Cardiovasoactive peptides in hemodialysis patients: diagnostic tools and predictors of outcome: a review of present knowledge and future directions.

The main cardiovasoactive peptides involved in cardiovascular adaptation to renal failure and dialysis are reviewed with a special focus on their possible role in pathophysiology, diagnosis of cardiovascular and fluid volume abnormalities, and prognostic information. The role of vasoactive peptides in cardiovascular stability during hemodialysis (HD) are best seen in sequential HD, where the release of vasoconstrictors is stimulated by volume reduction during ultrafiltration, but is blunted during isovolemic HD, whereas plasma vasodilators increase. Plasma levels of the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in fluid volume overload and heart failure and decrease during dialysis. Neuropeptide Y (NPY) is elevated in severe volume overload and hypertension and calcitonin gene-related peptide in large-volume overload. Plasma BNP increases with left ventricular failure and improves during dialysis. Activation of the sympathetic nervous system as reflected by increased plasma levels of NPY is associated with poor prognosis. High levels of the natriuretic peptides ANP and BNP are likewise predictors of poor prognosis. Determinations of plasma levels of cardiovasoactive peptides may be helpful in clinical practice to diagnose volume overload and heart failure and to assess the severity of heart failure and of hypertension, as a guide to the choice of dialysis treatment and pharmacotherapy and to monitor treatment. Clinical studies will be needed in HD patients to establish the value of measurement of plasma cardiovasoactive peptides in clinical practice. The research in this field is still in its infancy and promises to be exciting in the future. There appears to be a balance of vasomotor tone and cardiac response to meet any emergency and stress such as intermittent dialysis. Further knowledge will increase our chances for major therapeutic interventions.

Is neuropeptide Y a contributor to volume-induced hypertension?

Hypertension often occurs with fluid overload. The most common mechanism is considered to be mediated by increased cardiac output. Hemodialysis (HD) patients frequently have large amounts of fluid overload. Neuropeptide Y (NPY) is activated by stress and contributes to hypertension and heart failure. We speculated that NPY may be released by the stress of fluid overload and, by its vasoconstrictor effect, may contribute to hypertension and heart failure. Plasma levels of NPY and other vasoconstrictors were studied in 20 HD patients with varying degrees of fluid overload, and the relationship of NPY plasma levels to blood pressure was analyzed. The plasma concentrations of NPY correlated with the degree of fluid overload (r = 0.89; P < 0.0001) and the mean arterial blood pressure (r = 0.85; P < 0.0001). Seven patients had fluid overload of greater than 6% of body weight. They had higher blood pressures and higher plasma concentrations of NPY than 13 HD patients with less than 5% of fluid retention (systolic blood pressure, 179+/-8.2 v 145+/-3.7 mm Hg, P = 0.007; NPY, 61+/-4.6 v 26.8+/-2.7 pmol/L, P < 0.001). In stepwise multiple regression analysis, NPY alone explained blood pressure elevation when analyzed with fluid overload and angiotensin II, renin, noradrenaline, and adrenaline levels. We hypothesized that fluid overload in dialysis patients is a stress-inducing state that activates the sympathetic nervous system and releases the vasoconstrictor NPY. The resulting inappropriate vasoconstriction may contribute to volume-induced hypertension and heart failure in a vicious cycle. We conclude that determination of plasma NPY levels may be useful as a marker of the clinical threat of overhydration.

Decreased bioavailability of insulin-like growth factor-I, a cause of catabolism in hemodialysis patients?

