Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins.

While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WTI protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs.

Increased nuclear factor-kappaB and angiotensinogen gene expression in posttransplant recurrent focal segmental glomerulosclerosis.

In an attempt to identify potential markers of steroid-resistance in focal segmental glomerulosclerosis (FSGS) we evaluated intra-graft gene expression of IkappaBalpha, nuclear factor-kappaB (NF-kappaB), and angiotensinogen in 60 biopsies from 27 pediatric renal transplant recipients. Intra-graft NF-kappaB expression was significantly elevated in recurrent FSGS (R-FSGS) (218.3 + 55.6 ag/fg versus NON-FSGS 121.1 + 19.9, P=0.04) but not in acute rejection. NF-kappaB:IkappaBalpha ratios were higher in cadaveric donor versus living related donor recipients (15.7 + 2.8 vs. 8.8 + 1.3, respectively, P=0.015), and in African-American versus Caucasian recipients (15.6 + 2.9 vs. 9.1 + 1.3, respectively, P=0.03). Intra-graft angiotensinogen gene expression was significantly elevated in R-FSGS (30.5 + 8.8 ag/fg R-FSGS vs. 16.0 + 4.7 NON-FSGS, P=0.009). We conclude that increased NF-kappaB and angiotensinogen gene expression are associated with R-FSGS. Increased NF-kappaB:IkappaBalpha ratios are associated with cadaveric donor recipients and African-American race.

D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?

D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.

Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO3- exchanger.

Distal renal tubular acidosis (dRTA) is characterized by defective urinary acidification by the distal nephron. Cl-/HCO3- exchange mediated by the AE1 anion exchanger in the basolateral membrane of type A intercalated cells is thought to be an essential component of lumenal H+ secretion by collecting duct intercalated cells. We evaluated the AE1 gene as a possible candidate gene for familial dRTA. We found in three unrelated families with autosomal dominant dRTA that all clinically affected individuals were heterozygous for a single missense mutation encoding the mutant AE1 polypeptide R589H. Patient red cells showed approximately 20% reduction in sulfate influx of normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid sensitivity and pH dependence. Recombinant kidney AE1 R589H expressed in Xenopus oocytes showed 20-50% reduction in Cl-/Cl- and Cl-/HCO3- exchange, but did not display a dominant negative phenotype for anion transport when coexpressed with wild-type AE1. One apparently unaffected individual for whom acid-loading data were unavailable also was heterozygous for the mutation. Thus, in contrast to previously described heterozygous loss-of-function mutations in AE1 associated with red cell abnormalities and apparently normal renal acidification, the heterozygous hypomorphic AE1 mutation R589H is associated with dominant dRTA and normal red cells.

Autosomal recessive polycystic kidney disease: long-term sonographic findings in patients surviving the neonatal period.

OBJECTIVE: We studied the sonographic findings and the changes in renal function seen on long-term follow-up of children who had the initial diagnosis of autosomal recessive polycystic kidney disease made in the neonatal period. MATERIALS AND METHODS: The case records and sonograms of 14 children with biopsy evidence of autosomal recessive polycystic kidney disease were evaluated. Nine children who survived the neonatal period were followed up for a mean of 13 years (range, 5-19 years) after diagnosis and form the basis of this study. Serial changes in renal size, echogenicity, and function were assessed sonographically. The imaging findings were compared with those described in published reports. RESULTS: The sonographic findings showed that five of the nine children had a decrease in renal size, and three had stable renal size over a minimum follow-up period of 5 years. Only one of the nine survivors showed progressive increase in renal size. All had increased cortical echogenicity and large kidneys. Three patients showed a subjective change in renal echogenicity over time. A change in the echogenic pattern to one that resembles autosomal dominant polycystic kidney disease was noted with no evidence of increase in size of the kidneys. None of the surviving children had renal stones or massively enlarged kidneys. The renal function of seven of the nine survivors has remained stable with creatinine clearance nearly normal (> 60 ml/min/1.73 m2), and there was no correlation between renal size and renal function. CONCLUSION: In patients with autosomal recessive polycystic kidney disease who survive the neonatal period, kidney size as seen on sonograms does not continue to increase despite the patients' linear growth and maintained normal renal function. Rather, a decrease in kidney size and change in echogenicity occurs, producing a pattern that is similar to that seen on sonograms of patients with autosomal dominant polycystic kidney disease but without the marked increase in kidney size that occurs in that entity. This changing cystic pattern on follow-up sonograms may be the reason that previous descriptions of the sonographic findings in cases of autosomal recessive polycystic kidney disease have varied and why a decrease in size may not herald deteriorating renal function.

