Plasma cytokine levels predict mortality in patients with acute renal failure

BACKGROUND: Critically ill patients with acute renal failure (ARF) experience a high mortality rate. Animal and human studies suggest that proinflammatory cytokines lead to the development of a systemic inflammatory response syndrome (SIRS), which is temporally followed by a counter anti-inflammatory response syndrome (CARS). This process has not been specifically described in critically ill patients with ARF. METHODS: The Program to Improve Care in Acute Renal Disease (PICARD) is a prospective, multicenter cohort study designed to examine the natural history, practice patterns, and outcomes of treatment in critically ill patients with ARF. In a subset of 98 patients with ARF, we measured plasma proinflammatory cytokines [interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha)], the acute-phase reactant C-reactive protein (CRP), and the anti-inflammatory cytokine IL-10 at study enrollment and over the course of illness. RESULTS: When compared with healthy subjects and end-stage renal disease patients on maintenance hemodialysis, patients with ARF had significantly higher plasma levels of all measured cytokines. Additionally, the proinflammatory cytokines IL-6 and IL-8 were significantly higher in nonsurvivors versus survivors [median 234.7 (interdecile range 64.8 to 1775.9) pg/mL vs. 113.5 (46.1 to 419.3) pg/mL, P= 0.02 for IL-6; 35.5 (14.1 to 237.9) pg/mL vs. 21.2 (8.5 to 87.1) pg/mL, P= 0.03 for IL-8]. The anti-inflammatory cytokine IL-10 was also significantly higher in nonsurvivors [3.1 (0.5 to 41.9) pg/mL vs. 2.4 (0.5 to 16.9) pg/mL, P= 0.04]. For each natural log unit increase in the levels of IL-6, IL-8, and IL-10, the odds of death increased by 65%, 54%, and 34%, respectively, corresponding to increases in relative risk of approximately 30%, 25%, and 15%. The presence or absence of SIRS or sepsis was not a major determinant of plasma cytokine concentration in this group of patients. CONCLUSION: There is evidence of ongoing SIRS with concomitant CARS in critically ill patients with ARF, with higher levels of plasma IL-6, IL-8, and IL-10 in patients with ARF who die during hospitalization. Strategies to modulate inflammation must take into account the complex cytokine biology in patients with established ARF.     

Plasma homocysteine concentration in children with chronic renal failure

Hyperhomocysteinemia, a risk factor for vascular disease, is commonly found in adult patients with end-stage renal disease. Major determinants of elevated plasma homocysteine levels in these patients include deficiencies in folate and vitamin B₁₂, methylenetetrahydrofolate reductase (MTHFR) genotype and renal function. Little information is available for children with chronic renal failure (CRF). The prevalence and the factors that affect plasma homocysteine concentration were determined in children. Twenty-nine children with various degrees of CRF (15 were dialyzed, 14 were not dialyzed) were compared with 57 age- and sex-matched healthy children. Homocysteine concentrations were higher in patients than controls (17.3 μmol/l vs 6.8 μmol/l, P<0.0001) and hyperhomocysteinemia (>95th percentile for controls: 14.0 μmol/l) was seen in 62.0% of patients and 5.2% of controls. Folate concentrations were lower in patients (9.9 nmol/l) than controls (13.5 nmol/l), P<0.01. Vitamin B₁₂ was similar in patients (322 pmol/l) and controls (284 pmol/l). Dialyzed patients have a higher prevalence of hyperhomocysteinemia than nondialyzed patients (87% vs 35%). Dialyzed patients with MTHFR mutation have higher plasma homocysteine (28.5 μmol/l) than nondialyzed patients with the mutation (10.7 μmol/l), P<0.002. In our study, differences between controls and patients in plasma homocysteine concentrations are observed when age is greater then 92 months, folate less than 21.6 nmol/l and vitamin B₁₂ less than 522 pmol/l.Our study shows that hyperhomocysteinemia is common in children with CRF and is associated with low folate and normal vitamin B₁₂ status, compared to normal children. Among the patients, the dialyzed patients with the MTHFR mutation are particularly at risk for hyperhomocysteinemia. Further studies are needed to investigate therapeutic interventions and the potential link with vascular complications in these patients. Received: 26 January 2001 / Revised: 16 April 2001 / Accepted: 17 April 2001     

Plasma parathyroid hormone and erythropoietin levels in patients with noninflammatory acute renal failure

