Differences between women and men with chronic renal disease.

BACKGROUND: The purpose of the present study was to compare the participation of women and men in the protocols of the Modification of Diet in Renal Disease (MDRD) study, a multicenter prospective randomized clinical trial, and to assess gender differences in their renal outcomes. METHODS: Of the 840 participants in the MDRD study, 332 (39.5%) were women who were assigned randomly to the dietary protein and blood pressure groups and followed for a median of 2.2 years. A subgroup analysis of the MDRD study database was carried out to compare women and men participants in recruitment, baseline characteristics, adherence to protocol requirements, safety and outcomes, and progression of renal disease and its response to dietary and blood pressure interventions. RESULTS: Adherence by women to the requirements of the protocol including diet, record keeping, office visits, glomerular filtration rate (GFR) measurements and urine collections was equivalent to that of men. Women had different renal diagnoses, less proteinuria and lower serum creatinine levels for given GFRs than men. When participants were grouped above and below age 52, the younger women had lower mean arterial pressure than did the men. Older women compared with younger had higher mean arterial pressure, body weight and body mass index, and total low density lipoprotein cholesterol. These differences were not seen between males of the same two age groups. During follow-up, the rate of GFR fall was slower in women, especially in the younger group. However, the association between gender and the rate of fall in GFR was attenuated and became non-significant after adjusting for differences in blood pressure, proteinuria and high density lipoprotein cholesterol. In analyses of the full cohort, there were no significant differences between women and men in the effects of the low protein or low blood pressure intervention in patients with either moderate (study A) or advanced (study B) renal disease. However, in subgroup analyses of patients in study A, there was some evidence of a lesser effect in women than in men. CONCLUSIONS: This exploratory analysis of the MDRD study indicates a slower mean GFR decline in women as compared with men. The slower mean GFR decline and suggestive evidence of a lesser beneficial effect of the low protein diet and low blood pressure interventions in women suggest that gender differences should be considered in trials of the effects of these interventions on the progression of renal disease. Also, the participation of women in the MDRD study was excellent and equivalent to that of men.

Serum lipid changes associated with modified protein diets: results from the feasibility phase of the Modification of Diet in Renal Disease Study.

The use of low-protein diets for the management of progressive renal insufficiency may require increases in dietary fats to maintain caloric balance. This raises the concern that such diets might exacerbate the lipid problems already prevalent in chronic renal insufficiency. We present a study in which protein-restricted diets were followed by a group of patients with renal insufficiency without a compensatory increase in fat calories and without adverse effects on serum lipids. Ninety-six patients with renal insufficiency were enrolled in the feasibility phase of the Modification of Diet in Renal Disease Study and were assigned to dietary protein intakes of 1.3, 0.575, or 0.28 g/kg body weight/d. The last diet was supplemented with amino acids or their keto analogs. Of this group, 25 participants were excluded from the present study of lipids because of changes in their intake of medications with known effects on serum lipids, three were excluded because of proteinuria increasing by more than 2 g/d, and seven were excluded because of incomplete measurements. For the remaining 61 participants, median serum total cholesterol at baseline was 215 mg/dL. In 72% of participants it exceeded the age- and sex-adjusted median of the Lipid Research Clinics Prevalence Study. Glomerular filtration rates varied from 8 to 56 mL/min/1.73 m2. The patients' serum lipid levels were stable by 6 months on assigned diets. Serum total and low-density lipoprotein cholesterol levels tended to decrease with reduced protein intake. The baseline to follow-up change in protein intake calculated from urinary urea measurements was significantly correlated with the change in serum total cholesterol (Spearman r = 0.31, P < 0.05) and also with change in low-density lipoprotein cholesterol (r = 0.34, P < 0.01). Surprisingly, correlations between change in serum cholesterol and intake of fats were small in magnitude and did not approach statistical significance. Protein intake did correlate, however, with intake of cholesterol. We conclude that the use of low-protein diets for patients with renal insufficiency did not adversely affect serum lipids.

Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group.

The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 x 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.

Prediction of outcome in acute renal failure.