Genital abnormalities in females with Bardet-Biedl syndrome.

The major manifestations of the Bardet-Biedl syndrome are digital anomalies, tapetoretinal degeneration, obesity, renal abnormalities, and hypogenitalism (described mainly in males). We report on 2 girls with Bardet-Biedl syndrome who also had vaginal atresia. A similar association in females with Bardet-Biedl syndrome was suggested in published reports of 11 affected individuals who had structural genital abnormalities, (some of which were missed in childhood), including persistent urogenital sinus, ectopic urethra, hypoplasia of the uterus, ovaries and fallopian tubes, uterus duplex, and septate vagina. The association of atresia of the vagina and other malformations of female genital structures in individuals with Bardet-Biedl syndrome has often been missed in childhood and should be looked for more systematically.

Second renal transplantations. Ethical issues clarified by outcome; outcome enhanced by a reliable crossmatch.

OBJECTIVE: To determine whether the appropriate use of scarce donor resources has been accomplished by renal retransplantation by reviewing the initial and long-term outcomes of second-renal transplant recipients at the Massachusetts General Hospital, Boston. PATIENTS AND RESULTS: With a mean follow-up of nearly 5 years following transplantation, 54 (68%) of 80 second-transplant recipients had functioning allografts (allograft failure was defined by patient death or a return to dialysis). Rejection was the most common cause of failure (14 [54%] of 26 patients). The 1-, 3-, and 5-year actuarial allograft survival rates were 86%, 78%, and 69%, respectively, which were not significantly different from the survival rates of primary allografts at this center. These results support the continued approach of providing both cadaver-donor and living-donor renal allografts for recipients whose primary renal allograft has failed. The antiglobulin crossmatch may have contributed to the successful outcome by accurately determining compatibility and by averting early rejection failures. CONCLUSIONS: Health care policy reviewers should clearly distinguish the prospects for successful second renal transplants from the outcomes of extrarenal retransplantation. Moreover, because excellent second-renal allograft survival is attainable and comparable to primary-renal allograft survival and because the costs are comparable, restricting suitable patients to subsequent lifelong dialysis becomes unethical.

Varicella in pediatric renal transplant recipients.

As of November 1991, 8 of 83 children who had received renal transplants at Massachusetts General Hospital since January 1979 required admission for primary varicella. All 8 had cutaneous manifestations of disease, and 4 had evidence of visceral disease. Three of these 8 children received varicella zoster immune globulin (VZIG) after exposure to varicella; in the remaining children, exposure was not revealed until symptoms were present. All 8 children were treated with high-dose intravenous acyclovir. Two children died of complications of varicella infection, including 1 child who received VZIG on the day of exposure to varicella. Neither VZIG prophylaxis nor treatment with intravenous acyclovir offers complete protection against severe varicella infection to immunosuppressed children who have received organ transplants. A high priority should be given to the evaluation of alternative treatments, such as vaccination to the varicella virus, which could be administered to susceptible transplant candidates, preferably prior to transplantation.

Increased intraabdominal pressure and anuria in the newborn.

Elevated intraabdominal pressure as a cause of anuria in the critically ill newborn with ascites should be considered after hypovolemia and other causes of intrinsic renal disease or obstruction have been excluded. In the rare patient with ascites who develops anuria, paracentesis should be considered if urine output cannot be established.

Coexisting nephrolithiasis and cholelithiasis in premature infants.

Though the coexistence of nephrolithiasis and cholelithiasis in premature infants is extremely rare, we report four patients seen in a two year period. All patients weighed less than 1100 grams at birth, developed severe bronchopulmonary dysplasia, and all had Grade III or IV bilateral intraventricular hemorrhages. All four infants received prolonged furosemide therapy lasting at least 28 consecutive days. The renal stones disappeared in all four upon cessation of therapy, while in none have the gallstones disappeared after a mean follow-up period of 13 months. Ultrasound was superior in identifying and monitoring these stones. Their presence resulted in manipulating diuretic therapy which then was shown to limit renal and possibly biliary complications.

Infantile polycystic disease of the liver and kidneys.

Kidney and liver tissue from eleven patients with recessively inherited infantile polycystic disease (IPCD) were examined to document the extent of renal tubular cyst formation and hepatic fibrosis, to assess survival, and to examine the usefulness of current classifications. Four infants with 90% or more cystic renal change did not survive beyond twenty days. In contrast five of the seven less severely diseased patients with a 20-75% range of cystic change are still alive at six to twenty-one years of age. Liver samples showed hamartomatous bile duct proliferation in all patients studied with the most prominent portal fibrosis in the oldest patient. In both families with two affected siblings, the clinical course and pathological expression of renal disease were dissimilar. Tissue analysis from these cases is consistent with the idea that IPCD has a spectrum of phenotypic expression with prognostic implications from tissue diagnosis in the individual patient, but not necessarily as four genetically determined rigidly defined subgroups. It is concluded that each affected child with IPCD must be evaluated separately.

