Moderate Chronic Renal Insufficiency Research Articles

Free amino acids during chronic Cyclosporine A toxicity in intact and partially nephrectomized rats

The effects of 40 days of treatment with Cyclosporine A (CSA) on plasma and urine free amino acids were investigated in sham-operated (C) and partially nephrectomized (Pnx) female Fischer 344 rats. High Dose CSA (30 mg/kg/day ip) was associated with reduced weight gain, increased plasma urea nitrogen, and hypoproteinemia in C and Pnx animals. These animals also demonstrated increased plasma levels of alanine, markedly reduced levels of tryptophan, and an increase in urinary excretion of methylhistidines. C but not Pnx animals also showed a significant increase in plasma serine and a decrease in plasma taurine. CSA treatment of group C resulted in a progressive aminoaciduria involving substrates of the neutral and acidic renal amino acid transport systems; however, the renal excretion of taurine and β-alanine by these animals was markedly reduced as compared to vehicle treated controls. High dose CSA exacerbated aminoaciduria in Pnx animals, but in this group, the excretion of β amino acids was also increased. Our findings demonstrate that chronic CSA toxicity in rodents with normal renal function is characterized by increased muscle protein catabolism, significant reductions in plasma tryptophan, and an apparent decrease in whole body taurine pools. With the exception of the taurine abnormalities, CSA treatment had similar effects on Pnx animals; however, in this group, CSA-induced pathological changes were superimposed on the changes due to renal insufficiency per se. CSA toxicity as identified by the parameters investigated in this study was no more severe in Pnx animals with moderate chronic renal insufficiency than in controls with intact renal function.

Hyperkalemia Suppresses the Renal Adaptation to Chronic Respiratory Acidosis

A 48-year-old Hispanic man was admitted for resection of a squamous cell cancer of the lung. He had been known to have moderate chronic renal insufficiency for about 3 years, with stable serum creatinine levels (265 I'mollL [-3 mg/dL)). On admission he had a hyperchloremic, hyperkalemic metabolic acidosis without hypercapnia and a positive urine anion gap (UNa + UK UCI) of 51 (Table 1). Creatinine clearance was 21 mLimin. The urine sediment showed three to five RBCs per high-power field and a few tubular cells but no cellular casts. Renal ultrasound revealed normal-sized kidneys without evidence of hydronephrosis. Medication on admission included trimethoprim/sulfamethoxazole, acetaminophen, and diphenylhydantoin, of which only the latter was continued for a seizure disorder attributed to alcohol abuse. The preoperative cortisol levels were normal, 11 ng/dL in the morning and 22 ng/dL shortly after noon. The plasma renin activity was 1.6 ng/ mLih (normal, 1 to 3.0) and the plasma aldosterone was 4 ng/ dL (normal, 4 to 20), when the serum potassium was 5.8 mmol/L. Therefore, a diagnosis of type IV, generalized distal renal tubular acidosis (RTA) was made. No further work-Up of the cause of the renal insufficiency was performed preoperatively. The patient underwent tumor removal with resection of the right middle and lower lobes. His postoperative course was complicated by sustained hypercapnia and acidemia in addition to persistent hyperkalemia (Fig 1; Table 1). He remained euvolemic and his BP (150/90) and pulse rate (80 beats/min) were stable. Throughout the preoperative and postoperative course the patient received parenteral nutrition. He was always euglycemic and ketones in urine and blood remained negative. After more than three days of hypercapnia (postoperative day 4), plasma total CO2 did not increase, suggesting inadequate renal

Effects of nonsteroidal antiinflammatory drugs on renal function in patients with renal insufficiency and in cirrhotics.

We have assessed the effects of acute and chronic administration of etodolac, ketoprofen, and indomethacin on renal function in patients with mild to moderate chronic renal insufficiency (CRI). We studied 18 normal volunteers and 24 patients with CRI due to hypertension and/or diabetes mellitus with creatinine clearances between 19 and 83 mL/min/1.73 m2. Clearance studies were performed with the first dose of nonsteroidal antiinflammatory drug (NSAID) to compare acute effects of the agent with a no-drug control. Subjects then received the NSAID for three to five days and, on the last day of study, underwent another clearance study to assess the effects of a single dose of NSAID superimposed on chronic dosing. With each dose of each NSAID, inulin and paraaminohippurate (PAH) clearances and fractional excretion of NA+ decreased. However, the baseline control collections after chronic dosing did not differ from the no-drug control periods. Hence, the decline in renal function with each dose is transient, and no overall adverse effect on renal function occurred with chronic dosing. In five patients with cirrhosis, we assessed the renal sparing effects of sulindac. After equilibration on a fixed sodium intake, they received a 200-mg dose of sulindac. In one patient, no adverse effect occurred; the remaining patients suffered declines in creatinine clearance of 29%, 87%, 37%, and 37%, respectively. This effect was transient and returned to control values six to eight hours after sulindac administration. At the time of maximal depression of renal function, serum concentrations of sulindac sulfide were comparable to those in subjects with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency

Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decreases in GFR (K: from 36 +/- 3 to 20 +/- 4 ml/min, P = 0.001; I: from 37 +/- 6 to 30 +/- 7 ml/min, P = 0.032; in RPF (K: from 194 +/- 21 to 146 +/- 21 ml/min, P = 0.002; I: from 222 +/- 33 to 147 +/- 18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 +/- 0.25 to 0.08 +/- 0.02 ng/min, P = 0.05; I: from 0.34 +/- 0.06 to 0.18 +/- 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/CIn) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sulindac on renal function and prostaglandin synthesis in patients with moderate chronic renal insufficiency.

The renal effects of therapeutic doses of sulindac were studied in nine patients with stable renal insufficiency, mean creatinine clearance 37.0 +/- 2.2 ml min-1 1.73 m-2 (range 24.7-54.6 ml min-1 1.73 m-2). Nine days' treatment with sulindac produced a small, but significant, reduction in the mean creatinine clearance (37.0 +/- 2.2 to 34.7 +/- 2.2 ml min-1 1.73 m-2; P less than 0.02) and 99mTc diethylenetriaminepenta-acetate (DTPA) clearance (35.5 +/- 3.4 to 31.4 +/- 3.6 ml min-1 1.73 m-2; P less than 0.02) without altering body weight, effective renal plasma flow [131I]hippuran clearance), plasma renin activity (PRA), 24 h urinary volume or electrolyte excretion. After discontinuation of sulindac, creatinine clearance returned to pretreatment values. In five female patients, pretreatment urinary excretion of the 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a stable breakdown product of prostacyclin (PGI2), was significantly reduced (P less than 0.02) when compared with four healthy controls, whereas prostaglandin E2 (PGE2) was unchanged. Administration of sulindac did not significantly alter the excretion rate of PGE2 or 6-ketoPGF1 alpha in this group of patients. In chronic renal disease with moderate renal impairment, reduced renal prostacyclin synthesis may be an important predisposing factor to the renal toxicity associated with the use of non-steroidal anti-inflammatory drugs (NSAID). Short term use of sulindac in therapeutic doses does not appear to influence the excretion of prostaglandins and produces only a minor reversible change in renal function; used cautiously it may have advantages over other NSAID in these patients.

Pharmacokinetics of trimazosin and its effects on blood pressure, renal function and proteinuria during short-term therapy of patients with impaired renal function and hypertension.

The kinetics and short-term (10 weeks) effects of trimazosin, an alpha 1-adrenoreceptor antagonist, on renal function and blood pressure in patients with moderate chronic renal insufficiency and hypertension, have been studied for the first time. Eight patients in whom the blood pressure was not normalized with a diuretic alone underwent pharmacokinetic studies and assessment of the renal function during a 10-week period of trimazosin therapy. Trimazosin significantly lowered blood pressure (recumbent and upright) without significantly altering renal function. Renal vascular resistance was decreased by 14%. Fractional sodium excretion, proteinuria and laboratory serum tests remained unchanged. Neither body weight nor pulse rate were affected. Moderate renal insufficiency did not modify the pharmacokinetics of the drug. Thus, trimazosin, as second-step antihypertensive agent, appeared to be safe and effective in patients with moderate renal insufficiency and hypertension, without exerting favourable or adverse renal effects during short-term therapy.

Functional status of the liver during chronic renal failure: an experimental study in the rabbit.

Quantitative and qualitative measures of liver function were investigated in rabbits with chronic renal failure (CRF) induced 3 months earlier by surgical reduction of renal mass, and compared with a sham-operated control group. In the CRF group the galactose elimination capacity (GEC) was significantly decreased by 25%, but when related to liver weight the difference was not statistically significant. The clearance of antipyrine was unaffected. The serum activities of alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase were similar in the two groups. The prothrombin index was increased by 20%, and the serum albumin concentration decreased by 9%. By light microscopy no significant morphological changes were found in the livers of the CRF rabbits. The results do not indicate significant changes of the hepatic functional status during moderate chronic renal insufficiency.

