Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program.

Human leukocyte antigen (HLA)-identical sibling bone marrow transplantation is an effective treatment for Wiskott-Aldrich syndrome. However, most children with this disease lack such donors and many patients receive transplants from alternative donors. This study compared outcomes of HLA-identical sibling, other related donor, and unrelated donor transplantation for Wiskott-Aldrich syndrome. The outcome of 170 transplantations for Wiskott-Aldrich syndrome, from 1968 to 1996, reported to the International Bone Marrow Transplant Registry and/or National Marrow Donor Program were assessed. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. Multivariate proportional hazards regression was used to compare outcome by donor type and identify other prognostic factors. Most transplant recipients were younger than 5 years (79%), had a pretransplantation performance score greater than or equal to 90% (63%), received pretransplantation preparative regimens without radiation (82%), and had non-T-cell-depleted grafts (77%). Eighty percent received their transplant after 1986. The 5-year probability of survival (95% confidence interval) for all subjects was 70% (63%-77%). Probabilities differed by donor type: 87% (74%-93%) with HLA-identical sibling donors, 52% (37%-65%) with other related donors, and 71% (58%-80%) with unrelated donors (P =.0006). Multivariate analysis indicated significantly lower survival using related donors other than HLA-identical siblings (P =.0004) or unrelated donors in boys older than 5 years (P =.0001), compared to HLA-identical sibling transplants. Boys receiving an unrelated donor transplant before age 5 had survivals similar to those receiving HLA-identical sibling transplants. The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children.

Essential hypertension: historical perspective, mechanisms and an approach to treatment.

The mechanisms of essential hypertension have been reviewed and drugs useful in treatment discussed. Although much is known therapy remains largely empiric. Future control of hypertension depends on developments from the laboratory and carefully designed clinical trials that support the empirical. On the horizon, molecular biology promises to be progressing toward unraveling the tangle of the genetic origins of the disease. Perhaps only with this knowledge will completely rational therapy emerge.

Hyperkalemia: mechanisms, etiology, and treatment.

Hyperkalemia may follow failure of glomerular filtration or tubular secretion of potassium. Tubular secretory failure may be secondary to deficient aldosterone or tubular insensitivity to this hormone. In either case glomerular insufficiency magnifies the problem. Increased potassium intake alone is a rare cause of increased serum potassium. The well recognized sequential treatment of hyperkalemia is reviewed. Most important is the establishment of the cause of hyperkalemia as these emergency measures are being taken. A history of drug intake, establishment of the acid-base status of the patient and the presence of underlying disease must be ascertained. The management of hyperkalemia remains an intriguing challenge in the office and hospital practice of medicine.

Hyponatremia: manifestations and treatment.

All hyponatremic states have in common elevation of vasopressin. Without this the loss of salt would be followed by appropriate diuresis and normonatremia. If hyponatremia is triggered by a volume change as in heart failure or portal cirrhosis not only is ADH released but the mechanisms that control salt retention create an essentially sodium free urine, always less than 20 mEq/L. If the initial event is inappropriate ADH secretion whether it be cerebral disease, neoplasm, a pulmonary lesion or a growing list of drugs; there is no related signal for salt retention and urine sodium and tonicity are high, the latter usually higher than that of plasma. If salt loss is due to intrinsic renal disease, diuretics, osmotic or otherwise, or adrenal failure urinary sodium is variable depending upon the magnitude of the response to volume of salt retaining factors. Because hyponatremia is often present with major illness and because more than one factor may be involved in its genesis, the establishment of its origin and appropriate treatment remain a diagnostic and therapeutic challenge.

Histopathologic evaluation of lupus patients with transient renal failure.

Patients with lupus nephritis and severe renal failure progress to end-stage renal disease despite aggressive therapy to suppress immunologic function. Within this group is a small subset presenting with rapid progression of renal failure and requiring dialytic support. We reviewed the clinicopathologic data of four such patients who were able to terminate dialysis after acute renal failure due to lupus nephritis. Three of these patients have remained independent of dialysis up to 4 years, and one patient returned to dialysis 1 month following discontinuation. Although glomerular pathology was variable in the four patients, a lesion common to all at presentation was acute tubular necrosis. It is suggested that tubular necrosis may cause reversible renal failure when part of the nephropathy of disseminated lupus treated with corticosteroids.

Glomerular anionic site distribution in nonproteinuric rats. A computer-assisted morphometric analysis.