Percutaneous ultrasonic lithotripsy of symptomatic renal calculi in children.

Percutaneous ultrasonic lithotripsy of upper urinary tract lithiasis is a well-established procedure in adults. We successfully applied this technique to completely remove symptomatic renal calculi in two children with idiopathic hypercalciuria. The procedure was well tolerated and no complications occurred. Both patients were discharged within 4 days of the lithotripsy. This method is an alternative to surgery for the removal of large or impacted calculi from the upper urinary tracts of pediatric patients.

Parathyroid surgery in patients with renal failure.

A subtotal parathyroidectomy was performed in 32 patients with hyperparathyroidism and renal dysfunction. Minimal long-term sequelae were observed [two patients with recurrent hyperparathyroidism (6.2%), one patient with persistent hypoparathyroidism (3.1%)]. This experience is compared with reports in the literature advocating total parathyroidectomy and autotransplantation. A subtotal parathyroidectomy remains the preferred approach at this institution. Patients with elevated alkaline phosphatase levels before surgery should be monitored carefully for early postoperative hypocalcemia. The low incidence (3.2%) of hyperparathyroidism observed in patients following successful renal transplantation indicates that hypercalcemic allograft recipients should be observed for at least 4 months before contemplating surgical intervention.

Complications of pediatric percutaneous renal procedures: incidence and observations.

Successful definitive (complete) percutaneous renal procedures in the pediatric age group were performed in 97 per cent of antegrade pyelograms, in 94 per cent of ureteral perfusions (Whitaker test), in 98 per cent of nephrostomies, and 100 per cent of both retroperitoneal fluid drainages and renal aspiration biopsies. Significant complications, or those necessitating specific treatment or prolonged hospitalization, were 1.1 per cent. 0.7 per cent, 15.2 per cent, 0 per cent, and 0 per cent, respectively, for the above procedures. Not surprisingly, certain operators are more adept than others at successfully performing procedures and at avoiding some but not all complications (see Tables 2 and 3). Proper training, experience, and adherence to basic principles are important. However, there were no deaths, no kidneys lost, and no transfusions or operations required as a result of any complication from the pediatric percutaneous renal procedures; correction of any existing blood coagulation disorder is necessary prior to their performance to avoid potentially fatal hemorrhage.

Effects of interferon-alpha on cytomegalovirus reactivation syndromes in renal-transplant recipients.

We have previously demonstrated that six weeks of prophylaxis with interferon-alpha delays cytomegalovirus excretion and decreases viremia in recipients of kidney transplants. In a double-blind trial to evaluate the effects of a longer course of prophylaxis, we gave either 3 X 10(6) units of interferon or placebo intramuscularly to 42 patients before transplant surgery was performed. After surgery, doses were given three times a week for six weeks and then twice a week for eight weeks (total of 102 X 10(6) units). Clinical signs of cytomegalovirus infection were markedly reduced in interferon recipients. These signs developed in 7 of 22 placebo recipients and 1 of 20 interferon recipients (P = 0.03). Opportunistic superinfections (Aspergillus fumigatus and Pneumocystis carinii) occurred only in patients given placebo. Cytomegalovirus-associated glomerulopathy developed in one interferon recipient and three placebo recipients. Survival of patients and grafts was equivalent in both treatment groups, and minimal toxicity was observed with interferon. In seropositive renal-transplant recipients, interferon-alpha affords effective prophylaxis against serious cytomegalovirus infections.

Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections.

Forty-nine ambulatory children between 2-1/2 and 12 years of age with acute, clinically uncomplicated urinary tract infections caused by susceptible organisms were randomized to receive a single dose of amoxicillin based on weight or a 10-day course of amoxicillin therapy (conventional therapy). Patients receiving single doses of amoxicillin had a cure rate of 63%, which compares unfavorably with the cure rate of 92% in patients given conventional therapy. A failure of single-dose therapy predicted underlying radiologic abnormalities with a sensitivity of 60% and a specificity of 58%, making it a poor screening test for detecting those patients at risk for renal parenchymal damage. The antibody-coated bacteria assay had no predictive value in separating upper and lower tract disease, although it may predict underlying radiologic abnormalities. The data indicate that the response to single-dose amoxicillin therapy fails to separate upper from lower tract disease reliably and has a limited role in predicting response to conventional antimicrobial therapy.