Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study.

BACKGROUND: Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS: Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 ± 14.2 years, mean dialytic age 70 ± 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co-morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: Six hundred and fifty-one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non-fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS: ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation.

Interleukin-8 is a powerful prognostic predictor of all-cause and cardiovascular mortality in dialytic patients.

BACKGROUND: Cohort studies have demonstrated an association between C-reactive protein (CRP) and interleukin-6 (IL-6) and all-cause and cardiovascular mortality in end-stage renal disease (ESRD) patients. Interleukin-8 (IL-8) appears to be not only the plasma expression of the acute-phase response but also a direct pathogenetic mediator of the atherosclerotic process. METHODS: To evaluate the role of IL-8 in predicting outcome, 76 chronic dialytic patients were prospectively followed for 18 months. At baseline, blood samples were taken for analysis of high-sensitivity CRP, IL-6, IL-8 and other standard laboratory analyses. RESULTS: Median IL-8 was 5.2 mg/l, therefore near half of the patients had IL-8 values within the range of 'normal limits'. IL-6 and CRP were significantly correlated (r = 0.45, p < 0.001) and a positive correlation was also found between IL-6 and IL-8 (r = 0.39, p < 0.001). The correlation coefficient between IL-6 and CRP was 0.43 (p < 0.001) and 0.50 (p < 0.001) in patients without and with history and/or clinical signs of cardiovascular disease, respectively. After a follow-up of 1.5 years, 8 patients had died from cardiovascular causes and another 7 patients for other reasons; furthermore 9 major nonfatal cardiovascular events were recorded. Stepwise regression analysis showed IL-8 as the strongest independent predictor of all-cause and cardiovascular events (p = 0.0025) even after adjustment for age and dialytic age, followed by IL-6 and CRP (p < 0.01). CONCLUSION: Despite a small population and a relatively short follow-up period, this study firstly demonstrated that IL-8 is a powerful independent predictive factor for cardiovascular and overall mortality cause in ESRD patients.

Ceruloplasmin and acute phase protein levels are associated with cardiovascular disease in chronic dialysis patients.

BACKGROUND: The most frequent cause of death in hemodialysis (HD) patients is cardiovascular disease (CVD), and chronic inflammation has been identified as an epidemiologically important risk factor for CVD. Elevated levels of minor acute phase reactants, such as ceruloplasmin (Cp) and transferrin, have been related to an increased cardiovascular risk in the general population, but little information is available regarding dialysis patients. We investigated the correlation between Cp and copper concentration (Cu) with major acute phase reactants such as C-reactive protein (CRP) and interleukin-6 (IL-6) in a population of chronic dialytic patients. Furthermore, we evaluated the relationship between long-lasting acute phase proteins such as Cp and nutritional markers. PATIENTS AND METHODS: CRP (Berhing Diagnostic, high sensitivity modified nephelometric technique, detection limit 0.1 mcg/mL), IL-6 (EIA, RD Systems), serum albumin, prealbumin, Cp (Berhing, nephelometric assay), copper (mass spectrometry, Varian) and standard laboratory routine analysis were determined in 75 stable chronic dialysis patients (age 60 +/- 16 yrs; dialytic age 65 +/- 50 months ) starting a midweek dialytic session. RESULTS: Thirty-seven patients (49%) had clinical signs of cerebrovascular, cardiovascular or peripheral vascular disease. Fifty-one patients (67%) showed biochemical inflammation markers as suggested by elevated CRP levels (mean 12.4 mg/L, SD 11.5) and IL-6 (mean 21.3 pg/mL, SD 19.7) with a positive correlation (r=0.65; p<0.001) between CRP and IL-6. CRP and IL-6 also related negatively to nutritional markers such as albumin and prealbumin (r=-0.42; p<0.01). Cp related significantly to CRP (r=0.4; p<0.001) and IL-6 (r=0.41; p<0.001), and as expected to copper (r=0.96; p<0.001), but not with serum albumin and prealbumin. In a multivariate logistic regression analysis, age (p<0.001), dialytic age (p>0.01), IL-6 (p=0.04) and Cp (p=0.02) were the strongest risk factors for cardio-vascular disease (CVD). CONCLUSION: These data suggest that serum Cp could be useful in monitoring the ""chronic inflamed"" patient and support the suggestion that elevated metalloprotein levels are associated with an increased cardiovascular risk in a population of stable dialysis patients.

