Simultaneous postinfectious glomerulonephritis and thrombotic microangiopathy: a renal biopsy study.

The simultaneous occurrence of postinfectious glomerulonephritis and thrombotic microangiopathy is described in renal biopsy specimens from three patients. Each presented with diverse manifestations: two patients had hypertension and acute renal failure, and in the third, it was unclear whether an atypical postinfectious glomerulonephritis or an atypical thrombotic microangiopathy was present. All biopsy specimens disclosed a combination of irregular granular complement and immunoglobulin deposits in mesangial regions and capillary walls along with fibrin in a linear pattern in capillary walls by immunofluorescence. Light microscopy showed diffuse hypercellularity in some glomeruli, endothelial cell swelling, luminal thrombi and mesangiolysis in others, and both types of changes in a third group. Ultrastructurally, subepithelial hump-shaped deposits coexisted with widened and lucent subendothelial spaces. Possible pathogenic mechanisms for the synchronous lesions include endothelial injury, perhaps triggered by infection and immunologic tissue damage.

Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism.

Calcitriol, as used for treating secondary hyperparathyroidism, has a low therapeutic index. The safety and efficacy of the vitamin D analog, 1 alpha (OH)-vitamin D2, (1 alpha D2), which has less toxicity in animals than 1 alpha (OH)-vitamin D3, was tested in a multicenter study of 24 hemodialysis patients with secondary hyperparathyroidism [serum intact (i) PTH > 400 pg/ml]. Calcium-based phosphate binders alone were used to maintain serum phosphorus < or = 6.9 mg/dl. After eight weeks without calcitriol (washout), oral 1 alpha D2, 4 micrograms/day or 4 micrograms thrice weekly, was started, with the dose adjusted over 12 weeks to maintain serum iPTH between 130 and 250 pg/ml. Pre-treatment serum iPTH fell from 672 +/- 70 pg/ml (SEM) to 289 +/- 36 after treatment (P < 0.05). The maximal decrease in serum iPTH was 48 to 96%, with 87.5% of patients reaching target iPTH levels. The final dose of 1 alpha D2 average 14.2 micrograms/week. Pre-treatment serum calcium rose modestly from 8.8 +/- 0.2 mg/dl to 9.5 +/0 0.2 after treatment (P < 0.001). Only once did modest hypercalcemia (serum Ca > 11.2 mg/dl) necessitate stopping treatment. Neither the average serum P level, the incidence of hyperphosphatemia, nor the dose of phosphate binders changed from washout to treatment. Thus, oral 1 alpha D2 is highly efficacious in suppressing secondary hyperparathyroidism in hemodialysis patients and is safe despite exclusive use of calcium-based phosphate-binders. Future studies should clarify the optimal dosage regimen.

Fibroblasts of rabbit kidney in culture. II. Paracrine stimulation of papillary fibroblasts by PDGF.

To examine the role of tubulointerstitial cell interaction in the regulation of fibroblast growth, fibroblasts from the rabbit renal cortex (CF) and papilla (PF) were cocultured with epithelial cells from the same tissue location. Inner medullary collecting duct epithelial cells (IMCDE) or IMCDE-conditioned medium stimulated DNA synthesis in PF, whereas proximal tubule epithelium (PTE) had no effect on the proliferation of CF. PF and CF showed a similar mitogenic response to exogenous epidermal growth factor and insulin-like growth factor 1 (IGF-I). Transforming growth factor-beta 1 inhibited growth of both cell types, and basic fibroblast growth factor (bFGF) had no effect on proliferation of either cell type. In contrast, platelet-derived growth factor (PDGF) was a potent mitogen for PF but was only weakly mitogenic for CF. Both CF and PF expressed a similar number of a single-affinity class of PDGF receptors (Kd, 2-4 x 10(-10) M). Assay for growth factor activity in conditioned medium from IMCDE and PTE showed that only IMCDE produced detectable PDGF. IMCDE-stimulated proliferation of PF was partially blocked by an antibody to PDGF, whereas antibodies to IGF-I had no neutralizing effect. The data suggest a role for PDGF in the regulation of interstitial fibroblast proliferation by IMCDE in the renal papilla. This paracrine system may be important in the pathogenesis of some forms of interstitial fibrosis of the kidney.

The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial.

Fourteen nondialyzed patients with chronic renal insufficiency (serum creatinine 265 to 972 mumol/L [3.0 to 11.0 mg/dL]) and severe anemia (hematocrit less than 30%) were randomized to receive either recombinant human erythropoietin (r-HuEPO) or a placebo subcutaneously thrice weekly for 12 weeks or until reaching a hematocrit of 38% to 40%. Anemia was significantly ameliorated in the treated patients. No acceleration in the progression of renal failure (1/serum creatinine v time) or change in serum potassium was noted for either the placebo or treated group over the 12-week period. Six of seven treated patients had a significant decrease in serum ferritin and percent transferrin saturation (plasma iron/total iron-binding capacity). This resulted in functional iron deficiency and the requirement for iron supplementation. The average systolic and diastolic blood pressure did not differ significantly between the two groups of patients during the study. Quality of life was improved in all r-HuEPO-treated patients but not in those in the placebo group. This study demonstrates the safety and efficacy of r-HuEPO in the correction of anemia in predialysis patients without adverse effects on renal function over a 12-week period. Improved patient well-being as a result of the correction of anemia resulted in one patient refusing appropriate initiation of dialysis therapy.

