Pediatric urolithiasis in Armenia: a study of 198 patients observed from 1991 to 1999.

To study prospectively the risk factors and etiology of urolithiasis in all stone patients aged <15 years admitted from 1991 to 1999 to the Arabkir hospital in Yerevan. Stones were obtained by surgery (64%), extracorporeal shockwave lithotripsy (ESWL) (7%) or cystoscopic extraction (4%); 25% passed spontaneously. All were examined by infrared spectroscopy, and spot urines were analyzed chemically. 198 patients, 180 (68% males) with renal stones and 18 (83% males) with primary bladder stones, were studied. Calcium oxalate (CaOx) was the predominant constituent in 62% of the kidney stones, followed by struvite (17%), calcium phosphate (7%), uric acid (7%), ammonium acid urate (5%), and cystine (2%). Bladder stones contained CaOx in 72%, uric acid in 22% and ammonium acid urate in 6% of patients. Etiology was obviously metabolic in 5% and possibly metabolic in 26%. Twenty percent of stones were infectious, and 19% were endemic (9% bladder and 10% kidney stones); 4% were secondary to urinary stasis with malformation but no infection. Etiology in 26% remained unknown. Stone composition and metabolic etiology are similar to that in central Europe and North America. In contrast, infectious calculi and particularly endemic stones are still common, although becoming less so now. Urolithiasis in Armenia thus reflects the transition from a rural to an urban society.

Simultaneous occurrence of the haemolytic uraemic syndrome and acute post-infectious glomerulonephritis.

We report on two children, a 12-year-old boy and a 6-year-old girl, with simultaneous occurrence of clinical and laboratory features consistent with both diarrhoea-negative haemolytic uraemic syndrome (D-HUS) and acute post-infectious glomerulonephritis (APGN). Both presented with acute renal insufficiency, hypertension and oedema. Laboratory evaluation revealed micro-angiopathic anaemia with burr cells, thrombocytopenia, elevated lactic dehydrogenase and low complement C3. Urinalysis showed marked proteinuria and haematuria. Renal biopsy was characteristic of APGN, but not of HUS. The outcome was good in both children. Conclusion. The simultaneous occurrence of diarrhoea-negative haemolytic uraemic syndrome and acute post-infectious glomerulonephritis is rare. The outcome is generally good as is expected in the latter condition in contrast to the former.

[Pediatric kidney transplantation and living donors--invaluable by virtue of necessity]. / Pädiatrische Nierentransplantation und Lebendspende--aus der Not eine Tugend.

UNLABELLED: Renal transplantation is the treatment of choice for paediatric patients with end-stage renal failure. Living donor transplantation (LDT) has become an important therapeutic option due to the shortage of cadaver donors and increasingly long waiting times. METHODS: Between 1992 and 1999, a total of 48 paediatric and adolescent patients underwent renal transplantation in Zurich. Of these, 21 patients (44%) received a kidney from a living related donor. 11 patients had been dialysed before LDT over a period of 0.2-5.7 years (median 0.6), and 10 were transplanted preemptively. Triple immunosuppression consisted of cyclosporine A, azathioprine or mycophenolate mofetil (MMF; since 1998), and prednisone. The observation period was 0.5-7.3 years (median 2). RESULTS: Recipients were 2-18 (median 10.5) years old at transplantation. One third had either a congenital malformation, an inherited disease, or an acquired disorder. One patient died of an associated cardiac disease at 4 months with functioning graft, and one functional graft loss occurred after 2.8 years. 9 patients were switched from cyclosporine to tacrolimus, 7 for biopsy-proven rejection and 2 for cosmetic reasons (hypertrichosis). No antibody preparations were used. Median glomerular filtration rate (51Cr-EDTA), measured after one year in 11 donor/recipients, was 64 (55-95) and 54 (32-82) ml/min/1.73 m2, respectively. The most recent estimated renal function (Schwartz formula) of 19 functioning grafts was 37-79 ml/min/1.73 m2 (median 63). Median body height of 16 patients with no associated extrarenal disease was -0.9 SDS (standard deviation score); the remaining 3--with serious extra-renal disease--were considerably growth retarded. Main complications were reversible rejection episodes in 19 (90%), arterial hypertension (16), CMV disease (2) and asymptomatic CMV infection (3), pyelonephritis (3), and recurrence of the primary renal disease, seizures, diabetes mellitus and non-compliance (one each). Actuarial patient and graft survival (Kaplan-Meier) after 3 years was 95 and 83% respectively. This was not statistically different from the cadaveric donor group (n = 27) with 100 and 80% survival respectively. Overall rehabilitation was excellent. The donors were 12 mothers, 8 fathers and one grandmother aged 31 to 50 (median 39) years; none of them experienced serious postoperative problems. CONCLUSIONS: The paediatric transplantation programme would no longer be feasible in Switzerland without LDT. The results are very encouraging; preemptive transplantation makes it possible to avoid dialysis in half of the patients. The risk for the donor is small, and careful evaluation without putting pressure on the family is essential.

