Carolyn F. Piel

Hereditary macrothrombocytopathia, nephritis and deafness

Abstract Two unrelated families were studied in which two members of each have a syndrome of macrothrombocytopathia, nephritis and deafness. A third member of one family, a young child, has the platelet disorder and a mild hearing loss. The mode of inheritance of the syndrome appears to be dominant. Except for its severity in affected females, the renal disease is indistinguishable from the classic type of hereditary nephritis. Likewise, the high frequency sensorineural hearing loss is similar to that seen in Alports syndrome. The platelet disorder is characterized by thrombocytopenia, giant platelets with an abnormal ultrastructure, prolonged bleeding time and defective adherence of platelets to glass. Aggregation in response to collagen and epinephrine, and release of platelet factor 3 are impaired, and the release of nucleotide after exposure to collagen is abnormally low.

Serum parathyroid hormone levels and serum calcium levels from birth to senescence

1. Calcium and immunoreactive parathyroid hormone (iPTH) levels were measured in sera of 1334 normal subjects ranging from newborn to over 80 years of age. Albumin was measured in samples from the population of adults, which was 80% white, 15% black and 5% oriental. 2. Serum calcium and iPTH levels in children tended to be higher in the first three years of age; no sex differences were noted. Values for serum calcium and iPTH were higher in children than in adults. 3. Serum calcium, iPTH and albumin showed more variation in groups of white, black and oriental women than in similar groups of men. In white females the mean serum calcium remained fairly constant until age 60, whereas in black women it rose steadily from age 20-29 until age 50-59. Serum iPTH levels were lower in black women than in white women and usually were not measurable in oriental women. 4. In men (white, black and oriental) there was a steady decrease in mean serum calcium with age, and iPTH levels were not different from those observed in white women. 5. Although the number of samples from oriental women was small, the serum calcium was consistently lower and serum albumin was constantly higher than in white or black women, and iPTH levels usually were unmeasurable.

Familial hypophosphatemic rickets: Bone mass measurements in children following therapy with calcitriol and supplemental phosphate

SummaryFamilial hypophosphatemic rickets is characterized by defective skeletal mineralization resulting in abnormal growth and development. The pathologic and radiologic correlates of this syndrome have been given some investigation, but the effect of this mineralization defect on bone mineral density has not been adequately assessed. We measured axial and appendicular bone mineral in 17 children (mean age 5.59±4.87) with familial hypophosphatemia at baseline and at 6-month intervals after initiation of therapy with vitamin D3 (calcitriol) and phosphate supplementation. Noninvasive quantitative techniques included single photon absorptiometry (SPA) of the radius, combined cortical thickness (CCT) of the second metacarpal, and quantitative computed tomography (QCT) of vertebral trabecular bone. Thoraco-lumbar and hand/wrist radiographs were qualitatively assessed for the prevalence and severity of osteosclerosis, rickets, and other parameters indicative of metabolic bone disease as well as skeletal age. Quantitative determinations of bone mineral by each technique were compared with normal values for age and sex, and individual standardized scores (z-scores) were calculated at each measurement interval. Standard scores were also calculated for bone age-adjusted mineral values. At baseline, spinal trabecular bone by QCT was not significantly different from normal values; however, measurements of peripheral cortical bone by either SPA or CCT were significantly lower than values for normal children of the same age and sex (P=0.05 andP=0.01, respectively). Following therapy with calcitriol and phosphate, peripheral bone mass was not shown to improve significantly when contiguous standard scores were compared even when values were adjusted for bone age. Comparison of noncontiguous standard scores between longer measurement intervals also failed to achieve significance. In spite of a general increase in bone mass over time, we found that peripheral bone mass expressed as a standard score remained significantly low. To the contrary, vertebral trabecular bone density generally remained in the normal range. However, concomitant and persistent vertebral osteosclerosis, with a prevalence of greater than 50% throughout the study, may mimic these “normal” values. Though the treatment regimen under investigation may be effective in preventing and ameliorating the osseous lesions associated with this syndrome, it appears to have limited short-term value in improving abnormal bone density development.

Antibiotic-Associated Interstitial Nephritis and Nephrotic Syndrome

The combination of interstitial nephritis and minimal-change nephrotic syndrome has been well described in adults receiving nonsteroidal anti-inflammatory agents. The association of interstitial nephritis and minimal-change nephrotic syndrome has recently been described in 1 adult patient receiving ampicillin and in 1 patient receiving rifampin. We describe an 8-month-old child who developed reversible interstitial nephritis and minimal-change nephrotic syndrome while taking antibiotics.

