A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

The best game is the waiting game.

Chronic dialysis and renal transplantation have been developed over the last three decades of the 20th century. These two forms of renal replacement therapy have revolutionized the fate of children in established renal failure. Yet, chronic dialysis is a serious burden to both the patient and the family and the long-term results of renal transplantation are far from excellent. Moreover, both forms of treatment have serious complications, some of them fatal. It is therefore important to highlight what has been achieved in terms of conservative treatment of chronic renal failure. This paper describes in detail the progress made in this field with special emphasis on the great opportunity to slow down progression from chronic renal disease to end-stage renal failure. Renal replacement therapy can wait in many children and should be postponed as long as possible, ideally until they have reached adulthood.

Growth hormone therapy in chronic renal failure induces catch-up of head circumference.

Growth of head circumference was studied along with height, weight, and body mass index (BMI) in 21 prepubertal patients with chronic renal failure (CRF) before and during recombinant human growth hormone (rhGH) treatment. CRF was present from birth in 15 patients, in the 6 others it was acquired and existing for at least 1 year. Five patients were on chronic dialysis, and 16 children were on conservative treatment with a median glomerular filtration rate of 17 ml/min per 1.73 m2 at the start of rhGH therapy. rhGH was administered for 12 months in all patients, for 18 months in 19, and for 24 months in 12 patients. Mean height standard deviation score (SDS) increased significantly from -2.29 to -1.31 after 1 year and to -1.07 after 2 years. Mean BMI SDS was within the normal range throughout. Mean head circumference SDS improved significantly from -2.04 to -1.45 after 1 year and remained stable thereafter. Changes in head circumference differed between patients under 5 years and those over 5 years. In the former, the increase in head circumference SDS was already significant after 6 months of therapy, in the latter, significance was reached only after 1 year. It can be concluded that rhGH in CRF patients significantly improves head circumference SDS, albeit not to the same extent as height SDS.

The role of coagulation and fibrinolysis in the pathogenesis of diarrhea-associated hemolytic uremic syndrome.

The hemolytic-uremic syndrome (HUS) is a frequent cause of acute renal failure in childhood. It comprises acute acquired hemolysis, thrombocytopenia, and renal dysfunction. Very many disease processes can lead to this constellation, the most frequent one in childhood being an infection by bacteria that produce Shiga toxin or Shiga-like toxins (SLTs). In industrialized countries, the first identified human pathogen to cause HUS was Escherichia coli O157H7, and this organism remains the most common one. The mechanisms by which these bacteria cause hemorrhagic colitis and HUS are incompletely understood. The bacteria are able to adhere to the mucosa of the colon. The local and systemic effects that follow the intestinal invasion are responsible for the bloody diarrhea. In a further step, the SLTs reach the blood stream and attach to the endothelium of the small arterioles mainly in the kidney but also in other organs. The endothelial cells express a toxin-specific receptor that enables the contact between toxin and cells. Damage to the endothelium causes platelet aggregation and activation, which trigger fibrin deposition. Although thrombotic changes in the microcirculation have been recognized in many histological studies, it is only recently that coagulation studies have been able to demonstrate clearly localized intravascular coagulation. The finding that the fibrinolytic system is inhibited in HUS has been challenged. By using specific and sensitive tests to measure the active moiety of plasminogen activator inhibitor type 1 (PAI-1) and comparing the findings in HUS patients and appropriate controls, it has become clear that in diarrhea-associated HUS the fibrinolytic system is rather stimulated. In this contribution the pathophysiology of diarrhea-associated HUS is discussed with special emphasis on coagulation and fibrinolysis.

Growth hormone treatment enhances bone mineralisation in children with chronic renal failure.

UNLABELLED: Dual energy X-ray absorptiometry of the whole body and the lumbar spine was performed to study bone mineralisation before and after 1 year of recombinant human growth hormone (rhGH) treatment in ten children with chronic renal failure. At the start, median age was 7.3 years (range 2.0-8.8 years) and median glomerular filtration rate 15 ml/min per 1.73 m2 (range 7-41 ml/min per 1.73 m2). Total body mineral content (TBMC), lumbar spine mineral content (LBMC), total body bone mineral density (TBMD) and lumbar spine mineral density (LBMD) improved significantly (P < 0.05) after 1 year of treatment. Bone mineral data before and after treatment were compared with two groups of controls, i.e. ten healthy children matched for age and ten healthy children matched for height. Patients' TBMC, LBMC, TBMD and LBMD data before treatment were no different from those of height-matched controls; the same was true after 1 year of treatment except for the patients' significantly better LBMD (P < 0.05). When compared with age-matched controls, patients had significantly lower baseline TBMC and LBMC levels before treatment; after treatment LBMC was no longer different. However, there were no differences in TBMD or LBMD between patients and age-matched controls at baseline or after rhGH. CONCLUSION: Recombinant human growth hormone treatment for 1 year results in a significant increase in both growth velocity and bone mineralisation. Comparison with height-matched controls shows a similar bone mineralisation at baseline and a better bone mineral density after treatment.

