Antonia H. M. Bouts

Meningococcal Sepsis Complicating Eculizumab Treatment Despite Prior Vaccination

Recently, the monoclonal antibody against complementfactor C5, eculizumab, was successfully applied in the treatment of recurrent atypical hemolytic-uremic syndrome (aHUS) in renal transplant recipients (RTR) (1). Guidelines for its use include meningococcal vaccination prior to treatment. Late complement–pathway– component deficiencies predispose to meningococcal infections by the absence of meningococcal lysis via classical and alternative pathways (2). Consequently, protection against meningococcal disease by antibody-mediated killing becomes essential. However, vaccination of patients using immunosuppressive drugs may be ineffective (3,4). Different immunosuppressive regimens vary in their effects on humoral responses after vaccination. Previously, we demonstrated that RTR treated with prednisolone and everolimus mount adequate humoral vaccination responses, measured by ELISA, against immunocyanin, tetanus-toxoid (TT) and pneumococcal polysaccharide (PPS). In contrast, treatment with mycophenolic mofetil (MMF) and prednisolone completely disturbed vaccination responses against these same antigens (3). Although immune responses after vaccination are generally used as markers of efficacy of vaccination, they are not synonymous with protection. Furthermore, in immunocompromised patients vaccination-induced responses may wane rapidly. Protection provided by vaccines after renal transplantation may be limited in quality and/or duration. This is illustrated by the following case.

Growth in Very Young Children Undergoing Chronic Peritoneal Dialysis

Very young children with chronic kidney disease often have difficulty maintaining adequate nutrition, which contributes to the high prevalence of short stature in this population. Characteristics of the dialysis prescription and supplemental feeding via a nasogastric (NG) tube or gastrostomy may improve growth, but this is not well understood. Here, we analyzed data from 153 children in 18 countries who commenced chronic peritoneal dialysis at <24 months of age. From diagnosis to last observation, 57 patients were fed on demand, 54 by NG tube, and 10 by gastrostomy; 26 switched from NG to gastrostomy; and 6 returned from NG to demand feeding. North American and European centers accounted for nearly all feeding by gastrostomy. Standardized body mass index (BMI) uniformly decreased during periods of demand feeding and increased during NG and gastrostomy feeding. Changes in BMI demonstrated significant regional variation: 26% of North American children were obese and 50% of Turkish children were malnourished at last observation (P < 0.005). Body length decreased sharply during the first 6 to 12 months of life and then tended to stabilize. Time fed by gastrostomy significantly associated with higher lengths over time (P < 0.001), but adjustment for baseline length attenuated this effect. In addition, the use of biocompatible peritoneal dialysate and administration of growth hormone independently associated with improved length, even after adjusting for regional factors. In summary, growth and nutritional status vary regionally in very young children treated with chronic peritoneal dialysis. The use of gastrostomy feeding, biocompatible dialysis fluid, and growth hormone therapy associate with improved linear growth.

Eculizumab in Pediatric Dense Deposit Disease

BACKGROUND AND OBJECTIVES Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease affecting mostly children. Treatment options are limited. Debate exists whether eculizumab, a monoclonal antibody against complement factor C5, is effective in DDD. Reported data are scarce, especially in children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The authors analyzed clinical and histologic data of five pediatric patients with a native kidney biopsy diagnosis of DDD. Patients received eculizumab as therapy of last resort for severe nephritic or nephrotic syndrome with alternative pathway complement activation; this therapy was given only when the patients had not or only marginally responded to immunosuppressive therapy. Outcome measures were kidney function, proteinuria, and urine analysis. RESULTS In all, seven disease episodes were treated with eculizumab (six episodes of severe nephritic syndrome [two of which required dialysis] and one nephrotic syndrome episode). Median age at treatment start was 8.4 (range, 5.9-13) years. For three treatment episodes, eculizumab was the sole immunosuppressive treatment. In all patients, both proteinuria and renal function improved significantly within 12 weeks of treatment (median urinary protein-to-creatinine ratio of 8.5 [range, 2.2-17] versus 1.1 [range, 0.2-2.0] g/g, P<0.005, and eGFR of 58 [range, 17-114] versus 77 [range, 50-129] ml/min per 1.73 m(2), P<0.01). A striking finding was the disappearance of leukocyturia within 1 week after the first eculizumab dose in all five episodes with leukocyturia at treatment initiation. CONCLUSIONS In this case series of pediatric patients with DDD, eculizumab treatment was associated with reduction in proteinuria and increase in eGFR. Leukocyturia resolved within 1 week of initiation of eculizumab treatment. These results underscore the need for a randomized trial of eculizumab in DDD.

