Functional profile of the isolated uremic nephron. Evidence of proximal tubular "memory" in experimental renal disease.

In experimental models of glomerular and nonglomerular renal disease, single nephron filtration rate and proximal tubular reabsorption of fluid decrease or increase in parallel in the same nephron. To assess whether intrinsic adaptations in proximal tubular function, i.e., changes that are independent of the peritubular or humoral milieu, contribute to this phenomenon, segments of rabbit late superficial proximal convoluted tubules (PCT) were studied by in vitro perfusion. PCT were obtained from normal kidneys, from remnant kidneys, and from kidneys embolized with microspheres. Single nephron filtration rates are increased in the remnant and decreased in the embolized kidneys. Whereas the embolized-kidney rabbits were nonazotemic (the contralateral kidney was left in situ), the remnant-kidney animals were uremic. In order to study a nonazotemic model of increased single nephron filtration rate, PCT were also obtained from uninephrectomized rabbits. Significant compensatory hypertrophy occurred in the PCT of the remnant kidney. Net fluid reabsorption (Jv) per unit length was increased by approximately 60%; Jv per unit luminal surface area was the same as in the normal PCT. Transepithelial potential difference (PD) was significantly greater than normal. This was associated with a reversal of the normal permselective properties (P(Cl) > P(Na)) of the late superficial PCT so that P(Na) exceeded P(Cl). The changes could not be ascribed to some undetermined effect of the uremic state in vivo, since increases in tubule size, Jv per unit length, and PD also occurred in PCT from nonazotemic uninephrectomized rabbits. In contrast, Jv, per unit length or per unit luminal surface area, was decreased by approximately 50% in PCT from embolized kidneys and PD was also reduced. In these tubules, the normal permselective properties were also reversed. Tubule size, however, was not significantly different from normal. The increases or decreases in Jv that occurred in the different disease models were not dependent on tubular fluid flow rate or the uremic milieu in vitro. These studies indicate that intrinsic proximal tubular function is modified by the disease state in vivo and that the "memory" of this adaptation is expressed in the in vitro situation. The changes in Jv observed in vitro parallel the increases or decreases in single nephron filtration rates that occur in vivo. Compensatory hypertrophy, with an attendant increase in luminal surface area, could explain the increased Jv per millimeter in the remnant kidneys, but the adaptation observed in the embolized kidneys cannot be ascribed to changes in tubule size.

Hypouricemia due to renal tubular defect. A study with the probenecid-pyrazinamide test.

Hypouricemia with hyperuricosuria due to isolated renal tubular defects are rare conditions. Two patients with hypouricemia and hyperuricosuria were studied for derangements in the renal urate transport with the combined probenecid-pyrazinamide test. In the first patient a significant decrease (64.5%) in the urate clearance--creatinine clearance ratio was noted after pyrazinamide administration, suggesting a post-secretory urate reabsorption defect, whereas the significant rise (44.2%) in urate clearance after the administration of probenecid indicates that this defect may not be complete. In the second patient there was a rise of 96.9% in the urate clearance--creatinine clearance ratio after the administration of probenecid and a decline of 31.6% in that ratio after pyrazinamide. These results suggest a defect in the presecretory reabsorptive site, with a highly significant response most probably of the postsecretory reabsorptive site to probenecid.

Assessment of combined 24,25(OH)2D3 and 1 alpha (OH)D3 therapy for bone disease in dialysis patients.

An increasing body of experimental data suggests a role for 24,25(OH)2D3 in bone metabolism. The present study was carried out to assess a possible therapeutic role of this vitamin D metabolite in renal osteodystrophy. Twenty-two chronic dialysis patients, most of whom were previously maintained on 1 alpha (OH)D3 therapy, received additional treatment with 10 micrograms/day 24,25(OH)2D3 and were compared to 19 patients receiving 1 alpha (OH)D3 alone. Analysis of transiliac bone biopsies obtained at study entry and following 10-16 months of treatment revealed that the combined therapy produced a decrease in bone turnover. Specifically, the addition of 24,25(OH)2D3 inhibited an increase in trabecular bone volume (BV/TV) and suppressed osteoclastic parameters. Thus BV/TV increased from 26.2 +/- 8.6 to 32.1 +/- 7.5% (p < 0.01) in the 1 alpha (OH)D3 group, but it remained unchanged in the combined therapy group. In contrast, the eroded surface (ES/BS), the osteoclast surface (Oc.S/BS), and the osteoclast numbers were significantly suppressed in patients receiving both 24,25(OH)2D3 and 1 alpha (OH)D3, as compared with those receiving 1 alpha (OH)D3 alone (p < 0.01, p < 0.01, and p < 0.001, respectively). These improvements were independent of changes in 1 alpha (OH)D3 dosage. The extent of bone aluminium deposits was unrelated to the administration of 24,25(OH)2D3 or to its effect. 24,25(OH)2D3 therapy was not associated with any adverse effects.

