Frederick J. Kaskel

Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia

The imbalance between normal insulin-like growth factor-I (IGF-I) and markedly increased IGF binding protein (IGFBP) plasma levels plays a pathogenic role for growth retardation and catabolism in children with chronic renal failure. To investigate the mechanism of these alterations, experiments were performed in an experimental model of uremia in rats (5/6 nephrectomy) and in pair-fed and ad libitum-fed sham-operated controls. Using a specific solution hybridization/RNase protection assay, we observed a marked reduction of hepatic IGF-I messenger RNA (mRNA) abundance at steady state in uremic animals (37 ± 5% of control) compared both with pair-fed (65 ± 10%) and ad libitum-fed controls (100± 11%) (P < 0.001). Reduced IGF-I gene expression was clearly organ-specific; it was most pronounced in liver (significant vs.. pair-fed controls) and lung and muscle tissue (significant vs.. ad libitum-fed controls); no change was observed in kidney and heart tissue. To determine a potential mechanism of reduced hepat...

Posterior urethral valves in patients with Down syndrome

Renal and urological anomalies in Down syndrome (DS) have received little attention compared with the nephrourological findings described in other chromosomal abnormalities. Renal hypoplasia, hydroureteronephrosis, ureterovesical and ureteropelvic junction obstruction, and vesicoureteral reflux, but not posterior urethral valves, have been associated with DS. We report the occurrence of posterior urethral valves in three male infants with DS at a single institution. All had multiple urological procedures for correction or palliation of obstruction. Children with DS may have an increased risk for developing posterior urethral valves and obstructive uropathy. Furthermore, they may also develop chronic renal failure secondary to posterior urethral valves. Therefore, we suggests that infants with DS be screened with ultrasonography for renal and urological abnormalities early in life and, if abnormal, a contrast voiding cystourethrogram be performed to rule out posterior urethral valves or other bladder or urethral abnormalities. A review of the renal and urological anomalies in DS reported in the literature since 1960 is presented.

Role of endothelin in the development of dahl hypertension

To evaluate the possible role of endothelin in the development and/or maintenance of hypertension in Dahl rats, we examined the responsiveness of isolated vascular smooth muscle and glomerular mesangial cells, as well as deendothelialized vascular ring preparations to endothelin-1 (ET-1). Production of immunoreactive endothelin (ir-ET) was studied in freshly isolated glomeruli and renal medullary slices. Both glomerular mesangial cells and vascular smooth muscle cells obtained from prehypertensive Dahl-S rats exhibited an exaggerated [Ca2+]i response to ET-1, as compared with cells obtained from Dahl-R rats. This was paralleled by the enhanced isometric contraction of vascular rings obtained from prehypertensive Dahl-S rats. ir-ET production was doubled in response to 0.1 mM ouabain in tissue samples obtained from prehypertensive Dahl-S, but not Dahl-R rats. This effect was not observed in tissues obtained from animals fed a 4% NaCl diet (hypertensive). Immunocytochemistry of ET distribution in the outer medullary stripe showed approximately a 40% higher fluorescence intensity in sections obtained from Dahl-S rats fed 4% NaCl diet as compared with Dahl-R rats fed the same diet. Northern blot analysis of poly(A)+ RNA extracted from medullae of prehypertensive Dahl-S and -R rats using a full-length cDNA probe for rat ET-1 revealed a marginal induction of pre-pro-ET-1 message in Dahl-S samples after 30 and 60 min of incubation with 0.1 mM ouabain. In conclusion, increased responsiveness of target cells to ET-1 and inducibility of ir-ET production in prehypertensive Dahl-S rats are in favor of a possible role of this peptide in the pathogenesis of Dahl hypertension. We hypothesize that ouabain-like factor(s) may trigger production of ET, thus serving as a link between high-salt intake and the development of hypertension in Dahl-S rats.