Transition to the adult nephrologist does not induce acute renal transplant rejection

BACKGROUND In spite of the overall increased renal graft survival, long-term allograft survival has remained least successful in adolescent recipients. A major change in their care is the transition from the paediatric to the adult nephrology unit. METHODS To analyse the effect of transition on the acute rejection frequency and graft survival, we performed a historical cohort study in all patients transplanted at the paediatric unit between 1980 and 2004. Data were obtained by reviewing medical charts in two of the four Dutch pediatric renal transplantation centers from time of transplantation until 3 years after transition. For analysis, we used a Cox proportional hazards model. RESULTS The cohort consisted of 162 patients: 133 native Dutch and 29 immigrant patients. Transition occurred at a mean age of 18 years (range 14-22). At transition, 72% had a functioning allograft. Acute rejections occurred in 92/162 patients before (median follow-up 4.8 years, range 0.2-12.8) and in 15/116 patients after transition (median follow-up 3.0 years, range 1.6-3.0). Most rejections (62%) occurred within the first year after transplantation. The relative risk of acute rejections after transition in comparison to before transition was 0.10 [95% confidence interval (95% CI) 0.04-0.28] in Dutch patients and 0.69 (95% CI 0.33-1.40) in immigrant patients. In the 3 years before transition, 28/154 patients (18%) experienced graft failure compared to 19/116 patients (16%) in the 3 years after transition. CONCLUSIONS The risk for acute rejection decreases after transition to the adult unit. There is less risk reduction in immigrant patients. Nephrologists should pay special attention to these patients.

IgG and complement receptor expression in children treated by peritoneal dialysis

Children treated by peritoneal dialysis (PD) are at increased risk of infections. IgG receptors (FcγRs) and complement receptors (CRs) on white blood cells (WBCs) are important for the phagocytic process. We have investigated FcγR and CR expression on monocytes, macrophages and neutrophils in blood and in peritoneal dialysis effluent (PDE) of 39 PD children. WBCs were isolated from blood and PDE, labelled with FITC-conjugated CD16 (FcγRIII), CD32 (FcγRII), CD64 (FcγRI), CD11b (CR3) and CD35 (CR1) monoclonal antibodies, and analysed by flow cytometry. Peritoneal cells had lower percentages of FcγR-positive or CR-positive cells than blood. On the other hand, the receptor number per cell [mean fluorescence intensity (MFI)] was higher on peritoneal macrophages and neutrophils than blood, except for CD16. The FcγR and CR expression in blood and dialysate did not change significantly during the first year of PD treatment. During a peritonitis episode the MFI of all receptors in blood increased only on monocytes, with the exception of CD32. The percentages of FcγR-positive and CR-positive macrophages and neutrophils in the PDE increased, whereas the MFI did not increase consistently. Peritoneal cells of PD children showed a lower percentage of FcγR-positive and CR-positive neutrophils and macrophages, combined with an increased MFI, indicating a state of activation. Blood and peritoneal cells are capable of up-regulating the receptor expression during peritonitis but probably not to a maximum level.

Recovery of graft function in pediatric kidney transplantation is not affected by delayed introduction of cyclosporine.

Background. Delayed graft function and acute rejections adversely affect the long-term survival of kidney transplantation. To decrease the incidences of these phenomena, we changed the initial immunosuppressive protocol in pediatric kidney transplantation in the Netherlands. Methods. We compared a cohort (n=123) treated with basiliximab and delayed onset cyclosporine (CsA) with the preceding cohort (n=110) in which CsA was started already preoperatively. Both cohorts were treated with mycophenolate mofetil and corticosteroids as well. All consecutive transplantations were included. Results. The incidence of delayed graft function did not significantly differ between the cohorts (10% and 13%, in basiliximab and control group). Significantly fewer patients in the basiliximab group had acute rejection episodes (20% vs. 36% in control group, P=0.007). The mean estimated glomerular filtration rate at 1 year and graft survival at 2 years posttransplant did not differ between groups (62 vs. 64 mL/min 1.73 m2, and 89% vs. 92%, respectively). Conclusion. Postponed onset of CsA in triple immunosuppressive therapy (corticosteroids, CsA, and mycophenolate mofetil) with addition of basiliximab did not reduce the incidence of delayed graft function in pediatric kidney transplantation. Yet, fewer acute rejections were noted. Long-term favorable effects could not be detected in this study.

