A definition of proximal and distal tubular compliance. Practical and theoretical implications.

Micropuncture studies were carried out in the rat to evaluate the in situ distensibility characteristics of the proximal and distal tubules under a variety of experimental conditions. In the first phase, we determined the response of tubular diameter (D) to changes in tubular pressure (P) induced by partially obstructing single tubules. The response observed under these conditions (i.e., when interstitial pressure is presumed to be constant) has been defined as the compliance of the tubule. Over the range of tubular pressures studied (10-35 mm Hg for the proximal tubule, 5-25 mm Hg for the distal tubule) the compliance characteristics of the proximal and distal tubule were found to be markedly different; the proximal tubular pressure-diameter relationship was linear, DeltaD/DeltaP = 0.45 mum/mm Hg, whereas the distal pressure-diameter relationship was curvilinear, DeltaD/DeltaP = c(-0.1xP+2.2). In the second phase we used the compliance data to construct a series of theoretical pressure-diameter curves that define the response of the tubule to increments in interstitial as well as intratubular pressure. These curves indicate that changes in distal diameter should provide a sensitive index of a rise in interstitial pressure under conditions in which the transtubular pressure gradient is increased by a small amount, but that proximal diameter should provide a more sensitive index of changes in interstitial pressure when the transtubular pressure gradient is increased by a large amount. In subsequent experiments in which furosemide was administered, we observed that the pressure-diameter relationships for both the proximal and distal tubule were indistinguishable from the compliance curves, a finding consistent with the interpretation that interstitial pressure was not appreciably changed from control. By contrast, when mannitol was administered, both proximal and distal tubular pressure-diameter relationships were significantly altered in a fashion consistent with a large increase in interstitial pressure. Neither with furosemide nor mannitol administration did it appear likely that significant changes in tubular compliance could account for the observed behavior of the tubule.Finally, we propose that a knowledge of tubular compliance will be useful in exploring the interrelationships between tubular and peritubular pressures, tubular anatomy, and transtubular ionic permeability. Recent studies linking changes in the geometry of lateral intercellular spaces of the tubule to changes in passive ion movement suggest that an investigation of such anatomical-functional correlates should be productive.

Identification of risk for renal insufficiency from nonsteroidal anti-inflammatory drugs.

Risk for renal insufficiency (RI) resulting from nonsteroidal anti-inflammatory drugs (NSAID) exists in cirrhosis with ascites, nephrotic syndrome, decompensated congestive heart failure, and chronic renal disease. We saw seven cases of NSAID RI that demonstrate important additional clinical risk factors. These include advanced age (mean, 76 years), use of diuretic drugs (6/7 patients), and evidence of renal vascular disease as suggested by long-standing hypertension, diabetes, or atherosclerotic cardiovascular disease (7/7 patients). Analysis of past case reports of NSAID RI also showed these features. Treatment of acute gouty arthritis was the most common precipitating event. Evolving NSAID RI was suggested by rising serum urea nitrogen, serum creatinine, and serum potassium levels, and body weight gain associated with low fractional excretion of sodium. We conclude that since NSAID RI is preventable and reversible, it is important to recognize and monitor the conditions of those patients at risk.

Iatrogenic renal disease.

We studied iatrogenic problems in nephrology by classifying all patients for nephrology consultation into nine presenting syndromes and seven etiologic groups. One hundred (2.2%) of all admissions were seen in nephrology consultation. Acute renal failure was the most common presenting syndrome, accounting for 59% of the consultations. Forty-one of the 100 consultations (1% of all admissions) had a renewal syndrome of iatrogenic origin. Of these 41 patients, 38 had acute renal failure and three had fluid and electrolyte problems. Twenty of the 41 patients had drug-induced problems. Eighteen of these patients were dehydrated, and in three patients, acute renal failure occurred after surgery. Of the 20 patients with iatrogenic renal problems caused by drugs, seven problems were antibiotic related, five were due to diuretics, four were due to nonsteroidal anti-inflammatory drugs, three were due to angiotensin-converting enzyme inhibitors, and one was from the use of contrast medium. The 41 patients with iatrogenic-related renal disease were older than the other 59 patients (61.8 vs 49.3 years). Iatrogenic renal disease developed in 1% of all patients admitted to a tertiary care hospital, and 12% of these patients died. The most common renal syndrome is acute renal failure, most often caused by nephrotoxic drugs. The incidence can probably be decreased by better monitoring of body weight and fluid balance to prevent dehydration and by the avoidance of nephrotoxic drugs.

