Marina Charbit

Acute Neurological Involvement in Diarrhea-Associated Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES Neurologic involvement is the most threatening complication of diarrhea-associated hemolytic uremic syndrome (D+HUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We report a retrospective multicenter series of 52 patients with severe initial neurologic involvement that occurred in the course of D+HUS. RESULTS Verotoxigenic Escherichia coli infection was documented in 24. All except two patients had acute renal failure that required peritoneal dialysis, hemodialysis, or both techniques. A first group of eight patients remained with normal consciousness; five of them had protracted seizures. A second group of 23 patients had stuporous coma; five of these had protracted severe seizures, and 18 had a neurologic defect including pyramidal syndrome, hemiplegia or hemiparesia, and extrapyramidal syndrome. A third group of 21 patients had severe coma. Plasma exchanges were undertaken in 25 patients, 11 of whom were treated within 24 hours after the first neurologic sign; four died, two survived with severe sequelae, and five were alive without neurologic defect. Magnetic resonance imaging (MRI) for 29 patients showed that (1) every structure of the central nervous system was susceptible to involvement; (2) no correlation seemed to exist between special profile of localization on early MRI and the final prognosis; and (3) MRI did not exhibit any focal lesions in three patients. The overall prognosis of the series was marked by the death of nine patients and severe sequelae in 13. CONCLUSIONS Neurologic involvement is associated with a severe renal disease but does not lead systematically to death or severe disability.

Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults.

Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

Long term results of liver-kidney transplantation in children with primary hyperoxaluria.

Abstract. From 1990 to 2000, we performed eight liver-kidney transplants in eight children, aged 1–16 years, with end-stage renal failure (ESRF) due to primary hyperoxaluria (PH1). The duration of dialysis before transplantation ranged from 2 to 42 months (mean 14 months) and was <1 year in four patients. Only the first patient underwent postoperative hemodialysis; in the other five, we chose to induce maximal diuresis from the first hours with intravenous and intragastric hyperhydration (≥3 l/m2 per day). High water intake with nocturnal tube hydration was maintained for 6 months to 5 years, as long as oxaluria exceeded 0.5 mmol/day. A quadruple sequential immunosuppressive regimen was used. Two patients died during liver graft surgery. The other six patients are alive and well, with a mean follow-up of 7.4 years (range 5–11 years). Patient and graft survival is 75% at 5 years. At latest follow-up, liver tests were normal in all six patients; creatinine clearance ranged from 55 to 95 ml/min per 1.73 m2 (mean=74). Oxaluria was lower than 0.4 mmol/day in all patients (mean=0.22). The six patients underwent 15 renal biopsies, 1–11 years after transplantation. Chronic transplant nephropathy was present in four patients and mild cyclosporin nephrotoxicity in another. No oxalate crystals were seen and repeat ultrasonography has been consistently normal in all patients. The three patients with bone oxalosis showed progressive complete healing of bone lesions. All six children or adolescents now live a normal life. From this series, we conclude that early combined liver-kidney transplantation is the treatment of choice for children with ESRF due to primary hyperoxaluria.

Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS)

UNLABELLED Introduction. Recurrence of nephrotic-range proteinuria in patients with idiopathic nephrotic syndrome (INS) and focal and segmental glomerulosclerosis (FSGS) on native kidneys is associated with poor graft survival. Identification of risk factors for recurrence is therefore an important issue. In 2004, Columbia University introduced a histological classification of FSGS that identifies five mutually exclusive variants. In non-transplant patients, the Columbia classification appears to predict the outcome and response to treatment better than clinical characteristics alone. However, the predictive value of this classification to assess the risk of recurrence after transplantation has not been addressed. METHODS We retrospectively studied 77 patients with INS and FSGS on native kidneys who underwent renal transplantation. Of these, 42 recipients experienced recurrence of nephrotic range proteinuria. RESULTS At time of recurrence, minimal-change disease (MCD) was the main histological feature. On serial biopsies, the incidence of MCD decreased over time, while the incidence of FSGS variants increased. The variant type observed in the native kidneys was not predictive of either recurrence or type of FSGS seen on the allograft. Patients with complete and sustained remission did not developed FSGS. CONCLUSION In conclusion, the Columbia classification is of no help in predicting recurrence after renal transplantation or histological lesions in the case of recurrence of proteinuria.