Amyloid syndromes associated with hemodialysis.

A historical review and current clinical findings relating a new type of amyloid material to long term hemodialysis are presented, followed by a review of the biochemistry, metabolism and involvement of beta 2-M and theories for the pathogenesis of HRA. The syndromes develop several years after replacement of renal function by dialysis, and seem to be progressive over time. Preliminary clinical studies utilizing more permeable artificial kidney membranes suggest their potential usefulness in the prevention of HRA syndromes, specifically those attributable to persistent elevation of serum beta 2-M; however, caution in their employment is advised. The development of effective treatment for long-term hemodialysis patients afflicted with CTS, arthritic symptoms and skeletal manifestations of HRA is unfortunately constrained by deficiencies in our knowledge. Renal transplantation has been demonstrated to reduce the elevated serum beta 2-M levels in hemodialysis patients to normal; however, the effectiveness of this modality to treat clinical manifestations of HRA has not been reported. Thus, efficacious treatment strategies have lagged considerable behind diagnostic techniques. Intensive research is needed as the story of this new form of renal osteodystrophy unfolds.

Accidental salicylate intoxication in a hemodialysis patient.

A 61-year-old woman receiving long-term hemodialysis presented with symptoms of tinnitus, insomnia, malaise, and disequilibrium. On close questioning, it was discovered that she had received a prescription for salsalate (Disalcid) from a consulting physician who had evaluated her for joint pain. This tablet was similar in appearance to a dried aluminum hydroxide gel preparation (Alu-tab) that the patient was taking as a phosphate binder. She had mistakenly been taking six Disalcid tablets with each meal. Her salicylate level was 5.86 mmol/L, but she had no change in her serum electrolyte levels or acid-base status. When the salsalate treatment was stopped and regular dialysis treatments were continued, the symptoms of salicylism resolved. This case illustrates one of the potential dangers of polypharmacy in patients with chronic disease. The midl course was probably due to ongoing hemodialysis, which prevented the appearance of the usual acid-base abnormalities of salicylate intoxication.

Prognostic implications of renal hypertrophy in diabetes mellitus.

Early in the course of type 1 diabetes mellitus, hypertrophy of the kidney is a consistent finding that is easily diagnosed using current noninvasive methods, especially ultrasonography. Renal functional changes occur in association with hypertrophy, most notably glomerular hyperfiltration. The structural counterpart of this functional change is an early increase in capillary filtration surface area. In most forms of nondiabetic renal hypertrophy, kidney size is closely linked to GFR. In contrast, in diabetes, persistence of hypertrophy after the clinical onset of overt kidney disease (microalbuminuria, hypertension, decreased GFR, etc.) suggests that sustained release of one or more growth factors may continue even after kidney function declines. The fact that growth factors can act in both an autocrine and paracrine fashion raises the possibility that the local effects of such substances may act as local mediators of kidney growth. Failure of renal hypertrophy to reverse following strict glycemic control for a few months may turn out to be an important prognostic indicator of future progression of the renal disease, but this remains to be established. Prospective studies of kidney size in patients with newly diagnosed type 1 diabetes, using accurate noninvasive methods, may be helpful in establishing whether irreversible ("autonomous") hypertrophy of the kidney is indeed a useful prognostic indicator. As therapies are developed that target the different microvascular complications of diabetes (retinopathy, nephropathy, neuropathy), a noninvasive estimation of kidney size may be a cost-effective method of predicting ultimate renal involvement. Since microalbuminuria occurs relatively late in the disease process, early and persistent hypertrophy of the kidney may become a useful prognostic test in the earliest stages of the disease.

Glomerular filtration rate fails to increase following protein ingestion in hypothalamo-hypophyseal-deficient adults. Preliminary observations.

Oral protein loads are known to induce an increase in glomerular filtration rate (GFR) in man and animals. The mechanism underlying this phenomenon is currently unknown. In order to study the possible role of growth hormone (GH) or other hypothalamo-hypophyseal (HH) factors in the response of GFR to a protein meal, we studied 4 chronically GH- or HH-deficient adults and age-matched controls, free of renal disease, before and after ingestion of a large protein meal (red cooked meat). GFR, measured by inulin clearance and corrected for body surface area, was 18.5% lower during basal conditions (89.1 +/- 6.0 ml/min) in the GH- or HH-deficient population when compared to controls (109.7 +/- 9.1 ml/min), but this difference did not achieve statistical significance for this small patient population (p greater than 0.1, less than 0.2). For a 3-hour postprandial period, mean GFR increased by 25.3% in the control population (136.8 +/- 10.7 ml/min; p less than 0.01), while mean GFR failed to increase in the GH- or HH-deficient patients (86.8 +/- 10.9 ml/min; p greater than 0.10). Male control subjects, not pretreated with diethylstilbestrol, had no change in GH levels (p greater than 0.2). However, 1 female control was found to increase GH levels 10 times preprandial levels. These studies suggest that HH factors other than GH are mediators of the augmentation of GFR following a large protein load in human adults.