Jerry M. Bergstein

Aluminum Intoxication from Aluminum-Containing Phosphate Binders in Children with Azotemia Not Undergoing Dialysis

Aluminum intoxication developed in three infants with azotemia who were not undergoing dialysis and who had been treated with aluminum hydroxide from the first month of life. Biopsies of the iliac crest demonstrated the presence of severe osteomalacia and massive deposition of aluminum in the bone. Serum aluminum levels were significantly (P less than 0.001) higher in these 3 infants and in 1 other, all of whom received more than 100 mg of elemental aluminum per kilogram of body weight per day (mean +/- S.D., 371.0 +/- 178.9 ng per milliliter [13.75 +/- 6.6 mumol per liter] ) than they were in 8 older children with azotemia who were not undergoing dialysis and who received less than 100 mg of elemental aluminum per kilogram per day (27.0 +/- 18.6 ng per milliliter [1.0 +/- 0.68 mumol per liter] ), 7 such children who did not receive aluminum hydroxide (20.28 +/- 9.2 ng per milliliter [0.75 +/- 0.34 mumol per liter] ), and 16 children with normal renal function (21.04 +/- 4.9 ng per milliliter [0.78 +/- 0.18 mumol per liter] ). In all the children with azotemia who were treated with aluminum hydroxide, there was a positive correlation (r = 0.90; P less than 0.01) between the serum aluminum level and the daily dose of elemental aluminum. These studies indicate that gastrointestinal absorption of aluminum can lead to aluminum intoxication in children with azotemia, and that infants may be particularly susceptible to this complication of therapy.

Treatment of severe IgA nephropathy in children

We treated ten children with severe IgA nephropathy (IgAN) [proteinuria > 1g/day, hypertension, renal insufficiency, segmental sclerosis, crescent formation and/or glomerular basement membrane (GBM) deposition of IgA] with prednisone and azathioprine for 1 year. Following the year of therapy, seven of the ten children underwent a repeat kidney biopsy. All biopsies were scored for activity (percentage of glomeruli demonstrating crescent formation, degree of mesangial proliferation and interstitial infiltrate; maximum score = 9) and chronicity (percentage of glomeruli demonstrating fibrous crescents, segmental sclerosis, global sclerosis, and degree of tubular atrophy and interstitial fibrosis; maximum score = 12). After 1 year of therapy, the protein excretion of all the children decreased significantly (P<0.01) from 4052±3190 mg/day to 1692±1634 mg/day. The activity score decreased significantly (P<0.01) from 4.35±0.94 prior to therapy to 2.28±0.75 after therapy while the chronicity score was unchanged (5.42±1.7 vs 5.85±2.0). The percentage of glomeruli demonstrating cellular crescents decreased (P<0.05) from 21.2±21.7% prior to therapy to 0.94±2.4% after therapy. Mesangial deposition of IgA persisted but GBM deposition of IgA was less prominent after therapy. During the follow-up period (mean 2.6 years, range 9 months–7.5 years), one child required brief retreatment for biopsy-confirmed recurrence of active disease, two children have developed renal insufficiency due to progressive scarring in the absence of inflammation, while the remaining seven are stable. We suggest that treatment with prednisone and azathioprine may be beneficial in children with severe IgAN and that a controlled clinical trial is warranted.

Purine excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: Relationship to acute renal failure*

