Rudolph P. Valentini

International Pediatric Fistula First Initiative: A Call to Action

The Centers for Medicare & Medicaid Services and the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative have emphasized the need for increased arteriovenous fistula (AVF) use and decreased central venous catheter use. A Fistula First National Vascular Access Improvement Initiative was undertaken to achieve these targets in adult patients through change concepts and process improvement. Despite increasing numbers of children receiving hemodialysis in the United States, AVF use rates decreased during the past 10 years. Studies of children dialyzed using AVFs showed superior dialysis delivery, improved access survival, and markedly lower infection rates. The purpose of this article is to alert nephrologists to consider a fistula first in long-term pediatric hemodialysis patients. In this article, we describe the status of vascular access in the United States and worldwide in children, the importance of AVF creation, and the need for surgical expertise, including microsurgery, in this population. Additionally, we introduce the International Pediatric Fistula First Initiative, a multidisciplinary team consisting of pediatric nephrologists, vascular access surgeons, and interventional radiologists aiming to increase awareness, offer educational tools, and implement the fistula first initiative in children.

Membranous nephropathy in children: clinical presentation and therapeutic approach

The approach to the pediatric patient with membranous nephropathy (MN) can be challenging to the practitioner. The clinical presentation of the child with this histologic entity usually involves some degree of proteinuria ranging from persistent, subnephrotic-ranged proteinuria to overt nephrotic syndrome. Patients often have accompanying microscopic hematuria and may have azotemia or mild hypertension. Children presenting with nephrotic syndrome are often steroid resistant; as such, their biopsy for steroid-resistant nephrotic syndrome results in the diagnosis of MN. The practitioner treating MN in the pediatric patient must weigh the risks of immunosuppressive therapy against the benefits. In general, the child with subnephrotic proteinuria and normal renal function can likely be treated conservatively with angiotensin blockade (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) without the need for immunosuppressive therapy. Those with nephrotic syndrome are usually treated with steroids initially and often followed by alkylating agents (cyclophosphamide or chlorambucil). Calcineurin inhibitors may also be useful, but the relapse rate after their discontinuation remains high. The absence of controlled studies in children with MN makes treatment recommendations difficult, but until they are available, using the patient’s clinical presentation and risk of disease progression appears to be the most prudent approach.

Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients

Abstract:  The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post‐transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow‐up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.

Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose.

Abstract A 16-month-old female experienced a massive carbamazepine ingestion resulting in a peak serum carbamazepine concentration of 55 µg/ml. Clinical manifestations included generalized seizures, coma, shock, and gastrointestinal hypomotility. Gut decontamination was attempted using multiple-dose activated charcoal and cathartics. Because of the severity of illness, charcoal hemoperfusion was initiated. The patient underwent three sessions of charcoal hemoperfusion, each utilizing a fresh cartridge, with one session immediately following the other. Serum carbamazepine and carbamazepine-10,11-epoxide concentrations decreased from 54 µg/ml to 23 µg/ml, and 30 µg/ml to 17 µg/ml, respectively, during charcoal hemoperfusion. There were no complications. The patient recovered completely and was discharged on the 4th hospital day. Charcoal hemoperfusion should be considered for life-threatening carbamazepine intoxication, especially when drug-induced gastrointestinal hypomotility prevents elimination via the gut.

FAT1 mutations cause a glomerulotubular nephropathy

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Post-translational Processing and Renal Expression of Mouse Indian Hedgehog

The full-length mouse Indian hedgehog (Ihh) cDNA was cloned from an embryonic 17.5-day kidney library and was used to study the post-translational processing of the peptide and temporal and spatial expression of the transcript. Sequence analysis predicted two putative translation initiation sites. Ihh translation was initiated at both initiation sites when expressed in an in vitro transcription/translation system. Expression of an Ihh mutant demonstrated that the internal translation initiation site was sufficient to produce the mature forms of Ihh. Ihh post-translational processing proceeded in a fashion similar to Sonic and Drosophila hedgehog; the unprocessed form underwent signal peptide cleavage as well as internal proteolytic processing to form a 19-kDa amino-terminal peptide and a 26-kDa carboxyl-terminal peptide. This processing required His313 present in a conserved serine protease motif. Ihh transcript was detected by in situ RNA hybridization as early as 10 days postcoitum (dpc) in developing gut, as early as 14.5 dpc in the cartilage primordium, and in the developing urogenital sinus. In semiquantitative reverse transcription-polymerase chain reaction experiments, Indian hedgehog transcript was first detected in the mouse metanephros at 14.5 dpc; transcript abundance increased with gestational age, becoming maximal in adulthood. In adult kidney, Ihh transcript was detected only in the proximal convoluted tubule and proximal straight tubule.

Ceftriaxone induced hemolysis complicated by acute renal failure

Over the last decade, second and third generation cephalosporins have been the most common drugs causing hemolytic anemia (HA). Of these cases, 20% have been attributed to ceftriaxone. The clinical presentation of ceftriaxone‐induced HA is usually abrupt with sudden onset of pallor, tachypnea, cardio‐respiratory arrest and shock. Acute renal failure (ARF) has been reported in 41% of such cases with a high fatality rate. We report a pediatric patient with ARF complicating ceftriaxone‐induced HA who survived. Ceftriaxone is a commonly used drug, and early recognition of HA and institution of supportive care, including dialysis is likely to improve the outcome. Pediatr Blood Cancer 2008;50:139–142.

Prediction of Primary vs Secondary Hypertension in Children

J Clin Hypertens (Greenwich). 2012; 14:316–321. ©2012 Wiley Periodicals, Inc.

Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: A single-center experience☆☆☆★

Vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA) can be accompanied by a focal and necrotizing glomerulonephritis that carries a high morbidity. As many as 60% of reported children with ANCA-associated glomerulonephritis progress to end-stage renal disease. Seven children (13.0+/-0.89 years, mean age +/- SEM) with both a focal and necrotizing glomerulonephritis and a positive ANCA titer are described. Presenting symptoms were constitutional (100%) and sinopulmonary (71%); additional renal features included microscopic hematuria (100%), proteinuria (71%), and renal insufficiency (71%). Acute therapy (0 to 2 weeks from diagnosis) included intravenous corticosteroids and intravenous cyclophosphamide for all patients. Induction therapy (2 weeks to 6 months from diagnosis) consisted of cyclophosphamide (100%) and daily corticosteroids (86%) for a minimum of 6 months. Maintenance therapy that followed 6 months of induction therapy consisted of alternate day steroids (100%) combined with either oral azathioprine (50%) or oral cyclophosphamide (50%). Long-term follow-up for 48+/-12 months in all seven patients revealed that only one (14%) patient had end-stage renal disease, whereas the remaining patients had microscopic hematuria (100%), proteinuria (50%), and renal insufficiency (33%). These findings suggest that early recognition and aggressive treatment of children with ANCA-associated glomerulonephritis and vasculitis may result in an improved renal outcome compared with previous reports.

Neoral induction in pediatric renal transplantation

Abstract.Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4–6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 ± 1.1 months’ followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly.