Iron supplementation and mortality in incident dialysis patients: an observational study.

BACKGROUND: Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting. METHODS: In our observational single-center cohort study (INVOR study) we prospectively studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association. RESULTS: One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 vs 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08-0.58); p = 0.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31 (0.09-1.04); p = 0.06]. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality. CONCLUSIONS: Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.

Darbepoetin alfa once every 2 weeks effectively maintained hemoglobin in dialysis patients in an observational study: Austrian cohort of ALTERNATE.

ALTERNATE is an international observational study evaluating biweekly darbepoetin alfa (DA) in adult dialysis patients in clinical practice. Austrian ALTERNATE results are presented here (n = 505). The follow-up study ALTERNATE follow-up (AFU) followed Austrian ALTERNATE patients for an additional 12 months (n = 135). Data were collected 6 months before and 12 months after conversion to biweekly dosing and during 12 months of follow-up. The primary measures were hemoglobin concentration 12 months after conversion and at the end of AFU, respectively. Mean (95 % CI) hemoglobin (g/dL) was 11.87 (11.75-11.99) at conversion, 11.71 (11.58-11.83) at month 12, and 11.66 (11.45-11.86) at end of AFU. Geometric mean (95 % CI) weekly dose (µg/wk) was 32.97 (30.80-35.30) at conversion, 29.90 (26.71-33.46) 12 months after conversion, and 24.38 (18.40-30.35) at end of AFU. The studies show that hemoglobin and dose could be effectively maintained over an extended period of time after conversion from higher frequency erythropoiesis-stimulating agents to biweekly DA.

Homoarginine and progression of chronic kidney disease: results from the Mild to Moderate Kidney Disease Study.

BACKGROUND: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). METHODS: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. RESULTS: Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60-90 ml/min), 2.52±1.24 µmol/L (GFR 30-60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p = 0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06). CONCLUSIONS: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.

Lipoprotein kinetics in male hemodialysis patients treated with atorvastatin.

BACKGROUND AND OBJECTIVES: In vivo metabolism of atherogenic apolipoprotein B (apoB)-containing lipoproteins is severely impaired in patients undergoing hemodialysis (HD), resulting in markedly prolonged residence times of these particles. It is unclear whether treatment with statins improves LDL kinetics in HD patients as is known for the general population. Therefore, this kinetic study assessed apoB-containing lipoproteins in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kinetic measures were analyzed with stable-isotope technology in six men undergoing HD before and after 3 months of daily administration of 10 mg of atorvastatin. Patients were 18-65 years of age, had LDL cholesterol levels between 90 and 200 mg/dl, and had been treated with HD for >6 months. They consumed a standardized isocaloric diet for 3 days before analysis. Fractional catabolic rates (FCRs) and production rates of very-low-density lipoprotein (VLDL)-apoB, intermediate-density lipoprotein-apoB, and LDL-apoB were determined using multicompartment modeling after plasma lipoprotein separation, precipitation of apoB, and determination of tracer-to-tracee ratios using mass spectrometry. RESULTS: Plasma concentrations of VLDL- and LDL-apoB were significantly lower (mean ± SD, 7.77±2.62 versus 11.27±6.15 mg/dl, P<0.05; 56.9±23.9 versus 84.0±21.1 mg/dl, P=0.03) and their FCRs were significantly higher (7.20±3.08 versus 5.20±2.98 days(-1), P<0.05; 0.851±0.772 versus 0.446±0.232 days(-1), P<0.05) after 3 months of atorvastatin treatment. Accordingly, the residence times in plasma of VLDL- and LDL-apoB were significantly lower after treatment (0.14 versus 0.19 day and 1.2 versus 2.2 days, respectively). CONCLUSION: Lower plasma concentrations and improved kinetics of atherogenic lipoproteins were observed in HD patients after administration of low-dose atorvastatin.

The MAINTAIN study--managing hemoglobin variability with darbepoetin alfa in dialysis patients experiencing a severe drop in hemoglobin.

