Thomas R. Welch

C5a is important in the tubulointerstitial component of experimental immune complex glomerulonephritis

Interstitial injury is the hallmark of glomerulonephritis which is progressing to end‐stage renal disease (ESRD). In humans and experimental animals, we have shown that interstitial disease is accompanied by up‐regulation of complement components in tubular epithelial cells. Glomerulonephritis was induced in mice by the intraperitoneal injection of horse spleen apoferritin (HSA) and lipopolysaccharide (LPS). In addition to wild‐type C57/B6 mice, animals in which the C5a receptor had been deleted (C5aR KO) were used. Animals were killed after 3 or 6u2003weeks, and kidneys harvested. At three weeks, both groups had evidence of mild mesangial matrix expansion and increased cellularity; there were no crescents, sclerotic lesions, or interstitial disease. At six weeks, glomerular lesions were advanced, but identical in the two groups. Both groups had evidence of an identical pattern of C3 gene expression in the tubular epithelium by in situ hybridization. There was a marked difference, however, in the extent of interstitial injury. Wild‐type animals had significantly greater numbers of infiltrating interstitial cells, greater expansion of the peritubular space, more tubular atrophy, and more apoptotic tubular cells than did C5aR KOs. The anaphylotoxic fragment of C5, C5a, is not likely to be important in the glomerular component of this model of progressive glomerulonephritis. On the other hand, the interstitial component is markedly attenuated in knockout animals. These data support a role for complement in the interstitial component of this glomerulonephritis model. They are consistent with our hypotheses of a role for complement in the progression of some forms of glomerulonephritis to ESRD.

Total anatomic urinary tract replacement and renal transplantation: a surgical strategy to correct severe genitourinary anomalies.

During renal transplantation, the donor ureter is normally anastomosed to the recipient bladder. However, preexisting anomalies of the lower urinary tract or previous surgical interventions may render the recipient bladder unusable. Although in such situations urine may be externalized via cutaneous ureterostomy or an ileal conduit, both techniques are frequently complicated by bacterial colonization or chronic infection. To overcome these problems, the authors have been treating such children via extensive, staged, bladder reconstruction (augmentation) before transplantation. On rare occasions, however, the absence of a usable bladder necessitates the creation of a complete neobladder from other visceral tissues. The authors present two cases in which patients underwent complete anatomic reconstruction of the lower urinary tract before renal transplantation. This approach results in the optimal environment for allograft function and leads to a greater rehabilitation than that achieved with urinary diversion.

Humoral factor in children with neonatal Bartter syndrome reduces bone calcium uptake in vitro.

Abstract. The neonatal Bartter syndrome (NBS) is associated with a complex disorder of mineral metabolism in children, including hypercalciuria, nephrocalcinosis, and diminished bone mineral density. Although cyclooxygenase inhibition usually brings about improvement in these findings, there is a variable component which is resistant to such therapy in many children. The factor mediating this disorder has not been identified. Blood and urine from 12 children with NBS were examined. When compared with samples from normal children and adults, all (NBS) sera reduced bone calcium uptake in a bone disc bioassay. This effect persisted in the presence of parathyroid hormone (PTH) antibody and PTH receptor blockade, indicating that neither PTH nor PTH related peptide was responsible. It was eliminated by indomethacin, suggesting that prostanoid generation was essential. Protamine was also inhibitory, as was the addition of ecteola, an anion binder. Activity could be recovered from ecteola by elution with hypertonic buffer. Urine samples from children with NBS had the same calcitropic effect. The agent was removed by ecteola and recovered by hypertonic elution. Activity was eliminated by protamine and by heparinase, but not by trypsin digestion. Size exclusion centrifugation showed that the activity was associated with a material between 10 and 30 kilodaltons. Finally, urine ecteola eluates from NBS patients raised serum concentrations of calcium after intraperitoneal injection in rats. These data suggest that children with NBS have a calcitropic substance in their serum and urine which is not found in normal individuals. The substance is heparin like, and mediates its effects through prostanoid production. These studies provide additional evidence against a direct renal cause of the urinary calcium disturbance characteristic of the disorder.

The Hyperprostaglandin E Syndrome: A Hypercalciuric Variant of Bartter's Syndrome

C WAS THE PRODUCT of a 34-week pregnancy, complicated by polyhydramnios and preterm delivery. His neonatal course was unremarkable, except for marked electrolyte wasting requiring sodium and potassium chloride supplements. Over the ensuing months he had poor growth and required several hospitalizations for dehydration. A number of metabolic disturbances were evident, including hypokalemia, alkalosis, hypercalcemia, and hypercalciuria. He was noted to have a high output of dilute urine. At the age of 3 years, a number of investigations were undertaken to determine the cause of these findings. By physical examination, he was below the third percentile for height and weight, but otherwise normal. His development was age-appropriate. His serum electrolytes showed a mild hypokalemic alkalosis (serum potassium 2.3 mEq/l; serum bicarbonate 27 mEq/l). His serum calcium was 10.8 mg/dl, but his urinary calcium excretion was significantly elevated

STRONG ASSOCIATION OF HLA-DR8 WITH STEROID RESPONSIVE NEPHROTIC SYNDROME |[lpar]|SRNS|[rpar]| OF CHILDHOOD

We searched for possible immunogenetic markers in SRNS of childhood in 4 different families and children having SRNS. Family A had a boy with SRNS whose father had been treated for childhood SRNS. Family B had 2 first cousin girls and Family C had 2 first cousin boys with SRNS. Family D had a brother and sister with SRNS. HLA-A, -B, -DR antigens were typed, serum C4 and factor B alleles were tested and compared to a group of 30 children with SRNS and a control group of normal individuals. In SRNS the frequency of DRW-8 was 23.5% compared to the normal control 5.9%. DRW-8 was also present in the family with the 2 sibs and 1 family where first cousins had SRNS, but not in the other families. The relative risk of DRW-8 and SRNS measured 5.6. There was a decreased frequency of HLA-BW35 and DRW1, but other HLA-A, HLA-B locus antigens, C4 alleles and factor B alleles occurred in normal frequencies. This report involving families and an unrelated population of children with SRNS failed to find the previously associated increased frequency of DRW-7 and the HLA-B12 nor the increased frequency of relapsing SRNS in children with the factor B-F allele. The significance of genetic haplotyping and completyping in children with SRNS will be discussed and the possible relationship and pathogenesis to an MHC-linked Ir gene.