PTH is incriminated as an uraemic toxin involved in the pathogenesis of anaemia in chronic renal failure. This fact was the background of our present studies performed in 14 patients with noninflammatory acute renal failure (NARF). Plasma levels of erythropoietin (EPO) and parathyroid hormone (PTH) were estimated in the anuric/oliguric (a/o) and polyuric (p) phase of NARF. In the a/o phase plasma EPO levels were predominantly normal, although inappropriately low to the degree of anaemia. In 50% of patients with NARF episodic short-term increases of plasma EPO levels were noticed which were not caused by worsening of anaemia. In the p phase plasma EPO concentrations were in the normal range (17.9±3.3 mU/ml) in spite of the same degree of anaemia as in the a/o phase. Plasma PTH levels were significantly elevated during the a/o phase (1.14±0.1 ng/ml), with a tendency to decline in the p phase (0.87±0.2 ng/ml). No correlation was found between plasma EPO and PTH concentrations. Results presented in this study suggest presence of relative EPO deficiency both during the a/o and p phases of NARF. As plasma PTH levels were not significantly correlated with serum EPO concentrations, its role in the pathogenesis of suppressed EPO levels seems unproven. Results presented in this study suggest deterioration of the physiological feedback between EPO secretion and the magnitude of erythropoiesis in NARF.     

Exercise-induced acute renal failure in 3 patients with renal hypouricemia

Three cases of exercise-induced non-oliguric acute renal failure in patients with renal hypouricemia, an isolated defect of the renal urate transport system, are described. During acute renal failure, the serum uric acid levels were 5.6, 2.7 and 5.8 mg/dl, respectively, and were within normal limits. The values representing the fractional excretion of uric acid (FEUA) were 28.7, 60.0 and 12.7%, with accompanying serum creatinine levels of 8.1, 3.9 and 3.3 mg/dl, respectively. After recovery, the serum uric acid fell to 0.6, 0.7 and 1.0 mg/dl and the FEUA increased to 79.3, 52.8 and 43.2%, respectively. Two of the patients examined exhibited decreased reabsorption of filtered urate. These 3 examples of renal hypouricemia represented 23% of 13 cases of mild exercise-induced acute renal failure encountered within our experience.     

Enteral nutrition in patients with acute renal failure

BACKGROUND: Systematic studies on safety and efficacy of enteral nutrition in patients with acute renal failure (ARF) are lacking. METHODS: We studied enteral nutrition-related complications and adequacy of nutrient administration during 2525 days of artificial nutrition in 247 consecutive patients fed exclusively by the enteral route: 65 had normal renal function, 68 had ARF not requiring renal replacement therapy, and 114 required renal replacement therapy. RESULTS: No difference was found in gastrointestinal or mechanical complications between ARF patients and patients with normal renal function, except for high gastric residual volumes, which occurred in 3.1% of patients with normal renal function, 7.3% of patients with ARF not requiring renal replacement therapy, 13.2% of patients with ARF on renal replacement therapy (P= 0.02 for trend), and for nasogastric tube obstruction: 0.0%, 5.9%, 14%, respectively (P < 0.001). Gastrointestinal complications were the most frequent cause of suboptimal delivery; the ratio of administered to prescribed daily volume was well above 90% in all the three groups. Definitive withdrawal of enteral nutrition due to complications was documented in 6.1%, 13.2%. and 14.9% of patients, respectively (P= 0.09 for trend). At regimen, mean delivered nonprotein calories were 19.8 kcal/kg (SD 4.6), 22.6 kcal/kg (8.4), 23.4 kcal/kg (6.5); protein intake was 0.92 g/kg (0.21), 0.87 g/kg (0.25), and 0.92 g/kg (0.21), the latter value being below that currently recommended for ARF patients on renal replacement therapy. Median fluid intake with enteral nutrition was 1440 mL (range 720 to 1960), 1200 (720 to 2400), and 960 (360 to 1920). CONCLUSION: Enteral nutrition is a safe and effective nutritional technique to deliver artificial nutrition in ARF patients. Parenteral amino acid supplementation may be required, especially in patients with ARF needing renal replacement therapy.     