Pulse Cyclophosphamide Therapy and Clinical Remission in Atypical Hemolytic Uremic Syndrome With Anti–Complement Factor H Autoantibodies

We report 3 children with atypical hemolytic uremic syndrome associated with anti-complement factor H (CFH) autoantibodies who presented with sustained remission with low antibody titers and normal kidney function after plasma exchanges (PEs) and cyclophosphamide pulses. The 3 children initially presented with acute vomiting, fatigue, gross hematuria, hypertension, hemolytic anemia, thrombocytopenia, nephrotic syndrome, and acute kidney injury. C3 levels were normal in patients 1 and 3 and low in patient 2 (0.376 mg/mL [0.376 g/L]). CFH antibody titers were increased (15,000 to > 32,000 arbitrary units [AU]). Patient 1, an 11-year-old boy, was treated with 12 PEs, leading to a decrease in CFH antibody titer (to 800 AU). A first relapse 1 month later was treated with 6 PEs and 4 rituximab infusions. A second relapse 3 months later required 5 PEs, and the patient received oral steroids (0.5 mg/d/kg body weight) and 5 cyclophosphamide pulses (1 g/1.73 m(2)), leading to sustained remission with normal kidney function (estimated glomerular filtration rate [eGFR], 120 mL/min/1.73 m(2) [2.0 mL/s/1.73 m(2)]) and a stable decrease in CFH antibody titer (to 2,000 AU) 3 years later. Patient 2, a 5-year-old boy, required dialysis therapy for 2 weeks. He received 3 plasma infusions without remission. Six PEs associated with 2 cyclophosphamide pulses (0.5 g/1.73 m(2)) and steroids (1 mg/d/kg body weight) led to rapid remission, with eGFR of 107 mL/min/1.73 m(2) [1.78 mL/s/1.73 m(2)] and a prolonged decrease in CFH antibody titer after 15 months (1,300 AU). Patient 3, a 16-month-old boy, was treated with oral steroids (1 mg/d/kg body weight), 2 PEs, and 2 cyclophosphamide pulses (0.5 g/1.73 m(2)), resulting in a stable decrease in CFH antibody titer to 276 AU. Kidney function quickly normalized (eGFR, 110 mL/min/1.73 m(2) [1.83 mL/s/1.73 m(2)]) and has remained normal after 14 months. All 3 patients show a homozygous deletion mutation of the CFHR1 and CFHR3 genes. Cyclophosphamide pulses with PE may lead to a prolonged decrease in CFH antibody titers and a favorable outcome of atypical hemolytic uremic syndrome and kidney function.

In Vivo Confocal Microscopy and Anterior Segment Optical Coherence Tomography Analysis of the Cornea in Nephropathic Cystinosis

OBJECTIVE To analyze the corneas of patients with nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT). DESIGN Prospective case series. PARTICIPANTS Sixteen eyes of 8 patients with nephropathic cystinosis aged 8 to 21 years. METHODS The ophthalmologic evaluation included best-corrected visual acuity, evaluation of photophobia (0-4), slit-lamp biomicroscopy analysis, intraocular pressure measurement, evaluation of crystal density using a slit-lamp-based scoring of the cornea, as well as AS-OCT and IVCM analysis. MAIN OUTCOME MEASURES The depth of crystal deposition (DCD) in the central cornea and the central cornea thickness (CCT) were assessed using AS-OCT and IVCM. The IVCM images were evaluated for crystal density in each corneal layer and an IVCM score was calculated for each eye. RESULTS All eyes had corneal crystal deposits, with a mean slit-lamp photography score of 2.90+/-0.13 (range, 2.75-3.00). Using AS-OCT, corneal crystals were observed in all eyes. These crystals appeared as hyperreflective punctuate deposits, predominantly observed within the anterior stroma. Measured with AS-OCT, the mean depth of DCD in the central cornea was 291.40+/-81.42 microm (range, 200-531 microm); the mean CCT was 543.47+/-29.62 microm. Using IVCM, the crystals appeared as spindle, needle-shaped, and fusiform hyperreflective bodies measuring from 1 to 175 microm in length and 1 to 30 microm in thickness. Except for the endothelium, randomly oriented crystals were observed in all corneal layers, with the greatest density observed within the anterior stroma. Measured with IVCM, the mean DCD was 426.07+/-88.19 microm (range, 284-531 microm); the mean CCT was 531.87+/-34.77 microm. There was no significant difference between the CCT measurements obtained with IVCM and with AS-OCT (mean difference, 11.31 microm; P = 0.07). Nevertheless, the DCD was significantly higher with IVCM than with AS-OCT (mean difference, 126.25 microm; P<0.0001). CONCLUSIONS In patients with nephropathic cystinosis, IVCM could precisely quantify the density of crystals within the central cornea. Anterior segment OCT and IVCM should be used in further studies evaluating crystal deposition in patients with nephropathic cystinosis. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any materials discussed in this article.

De Novo Malignancy After Solid Organ Transplantation in Children

The aim of this study was to assess the prevalence of de novo malignancy after solid organ transplantation in childhood. A retrospective questionnaire-based survey was sent to 9 referral centers for pediatric organ transplantation in France. Among 1326 children who underwent solid organ transplantation since 1996, 80 (6%) presented with de novo malignancy posttransplantation during childhood: posttransplant lymphoproliferative disease was the most common (5% of pediatric recipients) comprising 80% of all tumors, with a disproportionately high prevalence among combined liver and small bowel recipients (18%). Various solid tumors were observed mainly among kidney recipients. No skin cancer was reported.