BACKGROUND: Dialysis patients, receiving erythropoiesis stimulating agents, typically show signs of hemoglobin variability as a consequence of their dosing patterns, bleeding, infection, etc., which is commonly managed adjusting the dose regimen of the erythropoiesis stimulating agent. However, information on dosing strategies used in daily clinical practice and their outcomes in relation to hemoglobin variability is limited. OBJECTIVES: To investigate clinical practice in Austria in relation with the management of hemoglobin variability, defined as a decrease of ³ 1 g/dL within 4 weeks from ³ 11 g/dL to £ 11 g/dL during maintenance therapy with darbepoetin alfa. The nature and incidence of clinical events related to the hemoglobin drop were also assessed. RESEARCH DESIGN AND METHODS: The MAINTAIN non-interventional study was conducted in hemodialysis patients, receiving darbepoetin alfa in accordance to the label approved in the European Union at that time. Patient data were documented retrospectively for the 3 months prior to the hemoglobin drop. Data for the 6 months post hemoglobin drop were collected retrospectively or prospectively, depending on the time of patient inclusion respective to the Hb drop. RESULTS: A hundred thirty six of 154 patients fulfilled all inclusion/exclusion criteria and had prospective documentation of 6 months. The main causes for the hemoglobin drop included surgical and medical procedures (36.1 %), and infections or infestations (24.4 %). The median treatment period was 273 days. The mean hemoglobin drop was - 1.74 g/dL (95 % confidence interval (CI): - 1.60 to - 1.87). Consequently, 81 % of the patients had their dose of darbepoetin alfa increased within a median Kaplan-Meier time to dose increase of 12.5 days (95 % CI: 6-22). The geometric mean weekly darbepoetin alfa dose increased by a factor of 1.1 from 29.1 mg (95 % CI: 24.6-34.4) in the 3 months before hemoglobin drop to 32.4 (95 % CI: 27.2-38.6) in months 4-6 post hemoglobin drop. Three patients had red blood cell transfusions before hemoglobin drop and nine patients after hemoglobin drop. The mean hemoglobin increase was 0.43 g/dL (95 % CI: 0.24-0.62) from immediately prior to 2 weeks after dose increase. The median Kaplan-Meier time to achieve a hemoglobin ³ 11 g/dL after hemoglobin drop was 36 days (95 % CI: 32-45). Frequent darbepoetin alfa dose adjustments were necessary to sustain maintenance levels. No drug-related adverse events were reported. CONCLUSIONS: This observational study describes physicians' reactions to a drop in hemoglobin in clinical practice. Using darbepoetin alfa, the drop was generally compensated without leading to overcorrection.

Coumarins and survival in incident dialysis patients.

BACKGROUND: The benefit and risk of oral anticoagulation in dialysis patients are debated controversially. METHODS: We prospectively followed 235 dialysis patients of the INVOR Study (Study of Incident Dialysis Patients in Vorarlberg) for up to 7 years and analysed the prevalence and incidence of atrial fibrillation (AF) and the impact of coumarin therapy on survival. Oral anticoagulation was monitored frequently. RESULTS: A total of 748 person-years were recorded with a median follow-up of 2.84 years. Twelve patients (5.1%) had AF at the start of dialysis. During follow-up, 40 patients (17.0%) developed AF, representing an incidence of 5.85 per 100 person-years. AF was positively associated with mortality (P = 0.004). Forty-six (19.6%) of the 235 patients were treated with coumarins. The majority (93.7%) had a clear indication for oral anticoagulation. In 65% of our patients, AF was the indication for coumarins. Patients without coumarins and without AF represented our reference group. The mortality risk of the coumarin-treated patients with AF or an alternative indication for coumarins was slightly lower compared to the reference group [hazard ratio (HR) 95% confidence interval (CI): 0.80 (0.28-2.29), P = 0.679 and 0.42 (0.16-1.10), P = 0.078, respectively]. No patient under sufficient oral anticoagulation experienced a stroke or a fatal bleeding event. Patients with AF and a contraindication for coumarins had a significantly higher mortality risk compared to the reference group [HR (95% CI): 3.90 (2.16-7.04), P < 0.001]. CONCLUSIONS: Our data suggest that coumarins might be less harmful than previously anticipated when clearly indicated and closely monitored.