In an attempt to predict outcome in acute renal failure (ARF) we have utilized multiple logistic regression to analyze clinical data from 151 patients with ARF seen over a 15-month period. Recovery of renal function occurred in 60% of patients with a 58% survival. Our analysis demonstrated sepsis, respiratory failure, and oliguria to be the major predictors of nonrecovery of renal function. A logistic equation was generated for prediction of outcome and was validated in a second independent group of patients with ARF. Prediction of outcome could be achieved with a sensitivity of 75% and a specificity of 80%. Maximum sensitivity (100%) was associated with a 17% specificity, while maximum specificity (98%) yielded a sensitivity of 20%.

Effects of lithium on the kidney.

We tested kidney function in 268 patients given lithium treatment for an average period of 37.6 months and in 59 manic-depressive patients never given lithium. No patients suffered serious renal damage during the course of our observations. Maximum concentration capacity was lower and serum creatinine concentration higher in the lithium treated patients than in the controls, but the differences did not achieve statistical significance. Females had poorer concentrating ability than males, both among the control subjects and during lithium treatment. Concomitant antipsychotic drug therapy may affect concentrating ability and possibly glomerular function adversely.

Adrenocortical hormone levels during cardiopulmonary bypass with and without pulsatile flow.

To determine the effect of hypothermic pulsatile and nonpulsatile cardiopulmonary bypass (CPB) with hemodilution on adrenocortical function we measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, and renin in two groups of patients. Group I, comprising 11 patients had routine CPB (nonpulsatile), and Group II, comprising 12 patients, had pulsatile flow during CPB (pulsatile). Both groups demonstrated comparable increases in cortisol, ACTH, and aldosterone with operation. Levels for all three hormones appeared to decline during CPB and then rose again in the post-CPB period. There were no significant differences between groups. Plasma renin activity gradually declined in a comparable manner in both groups. In the post-CPB period, renin activity was slightly higher in the nonpulsatile group (1.7 +/- 0.5 versus 0.8 +/- 0.2 ng/ml/hr, p less than 0.05). Correction for the effect of hemodilution demonstrated no decrease in cortisol and a slight increase in ACTH in both groups during CPB. Significant increases occurred in both groups during CPB in urinary Na+ excretion rate and urinary Na+/K+ ratio, more so for the nonpulsatile group. There was no correlation between urinary Na+/K+ ratios and either plasma cortisol or aldosterone levels. Thus routine CPB demonstrates no evidence of adrenocortical hypofunction and the addition of pulsatile flow produces little improvement.

Antidiuretic and growth hormone responses during coronary artery surgery with sufentanil-oxygen and alfentanil-oxygen anesthesia in man.

Antidiuretic hormone (ADH), growth hormone (GH), and cardiovascular responses to large (anesthetic) doses of alfentanil (1.2 +/- 0.02 mg/kg) and oxygen and sufentanil (13.1 +/- 0.4 microgram/kg) and oxygen were measured before and during surgery (including cardiopulmonary bypass) and at the end of surgery in 29 patients undergoing coronary artery bypass surgery. The data demonstrate that alfentanil-O2 and sufentanil-O2 result in little change in cardiovascular dynamics throughout anesthesia and surgery, and also prevent changes in plasma levels of ADH and GH at all times during the study. Our findings contrast with previous studies with other anesthetics, including fentanyl, in which plasma levels of ADH and GH become markedly elevated during bypass. The results suggest that alfentanil and sufentanil may block hormonal stress responses to surgical stimulus better than fentanyl does. The clinical significance of the difference in ADH and GH responses during fentanyl and during alfentanil or sulfentanil anesthesia remains to be determined. However, this difference may provide part of the explanation why alfentanil and sufentanil-O2 anesthesia require less frequent employment of other anesthetic adjuvants and are easier to use than fentanyl during coronary artery surgery.

Adrenal insufficiency from metastatic colonic carcinoma masquerading as isolated aldosterone deficiency. Report of a case and review of the literature.

A case of adrenal insufficiency secondary to metastatic colonic carcinoma is reported. Because the patient was taking prednisone for an unrelated condition, his initial presentation mimicked isolated aldosterone deficiency with an elevated serum potassium of 8.7 mmol/l. Cortisol deficiency was documented by ACTH testing. The diagnosis of metastatic disease causing adrenal insufficiency was suspected after a computed body scan of the abdomen revealed marked bilateral adrenal enlargement. Adrenal insufficiency secondary to metastatic cancer is reviewed.