Surgical correction of vesicoureteral reflux: 5-year follow-up with 99Tcm-DMSA scintigraphy.

AIM: To evaluate kidney function before and after surgical correction of vesicoureteral reflux. The long-term effect was measured with quantitative nephro-scintigraphy using 99Tcm labelled dimercaptosuccinic acid (99Tcm-DMSA). METHODS: Forty-five children with a history of urinary tract infections due to vesicoureteral reflux (VUR) were studied. VUR grade was determined with contrast voiding cystourethrography. Planar scintigraphy was performed with 99Tcm-DMSA and uptake measured as a percentage of injected dose. Kidney function was evaluated at baseline and 5 years after corrective surgery. RESULTS: Three months after surgery, persistent mild reflux was found in eight of 76 treated renal units. Kidney uptake at 5-year follow-up was unchanged in the majority of children, indicating preservation of renal function found at baseline. The split renal function showed an excellent correlation (r = 0.99) between baseline and follow-up studies (regression slope 1.01). Percentage uptake had a regression slope of 0.89 significantly different from unity (P<0.05). Empirical kidney-depth correction techniques were compared. The scintigraphic pattern worsened in six kidneys, indicative of increased scarring in a minority of children. CONCLUSION: Planar nephro-scintigraphy with 99Tcm-DMSA was well tolerated in our paediatric population, and appeared appropriate to evaluate kidney function in time. After surgical correction of VUR, the baseline function was maintained in 94% of kidneys.

Head circumference in chronic renal failure from birth.

AIMS: Chronic renal failure in childhood jeopardizes both growth and development. In children with chronic renal failure from birth, growth in height and weight have been found to be generally poor. Few data on head circumference are available. MATERIAL: A cohort of 19 children with chronic renal failure from birth was studied from the early weeks of life to the age of 5 years. There were 18 boys; and 18 patients had congenital renal hypoplasia or hypodysplasia associated with obstructive uropathies. Eight patients received recombinant growth hormone (rhGH) after the age of 2 years. Only 2 patients needed renal replacement therapy before the age of 5 years. Data after transplantation were not included. METHODS: The following variables were analyzed: body height, body mass index and head circumference. Data were expressed in median values of standard deviations scores (SDS). RESULTS: In the first 3 months of life there was a significant drop in height SDS, body mass index SDS and head circumference SDS. Thereafter, a stable growth velocity was observed for the rest of the study period, except for body mass index SDS. which improved after 36 months. There was a striking difference between patients who needed treatment or not with recombinant human growth hormone (rhGH). Patients without rhGH displayed a stable growth after the age of 3 months until 5 years of age. In the remaining 8 patients, rhGH treatment resulted in a significant increase not only in height SDS but also in head circumference SDS. CONCLUSIONS: In infants and young children with chronic renal failure from birth, growth in head circumference parallels growth in body height. This applies to all patients and to data before and during rhGH treatment.

Dysmorphic erythrocytes and G1 cells as markers of glomerular hematuria.

We aimed to assess the utility of the percentage of G cells and dysmorphic erythrocytes in the diagnosis of glomerular hematuria in pediatric patients. We determined the percentage of dysmorphic erythrocytes and G1 cells in urine samples from patients with glomerulonephritis and other renal diseases of non-glomerular origin. There was excellent correlation and agreement between results obtained by counting the cells in counting chambers and in urine sediments. With cut-off values of > or =1%, > or =2%, > or =5%, and 10% for G1 cells, sensitivities for the detection of glomerulonephritis were 62%, 40%, 28%, and 10% and specificities were 89%, 95%, 95%, and 98%. For the dysmorphic erythrocytes cut-off values of > or =10%, > or =20%, 50%, and > or =90% gave respective sensitivities of 95%, 95%, 93%, and 62% and specificities of 24%, 34%, 43%, and 85%. In 38% of cases of biopsy-proven glomerulonephritis no G1 cells were found. For cut-off values of > or =50% dysmorphic erythrocytes and > or =1% G1 cells, the sensitivity and specificity were 60% and 91%. For cut-off values of > or =50% dysmorphic or > or =1% G1 cells, sensitivity and specificity were 93% and 44%. Our results show that neither the percentage of dysmorphic erythrocytes nor the G1 cell count is of adequate sensitivity and specificity to enable reliable differentiation of glomerular and non-glomerular hematurias. Both tests are needed to achieve >90% sensitivity and specificity.

Enalapril in paediatric patients with Alport syndrome: 2 years' experience.