Enhanced urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats.

We delineated in rats, the relationship between trypsin inhibitory activity in the urine and the nephrotoxic effects of gentamicin, eg, proteinuria and deterioration of glomerular filtration rate (GFR), measured by creatinine clearance. Gentamicin, 70 mg/kg per day, was injected intraperitoneally for 6-10 successive days. Serum and urine gentamicin levels were determined by a microbiological test. Trypsin inhibitory activity was assayed by the casein digestion method. The results showed a steady increase in urinary trypsin inhibitory activity starting from the fourth injection day. The increased levels of urinary trypsin inhibitory activity were associated with increased levels of urinary gentamicin excretion (r = 0.36, p less than 0.02, n = 50 after the fourth injection day), and were significantly higher than in control groups (p less than 0.001). The urinary trypsin inhibitory activity was inversely correlated with the GFR (r = -0.45, p less than 0.01, after the second injection day). The serum trypsin inhibitory activity remained unchanged throughout the study period in all groups. These data suggest that increased urinary trypsin inhibitory activity may be involved in the pathogenesis of gentamicin-induced nephrotoxicity.

Residual renal function affects lipid profile in patients undergoing continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine whether lipoprotein abnormalities associated with continuous ambulatory peritoneal dialysis (CAPD) are influenced by residual renal function (RRF). DESIGN: Open, nonrandomized prospective and comparative study. SETTING: Single university teaching hospital dialysis unit and outpatient clinic. PATIENTS: Twenty adult patients on standard CAPD (1-38 months) were divided into two groups: group A (RRF < or = 0.8 mL/min, n = 10) and group B (RRF > or = 1.1 mL/ min, n = 10), Patients in the two groups were matched for age, time on dialysis, body weight, body mass index, serum urea and albumin levels, peritoneal and urinary albumin losses, and peritoneal transport characteristics such as overnight 8-hour peritoneal creatinine and beta 2-microglobulin clearances and overnight B-hour effluent glucose concentrations. RESULTS: The degree of uremia in patients with preserved RRF (group B) was obviously lower than in patients with negligible RRF (group A), that is, patients in group B had significantly lower serum creatinine and beta 2-microglobulin levels and significantly higher weekly KT/V than group A patients. Despite the prevalence of allele 4 of apolipoprotein E genotype in group A patients, their levels of serum total cholesterol, low-density lipoprotein cholesterol, lipoprotein (a) [Lp(a)], apolipoprotein B(ApoB), and apolipoprotein A1 (ApoA1) were significantly lower than those of patients with preserved RRF (group B). The two groups did not differ significantly in the serum levels of triglyceride or high-density lipoprotein cholesterol. Serum concentrations of Lp(a) and ApoA1, as well as ratios of ApoA1 to ApoB, were correlated significantly with RRF (r = 0.63, r = 0.51, and r = 0.61, respectively). CONCLUSIONS: The findings suggest that RRF affects the lipid profile of CAPD patients, especially serum levels of cholesterol-rich lipoproteins.

Lupus-like syndrome in a mother and newborn following administration of hydralazine; a case report.

A very-low-birth-weight infant died from pericardial effusion and cardiac tamponade confirmed by the post-mortem findings. The mother suffered from lupus-like syndrome consequent to hydralazine treatment for pregnancy-induced hypertension. The possible relationship between mother-infant pathology and hydralazine administration is discussed.

Axillary vein thrombosis: a rare complication following creation of arteriovenous fistula for hemodialysis.

