Treatment of vancomycin overdose using high-efficiency dialysis membranes.

Two children underwent acute hemodialysis using high-efficiency dialysis membranes for vancomycin intoxication (plasma levels 238 microg/ml and 182 microg/ml). During a 3-h treatment, plasma vancomycin removal was on average 60%, with a calculated vancomycin half-life (t(1/2)) of 2 h. This is in contrast to a recent report using charcoal hemoperfusion for vancomycin intoxication (plasma level of 137 microg/ml), which resulted in a 40% relative plasma clearance and a calculated vancomycin t(1/2) of 12.5 h for a 4-h treatment. The choice of optimal modality for clearing a toxin should take into account the availability of equipment, protein or lipid binding of the toxin, and inherent risks of charcoal hemofiltration (large extracorporeal circuit, reversible hypocalcemia, heat loss, reversible coagulation defects) versus risks of high-efficiency hemodialysis (large extracorporeal circuit).

Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose.

A 16-month-old female experienced a massive carbamazepine ingestion resulting in a peak serum carbamazepine concentration of 55 microg/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 microg/ml to 23 microg/ml, and 30 microg/ml to 17 microg/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.

Neoral induction in pediatric renal transplantation.

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.

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.

Beneficial effect of Sandoglobulin upon allograft survival in the pediatric renal transplant recipient.

The use of pooled immunoglobulin (IgG) has been shown to decrease panel reactive antibodies (PRA) in highly sensitized patients awaiting transplantation. IgG infusions have also been found effective for CMV prophylaxis. Analysis of 52 non-highly sensitized children (ages 1-18) who received kidney transplants from May 1991 through January 1995 was undertaken to determine if the immunoglobulin administered for CMV prophylaxis effected allograft survival. Comparison of the "Sando Pos" group (those who received Sandoglobulin for CMV prophylaxis) to the "Sando Neg" group demonstrates a significantly improved allograft survival at 1, 2, and 3 yr post-transplantation. Despite the Sando Pos group being younger [7.3 +/- 1.3 yr vs. 10.7 +/- 0.9 yr; (mean +/- SEM) p < 0.05] allograft survival was 95%, 95% and 88% in the Sando Pos group vs. 88%, 79% and 79% in the Sando Neg group at 1, 2 and 3 yr, respectively (p < 0.01 at all three time points). It is concluded that the potential mechanism of the immunosuppressive benefit of Sandoglobulin is speculative but presumed to be upon inhibition of anti-HLA class I antibodies. We conclude that Sandoglobulin may not only be useful for CMV prophylaxis but also as an adjunct to routine immunosuppression.

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.

The journal club.

As the body of medical literature continues to expand, physicians must develop the necessary skills to keep up with the vast amount of information available. The journal club provides a forum to allow residents to remain current with the literature while also teaching them the methods to evaluate it critically. Those readers wishing to start a journal club or revive an existing one should begin by designating a leader and defining the conference goals. Emphasizing the importance of this conference in the educational process while allowing it to be structured to optimise resident interest and attendance will help to ensure its success. Periodic evaluation of this conference will allow the organisers to assess the concordance of the resident's goals with those of the faculty. Formal evaluation will also provide an objective assessment of the knowledge gained by the house-staff through participation in journal club.

The nonspecificity of focal segmental glomerulosclerosis. The defining characteristics of primary focal glomerulosclerosis, mesangial proliferation, and minimal change.

We performed a detailed clinical review and pathologic analysis of the kidney biopsies of 134 children with nephrotic syndrome or asymptomatic proteinuria. This analysis challenges some of our concepts about the classification of conditions associated with these disorders. The presence of focal segmental sclerotic lesions does not define a unique disorder in childhood. Some children with such lesions will have unaffected glomeruli that are ultrastructurally completely normal. These patients, predominately black adolescents, present either with nephrotic syndrome or asymptomatic proteinuria. We classify this disorder as primary focal segmental glomerulosclerosis (FSGS) and have never found it to recur after transplantation. Most other children with FSGS have 1 of 2 specific glomerulopathies. Those with minimal change have generalized fusion of podocyte foot processes. Those with mesangial proliferation have similar foot process changes combined with mesangial expansion and proliferation and, frequently, thinning of the lamina densa and tubuloreticular inclusions. The presence of segmental lesions in these glomerulopathies appears to be nothing more than a marker of severity. Children with these glomerulopathies are generally younger white children, virtually all of whom have nephrotic syndrome. These disorders have a strong propensity to recur after transplantation. The presence of mesangial labeling of IgM or C1q has no significance in any of these 3 disorders. The classification of disorders associated with nephrotic syndrome or asymptomatic proteinuria must concentrate less on the presence or absence of focal sclerosis and more on the histologic appearance of the rest of the glomeruli.

