William B. Lorentz

Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: Results in three additional patients

After biochemical and radiographic studies, enzyme replacement therapy in three patients with the infantile form of hypophosphatasia was attempted by weekly intravenous infusions of bone alkaline phosphatase-rich (BAP) plasma from patients with Paget bone disease. Subsequently, circulating BAP activity was substantially increased in each patient, and in one was maintained in the normal range for nearly 2 months. Despite partial or complete correction of the deficiency of circulating BAP activity, we observed no radiographic evidence for arrest of progressive osteopenia or improvement in rachitic defects in any of the patients. Failure of infants with hypophosphatasia to show significant healing of rickets on correction of circulating BAP activity supports the hypothesis that this isoenzyme functions in situ during normal skeletal mineralization.

Clq Nephropathy: A Pediatric Clinicopathologic Study

We report on 15 children with proteinuria, at the nephrotic level in the majority of cases, who had no histologic glomerular alterations (eight cases), or focal and segmental glomerular scarring with (three cases) or without (four cases) mesangial proliferation. In all cases, immunofluorescence (IF) microscopy showed prominent mesangial C1q deposits with variable amounts of immunoglobulins. Ultrastructurally, most had conspicuous mesangial electron-dense deposits. Cases with no glomerular histologic alterations were histologically indistinguishable from minimal change disease (MCD), yet they uniformly had an unsatisfactory response to oral prednisone. Thus, the presence of immune deposits with a prominent C1q contribution identifies a group of cases that respond poorly to steroids and that, if light microscopy is considered in isolation, might otherwise be designated MCD.

Hypertensive Encephalopathy in Children: Neuroimaging and Treatment

nance imaging (MRI) scans of patients with hypertensive encephalopathy have indicated edema in the cortex and subcortical white matter of the occipital lobes. 6-8 However, the majority of these patients were either adults with nonobstetric problems or obstetric patients who had preeclampsia or eclampsia syndrome. Only a few cases were children. We report the findings of brain MRI and CT scans in two children who had hypertensive encephalopathy, discuss the similarities to adult cases, and relate these findings to pathogenesis and treatment.

Reversal of Bartter's syndrome by renal transplantation in a child with focal, segmental glomerular sclerosis.

A four-year-old girl with growth failure and clinical and laboratory evidence of Bartters syndrome responded to indomethacin treatment with decreased urinary prostaglandin excretion, symptomatic and chemical improvement, and accelerated growth. Large doses of aspirin produced a comparable decrease in prostaglandin excretion but no improvement in any other metabolic abnormality thus suggesting that abnormalities in prostaglandins were the result rather than the cause of the electrolyte abnormalities. Progressive renal insufficiency while on indomethacin prompted a renal biopsy, which revealed morphological changes of focal, segmental glomerular sclerosis. Subsequently, the child underwent renal transplantation with complete resolution of symptoms and abnormal metabolic findings. This observation suggests that extrarenal factors were not responsible for the development of Bartters syndrome in this child.

Mesangiolytic glomerulopathy in a bone marrow allograft recipient

A boy with null-cell leukemia received a bone marrow allograft after preparation with chemotherapy and total body irradiation. Cyclosporine A was not administered following transplantation. Renal biopsy performed 6 months after transplantation because of unexplained deterioration of renal function revealed diffuse mesangiolysis and glomerular sclerosis. The significance of this finding is discussed with reference to similar, recently reported cases.

Acute Renal Failure due to Pyelonephritis

Acute renal failure developed in a 3-year-old boy with acute pyelonephritis. Renal biopsy showed acute interstitial infiltration of neutrophils and macrophages. There were also glomerulitis and capillary tuft thrombosis. He required peritoneal dialysis, but subsequently recovered renal function. Prompt antimicrobial therapy is crucial to insure a favorable outcome. Pyelonephritis is an unusual cause of acute renal failure in infants and children.

Association of Crossed Fused Renal Ectopia and Multicystic Kidney

A male newborn presented with mild azotemia, an abdominal mass and non-visualized right kidney on excretory urography. Evaluation, including ultrasound and surgical exploration, revealed the simultaneous occurence of crossed fused renal ectopia and multicystic kidney.

Three-dimensional studies of acellular glomerular basement membranes in dense-deposit disease

After digestion removed the cells from glomeruli of frozen kidney tissue, we employed scanning electron microscopy to examine the acellular glomerular basement membranes (AGBM) from normal kidneys and from kidneys of patients with dense-deposit disease (DDD). The AGBM showed previously unrecognized three-dimensional patterns of pathologic changes. When compared to normal controls, the AGBM in DDD appeared “rigid” and thickened. Other pathologic features included coarsely granular or undulating epimembranous surfaces punctuated by single or clustered crater-like deformities. Although epimembranous crater-like deformities have been observed in other glomerulopathies, the combination of “rigid” -appearing AGBM punctuated by crater-like deformities is thus far unique to DDD.

240 HEMODYNAMIC RESPONSES OF LAMBS AND ADULT SHEEP TO HEMORRHAGE

Hemorrhage stimulates the secretion or cateoholamines by newborns and adults. This study directly compares the response of newborn and adult sheep to hemorrhage after alpha-blockade. We chronically instrumented 11 newborn lambs, and 8 adult sheep for continuous measurement of blood pressure (BP), heart rate (HR), and thermodilution cardiac output (CO). After pretreatraent with prazosin (P), an alpha-1 blocker, or vehicle (V) in a randomized, crossover fashion, each animal was hemorrhaged 20% of its blood volume. Cardiac output was measured at baseline; 20 mins after drug administration; after hemorrhage; at 100 mins, after which the animal was retransfused; and at 150 mins. Stroke volume (SV) and total peripheral resistance (TPR) were calculated. The effects of treatment with P and V on the measurements are shown in the table. All deviations from baseline were significant (p<.05). There were greater decreases in BP, CO, SV and TPR in P-treated versus V-treated ewes (indicated by *, p<.05). This difference was not seen in the lambs. (NC denotes no change.)We conclude that catecholamines do not play a major part in the response to hemorrhage in the lamb. (Supported by NIH Grant HD 17644.)

1581 EARLY EFFECTS OF A NEPHROTOXIC CEPHALOSPORIN ON RENAL CORTICAL AND MITOCHONDRIAL CALCIUM (CA) CONTENT AND MITOCHONDRIAL FUNCTION

Cephaloglycin (CG) is one of several nephrotoxic drugs in the cephalosporin family of antibiotics. The mechanism of injury produced by these drugs is uncertain. Since CA has been implicated in the damage sustained by the kidney following a variety of insults, the effects of CG on CA accumulation in the cortex (CTX) and cortical mitochondria (MITO) and the relationship of mitochondrial oxygen consumption to tissue CA content were studied. The CA content of whole renal CTX and renal cortical MITO was measured two hours after a toxic dose of CG (200mg/kg IV) in control (CTRL) and experimental (EXPT) rabbits. Mitochondrial oxygen consumption supported by succinate in the presence of ADP or CA was measured from the same preparations. Data are expressed as nanomoles/mg protein and as means±SD, n=6-10, *p<.05 or better compared to CTRL.CG leads to early accumulation of CA in the renal CTX and cortical MITO. There is a parallel decline in mitochondrial respiratory function. These results suggest that CA may play an important role in the proximal tubular necrosis and mitochondrial dysfunction caused by CG.