X-Linked Recessive form of Nephrogenic Diabetes Insipidus in a 7-Year-Old Boy.

Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family.

Factors affecting growth and final adult height after pediatric renal transplantation.

BACKGROUND: Growth retardation is a common problem for children with chronic kidney disease. Although renal transplantation (RTx) resolves endocrine metabolic and uremic disturbances, growth continues to be suboptimal. This study aims to describe changes in height from diagnosis to final adult height (FAH) in Korean renal allograft recipients and determine factors associated with posttransplantation growth. METHODS: We retrospectively reviewed 63 renal allograft recipients who underwent RTx at <15 years of age with regular follow-up for >3 years afterwards. Pre- and post-RTx growth was analyzed by height Z scores (Ht_Z) at RTx, 2 and 5 years follow-up, and at FAH. RESULTS: Ht_Z decreased from diagnosis to dialysis by -0.8 (P = .009) and from dialysis to RTx by -0.46 (P < .001). The mean baseline Ht_Z at RTx was -1.62 ± 1.36. The change in Ht_Z at 2 and 5 years after transplantation was 0.68 ± 0.88 and 0.48 ± 0.86, respectively. Both variables were negatively correlated with baseline age at RTx. Mean FAH was -1.22 ± 1.11 and was positively correlated with baseline height at RTx. Height at start of dialysis and dialysis duration were significant determinants of baseline height at RTx (P < .001). CONCLUSIONS: Although there is significant posttransplant catch-up growth among younger recipients and among those with greater baseline height deficit, catch-up growth is not sustained and greater FAH is attained in those who are taller at RTx. Achieving greater height before dialysis and decreasing dialysis duration leads to maximal height at RTx as well as greater FAH.

Transcriptome analysis of the response of cultured murine podocytes to puromycin aminonucleoside.

AIMS: Idiopathic nephrotic syndrome is known as a disease of the renal glomerular epithelial cells (podocytes). Recent advances in podocyte biology showed that podocytopathy is the culprit of nephrotic syndrome. To obtain comprehensive information about the response of podocytes to injury, we investigated the gene expression profile of podocytes in response to puromycin aminonucleoside (PAN)-induced injury. METHODS: Differentiated mouse podocyte cell line (MPC5) cells were treated with 25 microg/ml PAN for 24, 48, or 72 h. Gene expression profiles of these cells were analyzed. Real time PCR analysis was used to confirm the findings of microarray. RESULTS: Expression levels of 23 genes (differentially expressed genes, DEGs), including laminin alpha(1) and MMP3, were significantly different between PAN-treated podocytes and untreated cells. Gene ontology of DEGs indicated that their functional categories were cell adhesion, extracellular matrix (ECM) formation, and ECM degradation. Real-time PCR and indirect immunohistochemistry of PAN-treated and untreated podocytes confirmed the differential expression of DEGs. CONCLUSION: Using unbiased global gene expression profiling, we found that podocytes respond to PAN-induced injury by down-regulating the expression of genes involved in cell adhesion and extracellular matrix.

Ifosfamide nephrotoxicity in pediatric cancer patients.

The renal functions in pediatric cancer patients who received ifosfamide (IFO) treatment were evaluated and the risk factors related to IFO nephrotoxicity were determined. The medical records of all children treated with IFO were reviewed, and 62 with normal renal function before IFO treatment were selected. Nephrotoxicity was diagnosed by measuring urine beta2-microglobulin and glucose, and serum phosphate, bicarbonate, and creatinine. Forty-eight (77.4%) had a history of previous cisplatin treatment. Nephrotoxicity was detected in 20 patients (32.3%). beta2-Microglobulinuria was observed in all 20, hypophosphatemia in 10 (16.1%), hypocarbia in 2 (3.2%), glucosuria in 5 (8.1%), and decreased creatinine clearance in 7 (11.3%). The cumulative dose of IFO and a history of previous cisplatin therapy were related to nephrotoxicity. Among the 20 patients with nephrotoxicity, the median cumulative dose of IFO in patients with a low (<500 mg/m2) and high (>500 mg/m2) cumulative dose of previous cisplatin was 80 g/m2 (73-102 g/m2) and 45 g/m2 (11-76 g/m2), respectively. Most of the nephrotoxicity persisted after cessation of IFO treatment. In conclusion, close monitoring of IFO nephrotoxicity should be started earlier in patients with high-dose cisplatin pretreatment. Tubular proteinuria, as indicated by beta2-microglobulinuria, was the most-sensitive marker for IFO nephrotoxicity. Long-term follow-up study for reversibility of IFO nephrotoxicity is in progress.