Long-term cyclosporine therapy for pediatric nephrotic syndrome: a clinical and histologic analysis.

Cyclosporine (CsA) is effective in treating steroid-dependent (SDNS) and steroid-resistant (SRNS) nephrotic syndrome (NS) in children, but because of the potential for chronic nephrotoxicity, its long-term use is controversial. This study reports the results of long-term CsA treatment in 22 children with idiopathic NS. Indications for treatment included SDNS (N = 7) and SRNS (N = 15) children. Pre-CsA histology showed minimal change disease in three patients, immunoglobulin M nephropathy (IgM) in 14 patients, and focal segmental glomerulosclerosis (FSGS) in five patients. All patients had normal initial serum creatinine values. CsA was added to prednisone at 6.3 +/- 0.4 mg/kg per day (mean +/- SE) and adjusted to maintain whole blood trough HPLC levels of 70 to 120 ng/mL for a period of 6 to 53 months (mean, 22 months). Analysis by clinical course revealed that 13 of 15 patients with SRNS (87%) entered remission after a mean duration of CsA treatment of 58 days, whereas seven of seven patients with SDNS were able to be weaned off of daily prednisone therapy. Histologic analysis showed that all five patients with FSGS and 13 of 14 patients with IgM nephropathy either entered remission or were weaned off of daily steroids. Ten of the 22 patients (45%) with complete remission required CsA plus low-dose alternate-day prednisone to maintain remission. Hypertension was seen in eight of 22 patients (36%). No patient had a significant increase in serum creatinine concentration. Renal biopsies performed in 12 patients after 12 to 41 months (mean, 21 months) of CsA therapy showed no nephrotoxicity or disease progression in ten patients. Progression of the previous interstitial fibrosis and tubular atrophy was noted in two patients, suggesting a 17% incidence of CsA nephrotoxicity. This analysis of the long-term risks and benefits of CsA for childhood NS has identified two important findings: (1) combined CsA and alternate-day steroids can be highly effective in inducing complete remission in patients with SRNS and biopsy-proven IgM nephropathy, and (2) long-term use of CsA in moderate doses with closely monitored levels can result in a relatively low incidence of nephrotoxicity.

Dialysis modality comparison of insulin-like growth factor binding protein-3 removal in children: could this have a potential growth benefit?

Centers have reported superior growth in children on peritoneal dialysis (PD) as compared to hemodialysis (HD). Many factors may influence this outcome including diet, adequacy of dialysis, and control of metabolic acidosis. The role of insulin-like growth factor-1 (IGF-1) and its bioactivity in patients with end-stage renal disease (ESRD) have been recently examined. Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to be elevated in ESRD, possibly resulting in inhibition of the bioactivity of IGF-1. Potentially, the removal of IGFBP-3 may improve the bioactivity of IGF-1, with resulting improvement in growth. The molecular weight of IGFBP-3 (30.5 kDa) is in the range of other proteins cleared by PD (e.g., albumin-69 kDa). Therefore, we have analyzed 10 samples of IGFBP-3 in the dialysis effluent of 9 children on peritoneal dialysis, and have found that the mean level +/- SEM was 0.21 +/- 0.03 mg/L, while the 3 analyses of children on standard HD was 0.02 +/- 0.01 mg/L. In addition, the effluent of 2 children on a high-efficiency dialyzer had an IGFBP-3 level of 0.45 +/- 0.25 mg/L. Even though quite preliminary, these data may suggest another reason for improved growth in children on PD and a potential advantage to high-efficiency HD. Further analysis in a larger population of ESRD patients will be needed in order to confirm these preliminary findings.