Acute pulmonary edema as the initial hospital presentation of systemic lupus erythematosus.

Acute pulmonary edema is an unusual initial presentation for systemic lupus erythematosus. A 46-year-old woman required intensive care for life-threatening pulmonary edema of unknown etiology, which was unresponsive to conventional treatment. Her condition improved only when pulse corticosteroid therapy was initiated, with clinical and echocardiographic improvement in cardiac function. The diagnosis of systemic lupus erythematosus was then made, based on immunologic tests and renal biopsy. The patient's condition remained stable only with continuation of appropriate therapy for systemic lupus erythematosus.

Comparative effects of transdermal clonidine and oral atenolol on acute exercise performance and response to aerobic conditioning in subjects with hypertension.

We compared the effects of transdermal clonidine and oral atenolol on acute exercise performance and on conditioning response to an 8-week program of regular aerobic exercise in young, otherwise healthy subjects with mild hypertension. The study was a double-blind, randomized, parallel-group study with placebo control. Twenty-seven subjects (11 receiving transdermal clonidine, 8 receiving oral atenolol, and 8 receiving placebo) completed the study. Atenolol controlled blood pressure in all 8 subjects, vs 6 of 11 in the transdermal clonidine group and 0 of 8 in the placebo group. Both active drugs lowered systolic blood pressure during exercise. With clonidine treatment, the antihypertensive effect during exercise was smaller and was observed only at low and moderate workloads. Acute exercise performance (subjects receiving drug but still unconditioned) was assessed by endurance time at a constant workload equal to the highest workload completed on a previous 2-minute incremental exercise test. Endurance time was reduced 35% by atenolol but not by transdermal clonidine or placebo. Neither active drug interfered with the progress of the conditioning program, as measured by gradual lengthening of exercise time. However, as assessed by change in oxygen uptake standardized to a heart rate of 170 beats per minute, the improvement in conditioning was twice as great in subjects receiving transdermal clonidine and placebo (+20%, +18%) as it was in those receiving atenolol (+8%). Subjects receiving placebo and transdermal clonidine lost weight; subjects receiving oral atenolol gained weight. The changes in weight were small.

Idiopathic, sustained, inappropriate secretion of ADH with associated hypertension and thirst.

A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.

A tale of two homocysteines--and two hemodialysis units.

Pharmacologic doses of folic acid are commonly used to reduce the hyperhomocysteinemia of end-stage renal disease (ESRD). Vitamin B12 acts at the same metabolic locus as folic acid, but information is lacking about the specific effects of high doses of this vitamin on homocysteine levels in renal failure. We therefore compared the plasma homocysteine concentrations of maintenance hemodialysis patients in two McGill University-affiliated urban tertiary-care medical centers that differed in the use of vitamin B12 and folic acid therapy. Patients in the first hemodialysis unit are routinely prescribed high-dose folic acid (HI-F, 6 mg/d), whereas those in the second unit receive high-dose vitamin B12 in the form of a monthly 1-mg intravenous injection, along with conventional oral folic acid (HI-B12, 1 mg/d). Predialysis homocysteine was 23.4 +/- 6.8 micromol/L (mean +/- SD) in the HI-F unit and 18.2 +/- 6.1 micromol/L in the HI-B12 unit (P < .002). Postdialysis homocysteine was 14.5 +/- 4.1 in the HI-F unit and 10.6 +/- 3.4 micromol/L in the HI-B12 unit (P = .0001). Multiple regression analysis indicated that high-dose parenteral vitamin B12 was associated with a lower homocysteine concentration even after controlling for the potential confounders of sex, serum urea, serum creatinine, urea reduction ratio, and plasma cysteine. Because this was a cross-sectional observational study, we cannot exclude the possibility that unidentified factors, rather than the different vitamin therapies, account for the different homocysteine levels in the two units. Careful prospective studies of the homocysteine-lowering effect of high-dose parenteral vitamin B12 in ESRD should be undertaken.

