Steven McTaggart

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations

The publication of the Australasian Creatinine Consensus Working Groups position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m2. Age‐related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m2 is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing. If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD‐EPI formula has been validated as a tool to estimate GFR in some populations of non‐European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

BACKGROUND Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

Immunosuppression by mesenchymal stromal cells: From culture to clinic

Extensive in vitro studies have shown that multipotent mesenchymal stromal cells (MSC) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways. Their ability to be readily isolated from a number of tissues and expanded ex vivo makes them attractive candidates for systemic immunosuppressive therapy. In this article, we will review recent experimental data on the mechanisms by which MSC inhibit the alloproliferative response and the clinical relevance for their potential use in hematopoietic stem cell transplantation, solid organ transplantation, and treatment of autoimmune diseases. While in vitro data consistently demonstrate the immunosuppressive capability of MSC, current studies in animals and humans suggest that MSC are less effective in producing systemic immunosuppression. Further mechanistic studies and randomized controlled trials using standardized cell populations are needed to define the optimal conditions for the use of MSC as immunotherapy.

Clinical spectrum of Denys-Drash and Frasier syndrome

Abstract Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are two related conditions caused by mutations of the Wilms tumor gene, WT1. Both syndromes are characterized by male pseudohermaphroditism, a progressive glomerulopathy, and the development of genitourinary tumors. DDS and FS have previously been distinguished by differences in nephropathy, with DDS patients demonstrating diffuse mesangial sclerosis (DMS) in contrast to focal and segmental glomerulosclerosis (FSGS) in FS patients. The clinicopathological features and genotype analysis of two patients with WT1 mutations are presented in this report. Genotype analysis of the first patient revealed a previously undescribed mutation in exon 8 of the WT1 gene. The second patient presented with a rapidly progressive nephropathy characterized histologically by DMS, but was found to have the genetic mutation seen in FS patients. A summary of all reported patients with the characteristic mutation associated with FS demonstrates the clinical overlap of this syndrome with DDS. This suggests that both these conditions should be considered as part of the spectrum of disease due to WT1 gene mutations rather than as separate diseases. Clinical classification remains important for prognosis, as the underlying renal disease appears to predict the progression of nephropathy independently of the genetic abnormality.

Mesenchymal stem cells: Immunobiology and therapeutic potential in kidney disease

SUMMARY:  Mesenchymal stem cells (MSC) are non‐haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non‐immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non‐mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease.

Evaluation and long-term outcome of pediatric renovascular hypertension

Abstract Seventeen children with renovascular hypertension were managed at the Royal Childrens Hospital, Melbourne, over the 20-year period from 1975 to 1996. The age at presentation ranged from 10 days to 18 years. All children presented with severe hypertension with mean systolic blood pressure 7 standard deviations above age-matched averages and mean diastolic blood pressure 5.5 standard deviations above age-matched averages. Neurofibromatosis was the most common etiology (58% of patients) and there were no cases of Takayasus arteritis. Patients underwent a variety of biochemical and imaging investigations but in all cases renal angiography was necessary for definitive diagnosis and for planning therapy. Ten of the 17 patients had surgical procedures performed. Percutaneous transluminal angioplasty was performed in four patients but led to cure in only one patient following thrombosis of the affected artery producing segmental renal infarction. Other vascular reconstructive procedures, including the use of autologous or synthetic bypass grafts and autotransplantation, produced cure of hypertension in 50% of children with improvement in a further 30%. The long-term outlook for children treated with surgical reconstructive procedures was excellent. One patient underwent surgery for avulsion of an arterial graft following a pubertal growth spurt. No other patient originally cured by surgery has required reoperation with no cases of restenosis at a mean follow-up of 11 years 3 months.

Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Antibacterial honey for the prevention of peritoneal-dialysis-related infections (HONEYPOT): a randomised trial.