GROWTH HORMONE TREATMENT IN GROWTH RETARDED CHILDREN WITH END STAGE RENAL FAILURE : EFFECT ON FREE/DISSOCIABLE IGF-I LEVELS

Growth retardation in children with endstage renal disease (ESRD) is associated with normal to slightly low concentrations of insulin-like growth factor (IGF)-I and increased concentrations of IGF-binding proteins (IGFBPs) in serum. Consequently, IGF-I bioactivity is reduced in serum from uremic patients presumably due to a decrease in the concentration of free IGF-I. Improvement of linear growth with growth hormone (GH) treatment of uremic children is thought to be due to increased IGF-I/IGFBP ratio, thus resulting in increased free IGF-I levels during treatment. The purpose of the present study was to determine whether free/dissociable IGF-I levels are in fact low in uremic children and whether increased growth velocity during GH treatment is associated with an increase in the free IGF-I concentration. Serum total and free/dissociable IGF-I concentrations were measured in 5 children with ESRD before and during treatment with GH, and in control children matched for age, pubertal status, and body mass index. Height velocity increased from 3.7 +/- 1.0 cm/yr to 6.5 +/- 1.2 cm/yr with an increment in height SDS at the end of the first year of GH treatment. Free/dissociable IGF-I concentrations tended to be lower in uremic children compared to control children (3.0 +/- 0.3 vs 7.3 +/- 2.1 micrograms/l, respectively). During GH treatment, free/dissociable IGF-I levels increased significantly to 8.5 +/- 1.0 micrograms/l at 3 months and 6.9 +/- 1.4 micrograms/l at 6-24 months, p < 0.05 compared to pretreatment. Total IGF-I levels were 243 +/- 18 micrograms/l in children with ESRD before treatment and these values also increased during GH treatment (740 +/- 114 micrograms/l at 3 months and 442 +/- 44 micrograms/l at 6-24 months, p < 0.05, compared to pretreatment). Total IGF-I concentration in the control group was 439 +/- 114 micrograms/l. These results support the hypothesis that growth retardation in children with chronic renal failure is associated with a reduction in the concentration of free, biologically available IGF-I, and that increased growth velocity during GH treatment of these children is associated with restoration of free IGF-I concentrations.

Effects of insulin-like growth factor I on the renal juxtamedullary microvasculature

To characterize the effects on the rat renal preglomerular microvasculature of insulin-like growth factor I (IGF-I), experiments were performed using the in vitro blood-perfused juxtamedullary nephron preparation. IGF-I induced a reversible vasodilation of pre- but not postglomerular microvessels in a dose-dependent manner (10-9-10-7M). The IGF-I-induced vasodilation was similar in all preglomerular vascular segments: interlobular artery, 11.5 ± 1.2% of control ( n = 16); mid-afferent arterioles, 11.6 ± 1.7% ( n = 24); and juxtaglomerular afferent segments, 16.1 ± 2.8% ( n = 19). Renal autoregulatory capacity was not reduced by IGF-I. Pretreatment with the nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methyl ester (10-4 M) completely inhibited the vasodilatory response to IGF-I. IGF-I induced a rapid increase of NO concentration in intact renal microvessels, monitored by a NO-selective voltametric microelectrode. Pretreatment with the cyclooxygenase inhibitor indomethacin (10-5 M) not only abrogated the IGF-I-induced dilation, but, moreover, IGF-I elicited a small but significant (∼10%) vasoconstriction in all preglomerular vessels. These results indicate that the renal vascular effects of IGF-I involve activation of two endogenous vasodilators (NO and vasodilatory prostaglandins). In addition, IGF-I may also release an undefined vasoconstrictor.

Chronic peritoneal dialysis in a child with Down syndrome

Very little is known about renal failure and renal replacement therapy in patients with Down syndrome (DS) [1]. We would like to report our experience with a pediatric patient with DS who developed end-stage renal failure secondary to hemolytic-uremic syndrome, and has been treated successfully with continuous cycling peritoneal dialysis (PD) for more than 3 years. Our patient is a 14-year-old black female with DS and end-stage renal disease secondary to hemolytic-uremic syndrome. Her past medical history is significant for a ventricular septal defect which was repaired in 1982. In May 1990 she presented with vomiting, diarrhea, lethargy and decreased urine output. She was admitted to the intensive care unit for management of fluid overload, hypertension and encephalopathy; she also needed mechanical ventilation. Laboratory evaluation revealed hemolytic anemia, thrombocytopenia and uremia consistent with the hemolytic-uremic syndrome. She was started on PD, which initially functioned poorly, with poor ultrafiltration and leakage around the PD catheter, necessitating hemodialysis through a femoral catheter. Automated PD was instituted again in July 1990, with good results. Because of her difficult medical management and significant social problems she remained hospitalized until February 1991. Since then, the child has been maintained on continuous cycling PD at home with the assistance of a home nursing agency. She is tolerating dialysis well and has returned to her special education full time, in addition to attending a summer dialysis program for children. Malformations of the kidney and urinary tract in DS [2] include renal hypoplasia, hydronephrosis, ureteropelvic and ureterovesical junction obstruction, double pelvis, vesicoureteral reflux [3] and posterior urethral valves [4]. Glomerular disease has also been described in patients with DS [5, 6]. However, very little is known regarding renal failure and renal replacement therapy in this disabled population [1]. Acute renal failure may follow surgical correction of congenital heart malformation in DS [7]. Renal failure was the major cause of death in only 3.3% of institutionalized persons with DS in Texas [8]. Baird [9] and Sadovnick found only 2 patients who died of renal failure in their study of causes of death in 324 individuals with DS. Finally, patients with DS may also develop chronic renal failure secondary to congenital renal and urological anomalies. We have previously reported the association of DS and posterior urethral valves [4], and the possibility of developing chronic renal failure. Furthermore, Webb et al. [10] have recently reported two patients with DS receiving renal replacement therapy, both with functioning kidney transplants, and three patients with DS and chronic renal failure, two of them secondary to posterior urethral valves. In summary, we describe here a child with DS and endstage renal failure secondary to hemolytic-uremic syndrome who has been treated successfully with continuous cycling PD at home for more than 3 years. She is well adjusted socially and we believe is a candidate for renal transplantation. This case illustrates that PD can be performed successfully in children with DS.