Mechanisms of elevated blood pressure in human essential hypertension.

This review of the mechanisms of elevation of blood pressure in human essential hypertension first focuses on individual mechanisms and their interrelations. The authors then try to identify those forms of essential hypertension in which the major determinants are known. When the most significant processes associated with elevated blood pressure in individual patients are understood, a rational approach to therapy can be undertaken even though the ultimate cause of the disorder is not understood.

Pulmonary hemorrhage and acute renal failure in a patient with mixed connective tissue disease.

Mixed connective tissue disease (MCTD) is considered to have a benign clinical course. Recently, renal disease has been recognized as a frequent complication (20%). This report describes a patient with MCTD who developed pulmonary hemorrhage and acute renal failure. The renal biopsy, in addition to a long-standing membranous nephropathy, revealed a tubulointerstitial nephritis. Immunofluorescent and electron microscopy showed immune complex deposition along the tubular basement membrane. Life-threatening, immune complex-mediated events can occur in the course of MCTD, manifested as pulmonary hemorrhage and tubulointerstitial nephritis.

Hyperkalemia provoked by acute hepatic necrosis.

Six patients with varying degrees of renal insufficiency developed severe hyperkalemia following hepatic necrosis. The hyperkalemia was seen prior to or concomitant with marked elevations in hepatic enzymes. The basis of the liver disease appeared to involve congestive heart failure and/or hypotension. Necrotic liver cells released intracellular potassium into the blood of patients who were unable to handle the additional potassium load because of renal insufficiency and metabolic acidosis. Furthermore, a shift of potassium into the intracellular space is impaired in uremics by defective Na-K ATPase activity, possibly induced by uremic toxins. The 3 diabetic patients in our series may additionally have had aldosterone deficiency leading to impaired cellular potassium uptake.

Pulmonary edema: atypical anaphylactoid reaction to intravenous iron dextran.

Two cases of atypical anaphylactoid reactions to intravenous iron dextran in hemodialysis patients are described. Anaphylactic reactions to iron dextran in dialysis patients are not uncommon. Pulmonary edema is not generally seen in anaphylaxis. Our patients both developed significant pulmonary edema following intravenous infusion of iron dextran, which responded promptly to treatment of anaphylaxis. Potential mechanisms are discussed.

Glomerular permeability to neutral and anionic dextrans in experimental diabetes.

Renal clearances of polydispersed neutral and anionic dextrans were measured in diabetic rats. In addition, urinary protein and albumin excretion rates were determined. Measurements were performed 3 months after the induction of diabetes (i.v. alloxan 50 to 55 mg/kg of body wt) in rats which were either untreated or which received supplemental insulin (6 U of NPH daily) and were compared to those in age-matched SHAM-treated rats. Fractional clearances (relative to inulin) of neutral dextrans remained unchanged in insulin-supplemented rats and were slightly but significantly increased in untreated rats. The application of an isoporous model of the glomerular filtration barrier permitted the conclusion that the size-selective characteristics of the barrier were unaltered in diabetic rats. Fractional clearances of anionic dextrans were significantly reduced 50 to 60% in both diabetic groups suggesting an increase in the negative charge density of the filtration barrier and potentially an increase in restriction to the glomerular filtration of anionic proteins. However, urinary and albumin excretions tended to increase in both groups of diabetic rats, including a 164% increase in albumin excretion in untreated rats. This apparent discrepancy between reduced dextran sulfate clearances and increased protein excretions suggests that factors other than charge-selectivity may be of major importance in determining the filtration of proteins. The marked increase in albumin excretion observed in our diabetic rats appears to be a result of decreased tubular reabsorption rather than increased filtration of albumin.

Determinants of glomerular filtration and plasma flow in experimental diabetic rats.