Dialysis adequacy in patients with acute renal failure

Measurement of dialysis adequacy in patients with end-stage renal disease involves the use of urea kinetic modeling, which is a reflection of both dietary protein intake and efficiency of small solute clearance. Different dialytic modalities are available for patients in acute renal failure, including intermittent hemodialysis, continuous renal replacement therapies and peritoneal dialysis. In recent years, there has been a growing effort to measure dialysis adequacy in patients with acute renal failure using urea kinetic modeling. This initiative has been driven by the persistently high mortality rates in patients with dialysis-requiring acute renal failure, which may partly be related to inadequate dialysis dosing. In the setting of acute renal failure, dialysis adequacy has been measured using both single-pool and double-pool urea kinetics, as well as blood-based and dialysate-based urea kinetic modeling. Unfortunately, current goals and methods of measuring dialysis adequacy have been extrapolated from the end-stage renal disease patient population. These extrapolations are problematic because of differences in total body water, protein catabolic rate, and vascular access. Continuous renal replacement therapy has theoretical advantages over intermittent hemodialysis, including a decreased tendency to induce hypotension, and improved solute clearance and fluid removal, while allowing intensive nutritional support, and a better clearance of medium- to large-size molecules. The latter may play a significant role in patients with sepsis-associated acute renal failure. To date, comparative studies are scant and equivocal in establishing the superiority of a particular dialysis dose or modality.     

Thyroid function in patients with acute renal failure

Thyroid function was evaluated in a group of 36 patients with acute renal failure (ARF) during the oliguric/anuric, polyuric and postpolyuric phase. Serum thyroxine (T₄) and triiodothyronine (T₃) concentrations were significantly decreased in the oliguric/anuric phase, as compared with the mean values obtained in the postpolyuric phase and with controls.In contrast to T₃ and T₄, the concentration of serum reverse triiodothyronine (rT₃) was elevated in the oliguric/anuric phase and normal in the polyuric phase. The sephadex-T₃-binding index (T₃I) was significantly increased in oliguric/anuric patients and in the polyuric phase. The levels of serum thyreotropin were significantly elevated during all phases of ARF as compared with the controls. From the results obtained it is concluded that abnormal peripheral metabolism of T₄ seems to be the primary cause of altered plasma concentrations of thyroid hormones in patients with ARF.     

Plasma pteridine concentrations in patients with chronic renal failure.

BACKGROUND: Pteridine metabolism is impaired in the uraemic state. This may affect cardiovascular function and contribute to malnutrition. We wished to clarify further the impact of impaired pteridine metabolism. METHODS: Using the HPLC method, the plasma concentrations of endogenous pteridines were determined in 64 patients with chronic renal failure (33 on intermittent haemodialysis (HD) treatment vs 31 not yet on renal replacement therapy), and in 18 healthy controls. The patients were classified into three groups on the basis of creatinine clearance (Ccr): group (a), Ccr >60 ml/min; group (b), Ccr=10-60 ml/min; group (c), all patients receiving HD. RESULTS: Total neopterin (NP) and biopterin (BP) levels and the NP/BP ratio (a biomarker for macrophage activity) were significantly higher, whereas tetrahydrobiopterin (BH(4))/dihydrobiopterin (BH(2)) ratio (a biomarker for nitric oxide synthase and phenylalanine hydroxylase activities) was significantly lower in group (c) (118.9+/-11.7 ng/ml, 18.8+/-1.2 ng/ml, 6.79+/-0.53, and 0.26+/-0.06) than in healthy subjects (5.17+/-0.29 ng/ml, 2.83+/-0.19 ng/ml, 1.92+/-0.13, and 1.15+/-0.11; P<0.01). These significant differences were also observed between control and group (b) (12.4+/-2.20 ng/ml, 4.48+/-0.36 ng/ml, 2.81+/-0.48, and 0.74+/-0.08; P<0.01). In groups (a) and (b), significant negative correlations were found between Ccr and the total NP level (r=-0.663, P<0.01), the total BP level (r=-0.492, P<0.01), the BH(2) level (r=-0.677, P<0.01), and the NP/BP ratio (r=-0.493, P<0.01). Conversely, significant positive correlations were found between Ccr and the BH(4)/BH(2) ratio (r=0.602, P<0.01). CONCLUSION: The reduction of quinoid-type BH(2) to BH(4) is modified in patients with advanced chronic renal failure, before and after the initiation of regular HD treatment. These metabolic alterations may play a role in the impaired macrophage, endothelial constitutive nitric oxide synthase, or phenylalanine hydroxylase (PH) activities observed in such patients.     