Thrombosis of the axillary vein occurred in two patients following creation of an arteriovenous fistula for hemodialysis. The thrombosis developed before the fistula was used for dialysis, and was demonstrated by venography. Treatment in both cases involved anticoagulant therapy and ligation of the fistula; both patients experienced relief of pain and swelling, although the collateral venous congestion remained unchanged. This complication of arteriovenous fistula creation has not been previously described, probably because thrombosis does not usually occur in a high venous flow state.

Serum and effluent lysozyme (muramidase) activity in CAPD patients.

The elevated serum lysozyme activity in 13 chronic renal failure patients (n = 26) dropped significantly during their first three months of CAPD and subsequently returned to initial levels. When compared with peritoneal mass transfer of lysozyme and serum creatinine levels, a distinct correlation was observed between these and the fluctuations in serum lysozyme activity recorded up to three years of CAPD (r = 0.319, P less than 0.05 and r = 0.425, P less than 0.025, respectively). A notable drop in the mass transfer of this low molecular weight protein took place after the first hour of dialysis. We concluded that long-term CAPD does not affect serum lysozyme activity and that passive loss across the peritoneal membrane could account for the lysozyme found in the effluent fluid.

Serum levels and peritoneal loss of prolactin in CAPD patients.

We studied the serum levels and peritoneal transport of prolactin in 13 CAPD patients and compared with 8 patients on hemodialysis and 10 normal subjects matched by age (30-78 years), sex, body mass index and serum glucose concentrations. CAPD and hemodialysis patients were matched also by hematocrit, serum creatinine, albumin concentrations and duration and dialysis (0-79 months), the prolactin levels in serum and in effluent were measured by RIA and NB2 bioassay. CAPD patients had higher serum prolactin levels than did hemodialysis-treated patients and control subjects. The bioactive/immunoactive ratio of serum prolactin in CAPD patients was 0.7 +/- 0.1 versus 0.9 +/- 0.1 in the control subjects (P less than 0.05) and 0.8 +/- 0.04 in the hemodialysis patients, mean +/- SEM. A significant linear correlation was demonstrated between serum levels and 8 hr peritoneal mass transfer of this hormone. A notable drop of prolactin took place after the first hour of dialysis. Serum prolactin was not influenced by peritoneal protein loss, glucose absorption rate or duration of CAPD. From this study we may conclude that hyperprolactinemia associated with CAPD is not affected by continuous peritoneal loss of prolactin, demonstrating only a slight decrease in bioactivity.

Extracorporeal losses of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in adult patients on CAPD.

The effects of extracorporeal (urinary plus peritoneal) losses of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) on their respective serum levels were studied in 10 adult patients (aged 42-74 years) with end-stage renal failure and residual renal function of 0-4.5 mL/min. All patients had been on continuous ambulatory peritoneal dialysis (CAPD) for a period of 2-27 months. Morning serum, 24-hour urine, and 8-hour overnight peritoneal concentrations of IGF-I and IGFBP-3 were measured by radioimmuno- (Incstar) and immunoradiometric (Active) assays. CAPD patients showed extracorporeal losses (mean +/- SEM) of 118.7 +/- 10.6 micrograms (urinary 6.4 +/- 2.8 and peritoneal 112.3 +/- 8.5 micrograms) of IGF-I/24 hour and 1.5 +/- 0.1 mg (urinary 0.2 +/- 0.1 mg and peritoneal 1.3 +/- 0.1 mg) of IGFBP-3/24 hour. Extracorporeal losses of IGF-I accounted for about 4% of the daily production rate of this polypeptide, and the peritoneal and urinary concentrations of IGFBP-3 did not exceed 4% and 14%, respectively, of their serum levels. Serum concentrations of IGF-I (227.7 +/- 64.2 micrograms/L) and IGFBP-3 (5.3 +/- 2.4 mg/L) were not significantly correlated with extracorporeal, peritoneal, or urinary losses of these proteins or with residual renal function. We suggest that extracorporeal losses of IGF-I and IGFBP-3 in adult patients on CAPD do not influence their serum levels and that IGF-I may therefore be used as a marker of malnutrition.

Insulin-like growth factor-I in patients on CAPD and hemodialysis: relationship to body weight and albumin level.

