Intravenous immunoglobulin as adjunctive therapy in kidney transplant recipients with severe pneumocystis pneumonia.

Pneumocystis jirovecii is an opportunistic pathogen that may cause severe, life-threatening respiratory infections in immunocompromised patients such as those with kidney transplants. Although antimicrobial prophylaxis is now universally recommended in the early post-transplant period, Pneumocystis pneumonia (PCP) can occur later. If such infection occurs, mortality rates are high. Beyond standard therapy with trimethoprim-sulfamethoxazole, there is a lack of evidence-based options for intensifying treatment when initial therapy fails to show improvement. Moreover, it is usual to minimize immunosuppression in life-threatening infection, but graft damage may occur, particularly in kidney transplant recipients at above-average immunological risk. Here we present two cases of severe PCP in high immunological risk recipients who were managed with adjunctive intravenous immunoglobulin and withdrawal of immunosuppression. Both patients recovered and were discharged from hospital with functioning grafts.

Enterococcal peritonitis in Australian peritoneal dialysis patients: predictors, treatment and outcomes in 116 cases.

UNLABELLED: Background. Enterococcal peritonitis is a serious complication of peritoneal dialysis (PD), although reports of this condition in the literature are exceedingly limited. Methods. The frequency, predictors, treatment and clinical outcomes of enterococcal peritonitis were investigated in all 4675 patients receiving PD in Australia between 1 October 2003 and 31 December 2006. Results. One hundred and sixteen episodes of enterococcal peritonitis occurred in 103 individuals. Enterococcal peritonitis tended to be associated with older age, Maori and Pacific Islander racial origin, renovascular disease and coronary artery disease. Polymicrobial peritonitis, defined as recovery of two or more organisms from dialysate effluent, was significantly more common when an Enterococcus species was isolated than when it was not (45% vs 5%, respectively, P < 0.001, odds ratio 13.4, 95% CI 9.45-19.0). Although international guidelines recommend intraperitoneal ampicillin therapy, only 8% of patients with pure enterococcal peritonitis were treated with this agent, whilst the majority (78%) received vancomycin monotherapy. Overall, 59 (51%) patients with enterococcal peritonitis were successfully treated with antibiotics without experiencing relapse, catheter removal or death. The sole independent predictor of adverse clinical outcomes was recovery of additional (non-Enterococcus) organisms. Polymicrobial enterococcal peritonitis was associated with very high rates of hospitalization (83%), catheter removal (52%), permanent haemodialysis transfer (50%) and death (5.8%). In contrast, clinical outcomes were broadly comparable for pure enterococcal and non-enterococcal peritonitis (hospitalization 75% vs 69%, respectively; catheter removal 25% vs 21%; permanent haemodialysis transfer 17% vs 17%; death 1.6% vs 2.2%) although worse than non-enterococcal Gram-positive peritonitis (63%, 12%, 3% and 0.6%, respectively). Removal of the PD catheter within 1 week of enterococcal peritonitis onset was associated with a lower probability of permanent haemodialysis transfer than later removal (74% vs 100%, P = 0.03). CONCLUSIONS: Enterococcal peritonitis is associated with an increased risk of catheter removal, permanent haemodialysis transfer and death, particularly when other organisms are isolated in the same episode.

Review article: Hepatitis B and dialysis.

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of approximately 84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.

Association of a factor H mutation with hemolytic uremic syndrome following a diarrheal illness.

Hemolytic uremic syndrome (HUS) takes 2 forms: diarrheal HUS and nondiarrheal HUS. As its name suggests, diarrheal HUS classically follows an enteric infection. The classic infective organism is the Escherichia coli O157 serotype, although other bacteria, including Shigella species, can produce the verocytotoxin required to cause HUS. The usual clinical course is an episode of bloody diarrhea followed by thrombotic microangiopathy and acute renal failure. Supportive treatment sees recovery of renal function in the vast majority of patients. Most cases occur in children, but all age groups can be affected. Conversely, nondiarrheal HUS may have one of a number of predisposing factors, including drugs, irradiation, and hypertension. It also is well established that mutations in the genes encoding the complement regulator proteins factor H, factor I, and membrane cofactor protein predispose to nondiarrheal HUS. In patients with nondiarrheal HUS, recovery of renal function is much less common. Here, we present a case of HUS after a diarrheal illness in which the patient did not recover renal function in the long term. A novel mutation in exon 23 of the factor H gene was discovered. This is clinically important. If this patient underwent transplantation, he would be expected to have an 80% risk of graft loss at 2 years because of recurrent HUS. We recommend consideration of complement gene mutations in any patient with HUS after a diarrheal episode in which there are unusual features.