IgG and IgA classes of anti-neutrophil cytoplasmic autoantibodies in a 13-year-old girl with recurrent Henoch-Schonlein purpura

We describe a 13-year-old girl with recurrent Henoch-Schonlein purpura whose symptoms were precipitated by upper respiratory tract infections. Her serum was positive for both IgG and IgA classes of anti-neutrophil cytoplasmic autoantibodies by immunofluorescence. The titers of both autoantibodies correlated with disease activity. The immunopathology underlying these findings is discussed.

Megacystis-microcolon-intestinal hypoperistalsis syndrome

The megacystis-microcolon-intestinal hypoperistalsis syndrome is a congenital disorder characterized by urinary bladder distension and hypoperistalsis throughout the entire gastrointestinal tract. We present a new case with the typical clinical, radiological, and pathological findings of the syndrome. The diagnosis should be suspected in a patient who presents clinically with intestinal obstruction and urinary retention, and confirmed with imaging studies, including abdominal plain films, urinary tract ultrasonography, and contrast studies of the colon and the bladder. The prognosis is generally very poor. Our patient died secondary to sepsis on day 5 of life.

Recurrence of immunoglobulin A-κ crystalline deposition disease after kidney transplantation

Abstract Cases of immunoglobulin A heavy chain and kappa light chain deposition disease are rare and their clinical presentations vary. We report one patient with histopathologic and clinical findings of a microangiopathic glomerulonephritis due to immunoglobulin A-κ deposition. Ultrastructural studies revealed highly ordered deposits in the capillary lumen, mesangium, and basement membrane. The disease recurred at 2.5 years after a cadaveric kidney transplantation. Pulse steroid therapy was repeatedly effective in retarding further progression of renal deterioration in this patient.

Inhibition of myogenic autoregulation in cyclosporine nephrotoxicity in the rat

The mechanisms responsible for the impairment of renal blood flow (RBF) autoregulation in cyclosporine nephrotoxicity were investigated with clearance and micropuncture studies in anesthetized rats. Early chronic cyclosporine nephrotoxicity (CCN) was induced in male rats by daily intramuscular injection of 10 mg/kg/day cyclosporine-A in olive oil for 7 days; control (CON) rats received vehicle injections. Glomerular filtration rate and RBF were both reduced by 33% in CCN when compared to CON rats. RBF autoregulation was also significantly impaired in CCN, with an autoregulation index (AI) of 0.53 +/- 0.03 vs. 0.16 +/- 0.01 in CON rats. Micropuncture studies showed that the tubuloglomerular feedback (TGF) system is not impaired in CCN. Rather, in CCN there was a slight resetting such that the maximum TGF response was greater and the onset occurred at lower rates of perfusion than in CON. In contrast, further micropuncture studies demonstrated that TGF-independent autoregulation of glomerular capillary pressure was significantly impaired in CCN, with an AI of 0.86 +/- 0.09 vs. 0.57 +/- 0.06 in CON. These results indicate that the loss of autoregulatory ability in rats with CCN results from substantial impairment of the myogenic autoregulatory mechanism that is an intrinsic property of the preglomerular vasculature of the kidney.