Heparin-induced thrombocytopenia type II on hemodialysis: switch to danaparoid.

We report two pediatric patients with end-stage renal failure who developed heparin-induced thrombocytopenia type II (HIT II) on hemodialysis (HD). Both developed acute respiratory distress and chest pain within 30 min of initiating the 5th HD session. The platelets dropped during HD from 168 to 38x10(9)/l and from 248 to 109x10(9)/l, respectively. Marked clots were observed in the dialyzers. Substitution of heparin with the low molecular weight heparin dalteparin had no effect. Switching from anticoagulation to the heparinoid danaparoid resulted in immediate disappearance of all adverse effects, and further long-term HD was uneventful. HIT II was diagnosed clinically; heparin-induced platelet activation test (HIPA) and serum IgG, IgA, and IgM to heparin-platelet factor 4 complexes (HPF4) were both negative. We conclude that HIT II may occur in children on HD. HIT II is essentially a clinical diagnosis, as HIPA and antibodies to HPF4 are not always positive. Once HIT II is suspected, heparin (and low-molecular-weight heparins) should be stopped immediately. Long-term anticoagulation with danaparoid is a valuable option for patients on HD.

Urinary oxalate excretion in urolithiasis and nephrocalcinosis.

AIMS: To investigate urinary oxalate excretion in children with urolithiasis and/or nephrocalcinosis and to classify hyperoxaluria (HyOx). METHODS: A total of 106 patients were screened. In those in whom the oxalate: creatinine ratio was increased, 24 hour urinary oxalate excretion was measured. Liver biopsy and/or genomic analysis was performed if primary hyperoxaluria (PH) was suspected. Stool specimens were examined for Oxalobacter formigenes in HyOx not related to PH type 1 or 2 (PH1, PH2) and in controls. RESULTS: A total of 21 patients screened had HyOx (>0.5 mmol/24 h per 1.73 m(2)); they were classified into five groups. Eleven had PH (PH1 in nine and neither PH1 nor PH2 in two). Six had secondary HyOx: two enteric and four dietary. Four could not be classified. Seven patients had concomitant hypercalciuria. Only one of 12 patients was colonised with O formigenes compared to six of 13 controls. CONCLUSIONS: HyOx is an important risk factor for urolithiasis and nephrocalcinosis in children, and can coexist with hypercalciuria. A novel type of PH is proposed. Absence of O formigenes may contribute to HyOx not related to PH1.

Renal chloride channel, CLCN5, mutations in Dent's disease.

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. Patients with Dent's disease may also suffer from rickets and other features of the renal Fanconi Syndrome. Patients may have mutations in the X-linked renal chloride channel gene, CLCN5, which encodes a 746-amino-acid protein with 12-13 transmembrane domains. We have investigated the 11 coding exons of CLCN5 for mutations in eight unrelated patients with Dent's disease. Leukocyte DNA was used for the polymerase chain reaction amplification of CLCN5 and the products analyzed for single-stranded conformational polymorphisms (SSCPs). Abnormal SSCPs were sequenced and revealed eight mutations. These consisted of three nonsense mutations (Arg34Stop, Arg648Stop, Arg704Stop), four deletions involving codons 40, 86, 157, and 241, and one acceptor splice consensus sequence mutation tgcag --> tgaag. The mutations were confirmed either by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis. In addition, an analysis of 110 alleles from 74 unrelated normal individuals demonstrated that the DNA sequence changes were not common polymorphisms. All of the mutations predict truncated chloride channels that are likely to result in a functional loss. Thus, our findings expand the spectrum of CLCN5 mutations associated with Dent's disease and the results will help to elucidate further the functional domains of this novel chloride channel.

[Small patients--big costs: the economic aspects of treating young children with renal failure]. / Kleine Patienten--grosse Kosten: ökonomische Aspekte der Behandlung niereninsuffizienter Kleinkinder.

