Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13.

Autosomal dominant hypophosphatemic rickets (ADHR) is an inherited disorder of isolated renal phosphate wasting, the pathogenesis of which is unknown. We performed a genome-wide linkage study in a large kindred to determine the chromosome location of the ADHR gene. Two-point LOD scores indicate that the gene is linked to the markers D12S314 [Z(theta) = 3.15 at theta = 0.0], vWf [Z(theta) = 5.32 at theta = 0.0], and CD4 [Z(theta) = 3.53 at theta = 0.0]. Moreover, multilocus analysis indicates that the ADHR gene locus is located on chromosome 12p13 in the 18-cM interval between the flanking markers D12S100 and D12S397. These data are the first to establish a chromosomal location for the ADHR locus and to provide a framework map to further localize the gene. Such studies will permit ultimate identification of the ADHR gene and provide further insight into phosphate homeostasis.

Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.

Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries. Although autosomal dominant transmission of renal phosphate wasting has been described, previous studies included too few affected individuals to adequately characterize the disorder. We performed clinical and biochemical evaluations of individuals from a large kindred with autosomal dominant hypophosphatemic rickets/osteomalacia. We identified 23 affected members in this family, and for some individuals, follow-up was up to 25 yr. As patients were all members of the same kindred, we had the opportunity to determine the clinical manifestations of the disorder in patients who presumably all have the same genetic mutation. Affected individuals have isolated renal phosphate wasting and inappropriately normal serum calcitriol concentrations. The inheritance pattern was consistent with autosomal dominant transmission with variable penetrance. The family contained two subgroups of affected individuals. Group 1 consisted of patients who presented with renal phosphate wasting as adolescents or adults. These patients presented with bone pain, weakness, and insufficiency fractures, but did not manifest lower extremity deformity. Group 2 consisted of patients who presented with phosphate wasting, rickets, and lower extremity deformity as children. Surprisingly, some individuals in group 2 lost the renal phosphate-wasting defect after puberty. In conclusion, autosomal dominant hypophosphatemic rickets/osteomalacia is an inherited disorder of isolated renal phosphate wasting. The spectrum of disease includes delayed onset of penetrance and loss of the renal phosphate-wasting defect. Our results have implications in the evaluation of patients who present with renal phosphate wasting as either adults or children.

The effect of prednisone in a high-dose, alternate-day regimen on the natural history of idiopathic membranoproliferative glomerulonephritis.

Experience in 45 children with diffuse proliferative MPGN of all three types has provided evidence that a high-dose, alternate-day regimen of prednisone alters the natural history of the disease. The experience has been gained over a 17-year period and the patients have been followed on the regimen for an average of 6.5 years. Evidence that the regimen has a salutary effect was provided by several observations: Survival was better than that in four other series in which the patients were not treated or treated sporadically. The difference was particularly marked when survival was compared with that in series in which the patients had diffuse proliferative lesions exclusively. Mesangial proliferation was less in biopsies obtained after 2 or more years of the alternate-day regimen. This was quantitated as a significant increase in the estimated percentage of open glomerular capillary lumens and a significant diminution in the prominence of PAS-positive mesangial matrix. In the second biopsy, as compared to the pre-regimen biopsy, no patient had a diminution in the estimated percent of open capillary lumens and 65% had a meaningful increase. Likewise, only 3% had an increase in prominence of PAS positive matrix and 68% had a diminution in matrix prominence. Of 32 patients who were hypoalbuminemic when the regimen started, the level rose into the normal range in 62%. The level became subnormal in none of the 13 who had a normal level at the start of the regimen. While receiving the regimen, renal function, as measured by serum creatinine levels, continued to be normal or improved in 73% and deteriorated in 27%. Hematuria disappeared in 80% of the 41 in whom it was present when the regimen started. Urinalysis became completely normal in 27% and none of these have relapsed while under observation. Comparison of data from 20 patients who did not receive the regimen for an average of 42 months after clinical onset with data for 25 patients who likewise were, on the average, 42 months from clinical onset but who had received the regimen for an average of 38 of those months provided the most convincing evidence that the regimen altered the natural history. In those receiving the regimen, the frequency of hematuria, proteinuria, and hypoalbuminemia was significantly less.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical spectrum of intrinsic renovascular hypertension in children.