Male Sexual Dysfunction and Chronic Kidney Disease.

Male sexual dysfunction is common in chronic kidney disease (CKD), particularly in end-stage renal disease. Historically, this cause of considerable morbidity has been under-reported and under-recognized. The ideal approach to diagnosis and management remains unclear due to a paucity of good quality data, but an understanding of the pathophysiology is necessary in order to address the burden of this important complication of CKD. This paper will review the endocrine dysfunction that occurs in renal disease, particularly the hypothalamic-pituitary-gonadal axis, discuss the causes of erectile dysfunction, infertility, and altered body image and libido in these patients and suggest appropriate treatment interventions.

Human leukocyte antigen antibody-incompatible renal transplantation: excellent medium-term outcomes with negative cytotoxic crossmatch.

BACKGROUND: Human leukocyte antigen (HLA) antibody-incompatible renal transplantation has been increasingly performed since 2000 but with few data on the medium-term outcomes. METHODS: Between 2003 and 2011, 84 patients received renal transplants with a pretreatment donor-specific antibody (DSA) level of more than 500 in a microbead assay. Seventeen patients had positive complement-dependent cytotoxic (CDC) crossmatch (XM), 44 had negative CDC XM and positive flow cytometric XM, and 23 had DSA detectable by microbead only. We also reviewed 28 patients with HLA antibodies but no DSA at transplant. DSAs were removed with plasmapheresis pretransplant, and patients did not routinely receive antithymocyte globulin posttransplant. RESULTS: Mean follow-up posttransplantation was 39.6 (range 2-91) months. Patient survival after the first year was 93.8%. Death-censored graft survival at 1, 3, and 5 years was 97.5%, 94.2%, and 80.4%, respectively, in all DSA+ve patients, worse at 5 years in the CDC+ve than in the CDC-ve/DSA+ve group at 45.6% and 88.6%, respectively (P<0.03). Five-year graft survival in the DSA-ve group was 82.1%. Rejection occurred in 53.1% of DSA+ve patients in the first year compared with 22% in the DSA-ve patients (P<0.003). CONCLUSIONS: HLA antibody-incompatible renal transplantation had a high success rate if the CDC XM was negative. Further work is required to predict which CDC+ve XM grafts will be successful and to treat slowly progressive graft damage because of DSA in the first few years after transplantation.

Is complement factor H a susceptibility factor for IgA nephropathy?

There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of IgA nephropathy. Mesangial C3 deposition is seen in approximately 90% of patients and polymeric IgA has been shown to activate the alternative and lectin pathways. In addition there have been reports of deficiency and mutations in the serum complement regulator factor H (CFH) in association with IgA nephropathy. In this study we have examined the hypothesis that CFH is a susceptibility factor for IgA nephropathy. In 46 IgA nephropathy patients we undertook genotyping of three CFH SNPS (rs3753394, rs3753396 and rs1065489). There was no significant difference in the allele frequency of these 3 SNPs between the patients and normal controls. In the same group of patients we undertook mutation screening of CFH exons 18-23 using direct sequencing and found no abnormalities. All the patients had a normal serum factor H concentration. In this small cohort of IgA nephropathy patients we have not found evidence to support the hypothesis that factor H is a major susceptibility factor for the disease.

A novel non-synonymous polymorphism (p.Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity.

Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations, polymorphisms, and copy number variation in complement factors and inhibitors are associated with aHUS. In this study, we report the first functional non-synonymous polymorphism in the complement inhibitor C4b-binding protein (C4BP) alpha-chain (c.719G>A; p.Arg240His), which is associated with aHUS. This heterozygous change was found in 6/166 aHUS patients compared with 5/542 normal (chi2 = 6.021; p = 0.014), which was replicated in a second cohort of aHUS patients in which we found 5/170 carriers. The polymorphism does not decrease expression efficiency of C4BP. p.Arg240His is equally efficient as the wild type in binding and supporting degradation of C4BP but its ability to bind C3b and act as cofactor to its degradation both in fluid phase and on surfaces is impaired. This observation supports the hypothesis that dysregulation of the alternative pathway of complement is pivotal for aHUS. Three of the patients carry also mutations in membrane cofactor protein and factor H strengthening the hypothesis that individuals may carry multiple susceptibility factors with an additive effect on the risk of developing aHUS.