The aim of this study was to investigate the influence of hemodialysis on insulin-like growth factor-I (IGF-I) and the IGF binding proteins (IGFBPs) in patients with end-stage renal disease (ESRD). IGF-I and IGF-II circulate bound to IGFBPs which are known to influence the IGF-I bioavailability. Ten ESRD patients were studied before and after hemodialysis on low flux filters. IGF-I, insulin and IGFBP-I were measured by specific RIAs, and IGFBP-2 and IGFBP-3 were quantified by densitometry after Western ligand blotting. Diurnal curves of IGFBP-1 were performed in two additional patients. Before dialysis, the mean (+/- SEM) IGF-I level was 202.2 +/- 12.1 micrograms/l corresponding to a SD-score of 1.8 +/- 0.3. Basal IGFBP-1 was increased 2-fold compared to normal levels (82.4 +/- 24.1 micrograms/l) and increased further during hemodialysis to 118.1 +/- 28.5 micrograms/l (P < 0.007). The mean increase during dialysis in IGFBP-1 was 74 +/- 24%. Predialysis IGFBP-2 was increased to 184.8 +/- 32.5% of the reference serum and was not significantly changed by dialysis. The predialysis IGFBP-3, 38.5 kDa band was within normal levels 90.1 +/- 18.8% of the reference serum while the IGFBP-3, 41.5 kDa band was decreased to 62.4 +/- 11.3% of the reference serum. Both IGFBP-3 bands were not significantly changed after dialysis. The mean basal insulin level was high, 38.2 +/- 3.0 mU/L, in spite of normal glucose levels suggesting insulin resistance. The mean values of IGF-I, insulin and glucose were unchanged after dialysis. The ratio between IGF-I and IGFBP-1 decreased significantly after dialysis to 53% of the ratio before dialysis (P < 0.005). The ratio between IGF-I and IGFBP-2 or IGFBP-3 did not change after dialysis. The circadian variation of IGFBP-1 during dialysis days was impaired with a delayed decrease of IGFBP-1 compared to the non-dialysis day. In ESRD patients predialysis mean values of insulin, IGF-I SD-score, IGFBP-1 and IGFBP-2 were increased, while the mean densitrometric values of the IGFBP-3 bands on Western ligand blot were either normal or reduced. IGFBP-1 was raised significantly with a mean of 74% after dialysis, the predialysis level was more than 2-fold elevated with impaired circadian variation of IGFBP-1 on dialysis days. High levels of IGFBPs may bind free IGF-I and decrease IGF-I bioavailability thus contributing to the catabolism associated with dialysis.

Assessment of total body water in hemodialysis patients by a single oral dose of antipyrine.

Accurate determination of total body water in hemodialysis patients is important for calculation of the amount of fluid excess that should be removed by ultrafiltration, and for dialysis prescribing by KT/V. Indirect methods using 0.6 x body weight or pre and post serum urea concentrations are inaccurate and determination by tritiated water space requires the use of radioactivity. The authors measured the volume of distribution for antipyrine that is distributed in body water, and compared it to tritiated water space in hemodialysis patients. Sixteen patients on hemodialysis were given 500 mg antipyrine and saliva samples were collected at fixed time points. Concentrations of antipyrine in saliva were measured by high pressure liquid chromatography. Volume of distribution for antipyrine was calculated by pharmacokinetic methods. Fluid excess was determined as the difference between tritiated water space or volume of distribution for antipyrine and ideal total body water measured anthropometrically. Total body water as the volume of distribution for antipyrine was 24.8 to 61.5 (mean 44.0 +/- 10.3) L, or 68% of body weight, and tritiated water space 27.0 to 56.6 L (43.6 +/- 7.7), 67% of body weight. Volume of distribution for antipyrine correlated well with tritiated water space (r = 0.997 and p = 0.001). Fluid excess calculated from tritiated water space was between 2.5 and 12.4 (6.0 +/- 4.0) L, and from volume of distribution for antipyrine -0.7 to 13.3 (5.7 +/- 5.1) L (r = 0.80, p = 0.001). The authors conclude that by using a single oral dose of antipyrine, one can simply and accurately measures total body water in hemodialysis patients.

Effects of human atrial natriuretic peptide in patients after coronary artery bypass surgery.

