Elke Wühl

Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation

BACKGROUND Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression. METHODS The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months. RESULTS Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%). CONCLUSION Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.

Short dialyzed children respond less to growth hormone than patients prior to dialysis

Recombinant human growth hormone (rhGH) is a new treatment modality for short children with chronic renal failure (CRF) prior to and during dialysis. It is difficult to analyze whether dialysis patients respond less to rhGH than children with CRF on conservative treatment because they are older and often in a pubertal age range. One hundred and eight patients were treated with 28–30 IU rhGH/kg per week for at least 1 year. We analyzed the growth response to rhGH in 56 prepubertal patients aged less than 10 years at the start of rhGH treatment; 38 children with a mean age of 6.5±2.4 years were on conservative treatment (CT) and 18 patients with a mean age of 6.5±2 years on dialysis treatment (D). Mean height velocity was 4.9±2.3 cm/year in children on CT and 4.6±1.8 cm/year in children on D. During the 1 st treatment year, height velocity was 9.5±3.8 cm/year in CT patients and 7.3±1.3 cm/year in D patients (P<0.05). The change in height was +1.1±0.8 standard deviation (SD) in CT patients and +0.5±0.4 SD in D patients (P<0.005). During the 2nd treatment year, the change in height was again greater in CT patients (0.5±0.4 SD vs. 0.2±0.4 SD;P<0.05). The difference in height velocity and change in height standard deviation score was also significant when a subgroup of patients was matched for sex, age, height. Height velocity and the change in height velocity during rhGH treatment were not correlated with residual renal function, the degree of anemia, or metabolic acidosis. We conclude that short children on D respond less to rhGH than short children on CT, indicating a greater insensitivity to rhGH during D treatment.

IVIG and rituximab for treatment of chronic antibody‐mediated rejection: a prospective study in paediatric renal transplantation with a 2‐year follow‐up

Chronic antibody‐mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high‐dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant recipients. Donor‐specific HLA antibodies (HLA DSA) were quantified by Luminex‐based bead array technology. Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m² during 6 months prior to AHT to 2.1 ml/min/1.73 m² (P = 0.0013) during 6 months after AHT. Fourteen patients (70%) responded: nine of nine patients (100%) without and five of 11 (45%) with transplant glomerulopathy (P = 0.014). C4d positivity in PTC decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P = 0.002) in the follow‐up biopsy. In four of nine biopsies (44%) C4d staining turned negative. During 2 years of follow‐up, the median loss of eGFR in each of the four 6‐month periods remained significantly lower compared with prior to AHT. Class I DSA declined in response to AHT by 61% (p = 0.044), class II DSA by 63% (p = 0.033) 12 months after intervention. AHT with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation.

Neurodevelopmental deficits in Pierson (microcoria-congenital nephrosis) syndrome.

Pierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct eye abnormalities with microcoria reported as the most prominent clinical feature. LAMB2 mutations leading to lack of laminin β2 were identified as the molecular cause underlying Pierson syndrome. Although LAMB2 is known to be expressed in the neuromuscular system, and defects of the neuromuscular junctions had been found in laminin β2‐deficient mice, no consistent neurological phenotype has been described clinically in murine or human laminin β2‐deficiency before. This is likely due to the early lethality from renal failure. Here we provide a detailed description of neurological manifestations and development in four patients affected by Pierson syndrome, who survived until the age of 1.3–4.8 years owing to renal replacement therapy. Severe muscular hypotonia, psychomotor retardation, and blindness were present in three patients harboring truncating mutations on both LAMB2 alleles. These symptoms were not attributable to complications of chronic renal failure, thus representing a primary feature of the genetic disorder. Alterations in skeletal muscle tissue from one case were compatible with a chronic denervating process. One affected girl, however, exhibited a milder course of renal disease, normal development, and preserved vision, presumably owing to some residual LAMB2 function. Our findings indicate that severe neurodevelopmental deficits have to be considered as part of Pierson syndrome, at least in the presence of biallelic functional null mutations (complete lack of laminin β2). This is an important issue in the counseling of parents of an affected newborn or infant.

Impact of ACE I/D gene polymorphism on congenital renal malformations

Abstract To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo- /dysplasia, obstructive uropathy, reflux nephropathy; n=59), other congenital or hereditary diseases (n=23), or acquired glomerular disorders (n=13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal ’survival’ analysis was performed, using a GFR loss of 10 ml/min per 1.73 m2 as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n=163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P<0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P<0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P<0.001) and gross proteinuria (RR 4.7, P<0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria.