Circulating VEGF and TGF-beta1 in children with idiopathic nephrotic syndrome.

RATIONALE: The implications of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta) on the development of proteinuria were studied by measuring the mRNA and protein levels of VEGF and TGF-beta1 in 43 children with primary nephrotic syndrome. METHODS: Twenty-seven patients were in the active nephrotic phase at the time of sampling (Group 1), and 16 were in remission (Group 2). In Group 1, 16 were steroid-responders (Group 1a) and 11 were nonresponders (Group 1b). Minimal change lesion (MCL) in 11 patients and focal segmental glomerulosclerosis (FSGS) in 8 were confirmed by renal biopsy. The mRNA expressions of peripheral blood lymphocytes and the plasma levels of proteins were measured by semi-quantitative RT-PCR and ELISA, respectively. RESULTS: Plasma VEGF concentration was higher in Group 1 (204+/-137 pg/mL) than Group 2 (91+/-72 pg/mL) (P=0.002). However, there was no significant difference either between Group 1a (184+/-146 pg/mL) and Group 1b (258+/-134 pg/mL) or between patients with FSGS (330+/-122 pg/mL) and those with MCL (146+/-112 pg/mL). The VEGF mRNA expression showed changes similar to VEGF protein expression, and there was no statistical significance. Plasma levels and mRNA expressions of TGF-beta1 were similar in all groups. CONCLUSIONS: These results suggest that circulating VEGF is associated with proteinuria both in steroid-responsive and steroid-resistant primary nephrotic syndrome in children.

Recurrent focal segmental glomerulosclerosis following renal transplantation in Korean pediatric patients.

The recurrence of focal segmental glomerulosclerosis (FSGS) in transplants is a well-known problem in pediatric renal transplantation (Tx). Recently, the race of the recipient was recognized as a major variable associated with disease recurrence. In view of this finding, we report on our single-center experience of FSGS recurrence in Korean children, an ethnically homogeneous Far East Asian population. Clinical records and renal biopsy specimens, both native and graft, were reviewed for all pediatric renal Txs (recipient age < or = 18 yr) performed at Seoul National University Hospital from 1984 to 1999. Twenty-two children with primary FSGS received 22 allografts for renal replacement. The mean age of disease onset in these patients was 5.9 yr. The grafts were from 12 living-related, six living-unrelated, and four cadaveric donors, and all recipients were immunosuppressed with cyclosporin A (CsA)-based regimens. Post-transplant recurrence of FSGS was confirmed in nine patients (41%). Long-term graft survival in recurrent and non-recurrent groups was not significantly different. Risk factor analysis showed that patients with a disease duration shorter than 48 months (odds ratio 11.7, 95% CI 1.53-89.1) and a glomerulosclerosis percentage of < 55% by renal biopsy (odds ratio 16.0, 95% CI 1.45-176) were at greater risk of disease recurrence. These results suggest that Korean children are similar to non-African-American youngsters in the USA and Europe with respect to post-transplant recurrence of FSGS. The same may be true of other Far Eastern Asian children.

The effect of C677T mutation of methylene tetrahydrofolate reductase gene and plasma folate level on hyperhomocysteinemia in patients with meningomyelocele.

To evaluate the relationship between genotypes of methylene tetrahydrofolate reductase (MTHFR), and plasma folate and homocysteine (Hcy) levels in meningomyelocele, 21 Korean patients, 47 of their family members, and 43 healthy controls were recruited. The presence of C677T mutation in the MTHFR gene and plasma concentrations of folate/Hcy were investigated. The genotype frequency of C677T mutation was not higher in study groups (patients and family members). The plasma folate concentration showed no difference either between the study and the control groups or among MTHFR-genotypic groups. The plasma Hcy concentration in homozygotes in the study group was higher than that in the control group, and higher than that in heterozygotes when plasma folate levels were low (P=0.006). Although neither MTHFR genotype nor plasma folate/Hcy level plays a definite part on its own, they seem to have an additive effect on the occurrence of meningomyelocele. Our results support folate supplementation for the prevention of hyperhomocysteinemia and meningomyelocele.