UNLABELLED: Enalapril, a long-acting inhibitor of angiotensin-converting enzyme, was given for 2 years to seven children with Alport syndrome. Five patients had a classical X-linked form of the disease; two siblings had the autosomal recessive variant. Their age was between 5.15 and 13.75 years when enalapril was started. All patients had haematuria and proteinuria, creatinine clearance was > 80 ml/min per 1.73 m2 in all, and only one patient was hypertensive. The starting dose of enalapril (0.1 mg/kg body weight per day) was increased progressively according to individual clinical tolerance. The median doses were 0.13, 0.12, 0.21 and 0.29 mg/kg at 6, 12, 18 and 24 months, respectively. Median values of mean blood pressure were 95 mmHg at the start and 84 mmHg after 24 months. Median daily proteinuria decreased from 52 mg/kg to 18 mg/kg at 6 months, 21 mg/kg at 12 months, 12 mg/kg at 18 months and 30 mg/kg at 24 months. Serum creatinine increased over time from a median of 0.64 mg/dl at baseline to 0.77 mg/dl at 24 months. Concomitantly, there was a decrease in GFR from 104 to 83 ml/min per 1.73 m2 at 18 months and an increase again to 95 ml/min per 1.73 m2 at 24 months. Analysis of the individual data showed three patterns: no response (n = 2), temporary response (n = 2) and sustained response (n = 3). CONCLUSION: When given enalapril at the dosages mentioned, Alport patients as a group display a marked reduction in urinary protein excretion with a nadir of 23% of the baseline figure at 18 months, a decrease that cannot be accounted for by the slight decrease in glomerular filtration rate. Although these are preliminary data, it is recommended to try an angiotensin-converting enzyme inhibitor in every paediatric Alport patient with proteinuria.

Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1.

Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults. There is a 30-50-fold increased incidence of VUR in first-degree relatives of probands, compared with the general population. We report the results of the first genomewide search of VUR and RN; we studied seven European families whose members exhibit apparently dominant inheritance. We initially typed 387 polymorphic markers spaced, on average, at 10 cM throughout the genome; we used the GENEHUNTER program to provide parametric and nonparametric linkage analyses of affected individuals. The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16. Saturation with markers at 1-cM intervals increased the NPL to 5.94 (P=.00009). Hence, VUR maps to a locus on chromosome 1. There was evidence of genetic heterogeneity at the chromosome 1 locus, and 12 additional loci were identified genomewide, with P<.05. No significant linkage was found to 6p, where a renal and ureteric malformation locus has been reported, or to PAX2, mutations of which cause VUR in renal-coloboma syndrome. Our results support the hypothesis that VUR is a genetic disorder.

Extensive surgery on the trigone for complete ureteral duplication does not cause incontinence or voiding problems.

OBJECTIVES: To evaluate whether extensive trigonal surgery for duplicated kidneys is harmful for later bladder and urethral function. METHODS: Of 201 surgically treated children with kidney and ureteral duplication, 145 were followed up for at least 1 year. The mean follow-up was 5 years (range 1 to 15), and all patients were at least 7 years old at the date of their last follow-up visit. Trigone surgery was performed in 105 children; bilateral trigonal surgery in 26, unroofing in 25, and total excision in 5. On all later consultations, the presence of infection, voiding habits, continence pattern, and ultrasound findings for residual urine volume and kidney function were noted. Children with recurrent urinary tract infection or dysfunctional voiding for more than 2 years underwent a urodynamic examination. RESULTS: Nine children, of whom five were boys, had nocturnal enuresis only. Eight patients had day and nighttime wetting. Seven of the 8 patients had recurrent urinary infections; urodynamic evaluation revealed a high compliance (with residual urine) in three of these children and four had detrusor instability. One girl had an irregular bladder neck, with stress incontinence. All reflux, whether surgically or conservatively treated and also three of four occurring de novo, disappeared within 1 year after surgery. In the group without voiding dysfunctions, seven cystitis and five pyelonephritis attacks occurred. CONCLUSIONS: Neither extensive trigonal surgery nor pre-existing trigonal deformation by ureteroceles provokes later bladder dysfunction.

Urethral instability as an important element of dysfunctional voiding.

PURPOSE: We monitored detrusor and urethral behavior during bladder filling in girls with dysfunctional voiding (incomplete perineal relaxation) to determine the causes of this pathological condition. MATERIALS AND METHODS: In 15 girls without neuropathy but with a staccato voiding pattern in whom symptoms of urinary tract infection and urge incontinence were refractory to treatment we recorded urethral and bladder pressure, and anal sphincter needle electromyography throughout slow bladder filling. RESULTS: Urethral instability was observed in 8 of the 15 girls as urethral pressure decreases with short periods of electromyography silence (6) or as intermittent urethral pressure increases with short perineal spasms (2). Detrusor instability was noted in 12 girls, while bladder pressure was normal in 1 and hypoactive in 2. In 6 cases of an unstable bladder urethral pressure decreases with silent electromyography periods were also noted. In 1 case low basic urethral pressure had short periods of increased pressure with electromyography bursts. In another case high compliance bladder uninhibited sphincter contractions were noted throughout filling. CONCLUSIONS: Dysfunctional voiding is a misleading term since a pathological condition is also present during the bladder filling phase. Frequently observed detrusor and urethral instability may explain the urge sensation during filling and the staccato voiding phase.