Since 1985, 20 children have been followed with early onset of chronic renal failure (plasma creatinine > 120 mumol/l in first year of life). So far, 10 and 7 patients underwent peritoneal dialysis and renal transplantation, respectively. The aim of this study was to assess the overall costs. The recorded costs comprised both the direct costs of dialysis and transplantation, and the costs of all medical and psychosocial measures. The annual median costs of conservative treatment, peritoneal dialysis, the year of transplantation, and follow-up after transplantation amounted to 30,000, 93,000, 130,000 and 28,000 Swiss francs, respectively. The youngest patients caused the highest expenses. The active treatment permitted not only survival, but--in most patients--also a normal cognitive and psychosocial development.

An epidemic of acute postinfectious glomerulonephritis in Armenia.

AIM: To evaluate the presentation and course of acute postinfectious glomerulonephritis (APGN), which has increased dramatically in Armenia after serious deterioration in the living conditions. STUDY DESIGN: Observational study, based on case notes, of a large homogeneous group of patients hospitalised for APGN at one centre over a five year period (1992-6). PATIENTS: 474 patients aged < 16 years with a diagnosis of APGN. RESULTS: The annual number of patients increased tenfold from 19 (average 1992/3) to 196 in 1995. Sixty two per cent were in the age group 4-9 years and 65% were boys. Upper respiratory infections, scarlet fever, and skin infections preceded APGN in 51%, 23%, and 13%, respectively. All patients had haematuria (93% gross), 84% had oedema, and 72% had hypertension. C3 was initially decreased in 95% of the patients examined. Renal function was impaired (serum creatinine > 100 mumol/l) in 29%. Four patients with renal failure had crescentic glomerulonephritis at biopsy; of these, three required temporary haemodialysis. Main extrarenal complications were heart failure (10%) and convulsions (3%). One patient died and five (3%) did not recover completely. CONCLUSIONS: APGN in children is associated with considerable initial morbidity, and long term outcome is not uniformly benign. Outbreaks of APGN may occur anytime in countries such as Armenia that are suffering from a sudden decline in socioeconomic conditions.

Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease -- a newly recognized entity?

UNLABELLED: We describe two siblings (female and male) with progressive tubulo-interstitial nephropathy and cholestatic liver disease. The main characteristics were progressive renal failure and elevated liver enzymes (AST, ALT and gamma-GT). Dialysis was started at the age of 1.9 and 6.5 years, respectively. Renal histology disclosed sclerosed glomeruli and atrophic tubules; the interstitium was fibrotic and infiltrated by lymphocytes. Endoscopic retrograde cholangiopancreatography revealed segmental irregularities and narrowing of the intrahepatic bile ducts, consistent with early primary sclerosing cholangitis. Liver histology showed enlarged portal triads, mild proliferation and inflammation of bile ducts, and fibrosis. At 5.9 years the girl underwent a successful renal transplantation whereas the boy is still on dialysis. CONCLUSION: The association of progressive tubulointerstitial nephropathy and cholestatic liver disease, consistent with early primary sclerosing cholangitis, constitutes a distinct autosomal recessive entity.

Postrenal anuria after appendectomy in childhood.

An 11-year-old boy suffered from macroscopic haematuria and bilateral flank pain a few days after uneventful appendectomy for retrocaecal appendicitis phlegmonosa. Ultrasonography revealed a complete bilateral distal obstruction of the ureters. Renal failure due to postrenal anuria resolved completely after intravenous antibiotics.

Heterogeneity of atypical haemolytic uraemic syndromes.

Atypical, non-diarrhoea associated haemolytic uraemic syndrome (D-HUS) is a heterogeneous disorder with a generally poor outcome, although this view has now been questioned. The clinical and laboratory features of 23 children with D-HUS, representing a third of all patients with HUS seen during the last 26 years, were examined. The median age was 4.9 years (range 3 days-13.8 years). Twenty one children (91%) survived the initial phase. All patients except six infants aged < 18 months required dialysis (74%). Hypertension (43%), cardiomyopathy (43%), and cerebral convulsions (48%) were common. Nineteen (83%) children were followed up for a median period of 5.5 years (range 0.5-23.4). Only five (26%) patients, among them four infants, recovered completely. Six (32%) patients had one to 10 recurrences, including two siblings with neonatal onset, and eight (42%) developed end stage renal failure. Five children underwent cadaveric renal transplantation, with recurrence and subsequent graft failure in two. Four children died, resulting in an overall mortality of 26%. Atypical HUS is heterogeneous with regard to epidemiology, pathophysiology, and outcome. Children with a recurrent, familial, or neonatal course have worse outcomes; in contrast, infants not requiring dialysis in the acute phase have a better prognosis.