We measured serial urine levels of hypoxanthine, xanthine, and uric acid in 19 children with acute lymphocytic leukemia (ALL) receiving allopurinol therapy during tumor lysis; four of these children developed acute renal failure. The urinary excretion of uric acid rose moderately from 447 +/- 251 micrograms/dl glomerular filtrate before chemotherapy to 778 +/- 463 micrograms/dl glomerular filtrate during tumor lysis (P less than 0.05) whereas the urinary excretion of hypoxanthine (17.9 +/- 15 to 292 +/- 213 micrograms/dl glomerular filtrate) and xanthine (74 +/- 62 to 1091 +/- 1085 micrograms/dl glomerular filtrate) rose dramatically (P less than 0.001). The urinary excretion of uric acid, hypoxanthine, and xanthine per deciliter of filtrate was significantly higher (P less than 0.001) in those who developed acute renal failure than in those who did not, but the highest urine concentration of these purine metabolites did not differ in the two groups. In all 19 children, the highest urine concentration of uric acid and hypoxanthine during tumor lysis did not exceed the solubility limit of each in an alkaline urine specimen. In contrast, the peak urine concentration of xanthine exceeded its solubility limit in an alkaline urine specimen in 16 of 19 children. The urine sediment during the period of tumor lysis was examined by diffuse reflectance infrared spectroscopy; precipitated xanthine was found in sediment from eight of the 19 children, was significantly (P less than 0.001) associated with a urine xanthine level greater than 350 mg/dL, and occurred with equal frequency in those who did or did not develop acute renal failure. We conclude that urinary excretion of hypoxanthine and xanthine increases dramatically whereas uric acid excretion rises moderately in children undergoing tumor lysis while receiving allopurinol, that acute renal failure occurs in children with a higher purine load per deciliter of glomerular filtrate, but that factors other than tubular precipitation of purine metabolites are likely to be involved in the pathogenesis of renal failure during tumor lysis.

Role of Plasminogen-Activator Inhibitor Type 1 in the Pathogenesis and Outcome of the Hemolytic Uremic Syndrome

Abstract Background Deposition of fibrin in glomeruli and renal failure are characteristic features of the hemolytic uremic syndrome. An inhibitor of glomerular fibrinolysis has been detected in plasma from children with this disorder. In this study, we define the inhibitor and show that its plasma level is correlated with the outcome of the disease. Methods and Results Plasminogen-activator inhibitor type 1 (PAI-1) in plasma was measured with an assay employing a specific monoclonal antibody in 40 consecutive children hospitalized with the hemolytic uremic syndrome: 12 who recovered adequate renal function (serum creatinine, ≤2.0 mg per deciliter [111 μmol per liter]) without dialysis, 23 who recovered adequate renal function after peritoneal dialysis, and 5 who did not recover adequate renal function after undergoing dialysis. At presentation, plasma PAI-1 levels were higher in the patients with the hemolytic uremic syndrome than in nine children with other forms of acute renal failure. That the inhibit...

Postpubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty.

Evaluation of pituitary gonadotropins, gonadal steroids, spermatogenesis, and menstrual function was undertaken in 32 patients (19 males and 13 females) treated with cyclophosphamide because of nephrotic syndrome. Patients were treated before, during, or after puberty. Evaluations took place after or in very late puberty. Spermatogenic dysfunction occurred in six of 15 boys who received the entire course before and during puberty and was probably dose related. Menstrual dysfunction did not occur following treatment of six prepubertal or pubertal girls, though only low total doses were used. Therapy after puberty was associated with spermatogenic dysfunction in all four boys, but did not cause menstrual dysfunction in any of seven women. Tentative guidelines are suggested that many minimize gonadal toxicity when cyclophosphamide is used in children with nephrotic syndrome. Factors of particular importance in the interpretation of gonadotropin determinations and of sperm counts in young cyclophosphamide-treated patients are discussed.

Radiation nephritis following total-body irradiation and cyclophosphamide in preparation for bone marrow transplantation

Two children prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide developed hypertension, microscopic hematuria, proteinuria, diminished renal function, and anemia six months after transplantation. Light microscopy of the kidneys revealed mesangial expansion, glomerular capillary wall thickening, and lumenal thrombosis. Electron microscopy demonstrated widening of the subendothelial space due to the deposition of amorphous fluffy material. In one patient, immunofluorescence microscopy revealed glomerular capillary wall deposition of fibrin and immunoglobulins. The clinical and histologic findings support the diagnosis of radiation nephritis. Patients prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide should be followed closely after transplantation for the development of hypertension, proteinuria, and renal insufficiency.

