Richard S. Trompeter

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

Abstract This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac (n=103) or CyA microemulsion (n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baselinecharacteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute re-jection (36.9%) compared with CyA therapy (59.1%) (P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group (P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62±20 ml/min per 1.73 m2, n=84) than in the CyA group (56±21 ml/min per 1.73 m2, n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences (P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.

Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors

Abstract. Autosomal recessive polycystic kidney disease causes renal and hepatic dysfunction in childhood. We describe the clinical outcome of 52 children with this diagnosis born between 1950 and 1993. Currently 23 are alive, 24 dead and 5 have been lost to follow-up; 1 has been dialysed and 7 transplanted. Life-table analysis of the patients surviving the 1st month of life revealed an actuarial renal survival of 86% at 1 year and 67% at 15 years. The probability of requiring anti-hypertensive treatment was 39% at 1 year and 60% at 15 years of age. Bleeding from gastro-oesophageal varices occurred in 8 patients at a mean age of 12.5 years, and was preceded by haematological evidence of hypersplenism in 6 of them. The study indicates a relatively good prognosis for patients with this condition who survive the neonatal period and emphasises the importance of early detection and appropriate management of systemic and portal hypertension.

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

Long-term outcome of peritoneal dialysis in infants

Debate continues concerning the treatment of infants with end-stage renal disease. We evaluated progress and outcome of 20 infants with a mean age of 0.34 year (range, 0.02-1 year) in a long-term peritoneal dialysis program at a single center. Mean weight at the start of dialysis was 4.8 kg (range, 1.7-11.4 kg), and the duration of dialysis was 17.3 months (range, 1-59 months). Eleven infants received renal transplants, 4 were switched to hemodialysis and then received transplants, 4 died, and 1 continues to receive peritoneal dialysis. There was significant co-morbidity in 6 infants who died or required hemodialysis. Catheter interventions were frequent, with 12 infants requiring at least one replacement. There were 1.1 episodes of peritonitis per patient-year; 70% of infants had 0 to 1 episode. Mean weight standard deviation score (SDS) was -1.6 at the start, -0.3 at 1 year (P =.0008), and 0.3 at 2 years (P =.0008). Height SDSs were -1.8 at the start, -1.1 at 1 year (P =.046), and -0. 8 at 2 years (P =.06). Head circumference SDSs were -1.9 at the start, -1.3 at 6 months (P =.003), and -0.9 at 1 year (P =.015). Fourteen of 16 survivors are achieving normal developmental milestones or attend mainstream school. Peritoneal dialysis in infancy is a demanding treatment, but outcome for growth, development, and transplantation justifies this intensive approach. When parents are counseled, the importance of non-renal co-morbidity must be emphasized.

Long-term enteral nutrition in infants and young children with chronic renal failure

Abstract An inadequate nutritional intake is common in infants and young children with chronic and end-stage renal failure (CRF/ESRF), causing poor weight gain and growth retardation. In a programme of enteral feeding (EF), growth, nutritional intake and outcome for oral feeding were evaluated in 35 children with CRF/ESRF, mean (range) age 1.6 (0–4.9) years at start of EF for 30 (12–60) months. Twenty-nine had a glomerular filtration rate of 12.1 (6–26) ml/min per 1.73 m2 and 6 were on peritoneal dialysis. Mean (SD) weight standard deviation scores (SDSs) in the 0 to 2-year age group (n=26) were –3.3 (1.0) 6 months before EF, –3.1 (1.3) at the start, –1.7 (1.4) at 1 year, (P=0.0003) and –1.4 (1.8) at 2 years, (P=0.0008). Height SDSs were –2.9 (0.7), –2.9 (1.2), –2.2 (1.2) (P=0.008) and –2.1 (1.3) (P=0.004). Weight SDSs in the 2 to 5-year age group (n=9) were –2.3 (1.2), –2.0 (1.1), –1.1 (1.3) (P=0.002) and –0.9 (1.0) (P=0.04). Height SDSs were –2.8 (0.6), –2.3 (0.7), –2.0 (0.7) and –2.0 (0.8). There was no change in energy intake as a percentage of the estimated average requirement, nor was this exceeded. Percentage energy from the EF in the 0 to 2 year age group remained unchanged despite an absolute increase in energy intake with age. Twenty-one have had renal transplants, of whom 86% eat and drink normally. Long-term EF prevents or reverses weight loss and growth retardation in children with CRF/ESRF, with the achievement of significant catch-up growth if started before age 2 years.