In the past two decades, 853 children and adolescents have been evaluated for elevated BP as inpatients and outpatients by the hypertension service at Children's Hospital Medical Center, Cincinnati. Most children with hypertension secondary to coarctation of the aorta and all children with glomerulonephritis are managed by other services and are not included in that total. In a retrospective study, 27 children (3%) were identified as having hypertension secondary to intrinsic renal arterial stenosis. The age at presentation ranged from 5 months to 20 years. The mean BP at that time was 171.6/114.2 mm Hg. Ten categories of causes were identified, including fibromuscular dysplasia, arteritis, Williams syndrome, neurofibromatosis, congenital malformations, blunt abdominal trauma, surgical vascular trauma-irradiation, thrombosis, congenital rubella syndrome, and unknown. Overall, symptoms were not common. However, findings of end-organ response, such as left ventricular hypertrophy and retinal vascular abnormalities were prevalent. This is not surprising given the mean BP level at presentation. Physical examination, laboratory tests, and radiologic evaluations (exclusive of renal angiography) were not useful in detecting or identifying the location and extent of the renovascular lesions. Fourteen patients were treated surgically, and 13 were managed medically. The outcome was variable for both treatment modalities. The management of renovascular hypertension in children must be individualized depending on the cause, location, and severity of the lesion, as well as the size of the child. Some forms of renovascular pathology, particularly the arteritides, may resolve spontaneously, and children with these entities should have their BP treated medically until the inflammatory process has subsided.(ABSTRACT TRUNCATED AT 250 WORDS)

Minoxidil for control of acute blood pressure elevation in chronically hypertensive children.

Twenty-three episodes of acute elevation of BP related to renal disease in 13 chronically hypertensive children 2 to 18 years of age were treated with a single oral dose of minoxidil. All except one patient were receiving a diuretic and all but one a beta-blocking agent at the time of minoxidil treatment. The goal of lowering BP to or below the 95th percentile for age within four hours of minoxidil administration was achieved in 14 of 23 treatment episodes. The goal was achieved in nine of 11 (82%) when the dose of minoxidil was greater than or equal to 0.2 mg/kg and in five of 12 (42%) when the dose was less than 0.2 mg/kg (P less than .05). In patients treated with greater than or equal to 0.2 mg/kg of minoxidil, mean systolic and diastolic BP decreased significantly from pretreatment values within one hour. In patients receiving less than 0.2 mg/kg, mean systolic BP was never significantly reduced and mean diastolic BP did not change significantly for two hours. Adverse effects were minimal. The results indicate that minoxidil in a dose of 0.2 mg/kg in combination with a diuretic and beta-blocking agent will lower BP to safe levels in most patients with severe hypertension related to renal disease within four hours with minimal side effects.

Low-dose intravenous insulin infusion versus subcutaneous insulin injection: a controlled comparative study of diabetic ketoacidosis.

Fourteen paients, 5 to 17 years old, with 18 episodes of uncomplicated diabetic ketoacidosis were randomly allocated and studied prospectively. The study group received 0.1 units of insulin per kilogram of body weight per hour as a continuous intravenous infusion; the control group received insulin subcutaneously. In both groups, a gradual fall in serum glucose and ketone levels was achieved. Serum ketones persisted longer in the intravenous group. No complications were encountered. The study suggests that both regimens of insulin administration are equally effective, but a low-dose constant infusion may provide more simplified and controlled management than the standard subcutaneous regimen.

Glomerular membranopathy in adolescents with insulin-dependent diabetes.

Kidney biopsy specimens from 15 patients ranging in age from 11 to 19 years with two- to 14-year histories of insulin-dependent diabetes mellitus were evaluated electron microscopically. Although the mean duration of disease was only eight years, the glomerular basement membrane (GBM) in these patients showed a variety of alterations typical of insulin-dependent diabetes mellitus. Saccular glomerular microaneurysms, previously little recognized, were seen in six of the specimens. These lesions, always associated with breaks in the paramesangial BM, were morphologically distinct from the ectatic capillary loops and glomerular capillary aneurysms described previously in diabetic glomerulopathy. All of the patients with such aneurysms also had other severe GBM alterations. Lytic or mechanical injury to the structurally and biochemically altered diabetic GBM may be responsible for the formation of microaneurysms.

Experience with a low volume ultrafiltration cell in small children*.

A low volume (16 ml) ultrafiltration cell was used ten times in two small, fluid overloaded children to remove plasma water. The device was simple to use and, at slow blood flow rates (25-50 ml/minutes) and low transmembrane pressures (10-30 mm Hg), provided controlled removal of excess fluid. Although no major complications were encountered, hypothermia and hypotension (at ultrafiltrate flux rates exceeding 0.5 ml/kg/minute) were observed. The ultrafiltrate solute concentration was similar to plasma and no significant shifts in serum electrolytes were induced. The ultrafiltrate protein concentration of 64 to 2,760 mg/dl was much higher than previously reported.

Membranoproliferative glomerulonephritis: improved survival with alternate day prednisone therapy.