OBJECTIVES: To determine the effects of synthetic human atrial natriuretic peptide (ANP) on renal function, hemodynamics, and levels of vasoactive peptides when infused in the immediate postoperative period after coronary bypass surgery in patients with normal kidney function. DESIGN: A prospective, randomized, double-blind, placebo-controlled study. SETTING: The Department of Cardiothoracic Anaesthetics and Intensive Care of a university hospital. PARTICIPANTS: Thirty patients with normal kidney function scheduled for elective coronary bypass surgery. INTERVENTIONS: During the first 3 hours postoperatively, patients received an infusion of either ANP 7.5 pMol/kg/min (ANP) or vehicle alone (C). MEASUREMENTS AND MAIN RESULTS: No differences were found between the two groups in respect to sex, degree of coronary disease, preoperative medical treatment, or duration of cardiopulmonary bypass and aortic occlusion. Plasma ANP levels increased nearly 10-fold from a mean of 7.0 +/- 1.1 pMol/L in ANP and remained at baseline levels in C, (p < 0.001). In ANP, there occurred significant increases in urine flow (p < 0.001), inulin clearance (p < 0.001), filtration fraction (p = 0.007), and fractional clearance of sodium (p < 0.001) and of osmoles (p < 0.001) compared with C. During the study, no differences in mean arterial pressure, heart rate, and right atrial or pulmonary capillary wedge pressure were detected between the groups. Cardiac index decreased by 5% in ANP compared with a 9% increase in C (p = 0.027). Vasopressin levels significantly increased in C but remained at baseline levels in ANP (p = 0.031). There were no changes in levels of catecholamines or angiotensin II. CONCLUSIONS: The results of this study show that ANP increases diuresis, natriuresis, and glomerular filtration in the immediate postoperative period after coronary bypass surgery.

Renal and hemodynamic effects of diltiazem after elective major vascular surgery--a potential renoprotective agent?

A postoperative study was done of the effects of an infusion of diltiazem (DTZ), 1 microgram.kg-1.min-1 after a bolus dose of 0.28 mg.kg-1 on renal function and hemodynamics in 10 patients who were operated with insertion of an abdominal aortic graft. Urine flow, glomerular filtration rate (GFR) by inulin clearance, and renal plasma flow (RPF) by PAH clearance and fractional excretion of electrolytes and osmols were measured for three periods of 20 min during infusion of DTZ, in the morning after surgery. Systemic hemodynamic studies were conducted and serum levels of catecholamines were measured. GFR increased during the initial period of DTZ infusion. There were no significant changes during the study period in any of the other parameters, compared to baseline, except for a decrease in heart rate from 84 to 77 beats per minute. The absence of a sustained increase in GFR and a natriuretic and diuretic effect may possibly be ascribed to a preexisting nonconstricted status of the renal vasculature. The authors conclude that the dose of DTZ used in this study can be safely used for further investigations to elucidate the effects of peroperative infusion of DTZ on renal function in connection with major vascular surgery.

Renal effects of human atrial natriuretic peptide in patients after major vascular surgery.

The effects were studied postoperatively of an infusion of atrial natriuretic peptide (ANP) 7.5 pMol.kg-1.min-1 on renal function and haemodynamics in seven patients who had been operated with insertion of an abdominal aortic graft. Urine flow, glomerular filtration rate (GFR), renal plasma flow (RPF) and excretion of electrolytes and osmoles were measured for three periods of 20 minutes during infusion of ANP, in the morning of the day after surgery. Haemodynamic studies were conducted, and serum levels of ANP, catecholamines and plasma renin activity were measured. ANP levels increased from 52 to approximately 250 pMol.L-1 during ANP infusion and decreased after infusion to a level equal to baseline. GFR increased from 92 mL.min-1 by 58, 20 and 21%, respectively. RPF was unchanged. Urine flow rate increased from 1.99 mL.min-1 by 81, 151 and 173%, respectively. Fractional clearances of sodium, chloride and osmoles were increased during the second and third ANP periods whereas fractional potassium clearance did not change during the study. There were no changes in catecholamine levels or plasma renin activity during the study. Heart rate, mean arterial pressure and calculated systemic and pulmonary vascular resistance did not change whereas reductions occurred in cardiac index, mean pulmonary artery pressure, pulmonary artery wedge pressure and mean right atrial pressure. We conclude that infusion of ANP also in the postoperative situation increases GFR, diuresis and sodium excretion.