Nephrology ImageRenal infarction in a child with Henoch–Schönlein purpura

A 5-year-old boy with no relevant medical history presented with severe abdominal pain and purpura on the lower extremities, consistent with the diagnosis of Henoch–Schonlein purpura. Kidney function, blood pressure, and urinary parameters were normal. Repeated ultrasound investigations showed no evidence of intussusception and no renal abnormalities. The severity of the abdominal symptoms led to perform a digital subtraction angiography a week later, to rule out a vasculitis of medium- or large-sized arteries. No artery lesion was seen, but an infarction was present in the lower pole of the left kidney (Figure 1). At that moment, platelet count was decreasing (464 × 109/l at admission; 382 × 109/l on the day of angiography) and inflammatory parameters were high (C-reactive protein 93.9 mg/l; leukocytes 19.1 × 109/l). There was no evidence of volume depletion and no polycythemia. Blood pressure was normal. After 2 days, microhematuria was detected (>20 erythrocytes/high-power field). Genetic risk factors for thromboembolism, including protein C and protein S deficiency, activated protein C cell resistance and factor II mutation, were excluded. Lupus anticoagulant antibodies were negative. A diagnosis of Henoch–Schonlein purpura was established by immunoglobulin-A staining on skin biopsy, and was subsequently confirmed on renal biopsy, performed because of the onset of moderate transient proteinuria (1.48 g/l).

Hemolytic Uremic Syndrome in Post-Infectious Glomerulonephritis: Possible Pathophysiological Mechanisms

Malignant hypertension is able to induce glomerular Thrombotic Microangiopathy (TMA) and Hemolytic Uremic Syndrome (HUS) in the absence of Glomerulonephritis (GN). It is therefore commonly admitted that hypertension is the only cause of Glomerular Endothelial Cells (GEC) damage leading to TMA and HUS observed in GN. However, recent literature on TMA in IgA nephropathy calls this hypothesis into question. It is also questionable why so few cases of HUS are reported in association with Post-Infectious GN (PIGN) for which more than 50% of cases necessitate anti-hypertension treatment, we report the case of a 10 years old girl presenting with an extensive cutaneous streptococcal infection, hematuria, nephrotic syndrome, hypertension (146/106) and HUS needing dialysis. The kidney biopsy revealed a severe exudative GN, 30% of crescentic glomeruli and TMA. Immunofluorescence and electron microscopy suggested intense complement activation at the basal level of GEC and podocytes. Genotyping of complement factors was normal. A rapid recovery of a normal renal function was observed after intensive Plasma Exchange (PE) therapy. We speculate that a high amount of group A streptococcal (GAS) toxins produced in extensive cutaneous lesions might have facilitated TMA initiation by: 1/ a direct damage of endothelial cells; 2/ an intense complement activation induced by the binding of GAS toxins to the complement factor H (CFH), leading to GEC and podocytes’ lesions. The favorable effect of PE can be explained by removal of GAS toxins and inactivated CFH on one side and by supply of free CFH on another side. Multicentre studies should be initiated in order to evaluate the frequency and the pathophysiology of TMA and HUS in PIGN.

Clear peritoneal effluent in a child on CCPD with a phlegmonous appendicitis

Peritonitis as a result of a perorated appendicitis is a rare but life-threatening situation in a patient on peritoneal dialysis (PD). As far as we are aware, the combination of clear dialysate effluent and phlegmonous appendicitis in a patient on PD has not previously been described. We report a 16-year-old girl with acute onset of abdominal pain and vomiting who turned out to have phlegmonous appendicitis, despite having a clear dialysate effluent with normal cell count, and who subsequently developed E coli peritonitis after surgery.