Therapy with prednisone in an alternate day regimen over periods of 1.5 to 15 years in 27 children with membranoproliferative glomerulonephritis (MPGN) resulted in survival of 89% at 15 years after onset as compared with 50% survival at 6-12 years in the reports of other investigators. Therapy started, on the average, 1.5 years after onset in the 23 children with a good response and 5.2 years after onset in the 4 who developed irreversible renal failure. In most, clinical manifestations have diminished or, in many of those with Type I MPGN, disappeared. Glomerular scarring often increased with therapy but did not necessarily compromise function. Changes in morphology of functioning glomeruli varied with the type. In Type I, subendothelial deposits disappeared. In Types I and II, capillary walls became thinner and more capillary lumens were visiable. In Type III, glomerular morphology did not significantly change although clinically most of the patients have improved or are stable.

Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.

Seven patients with a form of membranoproliferative glomerulonephritis distinct in its glomerular ultrastructure from other forms are described. The use of silver impregnated electron micrographs revealed contiguous subepithelial and subendothelial deposits associated with basement membrane disruption, replication and layering of lamina densalike material. By light and fluorescence microscopy the appearance was distinctive but not diagnostic. Immunohistology consistently showed abundant C3 and properdin in a granular pattern while immunoglobulins and Clq were variably present. Low serum C3 concentrations were observed at some time in each patient, often accompanied by low levels of properdin, whereas the concentrations of Clq and C4 were normal. The patients were indistinguishable in their clinical course from those with other types of MPGN.

Observations on the evolution of idiopathic rapidly progressive glomerulonephritis.

Distinctive deposits of C3, C5 and properdin were identified in the minimally proliferative glomerular lesions of a patient with idiopathic rapidly progressive glomerulonephritis. Biopsies of her renal allograft at times of recurrences of her disease and of five other patients with progressive renal failure but less severe crescent formation showed deposits identical composition and position, giving evidence of a common pathogenesis. The deposits were subepithelial and located in that part of the basement membrane in apposition to the mesangium (capillary waist). Breaks in the basement membrane were often exclusively in this area suggesting the deposits were causative. Ancillary observations suggest that the subepithelial deposits become unidentifiable after the scarring of severe extracapillary proliferation develops. Three of the patients had, in addition, intramembranous dense deposits but in other ways their disease was not characteristic of membranoproliferative glomerulonephritis Type II. Instead, the evidence indicated that all six patients were in early or lage stages of idiopathic (non-streptococcal) rapidly progressive glomerulonephritis.

Membranoproliferative glomerulonephritis in two sibships.

In one sibship, a brother had membranoproliferative glomerulonephritis (MPGN) Type III and a sister, Type I. In both children, clinical and laboratory manifestations were typical. In another sibship, both boys had Type I MPGN by glomerular morphology but over a 4 year period of follow-up, neither had hematuria or hypocomplementemia, both common manifestations of this type. Several other reports give suggestive evidence of MPGN in siblings but details are scanty. The familial nature of the disease adds to the earlier observation of its predilection for the white race to strengthen the concept that genetic factors are involved in its origin.

Renal homotransplantation in children.

Ninety-six renal transplants in 77 pediatric patients are reported with follow-up as long as 12 1/2 years. Thirteen of the first 14 patients are living with a functioning kidney after eight to 12 1/2 years. The patient survival for the entire group is 78%. Sixty-four percent are living with a functioning transplanted kidney. Splenectomy was initially performed at the time of transplant but has been discontinued because of concern that splenectomy in the immunosuppressed patient was related to an increased occurrence of septic complications. Anencephalic newborn infants have been found to be a satisfactory source of cadaver donor kidneys. Growth and development have been satisfactory when the transplant is performed prior to 12 years of age, if it functions well, and if an alternate-day regimen of steroid administration is followed. Both boys and girls have now passed through puberty with their transplanted kidneys, have married, become parents, and are leading essentially normal lives. A plea is made for earlier transplantation in small children with irreversible progressive renal failure before they develop severe stunting of growth and before the need for prolonged dialysis.

Development of a high-precision continuous extracorporeal hemodiafiltration system.

A high-precision hemofiltration system appropriate for use in neonatal, pediatric, or adult patients has been developed. The system incorporates computer-monitored and -regulated pumps for control of blood, dialysate, and drain solutions and weighing scales for measurement of fluid infused into and removed from the patient. The overall accuracy of the fluid infusion and withdrawal is +/- 3.5 grams. The system incorporates four pressure transducers to monitor pressures. It includes alarm limits for pressure, solution volumes versus time, temperature, air leak, and blood detection in the drain effluent. The computer stops all pumps in alarm conditions. The system also can be easily adapted for other extracorporeal procedures such as hemofiltration, ultrafiltration, plasmapheresis, and extracorporeal membrane oxygenation.