BACKGROUND There is a paucity of evidence to guide the best strategy for prevention of peritoneal-dialysis-related infections. Antibacterial honey has shown promise as a novel, cheap, effective, topical prophylactic agent without inducing microbial resistance. We therefore assessed whether daily application of honey at the exit site would increase the time to peritoneal-dialysis-related infections compared with standard exit-site care plus intranasal mupirocin prophylaxis for nasal carriers of Staphylococcus aureus. METHODS In this open-label trial undertaken in 26 centres in Australia and New Zealand, participants undergoing peritoneal dialysis were randomly assigned in a 1:1 ratio with an adaptive allocation algorithm to daily topical exit-site application of antibacterial honey plus standard exit-site care or intranasal mupirocin prophylaxis (only in carriers of nasal S aureus) plus standard exit-site care (control group). The primary endpoint was time to first infection related to peritoneal dialysis (exit-site infection, tunnel infection, or peritonitis). The trial is registered with the Australian New Zealand Clinical Trials Registry, number 12607000537459. FINDINGS Of 371 participants, 186 were assigned to the honey group and 185 to the control group. The median peritoneal-dialysis-related infection-free survival times were not significantly different in the honey (16·0 months [IQR not estimable]) and control groups (17·7 months [not estimable]; unadjusted hazard ratio 1·12, 95% CI 0·83-1·51; p=0·47). In the subgroup analyses, honey increased the risks of both the primary endpoint (1·85, 1·05-3·24; p=0·03) and peritonitis (2·25, 1·16-4·36) in participants with diabetes. The incidences of serious adverse events (298 vs 327, respectively; p=0·1) and deaths (14 vs 18, respectively; p=0·9) were not significantly different in the honey and control groups. 11 (6%) participants in the honey group had local skin reactions. INTERPRETATION The findings of this trial show that honey cannot be recommended routinely for the prevention of peritoneal-dialysis-related infections. FUNDING Baxter Healthcare, Queensland Government, Comvita, and Gambro.

Familial occurrence of idiopathic infantile hypercalcemia

Abstract Idiopathic infantile hypercalcemia (IIH) is a rare cause of hypercalcemia in the 1st year of life and was initially considered part of a spectrum encompassing vitamin D intoxication, Williams syndrome, and idiopathic hypercalcemia. Identification of the gene for Williams syndrome now allows a clear separation of IIH from Williams syndrome. The inheritance and pathogenesis of IIH remains largely unknown, with only sporadic cases reported to date. This report describes a family with two siblings with IIH. The pedigree is consistent with autosomal recessive inheritance, but more complex inheritance is suggested by the occurrence of hypercalciuria in a number of family members. Although one affected patient demonstrated elevated 1,25-dihydroxyvitamin D3 levels, no conclusions regarding the pathogenesis of this condition could be drawn.

Factors influencing growth and final height after renal transplantation

Abstract: Growth retardation occurs commonly in children and adolescents with chronic renal insufficiency. While some children exhibit catch‐up growth following renal transplantation, for many children growth remains sub‐optimal. The aim of the current study was to review the factors influencing growth and final height following renal transplantation. Data from all children who had a renal transplant performed between 1985 and 1998 at the Royal Melbourne and Royal Childrens Hospitals, Melbourne (n = 85), were examined retrospectively. Two children who died in the first year post‐transplant and one patient lost to follow‐up within 6 months of their transplant were excluded. Children with multiple grafts had only growth following their most recent graft analyzed. The mean height standard deviation score (Ht‐SDS) at the time of transplantation was −2.11 (range: −5.05 to 0.27), improving to −1.50 (range: −3.67 to 1.27) at 7 yr post‐transplant. On univariate analysis, the dose of cyclosporin at 6 months and at 1 and 3 yr, and the graft function at 1 yr, had a significant positive correlation with the change in Ht‐SDS (ΔHt‐SDS) at each of those time‐points post‐transplant. At all time‐points there was a strong correlation between pretransplant height and subsequent growth. A sub‐group of children who were 16 yr of age or older at December 1999, and who were considered to have reached their final height, were examined to determine predictors of final height. Multiple regression analysis of clinical and laboratory parameters from the sub‐group of patients ≥ 16 yr of age showed that height at the time of transplant, age at the time of transplant, and final glomerular filtration rate, were significant independent predictors of growth (r2 = 0.82, p = 0.01). In addition, the immunosuppressive regimen at 1, 3, and 5 yr post‐transplant had a significant effect on growth. This study confirms the importance of each of these factors for post‐transplant growth.