Nutritional status and dietary manipulation in predialysis chronic renal failure patients.

OBJECTIVE: A properly implemented dietary treatment for patients with chronic renal failure (CRF) can correct several metabolic and endocrine disturbances and delay initiation of dialysis, but concerns exist about the risk of malnutrition and protein depletion. The goal of this study is to evaluate nutritional status and its relation to the dietary treatment in patients with advanced CRF. DESIGN: Cross-sectional survey. SETTING: Predialysis outpatient clinic. PATIENTS: Seventy patients (43 males, 27 females, 50 +/- 12 years) with severe CRF (glomerular filtration rate [GFR] <15 mL/min) being treated with a low-protein (0.6 g/kg/day) diet (LPD) or a very-low-protein (0.3 g/kg/day) diet supplemented with essential amino acids and ketoacids (KAD). Fifty-two healthy subjects with comparable age and sex served as controls. MAIN OUTCOME MEASURES: In all patients and controls, we performed biochemistry, anthropometry, bioelectrical impedance vector analysis (BIVA), and subjective global assessment (SGA), and the patients' outcomes were also assessed. RESULTS: Values of anthropometry and BIVA were similar in patients and controls. SGA scores showed a normal nutritional status (SGA-0) in 50 patients (71.4%) and mild to moderate SGA abnormalities (SGA-1) in 20 patients (28.6%); none had severe malnutrition. The SGA-1 patients differed from the SGA-0 patients by having higher serum urea, lower bicarbonate, and lower renal function (87% of SGA-1 patients had GFR <10 mL/min.). At the same GFR values (6.6 +/- 2.3 versus 6.6 +/- 2.3 mL/min) SGA-1 patients had lower bicarbonate (21.9 +/- 4.3 versus 25.3 +/- 2.7 mM, P <.01) and higher serum urea (115 +/- 29 versus 82 +/- 38 mg/dL, P =.01) and protein intake than SGA-0 patients; SGA-1 score was more prevalent with LPD compared with KAD treatment (45% versus 27%, P <.05). BIVA and anthropometry, serum levels of albumin, prealbumin, insulin-like growth factor-1, hematocrit, and lymphocyte count did not differ between SGA-1 and SGA-0 patients, but the number entering dialysis was higher in the group scoring as SGA-1 compared with SGA-0 (82% versus 47%, P <.05). CONCLUSIONS: With a planned dietary regimen, severe or overt malnutrition does not occur in predialysis CRF without other serious illnesses. However, some mild to moderate SGA abnormalities were detected in association with a more severe renal insufficiency, a lower serum bicarbonate, a higher serum urea and dietary protein levels and were predictive of poor renal outcome. This study emphasizes the role of proper dietary implementation, correction of metabolic acidosis, and clinical monitoring including SGA in the predialysis conservative care of CRF patients.

Severe hypotension during hemofiltration in an uremic patient with metabolic alkalosis.

We describe a case of medication induced metabolic alkalosis in a maintenance dialysis patient who developed severe hypotension while undergoing a lactate hemofiltration procedure. A 73-year-old man with ESRD due to renovascular disease was used to ingesting up to 30 grams per day of a non-prescription medication (Effervescent granulare 250 grams, CRASTAN, Pisa Italy) consisting of sodium bicarbonate, citric acid, glucose and lemon flavor. For technical problem lactate hemofiltration was performed and thirty minutes after dialysis was started a severe symptomatic hypotension occurred (blood pressure 65/35 mmHg). Lactate hemofiltration was suspended and one-hour later standard bicarbonate dialysis was performed without any clinical problem. The different mechanisms in acidosis buffering occurring in lactate and bicarbonate hemofiltration were discussed.

Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.

BACKGROUND: Despite the well known association between interleukin-6 (IL-6) and cardiovascular mortality, no study has so far verified whether IL-6 adds prognostic information to that provided by C-reactive protein (CRP). METHODS: A cohort of 218 haemodialysis patients from four different dialytic centres was followed-up retrospectively. Plasma IL-6 and CRP concentrations were determined. Full information on co-morbidities was available in 162 patients. RESULTS: With respect to the lowest quartile (< 3.6 pg/ml for IL-6, and < 2.2 mg/l for CRP), the crude relative risk (RR) of death from all causes of the upper quartile (> 13.9 pg/ml for IL-6, and > 12.8 mg/l for CRP) was 5.20 (95% confidence interval 2.06-13.011) for IL-6 and 3.16 (1.41-7.12) for CRP. When both variables were included, the estimates were 4.10 (1.30-12.96) for IL-6 and 1.29 (0.47-3.57) for CRP. As to continuous variables, the relationship between both variables and mortality tended to level off for the highest values, but became fairly linear after log transformation of the variables. For one unit SD of the log (variable), the RR was 2.09 (1.52-2.88) for IL-6 and 1.66 (1.23-2.24) for CRP. When they were included in the same model, the estimates were 1.90 (1.18-2.82) for IL-6 and 1.16 (0.81-1.66) for CRP. CONCLUSIONS: IL-6 has a stronger predictive value than CRP for cardiovascular mortality and provides independent prognostic information, while conveying most of that provided by CRP.

Effect of telmisartan on the proteinuria and circadian blood pressure profile in chronic renal patients.

Telmisartan is a type 1 angiotensin II (AT(1)) receptor blocker, effective and safe in the treatment of arterial hypertension. However, data with respect to circadian blood pressure (BP) monitoring and urinary protein (uP) excretion are lacking in normotensive or mild hypertensive patients with chronic renal diseases. This study has evaluated the effects of 80 mg telmisartan, given as monotherapy, on 24 h BP levels and uP loss in 16 non-diabetic patients affected by proteinuric renal disease. These patients did not meet the recommended values of mean BP, i.e. < 98 mmHg, when proteinuria was 0.5-1.0 g/d and mean BP < 92 mmHg, when proteinuria was 1-3 g/d. Patients with diastolic BP > 114 mmHg, nephrotic syndrome or severe renal failure (creatinine clearance < 20 ml/min) were excluded. After 4.2 +/- 2.7 month therapy, ambulatory BP monitoring showed a significant decrease (P < 0.001) of 24 h BP levels: systolic 135 +/- 11 vs. 122 +/- 13 mmHg, diastolic 84.4 +/- 8.1 vs. 75.9 +/- 8.5 mmHg, mean 101 +/- 8 vs. 91 +/- 9 mmHg. The effect was quite evident during either day-time or night-time. Clinic BP levels also significantly decreased (P < 0.001), and five patients reached the target values. uP excretion lowered by 37% (median) from 1.60 +/- 0.90 to 1.06 +/- 0.63 g/24 h (P < 0.01). No change in creatinine clearance (53.3 +/- 31.1 vs. 51.7 +/- 30.9 ml/min) or serum potassium level (4.3 +/- 0.3 vs. 4.4 +/- 0.4 mEq/l) was observed. Our results show that 80 mg of telmisartan, taken once daily, is effective in reducing uP excretion and BP throughout the 24 h, in normotensive or mild hypertensive renal patients. Since evidence exists that adequate control of BP, including during night-time, and reduction of proteinuria play a crucial role in the protection of renal function, telmisartan can be usefully considered in the conservative treatment of renal patients.