Conservative treatment for chronic renal failure from birth: a 3-year follow-up study.

Fifteen children with chronic renal failure from early infancy who did not require renal replacement therapy were followed for 3 years. Chronic renal failure was defined as a serum creatinine at or above 1 mg/dl for the entire 1st year of life. These patients were treated conservatively with diet and supplements of sodium bicarbonate and sodium chloride, calcium and vitamin D. Erythropoietin was given to 5 patients. Neither nasogastric nor gastrostomy tube feeding was used, and none of the patients received recombinant human growth hormone. We analyzed length, weight, and head circumference at 3, 12, 24, and 36 months of age. All three variables displayed a significant drop in the first 3 months, but remained stable for the whole observation period thereafter. At the age of 3 years, the patients' mean values of length, weight, and head circumference standard deviation score were -1.96, -1.37, and -1.07, respectively. Height velocity during the 1st, 2nd, and 3rd year was 22.2, 10.9, and 7.6 cm per year, respectively. The first two figures and the cumulative height velocity are significantly better than those from a large cohort of chronic renal failure patients collected by the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood; here the corresponding figures of height velocity were 12.3, 8.3, and 7.6 cm per year. Median serum calcium, phosphate, parathyroid hormone, and albumin levels remained within normal limits for the entire study period. Therapy-resistant hyperparathyroidism occurred in 1 patient and radiological signs of renal osteodystrophy in 4 patients. Kidney length, as measured by ultrasonography, showed almost no growth.

A review of ninety-two obstructive megaureters in children.

OBJECTIVES: The evolution of clinical presentation, age of surgery and therapeutic approach of obstructive nonrefluxing megaureters (OMU) in children throughout the years has been retrospectively evaluated. METHODS: 78 children with 92 stenotic ureterovesical junctions (UVJ) were reviewed. 66 underwent surgery at a median age of 20 months, after a median of 10.5 months of conservative treatment with prophylactic antibiotics. 21 OMU were diagnosed prenatally, 71 because of symptoms at later age. 15 ureters (12 children) (24% in the prenatal, 14% in the second group) were treated in a conservative way for 2 years with antibiotics. In the prenatal group 33% needed a reimplantation with tailoring and 10% without tailoring while in the other group the figures are reversed: 39% without and 21% with tailoring. 28% in the prenatal group and 17% of the second group were reimplanted at a mean of 15 months after a primary cutaneous ureterostomy. Three of 5 ureteroceles were treated by endoscopic incision; 4 had an immediate nephroureterectomy. The mean follow-up is >70 months. RESULTS: By prenatal diagnosis the number of conservatively treated cases increased from 14 to 24%. Indications for surgery remained unchanged: recurrent infection and poor kidney function. Both approaches resulted in stabilization of pretreatment renal function; nearly half of the DMSA scans showed a R:L difference of >20% at follow-up. Ureterostomy for infected deteriorating kidneys rapidly ameliorated the function and resulted in shrinking of the ureteral diameter making tailoring at reimplantation unnecessary. One of the 3 endoscopically incised ureteroceles required later reintervention. CONCLUSIONS: Male:female (3:1), left:right (2:1) prevalence and high associated urological (30%) and nonurological (19%) pathology is found. Unsatisfactory reliability of tests for obstruction diagnosis and a referral bias explains the larger number of conservatively treated ureters in the prenatal group. Despite prenatal diagnosis, the age for surgery was not altered since the indications remained identical. Most OMU can be treated by a simple or tailored reimplantation of the ureter after resection of the stenotic segment. A temporary ureterostomy in small children with refractory infections restores function and avoids the necessity for tailoring at final reconstruction. One of 3 endoscopically incised ureteroceles needed surgery at a later stage. DMSA shows stable function after reimplantation.

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Human complement factor H deficiency associated with hemolytic uremic syndrome.

This study reports on six cases of deficiency in the human complement regulatory protein Factor H (FH) in the context of an acute renal disease. Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome (HUS). Two of the children exhibited a homozygous deficiency characterized by the absence of the 150-kD form of Factor H and the presence, upon immunoblotting, of the 42-kD Factor H-like protein 1 (FHL-1) and other FH-related protein (FHR) bands. Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency. The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family. Factor H deficiency is the only complement deficiency associated with HUS. These observations suggest a role for FH and/or FH receptors in the pathogenesis of idiopathic HUS.