Plasma leptin concentration in kidney transplant patients during early post-transplant period

Background: Leptin, is produced by adipose tissue and is presumed to be involved in the regulation of appetite and energy balance. The kidneys are involved in the inactivation of circulating leptin, and elevated plasma leptin concentrations were reported in uraemic patients. Finally, glucocorticosteroids as used in transplanted patients stimulate leptin secretion. Methods: The present study aimed to assess the relationship between plasma leptin concentration and kidney graft function in the early post-transplant period. We studied 40 successfully transplanted haemodialysed uraemic patients (27 males, 13 females, mean age 34.3±1.6 years, mean body mass index 22.5±0.5 kg/m²). The circadian rhythm of leptinaemia and insulinaemia was assessed twice: 2-4 days after kidney transplantation and 1 day before discharge from the hospital when graft function was good. Plasma leptin concentration was measured at 8 am, 4 pm, and 12 pm. The control group consisted of 21 healthy subjects (13 males, 8 females, mean age 39.4±2.5 years, mean body mass index 24.1±0.7 kg/m²). Results: Before kidney transplantation, patients had elevated plasma leptin and insulin levels. A positive correlation was found between BMI and leptinaemia and BMI and insulinaemia respectively. An inverse relationship was found between leptinaemia and age. Successful kidney transplantation was followed by a significant decline of leptinaemia i.e. from 21.5±0.1 vs 7.1±1.3 ng/ml. Kidney transplantation did not influence the circadian rhythm of leptinaemia. Conclusion: Leptinaemia was not related to the excretory graft function or immunosuppression. In addition to renal excretory function, other factors must be involved in the post-transplant decline of leptinaemia.     

'Low-dose' dopamine worsens renal perfusion in patients with acute renal failure

'Low-dose' dopamine is frequently used in intensive care units (ICU) for its presumed renoprotective effects, but prospective and retrospective studies have so far not proven prevention or amelioration of renal injury. Data on renal perfusion following dopamine infusion are limited. In order to circumvent the problem of patient heterogeneity in the ICU setting, we used a crossover design in a prospective, double-blind randomized controlled study to investigate the effect of 'low-dose' dopamine on renal resistance indices, as determined by Doppler ultrasound. Forty patients, 10 without and 30 with acute renal failure (ARF, defined as doubling of baseline creatinine or an increase above 2 mg/dl), were included. Dopamine (2 mug/kg min) or placebo was given intravenously in alternating sequence for four subsequent periods of 60 min, starting randomly with either dopamine or placebo. Resistive (RI) and pulsatility index (PI) were closely correlated, positively related to serum creatinine values at baseline and highly reproducible during the two paired infusion periods. Dopamine reduced renal vascular resistance in patients without ARF (median RI/PI from 0.70 to 0.65/1.20 to 1.07, P<0.01) but increased resistance indices in patients with ARF (median RI/PI from 0.77 to 0.81/1.64 to 1.79, P<0.01) in the absence of effects on systemic hemodynamics. Subgroup analysis of patients with ARF revealed that dopamine induced renal vasoconstriction above 55 years (n=22) and in patients not receiving norepinephrine (n=20). In conclusion 'low-dose' dopamine can worsen renal perfusion in patients with ARF, which adds to the rationale for abandoning the routine use of 'low-dose' dopamine in critically ill patients.     

Indirect calorimetry in postoperative patients with acute renal failure

Oxygen consumption was measured and caloric expenditure calculated (indirect calorimetry) in ten adult patients with acute renal failure (ARF) following surgery. Eight patients recovered from ARF and six were discharged from the hospital. Caloric expenditure averaged 47 Kcal/kg/24 hours during the period of AFR. Attempts were made to match caloric replacement with expenditure based on indirect calorimetry, but was achieved in only one patient. Indirect calorimetry appears to be a practical method for guiding caloric replacement in these patients. Postoperative patients in ARF must undergo healing of incisions and bowel anastomoses, and contain infection. Since these patients are severely catabolic, it seems reasonable to treat them with adequate protein and calories and to use dialysis to control azotemia and water metabolism.     

Accumulation of aluminium in patients with acute renal failure

Serum aluminium was monitored in 19 patients admitted with acute oligo-anuric renal failure. The maximum serum aluminium obtained during the course of treatment was greater (p less than 0.05) in 4 patients treated by haemodialysis alone, mean +/- sem 3.78 +/- 0.71 mumol/l than in 4 patients treated only by haemofiltration, 0.60 +/- 0.22 greater (p less than 0.05) during treatment with haemodialysis, 2.7 +/- 0.62 mumol/l than during treatment with haemofiltration, 1.36 +/- 0.15 mumol/l. There was a significant positive correlation between the maximum serum aluminium during treatment with haemodialysis and the number of hours of haemodialysis given (r = 0.76, p less than 0.001). There was no significant increase in serum aluminium due to the administration of human albumin solutions. The aluminium content of dialysate water represents a major source of aluminium in patients with acute renal failure; prevention by reverse-osmosis water purification is recommended.     