The use of diuretics in varying degrees of renal impairment: an overview.

Administration of diuretics during acute renal failure in animals has been demonstrated to be of value with mannitol and/or loop-blocking diuretics, furosemide or ethacrynic acid. There is evidence that if these drugs are given very early in the controlled experimental environment that there will be some beneficial effect in maintaining renal function. However, in man the temporal relationship between the acute onset and the successful response to the administration of the drugs is, at best, coincidental and the use of diuretics in acute renal failure may not produce the same results as seen in the laboratory. One of the best guides to the underlying disease when there is acute decompensation in renal function is the utility of the renal failure index which utilizes urine and plasma sodium and urine and plasma creatinine ratios. Large doses of loop-blocking diuretics can be of benefit in patients with mild to moderate chronic renal insufficiency and fluid retention and/or hypertension. When renal insufficiency is severe in the pre-dialysis setting, furosemide, bumetanide or muzolimine may be of some benefit; however, as renal failure worsens the response of the kidney is sluggish and it is wise to begin to dialyze when glomerular filtration deteriorates below 5 ml per minute.

Sodium homeostasis in dogs with chronic renal insufficiency

Volume homeostasis in the fasting rate and 24-hr sodium balance are maintained in chronic renal insufficiency as a result of adaptations in the residual nephrons. This study evaluates the limitations to these adaptations and the dynamics of sodium excretion (UNaV) after an acute challenge with 100 mEq of sodium chloride in normal dogs (GFR 50 ml/min) and in dogs with one remnant kidney and moderate chronic renal insufficiency (GFR 15 ml/min). When food was administered with the sodium challenge, no or minimal changes in serum protein and hematocrit values occurred, and the natriuretic responses were small and equivalent in normal and remnant dogs. On the other hand, when the sodium challenge was given without food, the natriuretic response was large in normal dogs and markedly blunted in remnant. Within 5 hr of the sodium challenge, the various groups of normal dogs excreted 40 to 63% of the sodium load, but the remnant animals eliminated only 12 to 22% (P less than 0.001). The blunted natriuresis in remnant dogs was associated with a prolonged hemodilution of circulating proteins, indicating a longer lasting expansion of the intravascular volume. The blunted response was independent of sodium diet, of the administration route (p.o. vs. i.v.) or strength (isotonic vs. hypertonic) of the sodium load, and appears to result from an inability of the remnant kidney to rapidly excrete a sodium load. Thus, administration of sodium to dogs with chronic renal insufficiency leads to prolonged sodium retention, prolonged extracellular fluid (ECF) volume expansion, and requires a prolonged excretory cycle to restore 24-hr balance.

Surgical management of persistence or recurrence after subtotal parathyroidectomy for primary hyperparathyroidism

(1) In an experience with 44 patients requiring subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement, persistence was identified in 3 patients and recurrence in 3, resulting in a failure rate of 14 per cent. (2) The development of chronic renal insufficiency secondary to hyperparathyroidism appears to be an aggravating factor in the failure of subtotal parathyroidectomy to control hypercalcemia in such cases. An associated MEN-1 syndrome may possibly also be a predisposing factor. (3) Overlooked supernumerary hyperfunctioning parathyroid glands may be the cause of persistent hypercalcemia. (4) If reoperation is performed, ultrasonography of the neck and computerized tomography of the mediastinum are justified preoperatively for localization studies. (5) If hyperplasia of the preserved remnant of parathyroid is the only explanation for failure of subtotal parathyroidectomy, its removal is justified with autotransplantation of parathyroid tissue and freezing of additional tissue for possible future use. (6) The presence of moderate or severe chronic renal insufficiency, related to primary hyperparathyroidism, appears to justify total parathyroidectomy with autotransplantation for primary hyperparathyroidism due to multiple gland involvement. (7) Periodic reevaluation is indicated for all patients after operation, especially subtotal parathyroidectomy, for primary hyperparathyroidism due to multiple gland involvement. If mild or borderline hypercalcemia persists or recurs, close follow-up study is indicated.

Timolol kinetics in chronic renal insufficiency.

A single-dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function--(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; C cr, 20 to 50 ml/min); (3) 4 patients with end-stage renal disease (ESRD)--to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (C max) was 84.3 +/- 44.8 ng/ml at 0.8 +/- 0.4 hr for N and 87.1 +/- 22.8 ng/ml at 1.7 +/- 1.2 hr (p, NS) for MCRI. N and MCRI mean half-lives (5.2 +/- 2.6 hr and 4.0 +/- 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 N and 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration of timolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.