RADIORECEPTOR ASSAY FOR SOMATOMEDIN-A IN UREMIC CHILDREN

The suggestion that the low Somatomedin A (SM-A) found in uremic children is due to the presence of a serum inhibitor to the bloassay was investigated using the human placenta radio-receptor assay. Twenty three children with chronic renal failure were divided into 3 groups based on the degree of renal failure.In the children in group II, there was no correlation between SM-A and GFR, BUN, creatinine, chronological age, bone age, or serum lipids. A correlation was found to growth expressed as a percentage of expected growth (r=0.30). A negative correlation was found to transferrin levels (p < 0.01). Six patients ingesting calories < 80% recommended dietary allowances (RDA) for height age had SM-A levels of 3.03 ± .68 U/ml. Nine patients ingesting > 80% RDA had values of 4.59 ± .81 U/ml (p < 0.05). In 3 patients paired SM-A levels rose with caloric supplementations from 3.22 U/ml to 5.1 U/ml (p<0.05). These findings demonstrate that: 1) SM-A levels are elevated in uremic children, 2) these levels correlate with growth, 3) nutritional status influences SM-A levels, 4) there may be an inhibitor in the serum of uremic children thai interferes with bioassay.

UNEXPLAINED HEMATURIA: HISTOLOGIC DIAGNOSIS IN 61 CHILDREN

Percutaneous renal biopsies were performed in 61 non-uremic children between 1963 and 1982 for unexplained hematuria. In 26 biopsies, only attenuation of the lamina densa of the glomerular capillary wall (BM) was found by electron microscopy (EM), a finding consistent with BM nephropathy. Of these 26 children, 16 had microscopic hematuria (MH) found on routine urinalysis and 10 had gross hematuria (GH) (7 associated with fever or physical exercise, 3 with no associated event). In 18 biopsies, findings diagnostic of IgA nephropathy were present. Of these 18 children, 12 had GH (5 with fever or phsyical activity and 7 without associated event). In the last group of 17 biopsies, no specific diagnostic findings were present, the biopsies being either normal (12 cases) or showing only mino non-specific glomerular alterations (5 cases). Of these 17 children, 10 had MH and 7 GH, all without associated event.Conclusion: The renal biopsy is diagnostic in 72.1% of children with unexplained hematuria.

Excretion of D- and L-methionine in children with generalized aminoaciduria.

T ~ E aminoaciduria associated with glycosuria and phosphaturia in the Fanconi syndrome or in patients with mental retardation and congenital cataracts as described by Lowe, Terrey, and MacLachlan 1 is generally agreed to be the result of insufficient reabsorption of amino acids by the renal tubule. The nature of the defect of the renal tubule, however, is unknown at the present time. The reabsorption by the kidney of the naturally occurring L-form of the individual amino acid is thought to be a process of active transport which involves, perhaps, a mechanism of the membrane carrier type? -4

Mitochondrial granulation in the proximal renal tubule in uremia.

Mitochondria contain electron-dense particles, partly composed of an amorphous form of calcium phosphate. We have used electron microscopy from percutaneous renal biopsy material to analyze mitochondrial granulation in the proximal renal tubule of nonuremic and uremic children. Based on a technique of cutting mitochondria from ten electron micrographs per biopsy, counting the granules in each mitochondrion and weighing the paper, we found that mitochondria of nonuremic children averaged 23.7 +/- 1.2 granules/g paper while uremic children had only 11.8 +/- 1.1 granules/g. The number of granules per gram was unrelated to the serum calcium phosphate solubility product. A significant decrease in calcium granulation in uremia can also be produced experimentally in rats. Control rats averaged 14.7 +/- 1.5 granules/g, while rats made uremic by partial nephrectomy had 6.0 +/- 0.7 granules/g. Treatment of uremic rats with a pharmacological dose of vitamin D restored granulation to normal within 24 h. The significant decrease in calcium phosphate granulation in the renal proximal tubule in uremic children and in experimental animals is probably related to the documented loss of 1 alpha-hydroxylation of vitamin D in uremia.

45 Accelerated Intravascular Coagulation in the Hemolytic Uremic Syndrome

Renal tissue was obtained by percutaneous biopsy in 11 patients with hemolytic uremic syndrome from 9 to 365 days after onset of disease; by autopsy in 5 after 6 to 58 days of illness. By light microscopy, the early histologic lesion (up to 30 days) was characterized by glomerular capillary ectasia and intracapillary eosinophilic depositions (fibrin-like material). Regardless of duration or severity, electron microscopy revealed irregular swelling and fragmentation of basement membrane, swelling of endothelial cytoplasm and deposition of granular and fibrillar electron-dense material with periodicity of fibrin between the basement membrane and endothelium and in the mesangium, most pronounced during the early course of disease. Tissue from 8 patients was studied by immunofluorescent technics after 6 to 42 days of illness. Fluorescein-conjugated rabbit anti-human IgG, IgM, IgA and B1A–1C sera produced no staining; antifibrinogen serum produced intense smooth staining along capillary walls and diffuse staining in cytoplasm of endothelial and mesangial cells. The thrombocytopenia responded to heparinization in 6 patients; in 3, heparinization was discontinued prematurely—in each, platelet counts fell and rose again coincident with cessation and reinstitution of heparin therapy.These findings support the hypothesis that accelerated intravascular coagulation occurs in the hemolytic uremic syndrome. (SPR)

Rickets in children.

A brief survey of rickets is presented. Specific biochemical determinations establish whether rachitic changes are primary or secondary to systemic disease. If no underlying disease is present, the most likely diagnosis is vitamin D-refractory rickets. The difficulties in management of this form of the disease are emphasized. The rare disease hypophosphatasia is described.