Association of angiotensin I converting enzyme gene polymorphism with reflux nephropathy in children.

Deletion polymorphism of angiotensin I converting enzyme (ACE) gene has been studied as a risk factor in various cardiovascular diseases and chronic nephropathies. Perturbation of local and systemic renin-angiotensin systems is one of the possible mechanisms of the progression of reflux nephropathy. In this study, the implication of ACE gene polymorphism in renal scarring and deterioration of renal function was analyzed in 66 children with vesicoureteral reflux. The genotype for the polymorphism was determined by PCR, and renal scar was identified by (99m)Tc-DMSA renal scan. The allelic frequency of the deletion polymorphism showed no significant difference either between patients with normal renal function and those with decreased renal function or between patients with renal scar and those without. We conclude that deletion polymorphism of ACE gene, as an independent variable, is not associated with reflux nephropathy in children with vesicoureteral reflux.

Mutational analysis of COL4A5 gene in Korean Alport syndrome.

Mutational analysis of the COL4A5 gene in X-linked Alport syndrome (AS) requires an expensive and time-consuming procedure with a detection rate of 50%, at best. There have been three multicenter collaborative studies of mutation analysis in the COL4A5 gene using systematic screening of entire coding regions of the gene. This is a similar study executed in a single center in Korea. Twenty-five unrelated Korean patients with AS in whom the diagnosis was confirmed pathologically were included in the study. By systematic screening of all 51 exons of the gene using polymerase chain reaction/single-strand conformation polymorphism analysis, ten mutations were detected in 10 unrelated patients. These included one medium-sized deletion involving exon 49-51, one single base pair deletion, one nonsense point mutation, one splice site mutation, and six missense point mutations. Of the six missense mutations, four involved a glycine residue and disrupted the Gly-X-Y repeats in the collagenous domain. The overall detection rate of mutations was 40%. Although DNA analysis in AS is currently not applicable to routine clinical diagnosis due to several practical and technical problems, it is likely to replace morphological diagnosis in the near future.

Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis.

BACKGROUND: We analysed risk factors to predict the recurrence of nephrotic syndrome and the therapeutic efficacy of plasmapheresis combined with oral cyclophosphamide (PE+CPM) in early recurrent nephrotic syndrome after transplantation in children with focal segmental glomerulosclerosis (FSGS). METHODS: Medical records after 1990 of 16 children with biopsy-proven idiopathic FSGS and renal transplantation before the age of 18 years were reviewed. RESULTS: Early recurrence of nephrotic syndrome developed in six cases (37. 5%). While early kidney graft biopsies, performed within the first week after the onset of recurrence, revealed diffuse effacement of foot process only, late biopsies contained segmentally sclerosed glomeruli as well. Among several possible risk factors, the mean duration from onset of original nephrotic syndrome to development of end-stage renal disease was shorter in the recurrent group (P=0.045) and the percentage of globally sclerosed glomeruli was higher in the non-recurrent group (P=0.001). PE+CPM therapy resulted in complete remission of nephrotic syndrome if it was started early and if there was no evidence of accompanying acute rejection. CONCLUSION: These results support more liberal use of living-related donors for renal transplantation of children with FSGS and ESRD, considering the shortage of cadaveric donors in our society and relatively good efficacy of the early and intensive PE+CPM therapy for early recurrent nephrotic syndrome.

Hereditary glomerulopathy associated with a mitochondrial tRNA(Leu) gene mutation.

Several cases of hereditary glomerulopathy associated with an A to G transition at position 3243 in mitochondrial DNA, which is known to be associated with most cases of MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), have been recently reported. These patients share the characteristics of hereditary progressive glomerular disease and hearing loss with Alport syndrome. We therefore screened 27 patients with kidney disease clinically mimicking Alport syndrome for the presence of the 3243 mitochondrial mutation, and found one girl with the mutation and a positive family history. Her clinical features were very similar to those of all cases reported to date. An absence of hematuria, severe kidney involvement in a female, pathological changes of focal segmental glomerulosclerosis with no basket-weave change of the glomerular capillary wall, and the frequent association of steroid-induced diabetes are the major features that distinguish this condition from Alport syndrome. Careful neurological examination may detect neuromuscular symptoms compatible with mitochondrial cytopathies. In conclusion, progressive glomerulopathy should be included in the broad spectrum of mitochondrial cytopathies, especially in cases of MELAS syndrome. This mutation should also be included in the etiologies of secondary focal segmental glomerulosclerosis and in the differential diagnosis of Alport syndrome.