The relationship between insulin-like growth factor-I (IGF-I), body weight, and serum albumin was studied in 17 patients on continuous ambulatory peritoneal dialysis (CAPD) and 17 patients on hemodialysis. Patients were matched for gender, age (33-83 years), body mass index (16.7-36.1 kg/m2), hematocrit, concentrations of serum growth hormone, and duration of dialysis (1-210 months). Serum IGF-I concentration was measured by radioimmunoassay (Incstar) and albumin by a standard laboratory technique. CAPD patients had significantly lower serum albumin concentrations than hemodialysis patients, whereas IGF-I levels in the two groups were similar and did not differ from those in 18 normal subjects. We did not find significant positive correlations between IGF-I and serum albumin levels in CAPD or in hemodialysis patients. On the other hand, IGF-I showed a strong positive correlation with body weight (for the CAPD group r = 0.523; for both groups together r = 0.493). Both groups (CAPD and hemodialysis) and CAPD patients who weighted less than 60 kg (44%) had significantly lower serum IGF-I levels (113.5 +/- 10.2 and 108.8 +/- 15.7 micrograms/l +/- SEM, respectively) than patients who weighed 60-80 kg (38.3%; 181.2 +/- 20.9 and 196.6 +/- 27.2 micrograms/L +/- SEM, respectively) or above 80 kg (17.6%; 205.2 +/- 37.7 and 229.5 +/- 43.5; micrograms/L +/- SEM, respectively). It therefore appears that a low serum IGF-I level is a better indicator of malnutrition in CAPD and hemodialysis patients than low serum albumin.

[Transient hypophosphatemia associated with hairy-cell leukemia].

A 43-year-old man with hairy-cell leukemia and marked splenomegaly developed severe hypophosphatemia which improved after splenectomy. Since splenic tissue phosphorus was significantly elevated, and since serum phosphorus returned to normal levels immediately after the operation, it is postulated that excessive uptake of phosphorus by the rapidly dividing leukemic cells might have caused the transient decrease in serum phosphorus.

[Subclinical renal involvement in rheumatoid arthritis].

No evidence of renal involvement was found in 104 patients with rheumatoid arthritis in routine laboratory tests, including serum creatinine, urea, uric acid, sodium, potassium, calcium, phosphorus, and urinalysis. In view of recent publications (1-9) which report renal involvement in rheumatoid arthritis, we studied 16 patients of our group (nonrandomized, 3 men and 16 women, average age 55.4 years, average duration of disease 11.9 years). We examined creatinine clearance, urinary excretion of alpha-2 microalbumin, beta-2 microglobulin, cystine, and urine concentration and acidity after a 10-hour fast. 10 patients had disturbances in 1 or more of the functions examined, in 9 of whom tubular functions were involved. In 6 there was no evidence of renal involvement. There was no correlation between renal involvement and past or present therapy, but there were direct correlations between renal involvement, duration of disease and age. Thus we found evidence for subclinical renal damage not revealed by routine laboratory tests in patients with rheumatoid arthritis. This damage should be taken into consideration when operation, examination with contrast material, or treatment with other nephrotoxic agents are being considered in these patients.

ECG changes and cardiac arrhythmias in chronic renal failure patients on hemodialysis.

Serial 12-lead electrocardiogram (ECG) recordings and 24-hour Holter monitoring were carried out in 39 patients with chronic renal failure, starting just before a routine dialysis session. In an attempt to identify risk factors for cardiac arrhythmias, the results obtained from each patient were correlated with a variety of clinical, hematological, and biochemical data. All patients exhibited ECG changes, which were most pronounced during the first 2 hours of dialysis. The most frequent of these changes were a decrease in T wave amplitude and increase in Tmax time (all patients), an increase of QRS amplitude (61% of patients), shortened or prolonged QTc interval (61%) and ischemic-like ST-T changes (22% and 39%, respectively). Potentially clinically significant arrhythmias occurred in 12 patients (31%) of which 8 were supraventricular, 3 were combined ventricular and supraventricular, and 1 was pure ventricular. The only clinically identified risk factor for complex ventricular and supraventricular arrhythmia was advanced age. The arrhythmia and nonarrhythmia groups differed significantly in their predialysis hematocrit, O2 content, serum urea, and osmolarity, and in their postdialysis serum phosphorus and osmolarity. The results indicate that patients with chronic renal failure frequently exhibit ECG changes and a high incidence of ventricular and supraventricular arrhythmias, which may be prognostically significant, during and after hemodialysis.