Effect of ramipril on ambulatory blood pressure and albuminuria in renal hypertension

Abstract Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5–18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24–83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

SRL-based immunosuppression vs. CNI minimization in pediatric renal transplant recipients with chronic CNI nephrotoxicity

Abstract:  Because calcineurin inhibitor (CNI)‐induced nephrotoxicity contributes significantly to late renal allograft loss, sirolimus (SRL)‐based, CNI‐free maintenance immunosuppression has been advocated, but data in the pediatric population are scarce. We therefore analyzed the efficacy and safety of an SRL‐based immunosuppressive regimen plus mycophenolate mofetil (MMF) and corticosteroids vs. CNI minimization (mean dose reduction by 39%) plus MMF and corticosteroids in 19 pediatric recipients with biopsy‐proven CNI‐induced nephrotoxicity in a single‐center case–control study. In the SRL group, we observed, one yr after study entry, an improvement of glomerular filtration rate (GFR) by 10.3 ± 3.0 mL/min/1.73 m2 (p < 0.05 vs. baseline) in seven of 10 patients and a stabilization in the remaining three, while in the CNI minimization group GFR improved by 17.7 ± 7.1 mL/min/1.73 m2 (p < 0.05) in six of nine recipients and stabilized in the remaining three. No patient in either group experienced an acute rejection episode. The main adverse event under SRL therapy was a transient hyperlipidemia in 70% of patients. In pediatric renal transplant recipients with declining graft function because of CNI‐induced nephrotoxicity, CNI withdrawal and switch to SRL‐based therapy or CNI minimization are associated with a comparable improvement of GFR after 12 months of observation.

Effects of Growth Hormone in Patients with Chronic Renal Failure: Experience in Children and Adults

Recombinant human growth hormone (GH) has proven effective in promoting growth in short children with chronic renal failure before and after renal transplantation. The action of GH and its mediator insulin-like growth factor 1 on body composition, protein, glucose and bone metabolism offers additional therapeutic options. One might be the improvement of the catabolic state in adults with end-stage renal failure. In few pilot studies and two placebo-controlled studies of 6 months duration, GH treatment in adults on dialysis showed clear anabolic effects resulting in a significant increase in lean body mass.

Analysis of genes encoding laminin β2 and related proteins in patients with Galloway–Mowat syndrome

Galloway–Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the central nervous system. GMS likely represents a heterogeneous group of disorders with hitherto unknown genetic etiology. The clinical phenotype to some extent overlaps that of Pierson syndrome (PS), which comprises congenital nephrotic syndrome and distinct ocular abnormalities but which may also include neurodevelopmental deficits and microcephaly. PS is caused by mutations of LAMB2, the gene encoding laminin β2. We hypothesized that GMS might be allelic to PS or be caused by defects in proteins that interact with laminin β2. In a cohort of 18 patients with GMS or a GMS-like phenotype we therefore analyzed the genes encoding laminin β2 (LAMB2), laminin α5 (LAMA5), α3-integrin (ITGA3), β1-integrin (ITGB1) and α-actinin-4 (ACTN4), but we failed to find causative mutations in these genes. We inferred that LAMA5, ITGA3, ITGB1, and ACTN4 are not directly involved in the pathogenesis of GMS. We excluded LAMB2 as a candidate gene for GMS. Further studies are required, including linkage analysis in families with GMS to identify genes underlying this disease.

Renal function in predialysis children with chronic renal failure treated with erythropoietin

Abstract. To assess the effect of long-term administration of human recombinant erythropoietin (EPO) on renal function, 11 anemic children aged 1.4 – 17.2 years were followed for 10 – 61 (mean 31) months on treatment. During EPO therapy the mean hemoglobin rose from 8.1 to 11.1 g/dl at the last observation. The final maintenance dose ranged between 70 and 300 U/kg per week. The rate of deterioration of renal function was calculated by comparing the slope of the regression lines of reciprocal serum creatinine values (SCr) derived from a mean of 20 values per patient obtained over 8 – 50 (mean 29) months before and a mean of 24 SCR values during EPO therapy. The individual slopes improved after initiation of EPO therapy in all but 3 patients, but the mean change of slope (from –0.0521 to –0.0299) was not significant. The study suggests that in most children with predialysis chronic renal failure long-term administration of EPO is not associated with accelerated deterioration but rather with delayed deterioration of renal function.