Gastrostomy feeding in infants and children on peritoneal dialysis

The majority of infants and young children on peritoneal dialysis (PD) require enteral feeding to achieve their growth potential. We report our experience of gastrostomy feeding in 29 children on PD over 11 years. Fifteen children, median age 3.9 (0.5–13.3) years had a percutaneous gastrostomy (PEG) or Nissen fundoplication and gastrostomy (N and G) or open gastrostomy (OG) before starting PD (group1). Nine children, age 0.7 (0.5–12.4) years, had a N and G or OG (group 2) and 5, age 5.1 (1–15.1) years, a PEG (group 3) after PD catheter insertion/start of PD. In group 1 (257 months gastrostomy feeding with PD), there were 0.6 episodes of peritonitis/patient year. Nine PEGs were replaced electively after 27 (19–50) months, with bleeding from an embedded flange the only complication. One PEG replaced by a button ruptured the track, causing Candida peritonitis. In group 2 (130 months G and PD), there were 1.4 episodes of peritonitis/patient year. Two children developed paraoesophageal hernias, which were successfully repaired. Four children in group 3 developed peritonitis soon after PEG placement. Two transferred to haemodialysis, 1 remained on PD after treatment of Candida peritonitis and 1 subsequently died. Only 2 of the 17 children who have had renal transplants still need gastrostomy feeds. We recommend placement of a PEG or OG if an anti-reflux procedure is necessary prior to starting PD. Placement of a PEG while on PD is contraindicated, but an OG is a safe alternative procedure.

Retrospective study of plasma exchange in patients with idiopathic rapidly progressive glomerulonephritis and vasculitis.

A retrospective study of 48 patients was conducted to evaluate the efficacy of plasma exchange in children with idiopathic rapidly progressive glomerulonephritis (IRPGN), and renal or non-renal vasculitis. All patients were followed up at a single centre over a 15 year period. Treatment consisted of corticosteroids and/or cytotoxic agents. Plasma exchange was used in all patients because of severe renal involvement and/or clinical deterioration. One hundred per cent of patients with renal vasculitis who started plasma exchange within one month of disease onset and 58% of cases with IRPGN had significant improvement in renal function. No relapses of vasculitis were observed after treatment with plasma exchange in patients with renal and non-renal vasculitis. The results suggest that plasma exchange associated with immunosuppressive treatment could be of benefit in cases of IRPGN or vasculitis in terms of both renal and extrarenal recovery.

Perinatal renal venous thrombosis: presenting renal length predicts outcome

Background: Renal venous thrombosis (RVT) is the most common form of venous thrombosis in neonates, causing both acute and long term kidney dysfunction. Historical predisposing factors include dehydration, maternal diabetes, and umbilical catheters, but recent reports highlight associations with prothrombotic abnormalities. Study: Twenty three patients with neonatal RVT were analysed over 15 years. Predisposing factors, presentation, and procoagulant status were compared with renal outcome using multilevel modelling. Results: Median presentation was on day 1: 19/23 (83%) had pre/perinatal problems, including fetal distress (14), intrauterine growth retardation (five), and pre-identified renal abnormalities (two); 8/18 (44%) had procoagulant abnormalities, particularly factor V Leiden mutations (4/18). Long term abnormalities were detected in 28/34 (82%) affected kidneys; mean glomerular filtration rate was 93.6 versus 70.2 ml/min/1.73 m2 in unilateral versus bilateral cases (difference 23.4; 95% confidence interval 6.4 to 40.4; p  =  0.01). No correlation was observed between procoagulant tendencies and outcome, but presenting renal length had a significant negative correlation: mean fall in estimated single kidney glomerular filtration rate was 3 ml/min/1.73 m2 (95% confidence interval 3.7 to −2.2; p  =  0.001) per 1 mm increase, and kidneys larger than 6 cm at presentation never had a normal outcome. Conclusions: This subgroup of neonatal RVT would be better termed perinatal RVT to reflect antenatal and birth related antecedents. Prothrombotic defects should be considered in all patients with perinatal RVT. Kidney length at presentation correlated negatively with renal outcome. The latter, novel observation raises the question of whether larger organs should be treated more aggressively in future.

Renal transplantation in children under 5 years of age

Abstract Between March 1987 and December 1997, 59 renal transplants [49 cadaveric, 10 live related (LRD)], were performed in 54 children aged 5 years and younger. Six children required a second transplant. The median (range) age of the recipients was 2.9 (1.4–5.0) years; mean weight was 12.6 kg (7.4–23) and donor age 11 (2–50) years. Immunosuppression was cyclosporin or FK506, prednisolone, and azathioprine. Antithymocyte globulin was given as induction therapy for second transplants. Patient survival was 98.3%; 1 patient died from upper gastrointestinal haemorrhage. Graft survival was 67.7% at 1 year, 57.4% at 5 years, and 45.2% at 10 years. No LRD graft was lost during 7 years of follow-up. Thrombosis was the main cause of graft loss (10 cases) followed by vascular rejection (2 cases). There was no significant difference in graft survival between recipients aged less than 2, 2–3, and 3–5 years. The height standard deviation score (±SD) improved from –2.1±1.3 at transplantation to –1.0±1.3 at 1 year, –1.1±1.5 at 5 years, and to –0.14±1.1 at 10 years.

Congenital cutis laxa and lysyl oxidase deficiency.

We report two phenotypically similar patients with primary cutis laxa associated with deficiency of lysyl oxidase, an extracellular copper enzyme the gene for which is located on chromosome 5. Previous reports of this condition have had characteristic occipital projections, abnormality of copper metabolism and X‐linked inheritance. The two reported patients have no occipital projections, normal copper metabolism, Wormian bones, and a pattern of inheritance consistent with the autosomal recessive inheritance of the lysyl oxidase gene.