESULTS IgG(4) was the most common isotype for all antibodies; IgG(1) and IgG(3) were nearly negligible. IgG(4) levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; αENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P<0.005). Anti-NEP IgG(4) did not differ from normal controls (P=0.12). Anti-PLA2r IgG(4) was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-αENO IgG(4) (P<0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P<0.05). CONCLUSIONS Our data suggest that IgG(4) is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, αENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

Background. In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. Methods. De novo RTR were randomized to standard exposure EVL (C0 3–8 ng/mL) with low-concentration CsA (C2 maintenance levels 350–500 ng/mL, group A) or higher EVL exposure (C0 8–12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150–300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. Results. Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5±20.7 vs. 61.3±22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. Conclusions. EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.

Luminex technology for anti-HLA antibody screening: Evaluation of performance and of impact on laboratory routine

The recent introduction of new technologies such as Luminex has provided alternative methods to the Complement Dependent Cytotoxicity (CDC) test for HLA specific antibody detection. In this study we compared the results obtained with CDC to those obtained using a Luminex method with the aim of evaluating the impact of this new technology on antibody screening policies in our transplant setting.

Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease.

Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis.

Natural history of hepatitis B and C in renal allograft recipients.

Background. In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. Methods. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. Results. At enrollment in 1989 (5.5±4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. Conclusions. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.