IgA nephropathy in children: significance of glomerular basement membrane deposition of IgA

Seventeen children with IgA nephropathy were grouped according to the absence (group I, n = 10) or presence (group II, n = 7) of glomerular basement membrane (GBM) deposition of IgA to determine whether GBM deposition of IgA correlated with laboratory or pathologic data at diagnosis or clinical status at follow-up. Children in group II had significantly (p less than 0.01) more proteinuria at diagnosis than children in group I. The percentage of glomeruli demonstrating crescent formation was significantly (p less than 0.05) higher in group II biopsies. Chronic changes of fibrous crescents, segmental sclerosis, global obsolescence, tubular atrophy, and interstitial fibrosis were also significantly (p less than 0.001) more common in group II biopsies. After a mean follow-up period of 2 years, all children in group II have persistent proteinuria of more than 1 g/24 h, and 3 of 5 have renal insufficiency (2 require dialysis). In contrast, 2 of 9 group I children have proteinuria exceeding 1 g/24 h, and only 1 has renal insufficiency. We conclude that, as compared to children with IgA localized to the mesangium, children with IgA nephropathy and GBM deposition of IgA have a higher urinary protein excretion at the time of diagnosis, more severe histologic alterations including a greater percentage of glomeruli demonstrating crescent formation, more chronic changes of segmental or global sclerosis, tubular atrophy, and interstitial fibrosis. Such children usually have persistent proteinuria and are more likely to develop progressive renal disease.

Interstitial Nephritis with Anti-Tubular-Basement-Membrane Antibody

To determine the pathogenesis of interstitial nephtitis, immunopathological studies were performed with kidney and serum from a six-year-old boy. The kidney revealed linear staining of tubular basement membranes with antiserums specific for human IgG and C3; the membranes also showed fixation of heterologous complement. After incubation of the patients serum on frozen sections from normal human kidneys, linear staining with IgG was detected by indirect fluorescence. This staining was eliminated by absorption of the serum with purified tubular basement membranes, but was unaltered by absorption with purified glomerular basement membrane. The antibody reacted with mouse, rabbit, dog, sheep, monkey, Sprague-Dawley and Lewis/Brown Norway rat tubular basement membranes, but not with that of Lewis rat or guinea pig, or with human skin, thyroid, parotid, lung, liver or pancreas. Anit-tubular-basement-membrane antibody may be involved in the pathogenesis of the patients disease.

Development of insulin-dependent diabetes mellitus during the hemolytic-uremic syndrome

Three children developed hyperglycemia and ketoacidosis three, eight, and 60 days after the onset of hemolytic-uremic syndrome. During hyperglycemia, the two patients studied had dramatically low insulin concentrations. Circulating islet-cell and insulin antibodies were not detected. These studies suggest that pancreatic beta cell dysfunction may occur during hemolytic-uremic syndrome, and that the serum glucose concentration should be closely monitored during this disease.

Calcium Carbonate Is an Effective Phosphorus Binder in Children With Chronic Renal Failure

We evaluated the effectiveness of calcium carbonate as a phosphate binder in 19 children with chronic renal failure; ten children were undergoing dialysis therapy (eight maintained by CAPD and two by hemodialysis). Twelve children had previously received aluminum hydroxide, while calcium carbonate was the primary phosphate binder used in seven children. Among all the children, the serum phosphorus level on no phosphate binder was 7.4 +/- 0.9 mg/dL, which decreased significantly (P less than .001) to 5.9 +/- 0.8 mg/dL during calcium carbonate therapy, while the serum calcium, bicarbonate, and creatinine were unchanged. The reduction in the serum phosphorus level occurred while dietary intake of calcium and phosphorus were unchanged, as demonstrated by three-day dietary records. The dose of calcium carbonate required to maintain the serum phosphorus in the normal range varied from 600 mg to 15 g/d (mean 7.4 g/d). Among the 12 children and four others who had received aluminum hydroxide, serum aluminum levels fell from 108.8 +/- 121.8 ng/mL to 36.1 +/- 29.1 ng/mL after aluminum hydroxide was stopped (P less than .05). Serum alkaline phosphatase and parathyroid hormone (PTH) levels during aluminum hydroxide therapy were similar to levels obtained during calcium carbonate therapy, while PTH levels fell in children treated initially with calcium carbonate. All the children have been observed for a mean of 12.0 months (range 4 months to 3 1/2 years). Hypercalcemia occurred in seven children, usually when vitamin D therapy was initiated or the dose changed. Hypercalcemia resolved with adjustment of the vitamin D or calcium carbonate dose in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)