[Kidney transplantation in the child]. / Nierentransplantation beim Kind.

The goal of treatment of end-stage renal failure in pediatric patients is a functioning transplant. Due to the serious shortage of cadaver kidneys, we have to consider living related donor transplantation (tpl) more frequently. Certain features are characteristic of pediatric patients before transplantation: underlying disease (over 2/3 are congenital or hereditary), the form of dialysis (automated peritoneal dialysis at home in young children) and the frequent need for tube feeding and treatment with growth hormone. Patients weighing 10 kg or more can be given an adult kidney. Young recipients are at risk for vascular thrombosis and hence the CVP should be kept high to allow good circulation, and continuous heparinization (10 units per kg and hour) is advocated. Minor rejection episodes may be overlooked in the presence of a large graft in a small child. Bladder dysfunction is a problem in many children with obstructive uropathy. Later on, viral infections (CMV, EBV) may pose serious problems since most children have not previously been exposed to them. Further problems are pyelonephritis in the graft and recurrence of the underlying disease. Long-term results are very satisfactory in terms of survival and quality of life including later social integration.

Pyelonephritis and vesicoureteral reflux after renal transplantation in young children.

PURPOSE: We assessed morbidity and risk factors of pyelonephritis in children after renal transplantation. MATERIALS AND METHODS: Between 1986 and 1995, 41 children underwent transplantation and all who had documented pyelonephritis were evaluated. RESULTS: Six children who underwent transplantation before age 7 years had 1 to 3 episodes of pyelonephritis with significant renal dysfunction and vesicoureteral reflux into the grafted system. An antireflux reimplantation procedure in 5 children was complicated by temporary functional obstruction in 3. No further infection occurred after correction of vesicoureteral reflux. After a median of 4.5 years post-transplantation all patients have a functioning graft. CONCLUSIONS: After renal transplantation vesicoureteral reflux and young recipient age are major risk factors for pyelonephritis with subsequent graft dysfunction.

New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels.

Nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine in response to vasopressin. The autosomal recessive form of NDI is caused by mutations in the AQP2 gene, encoding the vasopressin-regulated water channel of the kidney collecting duct. This report presents three new mutations in the AQP2 gene that cause NDI, resulting in A147T-, T126M-, or N68S-substituted AQP2 proteins. Expression of the A147T and T126M mutant AQP2 proteins in Xenopus oocytes revealed a relatively small, but significant increase in water permeability, whereas the water permeability of N68S expressing oocytes was not increased. cRNA encoding missense and wild-type AQP2 were equally stable in oocytes. Immunoblots of oocyte lysates showed that only the A147T mutant protein was less stable than wild-type AQP2. The mutant AQP2 proteins showed, in addition to the wild-type 29-kd band, an endoplasmic reticulum-retarded form of AQP2 of approximately 32 kd. Immunoblotting and immunocytochemistry demonstrated only intense labeling of the plasma membranes of oocytes expressing wild-type AQP2. In summary, two mutant AQP2 proteins encoded in NDI are functional water channels. Therefore, the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutant proteins.

A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type 1: lack of relationship between genotype, enzymic phenotype, and disease severity.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of alanine:glyoxylate aminotransferase (encoded by the AGXT gene). Primary hyperoxaluria type 1 is characterized by the elevated urinary excretion of oxalate and glycolate, and the deposition of insoluble calcium oxalate in the renal parenchyma and urinary tract. In the present study, we investigated an unusual family containing four affected individuals in two different generations. Based on our genetic, enzymic, metabolic, and clinical analyses, we have come to the following conclusions. First, although the pattern of inheritance of PH1 is usually horizontal (ie, all patients in the same generation), as expected for an autosomal recessive disease, it can sometimes show a vertical (pseudodominant) pattern of inheritance (ie, patients in more than one generation) due to the segregation within a family of three, rather than two, mutant AGXT alleles. Second, affected members of such a family can manifest very different clinical phenotypes both within and between generations. Although the clinical differences between generations might be at least partly due to differences in AGXT genotype, differences can equally occur within the same generation in individuals who possess the same AGXT genotype. Finally, individuals with PH1 at the level of the AGXT genotype might remain asymptomatic and undiagnosed for many years. The consequences of these findings for the clinical management and genetic counseling of families with PH1 are profound and wide-ranging.