Calcitonin gene-related peptide attenuates experimental ischemic renal failure in a rat model of reversible renal ischemic insult.

Calcitonin gene-related peptide (CGRP) has been shown to decrease vascular resistance and increase renal blood flow. To study the effects of CGRP in acute renal failure (ARF) of moderate degree, we used a rat model of bilateral temporary renal artery occlusion (RAO) inducing ARF with spontaneous recovery within 1 week, resembling a clinical situation. Three groups were studied: CGRP 10 (CGRP10) and 25 (CGRP25) pmol.kg-1.min-1 and vehicle alone (control), respectively, infused from 10 min before until 2 h after declamping. Serum urea levels reached a peak after 24 h at 13.0 +/- 1.3, 8.1 +/- 1.1, and 8.5 +/- 1.0 mmol.L-1 in the control, CGRP10, and CGRP25 group, respectively. They were significantly lower postischemia in the two CGRP-treated groups than in the control group. Mean arterial pressure (MAP) decreased to 90%, 80%, and 60% of baseline MAP in the control, CGRP10, and CGRP25 group, respectively. Histologically there was no significant difference between the three groups. Our data indicate that CGRP preserves renal function in experimental ARF despite reductions in MAP. We conclude that further investigations of the renal effects of CGRP are needed in order to clarify whether CGRP might be used clinically to maintain or improve renal function in ARF.

Vasoactive agents and blood pressure regulation in sequential ultrafiltration and hemodialysis.

Hypotension is a common and sometimes dangerous side effect of hemodialysis. Its etiology is multifactorial and largely unknown. Earlier studies on the role of endogenous blood pressure regulating agents such as catecholamines and renin have rendered conflicting results. We studied the influence of ultrafiltration and isovolemic hemodialysis separately on the plasma concentrations of the following blood pressure regulating agents: adrenaline, noradrenaline, dopamine, neuropeptide Y, calcitonin gene-related peptide (CGRP), renin (PRA), angiotensin II, vasopressin, aldosterone and cortisol. During isolated ultrafiltration, plasma levels of two strong vasoconstrictors (noradrenaline and angiotensin II) and one strong vasodilator (calcitonin gene-related peptide, CGRP) increased significantly (noradrenaline 3.24 +/- 0.60 nM to 4.31 +/- 0.55 nM; p = 0.032, angiotensin II 19.74 +/- 3.46 pmol/l to 28.49 +/- 7.24 pmol/l; p = 0.047) No symptomatic hypotension occurred. At the end of isovolemic hemodialysis, plasma levels of all the vasoconstricting agents had decreased to pretreatment values, but those of CGRP had continued to rise (from 85.3 +/- 17.6 pmol/l to 114.5 +/- 25.3 pmol/l, p = 0.031). During isovolemic hemodialysis, blood pressure fell to symptomatic levels, but was restored at the end of treatment. The study shows that hemodialysis patients respond to fluid removal by ultrafiltration with an increase in plasma levels of CGRP, noradrenaline and angiotensin II. The net effect is an appropriate vasoconstriction and adequate blood pressure is maintained during isolated ultrafiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive endogenous digoxin-like substances: plasma levels are dependent on the hypothalamic-pituitary-adrenal axis for release and on kidney function for elimination.