Renovascular hypertension in children with moyamoya disease.

OBJECTIVES: To examine the incidence, clinical and radiologic findings, and response to treatment of renovascular hypertension (RVHT) in moyamoya disease (MMD). METHODS: A retrospective analysis of medical records in six RVHT cases (8.3%) among 72 MMD patients observed from November 1987 to December 1995. RESULTS: The age at onset of MMD ranged from 9 months to 7 years 1 month (mean, 3.3 years). The most common initial manifestation of MMD was transient ischemic attack. Hypertension was detected between 4 years 4 months and 12 years 3 months (mean, 7.87 years). Unstimulated plasma renin activity was elevated in all six cases. Renal ultrasonography and captopril technetium 99m-labeled dimercaptosuccinic acid scan showed abnormal findings in four of five and in three of four available studies, respectively. However, both imaging studies showed abnormal findings only in the most severely affected kidneys even with bilateral renal artery stenosis. Renal arteriography revealed bilateral lesions in three of the patients and unilateral lesions in the others. Renal angioplasty was performed in four cases but was successful in only one and partially successful in another. A renal artery specimen obtained during renal autotransplantation showed intimal fibroplasia. At the last follow-up, one patient had normal blood pressure without the use of antihypertensive agents, but the other five patients needed this medication to control blood pressure. CONCLUSION: Because RVHT may be more commonly associated with MMD than has hitherto been appreciated, it is recommended that blood pressure be carefully followed and that diagnostic procedures for RVHT be carried out in hypertensive patients with MMD.

Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is caused by the complete deficiency of hypoxanthine guanine phosphoribosyl-transferase (HPRT). By the analysis of genomic DNA and mRNA using the polymerase chain reaction (PCR) technique coupled with direct sequencing, five independent mutations in HPRT genes have been identified in Korean Lesch-Nyhan families. Two novel mutations and three previously reported mutations have been found in five independent families. Heterozygous carriers were detected in all the families, and prenatal diagnosis was carried out in two families.

Six novel mutations in the vasopressin V2 receptor gene causing nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease caused by mutations in the vasopressin V2 receptor (AVPR2) gene. We analyzed the AVPR2 gene in 6 unrelated Korean families with X-linked NDI, and found 6 novel mutations. Two of them were missense point mutations, 2 were short deletions causing frameshifts, 1 was a duplication of 9 bases, and 1 was a compound gene rearrangement. Four mutations cosegregated with the clinical phenotype in corresponding family members, and one was a de novo mutation. In 1 family, prenatal diagnosis was made by amniocentesis. In conclusion, we found 6 novel mutations in the AVPR2 gene causing X-linked NDI in 6 families, and direct mutational analysis is now applicable for carrier detection and early (prenatal) diagnosis.

Diagnosis of Yersinia pseudotuberculosis infection by polymerase chain reaction.

BACKGROUND: The diagnosis of Yersinia pseudotuberculosis infection is usually based on serologic and/or bacteriologic tests. However, successfully culturing Y. pseudotuberculosis is difficult, and serologic tests in many cases require at least two serial sera obtained during 1-week intervals to confirm rising agglutination antibody titers. METHODS: We applied a nested polymerase chain reaction method for rapid diagnosis of Y. pseudotuberculosis infection. The DNAs extracted from the peripheral blood and urine of patients and from mountain water, a suspected source of infection, were used as templates for the polymerase chain reaction with consequent amplification of a fragment of the inv gene in the chromosomal DNA of Y. pseudotuberculosis. RESULTS: The overall rate of diagnosis with the polymerase chain reaction, which was based on a positive result with a single blood sample or one or more positive results with serial samples, was 93.3%. The polymerase chain reaction was also positive in two mountain water samples that were thought to be a source of infection. CONCLUSION: Based on our results the nested polymerase chain reaction method can be used clinically for rapid and precise diagnosis of Y. pseudotuberculosis infection.