Measurement of serum leptin in patients with chronic renal failure on hemodialysis.

BACKGROUND: Leptin, the product of the obese gene, is produced exclusively in fat cells. SUBJECTS, MATERIALS AND METHODS: To evaluate the clinical significance of measuring serum leptin in 56 patients with chronic renal failure on hemodialysis (HD), we measured leptin levels using radioimmunoassay in 34 normal volunteers and in 56 patients on HD. RESULTS: Normal serum leptin averaged 5.7 +/- 0.7 (mean +/- SEM) ng/ml, which correlated significantly (p < 0.001) with the body fat percentage as measured by bioelectrical impedance analysis. Serum leptin in HD patients ranged from 1.3 to 142 ng/ml. The mean serum leptin analyzed after the logarithmic conversion was 5.6 ng/ml, which was not significantly different from the normal control value, although the body fat percentage was significantly lower than normal volunteers. There was a significant (p < 0.01) positive correlation between body fat percentage and serum leptin in both normal controls and HD patients. The slope of the regression curve was steeper in HD patients than in normal controls. CONCLUSION: (1) serum leptin levels to body fat mass are significantly higher in HD patients than controls; (2) the variability is much wider in HD patients; and (3) a significant relation exists between percent body fat and log serum leptin, the relation being steeper in HD patients than in controls.     

Plasma lipoproteins in patients with chronic renal failure (CRF)

The clinical picture in chronic renal failure (CRF) shows great variability depending on age, sex, aetiology of disease, grades of renal injury and type of treatment. Significant increases of triglycerides (TG), low-density lipoprotein cholesterol (LDL-chol) and apo B concentrations, significant decreases of high-density lipoprotein cholesterol (HDL-chol) levels and apo A and apo AI concentrations, and no significant changes in total cholesterol (TC) have been shown in CRF patients. Significant increases of TC/HDL-chol, LDL-chol/HDL-chol, apo B/apo AI and apo B/LDL-chol ratios were also demonstrated. That indicates a high risk of atherosclerosis even when total cholesterol levels are in the normal range. There were highly significant and positive correlations between TC/HDL-chol and LDL-chol/HDL-chol ratios, apo B and LDL-chol concentrations as well as between the apo B/apo AI and LDL-chol/HDL-chol ratios.     

Plasma renin activity and plasma aldosterone in acute renal failure

Plasma renin activity and plasma aldosterone were determined by radioimmunoassay methods in 20 patients in oliguric phase, in 11 patients in polyuric phase and in 7 patients in convalescent phase of acute renal failure of various origin. The oliguric phase of acute renal failure was characterized by significant increase of plasma renin activity and plasma aldosterone. There was no direct dependence between them. Direct dependence was found between plasma aldosterone and serum potassium in the oliguric phase of acute renal failure, indirect dependence between plasma aldosterone and serum sodium was found before as well as after haemodialysis. These findings prove a direct influence of hyperkalemia and depletion hyponatremia upon aldosterone secretion in the oliguric phase of acute renal failure. Haemodialysis led to a further increase of plasma renin activity caused by ultrafiltration as well as successive dehydration and application of some drugs. The mean value of plasma aldosterone was not significantly changed after haemodialysis. Plasma renin activity decreased very slowly in the polyuric and convalescence phase of acute renal failure, while plasma aldosterone concentration was already in polyuric phase non-significantly different from the control group. There was no direct dependence in the various phases of acute renal failure between plasma renin activity, plasma aldosterone, systolic and diastolic pressure.The renin-angiotensin-aldosterone system significantly participates in the pathogenesis of acute renal failure in man, but various causes of acute renal failure, different drugs, as well as therapeutic procedures do not make it possible to quantify it in detail.Charcoal haemoperfusion in acute poisonings led only to non-significant increase of plasma renin activity and decrease of plasma aldosterone.     

Plasma calcitonin in rats with renal failure

Summary To study the effect of the kidney on blood calcitonin (CT), rats were made uremic by either total or partial nephrectomy or bilateral ligation of the ureters. Plasma CT concentrations were measured by radioimmunoassay before and after calcium infusion. Uremia induced by total or partial nephrectomy produced an increase in plasma CT. Rats had higher plasma CT levels (49.3±1.7 pg/ml, mean ±SE) after total nephrectomy than after ureteral ligation (30.9±1.5 pg/ml) even though no significant difference was observed between the blood urea nitrogen (BUN) levels of these two groups. These results indicate that the kidney contributes to the degradation of CT.