GFR and, to a lesser extent, RPF are elevated soon after the onset of human diabetes mellitus. The mechanisms involved in these functional changes are unknown. Since the experimental diabetic rat has renal morphological changes similar to those observed in man, we investigated whole-kidney and superficial-nephron glomerular function in this animal model early during the course of the disease. Alloxan-induced diabetes (50 mg/kg BW) is frequently characterized by severe hyperglycemia and retarded body growth. Supplemental insulin administration (6 U of NPH insulin daily) results in normal body growth, although hyperglycemia persists. As a result, we studied four groups of diabetic rats (1) after 1 month of untreated diabetes, (2) after 3 months of untreated diabetes, (3) after 3 months of untreated diabetes followed by 1 month of insulin supplementation, and (4) after 3 months of insulin-supplemented diabetes. After 1 month of untreated diabetes, GFR and SNGFR each declined by 20% compared to age-matched control rats. RPF and SNGFR were both reduced by 33% as a consequence of a 41% increase in RT. Reduced SNGPF together with a 7 mm Hg reduction in PGC caused the fall in GFR and SNGFR. KWs were not significantly different from those of control rats. The functional changes that occurred after 1 month of untreated diabetes did not significantly deteriorate after 3 months of the disease. Insulin supplementation, when instituted for 1 month after 3 months of untreated diabetes, produced no significant improvement in either whole-kidney or superficial-nephron hemodynamics even though body and kidney growth were stimulated. In contrast, insulin supplementation initiated at the onset of diabetes increased both SNGFR and SNGFR to 23% above control values. GFR and RPF each increased in proportion to the 18% increment in kidney size. RT was reduced in these rats, and the pressures that govern glomerular ultrafiltration were not altered from control values. We conclude that in untreated diabetic rats, an increase in RT is the predominant hemodynamic alteration which produces reduced glomerular hemodynamic function. Once established, this defect may not be reversed with 1 month of insulin supplementation. In contrast, small doses of insulin initiated at the onset of diabetes result in renal hypertrophy and proportionate increases in GFR and RPF with a reduction in RT.

Intermittent hemodialysis in terminal chronic renal failure.

Seven patients with chronic renal failure underwent intermittent hemodialysis for five to 37 months (111 patient-months on a twice-weekly basis) employing arteriovenous Teflon-Silastic cannulas and the modified two-layer Kiil hemodialyzer. A single-pass 37 degrees C. dialysate system has been used. One patient died of an indirectly related cause. All other patients have been successfully rehabilitated and now carry on normal activity of moderate sedentary type. Complications included recurring infection and clotting of arteriovenous cannulas. Hypertension and anemia were common complications requiring careful control. Peripheral neuropathy was noted in five of the seven patients but was of clinical significance in only one patient. Metastatic calcification, osteoporosis and urolithiasis also occurred in this patient. Peptic ulcers with hemorrhage developed in two patients. The degree of rehabilitation and psychological adjustment achieved by this group of patients strongly indicates the need for expansion of dialysis facilities and further research into the medical and economic aspects of dialysis.

Idiopathic hypercalciuria associated with hyperreninemia and high urinary prostaglandin E.

A patient with idiopathic hypercalciuria and some features suggestive of Bartter syndrome is reported. Excessive urinary prostaglandin E (PGE) excretion and renal calcium leak were documented in this child. Treatment with aspirin and indomethacin reduced urinary PGE excretion and was associated with a decrease in daily calcium excretion. At the lowest levels of urinary PGE, the renal calcium leak was no longer evident although mild hypercalciuria persisted. These results suggest that PGE may play a role in some cases of idiopathic hypercalciuria.

Proximal tubulare dysfunction associated with Burkitt's lymphoma.

Generalized aminoaciduria, uricosuria, glycosuria and phosphaturia were discovered in a patient with advanced Burkitt's lymphoma with renal infiltration. The literature is reviewed and three pathogenetic mechanisms are discussed. It is presumed that proximal tubular dysfunction in this case was related to the marked peritubular infiltrate causing cell mediated immunological injury or direct tubular destruction by tumor.

Wegener's granulomatosis and relapsing polychondritis: a case report.

Relapsing polychondritis, a rare disorder characterized by inflammation of cartilaginous tissue, is often associated with vasculitic features. Wegener's granulomatosis is an uncommon form of vasculitis, usually responsive to treatment with cyclophosphamide. A 59-yr-old man with relapsing polychondritis, initially well controlled by corticosteroid therapy, developed pulmonary infiltrates and glomerulonephritis. After pathological confirmation of Wegener's granulomatosis, cyclophosphamide therapy was instituted and remission achieved.