UROLOGICAL COMPLICATIONS AFTER RENAL TRANSPLANTATION USING URETEROURETERAL ANASTOMOSIS IN CHILDREN

PURPOSE Ureterovesical reimplantation is most often performed for renal transplantation in children. We reviewed our experience to evaluate the safety and efficacy of ureteroureteral reimplantation in pediatric renal transplantation. MATERIALS AND METHODS We retrospectively evaluated the charts of 92 boys and 72 girls who underwent a total of 166 ureteroureteral anastomoses for renal transplantation from January 1990 to December 1999. Spatulated end-to-end anastomosis was performed between recipient and graft ureters without stenting and with a bladder catheter for at least 10 days. RESULTS Mean patient age at transplantation was 11.2 years (range 1 to 21.5). There were 22 living related donor and 144 cadaveric grafts. Urological anomalies and nephropathy were the cause of end stage renal disease in 146 and 20 patients, respectively. Urological complications were noted in 14 of the 166 transplantations (8.4%) in 10 boys and 4 girls, including 12 initial and 2 repeat grafts from 2 living related and 12 cadaveric donors. Five of these patients had undergone previous urological surgery. The 2 children (1.2%) with acute ureteral obstruction underwent repeat intervention after stent failure. Anastomotic leakage in 7 cases (4.2%) was treated conservatively in 1 and with a Double-J stent (Medical Engineering Corp., New York, New York) only required in 3. Reoperation was required in 3 cases. One patient (0.6%) with late ureteral stenosis underwent repeat anastomosis, 1 (0.6%) required reimplantation for recurrent pyelonephritis due to vesicoureteral reflux in the graft, 1 (0.6%) with a valve bladder required bladder augmentation and ureteral reimplantation, and 1 (0.6%) with lymphocele and 1 (0.6%) with lithiasis were successfully treated conservatively. Complications were associated with acute rejection in 6 cases. Mean followup without graft loss in patients who presented with versus without complications was 58.3 months (range 1 to 112) versus 75 (range 1 to 118). In the former patients with a mean age of 16 years 9 months versus those without urological complications mean serum creatinine was 116 and 108 mol./l., respectively. Two grafts were lost in patients with urological complications, including 1 who died of pulmonary embolism and 1 with refractory chronic rejection. Seven patients were lost to followup after 54 months (range 12 to 113) of adequate graft function. CONCLUSIONS Ureteroureteral anastomosis is a safe and effective technique for pediatric renal transplantation with a low complication rate, which may be due to better vascularization of the shorter ureteral end of the graft. Our results should encourage the use of this technique in pediatric renal transplantation. Efforts to preserve the recipient ureters should be made at nephrectomy.

Complement Factor H Deficiency and Posttransplantation Glomerulonephritis With Isolated C3 Deposits

We report the first cases of atypical hemolytic and uremic syndrome associated with complement factor H (CFH) deficiency in native kidneys and glomerulonephritis with isolated C3 deposits after kidney transplantation. Two boys developed atypical hemolytic and uremic syndrome at 16 and 11 months of age, associated with low C3 and CFH levels. Both rapidly progressed to end-stage renal failure and received a kidney transplant. Patient 1 had combined CFH and complement factor I (CFI) heterozygous mutations and a membrane cofactor protein (gene symbol, CD46) gene polymorphism. Five years posttransplantation, an allograft biopsy specimen showed numerous mesangial and extramembranous C3 deposits, although the patient had no biological sign of glomerulopathy. Nine years after transplantation, he was well with stable kidney function. Patient 2, who had a homozygous CFH mutation, developed glomerulonephritis with isolated C3 deposits 5 months after kidney transplantation while he was treated for early recurrence of hemolytic anemia. Four years later, the second kidney transplant biopsy specimen showed recurrence of thrombotic microangiopathy. Six years posttransplantation, kidney function was stable and complete blood cell count was normal with regular plasma therapy. These observations suggest that constitutional dysregulation of the alternative pathway is associated with a wide spectrum of kidney diseases, and glomerulonephritis with isolated C3 deposits and thrombotic microangiopathy may be different expressions of the same condition. Several factors could influence the disease, such as degree of CFH haploinsufficiency and other complement alternative pathway regulator abnormalities, such as a membrane cofactor protein polymorphism.

Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and vitamin D-fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median eGFR 51 ml/min per 1.73 m(2)), serum 25-hydroxyvitamin D (25(OH)D), FGF-23, and Klotho levels were measured at baseline and after a median 8 months on ACEi. Children with lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum vitamin D-binding protein were not associated, but 25(OH)D ≤50 nmol/L associated with higher diastolic BP (P=0.004). ACEi therapy also associated with increased Klotho levels (P<0.001). The annualized loss of eGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survival was 75% in patients with baseline 25(OH)D ≥50 nmol/L and 50% in those with lower 25(OH)D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of eGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D ≥50 nmol/L was associated with greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy.