Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Soluble Fas and soluble Fas-ligand in children with Escherichia coli O157:H7-associated hemolytic uremic syndrome.

We measured soluble Fas-ligand (sFas-L) and soluble Fas (sFas) levels by sandwich enzyme-linked immunosorbeny assay and compared them among (1) healthy controls (n = 11), (2) children with hemorrhagic colitis (HC) caused by a non-verotoxin-producing pathogen (n = 23), (3) patients with uncomplicated Escherichia coli O157:H7 HC (n = 14), and (4) children with O157:H7-associated hemolytic uremic syndrome (HUS) (n = 24). Children with uncomplicated E coli O157:H7 HC and HUS were matched for duration of enteric prodrome before blood sample collection. We also compared sFas-L and sFas levels among patients with HUS according to severity of renal dysfunction; abnormally increased sFas-L levels were noted in only 4% of the children (n = 3). Abnormally high concentrations of sFas were noted in 9% of the children with HC caused by a non-verotoxin-producing pathogen, 29% of the patients with uncomplicated E coli O157:H7 HC, and 69% of the children with O157:H7-associated HUS. Compared with healthy controls, patients with HUS had twofold greater concentrations of sFas (P: < 0.0001). Levels of sFas were not statistically different between 14 patients with uncomplicated O157:H7 HC and 14 children with HUS (8.2 +/- 4.7 versus 11.0 +/- 4.6 U/mL, respectively; P: < 0.07) when matched for time after onset of enteritis (7.0 +/- 3.7 versus 7.3 +/- 3.8 days, respectively). Greater concentrations of sFas were noted in patients with HUS who developed oligoanuria (n = 10; P: < 0.007), required peritoneal dialysis (n = 10; P: < 0.007), or had a decreased glomerular filtration rate (n = 5; P: < 0.002) 1 year later. Our data show that plasma concentrations of sFas but not sFas-L are abnormally increased in children with O157:H7 infections. Levels of sFas are associated with severity of renal dysfunction during HUS. Further studies are needed to clearly determine the role and origin of circulating sFas among children with infections caused by E coli O157:H7.

Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome.

BACKGROUND: Fewer than 10% of children with Escherichia coli O157:H7 enteritis develop hemolytic-uremic syndrome (HUS). OBJECTIVE: To determine whether circulating leukocytes are independent risk markers of developing HUS during E. coli O157:H7 enteritis. METHODS: We reviewed the charts of all children with culture-proved E. coli O157:H7 infections seen at Sainte-Justine Hospital between 1987 and 1997. Epidemiologic data, laboratory indices and circulating leukocytes counts were noted. HUS diagnosis was validated with independent HUS patient lists from the pediatric nephrology services of tertiary care hospitals in the Montreal metropolitan area. The date of onset of enteritis was determined by two independent observers. Leukocyte counts were compared among the following independent groups: (1) uncomplicated O157:H7 enteritis (Group 1); (2) O157:H7 enteritis with the subsequent development of HUS (Group 2); (3) HUS already present at the time of medical consultation (Group 3). RESULTS: There were 369 children with E. coli O157:H7 infection. A complete blood count was not performed in 114 (31%) patients. Observers disagreed on the date of onset of gastroenteritis in 34 (9%) children only (kappa 0.92). The study population thus included 221 patients: Group 1, n = 161; Group 2, n = 27; and Group 3, n = 33. Patients developing HUS (Group 2) presented greater total leukocyte (P < 0.008), polymorphonuclear (P < 0.008) and monocyte (P < 0.07) counts than those with an uncomplicated course (Group 1). Logistic regression analysis showed that young age [odds ratio (OR), 0.98; 95% confidence interval (CI), 0.96 to 0.99], duration of enteric prodrome < or =3 days (OR 4.8, 95% CI 1.13 to 20.7) and initial leukocytosis (OR 1.22, 95% CI, 1.11 to 1.35) were independent predictors of HUS. CONCLUSIONS: Based on the variables identified above, further studies are needed to determine whether the inflammatory response of the host represents only a marker of the severity of gastrointestinal infection or whether, alternatively, it is a pathophysiologic factor that leads to HUS.

Study of psychosocial parameters related to the survival rate of renal transplantation in children.

The purpose of the present study was to assess the effect of intelligence, schooling, psychomotor, emotional, and social status on renal graft survival in children. Sixty-two cadaver renal transplant recipients were evaluated retrospectively and the influence of sex, age, weight, and the use of cyclosporin A (CyA) on the success rate of the graft from 1 to 5 years later was analyzed. Psychological and social scores were devised and included as factors predictive of survival of the graft. Univariate analysis showed that the following variables predicted renal graft survival: the use of CyA (P = 0.0002), pre-transplant dialysis (P = 0.04), weight at the time of transplantation (P = 0.072), and psychological scores (P = 0.064). Association analysis demonstrated that pre-transplantation dialysis was only a chance association and therefore the parameter was discarded. Multivariate analysis showed that the predictive parameters were the use of CyA, sex, weight in kilograms, and the psychological score. An equation was then derived from variables that predict the probability that a specific patient's graft will survive more than t months. This equation is the estimated survival distribution function and is as follow: S (t) = Exp {-Exp[-(0.8882x1 - 1.827x2 + 0.037x3 - 0.1746x4) + ln t - 4.7862]} where S (t) = the survival at t months post transplantation, x1 = sex (male 1, female 2), x2 = CyA (yes 1, no 2), x3 = weight in kilograms, and x4 = psychological score. The major impact of psychological factors on renal graft survival was surprising.

Focal segmental glomerulosclerosis (FSG) 20 years later. From toddler to grown up.

In 1981, we reported the outcome of 25 children with FSG after a follow-up of 10 years. In 1991, all the living patients were reevaluated. Ten patients are now in sustained remission. Four patients still present heavy proteinuria with a normal glomerular filtration rate, four required dialysis and seven patients have died. The renal survival curve has stabilized at 56%. These data show an overall outcome slightly more favourable than we had initially reported in 1981. The difference probably stems from our referral system which enables us to see the patients at an earlier stage of their disease. The percentage of deaths is important. Among the various clinical or histological factors of predictive prognostic value only the degree of interstitial damage has reached statistical significance (p < 0.02).

[Development of organ transplantation in Quebec from 1985 to January 1990]. / Evolution de la transplantation d'organes au Québec de 1985 à janvier 1990.

In Québec, the first organ transplantations have been realized in 1958. Several kidney transplant programs started at that time. Cardiac, liver, pancreas and lungs programs followed and reached a full development in the eighties when Cyclosporin became available. Today, there are 4 university transplant programs in Québec (McGill, Montréal, Laval and Sherbrooke) with a total of 7 kidney, 4 liver, 4 heart, 2 pancreas and 2 lungs centers. More than 2,900 transplantations have been realized. Since 1970, organ procurement and distribution is organized by a central agency called Québec-Transplant (previously Métro-transplantation). Organ donation is done on a voluntary basis as every where in North America. More than 90% of the organs comes from cadaveric donors and more than 90% of the relatives accept organ donation. 50% of the donors have deceased from head trauma and 50% from cerebral hemorrhage. In 1989, multi-organ harvesting has been realized in 64% of the donors. Despite efforts and progresses, the number of patients awaiting an organ transplant is steadily growing and outlast the number of available organs. It is hoped that maximal utilisation of the donors and growing exchanges at a national and international level will help to solve this crucial problem.

The concept of corticosteroid cataractogenic factor revisited.

Formation of posterior subcapsular cataracts is a known complication of systemic corticosteroid therapy. However, the relation between steroid dosage, cumulative dose and type of steroid on one hand and the subsequent formation of cataract on the other is unclear. We carried out a study to determine the incidence of posterior subcapsular cataracts in 64 children who had undergone renal transplantation and to attempt to determine what factors were associated with cataract formation. Cataracts were detected in 17 (26%) of the patients. The steroid dosage, cumulative dose and duration of therapy were not associated with cataract formation. There was a significant difference in the distribution of HLA-CW3 antigen between the patients with cataracts and those without cataracts. The reason for the link between corticosteroid therapy and formation of posterior subcapsular cataracts remains unclear.

[Continuous peritoneal dialysis in children]. / La dialyse péritonéale chronique chez l'enfant.