Renal function monitoring in patients receiving lithium carbonate.

As a screening test for renal function, urine concentration was measured following a 12-hour overnight fast in 54 outpatients taking lithium carbonate and 19 patients receiving antidepressant drugs. A significantly greater percentage of lithium patients failed to achieve a maximum urine concentration of 600 mOsm/kg (63% versus 33% in the antidepressant group, p less than .001). This level, a compromise between the sensitivity and specificity of the test, is viewed as a cutoff point for further testing. It is concluded that urine concentration testing is a feasible first-line screen for renal function among lithium-treated patients. Other preliminary studies include routine urinalysis, serum creatinine determination, and estimated creatinine clearance. Second-line testing includes a repeated dehydration test and administration of DDAVP.

Attenuation of the stress response to cardiopulmonary bypass by the addition of pulsatile flow.

The effect of pulsatile flow during cardiopulmonary bypass on the hormonal stress response was studied in 26 patients. Thirteen had routine and 13 had pulsatile bypass with an average pulse pressure of 30 mm Hg. Plasma vasopressin levels were significantly elevated during bypass in both groups, but were lower with pulsation (66 +/- 11 vs 36.3 pg/ml, p less than 0.05). Epinephrine levels increased in both groups during bypass, but were higher after bypass (1179 +/- 448 vs 713 +/- 140 pg/ml, p less than 0.05) and in the recovery room (1428 +/- 428 vs 699 +/- 155 pg/ml, p less than 0.05) in the nonpulsatile group. The same response was noted in the norepinephrine levels (924 +/- 225 vs 465 +/- 90 pg/ml, p less than 0.05; 1015 +/- 491 vs 717 +/- 112 pg/ml, p less than 0.05). There were no significant changes in renin activity in either group, but the increase after cardiopulmonary bypass was greater in the nonpulsatile group (2.0 +/- 0.7 vs 1.36 +/- 0.4 ng/ml/hr, NS). These data suggest that pulsatile flow significantly attenuates the vasopressin and catecholamine stress response to cardiopulmonary bypass. This may explain the increased flow requirements and better tissue perfusion and organ function and the decreased incidence of postoperative hypertension after bypass using pulsatile flow.

Renal function and stress response during halothane or fentanyl anesthesia.

The effects of anesthesia on hormonal stress response and renal function were measured before institution of cardiopulmonary bypass in two groups of patients undergoing elective coronary artery surgery. Group 1 (10 patients) received fentanyl, 100 microgram/kg, and N2O/O2; group 2 (12 patients) received halothane and N2O/O2. Patients in group 1 showed no significant changes in plasma levels of vasopressin, renin, or aldosterone during anesthesia or operation. This same group, however, demonstrated significant decreases in plasma levels of cortisol (8.4 +/- 1 to 4.2 +/- 1 microgram%, p less than 0.01), epinephrine (260 +/- 72 to 97 +/- 28 pg/ml, p less than 0.05), and norepinephrine (715 +/- 177 to 322 +/- 46 pg/ml, p less than 0.05) during operation. This was accompanied by an increase in urine volume (2.1 +/- 0.8 to 7.6 +/- 2 ml/min, p less than 0.05), a decrease in urine osmolality (610 +/- 82 to 166 +/- 60 mOsm/kg, p less than 0.01), and urine Na+ (54 +/- 12 to 16 +/- 4 meq/L, p less than 0.01) and no change in creatinine clearance. In contrast, in the group 2 patients during operation plasma levels of cortisol (11.7 +/- 2 to 31.1 +/- 2 microgram%, p less than 0.01), aldosterone (60 +/- 14 to 106 +/- 2 pg/ml, p less than 0.01), and vasopressin (10.4 +/- 1 to 23.3 +/- 3 pg/ml, p less than 0.01) all increased. This was accompanied by a significant decrease in creatinine clearance (148 +/- 52 to 92 +/- 12 ml/min/m2, p less than 0.05). The data demonstrate that high dose fentanyl anesthesia can significantly attenuate the hormonal stress response to operation and preserve renal function. They also suggest that decreases in renal function observed with anesthesia and operation may be a reflection of the hormonal changes associated with surgical stimulation.

Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow.

The use of pulsatile perfusion during bypass should create a more physiological milieu and thus attenuate the vasopressin stress response. To determine this, 20 patients scheduled for elective coronary artery bypass operation were studied in two groups. Group 1 had a standard nonpulsatile perfusion, and in Group 2 a pulsatile pump was used. Measurements were made before and after anesthesia, after surgical incision, and at 15 and 30 minutes during and after cardiopulmonary bypass. In both groups, vasopressin levels were significantly elevated after sternotomy (4.5 +/- 1.5 to 37 +/- 10 pg/ml in Group 1 and 3.1 +/- 1.2 to 33 +/- 9 pg/ml in Group 2, p less than 0.05) and during bypass (198 +/- 19 pg/ml in Group 1 and 113 +/- 16 pg/ml in Group 2) but were higher in Group 1 (p less than 0.05). With comparable perfusion pressures in both groups, Group 2 required higher flow (4.2 +/- 0.2 versus 3.5 +/- 0.3 L/min, p less than 0.05) and had lower resistance (1,351 +/- 182 versus 1,841 +/- 229 dynes sec cm-5, p less than 0.05) and higher urine Na+ (123 +/- 5 versus 101 +/- 8 mEq/L, p less than 0.05). These data demonstrate that pulsatile flow can significantly attentuate the vasopressin stress response to bypass. Since vasopressin, at these concentrations, is a potent vasoconstrictor and is capable of producing a Na+ diuresis, this may partially explain the higher flow requirements and the decrease in Na+ excretion.

Water metabolism and antidiuretic hormone (ADH) response following thermal injury.

ADH has been implicated in the development of a positive water balance in thermal injury. However, the association of plasma ADH levels to the hemodynamic response and water and electrolyte balance of early thermal injury has not been defined. Plasma ADH was measured by radioimmunoassay in 13 patients with greater than 15% body surface area burns. In three patients frequent hemodynamic measurements were also made. Large individual variations of ADH were noted, but in general the ADH levels peaked early in the postburn period and declined thereafter. The highest mean ADH value was on day 2 (53.8 = 27 pg/ml); the lowest value on day 7 (13.4 +/- 8 pg/ml). Urine electrolytes demonstrated wide variation (Na+, 2 to 236 mEq/L; K+, 2 to 228 mEq/L) as did serum (261--331 mOsm/kg) and urine (557--785 mOsm/kg) osmolalities. No correlation was noted between ADH levels and osmolalities or hemodynamic variables. These data suggest that ADH response following burns is a stress response producing levels beyond the physiologic range for an antidiuretic effect and that the osmolar, hypovolemic, and hypotensive feedback loops are not involved: ADH seems to act as a vasoconstrictor and to have no significant effect on quality or quantity of urine. We conclude that the positive water balance following burns is not ADH mediated.

The effects of anesthesia on antidiuretic hormone.

Arginine vasopressin, the antidiuretic hormone in man, in low concentrations increases reabsorption of water in the collecting ducts of the kidney, producing a concentrated urine. It is also a potent vasoconstrictor because of its direct effect on arteriolar smooth muscle, particularly the splanchnic, renal, and coronary vascular beds. This appears to be a dose-dependent response. In very high concentrations it is capable of producing a diuresis with increased urinary sodium excretion. The preponderance of evidence today has failed to show any significant increase in antidiuretic hormone levels with anesthesia alone, provided significant hemodynamic changes do not occur. It seems unlikely, then, that the inhalation anesthetics or high-dose narcotic anesthesia are a direct stimulus to ADH release. If a decrease in urine flow does occur, it is more likely caused by either the renal hemodynamic effects of the anesthetic or a secondary release of ADH. Surgical stimulation is capable of significantly increasing ADH levels. This apparently is a stress response that can be attenuated by the depth of anesthesia. Such a response to operation may produce ADH levels that can indeed decrease urinary flow, but more importantly may succeed in achieving levels that can exert a significant vasopressor effect. In unusual circumstances, vasopressin levels can occur that are capable of producing a diuresis and increased urine sodium excretion.