The cationic ultrastructural tracer polyethyleneimine (PEI: pI approximately equal to 11.0), binds electrophysically to uniformly spaced discrete electron-dense anionic sites present in the laminae rarae of the rat glomerular basement membrane (GBM), mesangial reflections of the GBM, Bowman's capsule, and tubular basement membranes when administered intravenously. Computer-assisted morphometric analysis of glomerular anionic sites reveals that the maximum concentration of stainable lamina rara externa (lre) sites (21/10,000 A GBM) occurs 60 minutes after PEI injection with a site-site interspacing of 460 A. Lamina rara interna (lri) sites similarly demonstrate a maximum concentration (20/10,000 A GBM) at 60 minutes with a periodicity of 497 A. The concentration and distribution of anionic sites within the lri was irregular in pattern and markedly decreased in number, while the lre possesses an electrical field that is highly regular at all time intervals analyzed (15, 30, 60, 120, 180, 240, and 300 minutes). Immersion and perfusion of renal tissue with PEI reveals additional heavy staining of the epithelial and endothelial cell sialoprotein coatings. PEI appears to bind to glomerular anionic sites reversibly: ie, between 60 and 180 minutes the concentration of stained sites decreases. At 300 minutes, the interspacing once again approaches the 60-minute concentration. This suggests a dynamic turnover or dissociation followed by a reassociation of glomerular negatively charged PEI binding sites. In contrast, morphometric analysis of anionic sites stained with lysozyme and protamine sulfate reveals interspacings of 642 A and 585 A, respectively; in addition, these tracers produce major glomerular ultrastructural alterations and induce transient proteinuria. PEI does not induce proteinuria in rats, nor does it produce glomerular morphologic alterations when ten times the tracer dosage is administered intravenously. These findings indicate that the choice of ultrastructural charge tracer, the method of administering the tracer, and the time selected for analysis of tissue after administration of tracer significantly influences results. Morphometric analysis of the distribution of glomerular anionic sites in nonproteinuric rats provides a method of evaluating quantitative alterations of the glomerular charge barrier in renal disease models.

Diabetic glomerulonephropathy: histopathologic, immunofluorescent, and ultrastructural studies of 16 cases.

Sixteen cases of diabetic glomerulopathy are reported. Direct immunofluorescent and ultrastructural studies of renal biopsy tissues demonstrated that two patients had linear deposits of IgM and C'3 in the absence of IgG, four diabetic patients had sclerosis-induced entrapment of immunoglobulins and complement, and one patient had granular immune complexes in the subepithelial and intramembranous portion of the glomerular basement membrane. In one patient, who had nodular glomerular lesions, diffuse fibrillar deposits of electron-dense material were observed in the mesangium. In this mesangial infiltrate, light microscopy revealed the absence of amyloid and direct immunofluorescence revealed the absence of all immunoglobulins, complement components, and fibrinogen. Our study suggests that the morphologic alterations observed in diabetic glomerulopathy might be mediated by either immune mechanism or by abnormal biochemical or functional factors, such as impairment of the mesangial IgA clearance mechanism.

Dialysis enhances renal epithelial proliferations.

Study of 115 kidneys from 60 patients with chronic renal failure maintained by dialysis for two months to five years revealed an unexpected number and variety of epithelial proliferative processes, several types of which are hitherto unreported. Proliferative activity was defined either by the presence of epithelial structures in ectopic situations, continuity with existing structures being demonstrable by serial sections, or by mitotic figures, or by both. The tendency for renal carcinoma development may relate to these dialysis-related epithelial proliferations originating in both glomerular and tubular epithelia. Enhanced renal epithelial proliferative capacity in dialysis may be employable in the experimental study of renal regeneration and in the therapy of patients with preterminal renal disease.

Studies of end-stage kidneys. III. Glycogen deposition in interstitial cells of the renal medulla.

Examination of kidneys of ten patients with uremia and severe hypertension treated by chronic intermittent hemodialysis revealed a deposition of glycogen within interstitial cells of the renal medulla. This is unlike any described renal distribution of glycogen. Electron microscopic studies performed in one case demonstrated monoparticulate glycogen both diffuse in the interstitial cell cytoplasm and locally aggregated beside lipid droplets. The findings provide evidence for a metabolic abnormality of renal medullary interstitial cells in patients who have protracted uremia.