Thirty-two uremic children were treated by chronic peritoneal dialysis (CPD) since February 1982. Fifteen chose chronic ambulatory peritoneal dialysis (CCPD) while the 17 others were treated by continuous cycle peritoneal dialysis (CCPD). To this day, 10 patients (31%) are alive with a functioning kidney transplant, 16 (50%) are still treated by CPD awaiting a transplant, 5 have died (16%) and one went back to hemodialysis (3%). Complication in ranking order were peritonitis, mechanical drainage problems of the catheter and hernias. Linear growth was from good to excellent in the majority of patients. Globally, CPD was found to be attractive mainly because it allows a good quality of life.

Reliability of plasma creatinine measurement in infants and children.

Plasma creatinine (Pcr, mg/dl) is often used to estimate glomerular filtration rate (GFR) in children. To establish whether the clinician can rely on the commonly used methods for measuring Pcr, the authors analyzed data from their own modified Technicon Autoanalyzer reference method and compared them to those obtained simultaneously from a Beckman Astra 8 kinetic Jaffe technique or a Technicon continuous flow Jaffe endpoint SMAC method. The SMAC method consistently overestimated Pcr by 0.1 mg/dl, whereas the kinetic method resulted in a large spread around the reference values. Neither laboratory gave consistent results for Pcr below 0.55, the normal range for infants and young children. The SMAC technique tended to underestimate GFR by 20 to 30 percent, whereas the kinetic method resulted in a great deal of scatter (only 37% of the measurements fell within +/- 25% of the values for GFR obtained by the reference method). The results suggest that the subtraction of 0.1 mg/dl from the Pcr measured on the SMAC system would give a value similar to that obtained with the reference method. This correction would permit the use of an estimate of GFR from kL/Pcr, where L is body length in cm and k is a constant (equalling 0.45 in term infants, 0.55 in children, and 0.7 in adolescent boys). The kinetic method requires repetitive determinations of Pcr before any firm conclusions can be drawn about GFR because of the scatter. The reliability of the clinician's laboratory can be tested by sending half the plasma to the laboratory on one day and the other half the next.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism by taurine of morphine induced growth hormone secretion.

The intraperitoneal (IP) or intraventricular (IVT) administration of small amounts of taurine did not modify pentobarbital-induced sleep or pituitary hormone release. However, the drastic increment in plasma GH values induced by morphine administration was completely blocked by the IVT injection of the amino acid. Whether taurine plays a physiological role in the control of GH secretion is highly speculative.

Effects of thyrotropin-releasing hormone on prolactin, growth hormone and corticosterone secretions in adult male rats treated with pentobarbital or morphine.

Thyrotropin-releasing hormone (TRH) injected either IP (10 mg/kg) or intraventricularly (10 mug/rat) antagonized the pentobarbital-induced secretion of prolactin (PRL). This effect was not blocked by propranolol. In thyroidectomized animals the effect was not apparent; tri-iodothyronine (T3) injection was however ineffective. The injections of luteinizing hormone-releasing hormone (LH-RH) and of melanocyte stimulating hormone release-inhibiting factor (MIF) were also ineffective. Of six TRH analogues, only those containing histidine antagonized pentobarbital-induced PRL release, but none modified plasma levels of growth hormone (GH) or corticosterone (B). Brain levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were not modified by TRH. Morphine-induced secretion of PRL and GH was also significantly antagonized by TRH. Since pentobarbital and morphine-induced hormonal changes are probably exerted through a central nervous system depressant action, these data indicate that TRH can influence brain activity through an extrapituitary mechanism.

Inhibition of pentobarbital-induced release of growth hormone by thyrotropin releasing hormone.

TRH antagonized the GH releasing effect of pentobarbital anesthesia as well in normal as in thyroidectomized rats, and significantly increased plasma B levels in normal animals. This effect was also observed when TRH was administered into a lateral ventricle of the brain in ug amounts, and was suppressed by the beta-adrenergic receptor blocker propranolol. T3 also antagonized the pentobarbital-induced release of GH; however, plasma B levels were not modified, and the effect on plasma GH levels was not suppressed by propranolol.