To identify factors that regulate the levels of immunoreactive digitalis-like substances (irEDLS) in body fluids, two studies were carried out. Plasma and urine levels of irEDLS were measured in uremic and normal subjects. Extracted material was fractionated (12 fractions) and assayed by digoxin radioimmunoassay. In four fractions, higher levels of irEDLS were found in uremic than in normal plasma. Urine from healthy subjects contained very high levels of irEDLS, but in urine collected from uremic patients irEDLS levels were similar to those in plasma. In another study, eight healthy subjects were given dexamethasone 1 mg orally and tetracosactide [an adrenocorticotropic hormone (ACTH) analogue] 0.25 mg i.v., on separate occasions. Dexamethasone suppressed the plasma and urine levels of cortisol and irEDLS. ACTH increased the levels of cortisol in plasma and urine, and of irEDLS in plasma. Taken together, these results support the hypothesis that irEDLS are of adrenal origin. However, decreased renal clearance, rather than increased production or release, may be the main cause of increased plasma levels of irEDLS in uremia.

Ischemic colitis of the cecum after renal transplantation masquerading as malignant disease.

Fourteen years after kidney transplantation and following protracted rejection of the transplant, a patient developed abdominal pain, fever, and leukocytosis. Ultrasound demonstrated a pericolic abscess, and barium enema a deformity of the ascending colon suggesting malignant growth. Colonoscopy showed ulcerative and necrotic lesions of the cecum, and colonic carcinoma was suspected. At surgery, a granulomatous inflammatory reaction with fibrosis involving the kidney transplant and cecum was found. Histological examination revealed ulcerations secondary to ischemic colitis, but no malignancy. Thus, ischemic colitis should be ruled out in cases with a presumptive diagnosis of colonic malignancy at x-ray or endoscopy.

Plasma concentrations of calcitonin gene-related peptide in fluid overload.

To investigate the hypothesis that calcitonin gene-related peptide (CGRP), a potent vasodilator, is an important physiological defence against fluid overload, plasma CGRP concentrations were measured in various degrees of fluid overload in 26 haemodialysis patients, for whom diuresis, mediated by atrial natriuretic peptide (ANP), is not a possible defence mechanism. Plasma CGRP concentrations were positively correlated with the degree of fluid excess (r = 0.815, p = 0.0001) and were significantly higher in 5 patients with severe fluid overload than in those less severely affected (143 [SE 14] vs 52 [11] pmol/l; p less than 0.001). CGRP may be an effective defence against complications of fluid overload since it can increase capitance by vasodilatation.

Antidiuretic hormone regulation in hemodialysis.

The relative influence of stimulation and suppression of osmoreceptors and low and high pressure baroreceptors was studied in 12 patients on hemodialysis. The stimuli were separated by ultrafiltration and dialysis. When high and low baroreceptors were deloaded by volume contraction during ultrafiltration, but there was no change in osmolality, the antidiuretic hormone (ADH) level rose steeply. When osmoreceptors were suppressed, but there was no influence on baroreceptors during dialysis, ADH level declined by the same amount it had increased during ultrafiltration. When osmoreceptors were stimulated by an increase in osmolality in the phase between dialyses, but baroreceptors were loaded by an increase in volume, ADH levels did not change. Others showed that when baroreceptors are stimulated and osmoreceptors suppressed during simultaneous ultrafiltration and dialysis, there is also no change in ADH levels. These results indicate that the hierarchy of receptors regulating ADH is osmoreceptors followed by high and low baroreceptors. Simultaneous stimulation or suppression of both baroreceptors appears equal to the influence by osmoreceptors.

Hypertension profiling by total body water (TBW) determinations in patients on chronic hemodialysis.

Hypertension is an important risk factor in hemodialysis patients. Fluid overload and increased peripheral resistance are considered the two main causes. We studied the relation between volume state and blood pressure in 18 hemodialysis patients. Actual total body water (aTBW) was measured as tritium space and "ideal" total body water (iTBW) by an anthropometric method. The difference between aTBW and iTBW was considered a measure of fluid excess or deficit. Twelve patients were overhydrated, 5%-23%. Their predialysis blood pressure was significantly correlated to their degree of fluid excess; systolic BP:r = 0.71, p = 0.03, diastolic BP:r = 0.73, p = 0.02, mean arterial BP:r = 0.76, p = 0.03. Five of these patients had multiple antihypertensive drugs instead of adequate ultrafiltration. Five patients had a fluid deficit of -3 to -13% and hypertension due to vasoconstriction. Four of these were adequately treated with antihypertensive drugs but had exaggerated ultrafiltration. TBW determination with tritium is simple to perform and gives information on the volume state and thereby on the cause of hypertension in hemodialysis patients. Based on this, appropriate treatment can be chosen.

Nifedipine as an antihypertensive drug in patients with renal failure--pharmacokinetics and effects.

Pharmacokinetics and pharmacodynamics of nifedipine were studied in 12 patients with renal failure and hypertension, after a single dose and during an 18-week treatment period. The plasma concentrations of nifedipine and its first pyridine metabolite were measured by gas chromatography mass spectrometry. The oral plasma clearance of nifedipine was 1189 +/- 876 ml min-1, and the mean plasma half-life (t1/2) was 5.99 +/- 3.05 h. The pyridine metabolite was not retained. Plasma concentrations of nifedipine were found to be significantly correlated with the effects on blood pressure, forearm blood flow and peripheral resistance, and these effects did not vary with the degree of renal failure. Normotension was achieved in eight of the nine patients observed over a period of 4 months with doses in the range 20-40 mg, administered twice daily. The mean Cr-EDTA clearance remained unchanged during the study (initial value 31.4 +/- 12.3 ml min-1; final value 32.7 +/- 14.4 ml min-1), and in three patients it increased. Nifedipine induces a slight increase in metabolic rate in patients with renal failure, but it is not necessary to modify the dose. It is effective in lowering blood pressure, has mild side-effects and may improve renal function in some patients.

Glucuronidation of codeine and morphine in human liver and kidney microsomes: effect of inhibitors.

Glucuronidation of codeine was detected and compared with that of morphine in microsomes from human livers and kidneys. Vmax values for codeine-6-glucuronide (C6G) were 0.54 +/- 0.24 and 0.74 +/- 0.35 nmol/mg/min. in the livers and 0.10 and 0.13 nmol/mg/min. in the kidney, respectively, when codeine and UDP-glucuronic acid (UDPGA) were incubated with microsomal preparation. The corresponding Km values were 2.21 +/- 0.68 and 1.41 +/- 0.36 mM in the livers and 6.69 and 4.12 mM in the kidney. The average codeine glucuronyltransferase (GT) activity was 14-fold lower in the six kidneys than in the 11 livers. Higher GT activities were observed in liver microsomes from patients who had been exposed to enzyme inducers. Rates of glucuronide formation from morphine correlated significantly with those from codeine in both human liver and kidney microsomes. Morphine, amitriptyline, diazepam, probenecid and chloramphenicol inhibited codeine glucuronidation with Ki values of 3.6, 0.13, 0.18, 1.7 and 0.27 mM, respectively.

Plasma concentrations of calcitonin gene-related peptide increase during haemodialysis: relation to blood pressure.

The authors measured the plasma levels of calcitonin gene-related peptide (CGRP), the most potent vasodilatator known, during sequential ultrafiltration and haemodialysis in 12 patients using a radio-immunoassay method. Mean plasma levels of CGRP were 70.3 +/- 16.5 (mean +/- SE) pmol l-1 at the start of treatment, it increased to 85.3 +/- 17.6 pmol l-1 during ultrafiltration and to 114.5 +/- 25.3 pmol l-1 during dialysis. Systolic blood pressure decreased during haemodialysis. Plasma levels of CGRP were negatively correlated to systolic blood pressure before and at the end of dialysis, and changes in plasma levels of CGRP were strongly correlated to changes in systolic blood pressure. The increase in CGRP levels was not correlated to the fluid removal, toxin removal or changes in osmolality. The increase in plasma levels of CGRP observed during dialysis may be an important cause of dialysis induced vasodilatation and fall in blood pressure.

Influence of renal failure, rheumatoid arthritis and old age on the pharmacokinetics of diflunisal.

The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r = +0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r = +0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0-96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r = -0.79). When the plasma concentration exceeded 200 mumols.l-1, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.