Vitamin D deficiency is associated with poor response to active hepatitis B immunisation in patients with chronic kidney disease.

Vitamin D deficiency is highly prevalent in patients suffering from chronic kidney disease. At present it is not known whether this condition is associated with poor response to hepatitis B vaccination in these patients. We performed a retrospective analysis of 200 patients with chronic kidney disease stages 3-5D, who had undergone hepatitis B vaccination with three 40 µg recombinant hepatitis B vaccine doses in a single centre. Anti-HBs antibody titres and 25-hydroxyvitamin D (25(OH)D) levels were measured by chemiluminescence immunoassays. Vitamin D deficiency with serum levels <10 ng/mL was found in 35.5% of patients. These patients had a lower seroconversion rate than did patients with levels ≥10 ng/mL (45% vs 64%; P=0.011) and their median (25th, 75th percentile) anti-HBs antibody titres were lower (0 (0, 117)IU/L vs 48 (0, 236.5)IU/L). Non-responders had lower 25(OH)D concentrations than did responders (12.9±6.5 ng/mL vs 15.1±7.4 ng/mL; P=0.034). Treatment with a vitamin D receptor activator had no influence on the immune response. In a multiple logistic regression analysis vitamin D deficiency (OR 0.480; P=0.023) and diabetes (OR 0.496; P=0.038) remained independent and significant negative predictors of seroconversion. In conclusion, in patients with chronic kidney disease vitamin D deficiency is associated with a poor antibody formation upon hepatitis B vaccination.

Interaction of time-varying albumin and phosphorus on mortality in incident dialysis patients.

BACKGROUND AND OBJECTIVES: Hypoalbuminemia and hyperphosphatemia have been shown to be strong predictors of mortality in dialysis patients that might not be independent from each other. We prospectively investigated the relationship and interaction between serum albumin and phosphorus with all-cause mortality in an inception cohort of incident dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We followed 235 incident dialysis patients in a prospective single-center cohort study (INVOR study) applying a time-dependent Cox proportional hazards model using all measured laboratory values (2887 albumin and 10306 phosphorus values). RESULTS: Eighty-two patients (35%) died during a median follow-up of 35.1 months. Albumin was inversely associated with mortality (hazard ratio [95% confidence interval]: 0.23 [0.14 to 0.36]; P < 0.001), whereas higher phosphorus concentrations showed a trend to an increasing risk for mortality (hazard ratio 1.57 [95% confidence interval 0.97 to 2.54]; P = 0.07). Importantly, we observed a significant interaction between albumin and phosphorus (P = 0.01). The lowest risk was found with concurrent low phosphorus and high albumin values, whereas risk was increased with either concurrent low phosphorus and low albumin values or high phosphorus and high albumin values. CONCLUSIONS: In incident dialysis patients the associations of serum phosphorus and albumin concentrations with mortality are modified by each other over time. Phosphorus-lowering interventions that concomitantly can cause a fall in serum albumin level may be harmful and warrant additional studies. If confirmed, epidemiologic studies and therapeutic guidelines aiming for target values should consider this interplay.

Association of HbA1c values with mortality and cardiovascular events in diabetic dialysis patients. The INVOR study and review of the literature.

BACKGROUND: Improved glycemic control reduces complications in patients with diabetes mellitus (DM). However, it is discussed controversially whether patients with diabetes mellitus and end-stage renal disease benefit from strict glycemic control. METHODS: We followed 78 patients with DM initiating dialysis treatment of the region of Vorarlberg in a prospective cohort study applying a time-dependent Cox regression analysis using all measured laboratory values for up to more than seven years. This resulted in 880 HbA(1c) measurements (with one measurement every 3.16 patient months on average) during the entire observation period. Non-linear P-splines were used to allow flexible modeling of the association with mortality and cardiovascular disease (CVD) events. RESULTS: We observed a decreased mortality risk with increasing HbA(1c) values (HR = 0.72 per 1% increase, p = 0.024). Adjustment for age and sex and additional adjustment for other CVD risk factors only slightly attenuated the association (HR = 0.71, p = 0.044). A non-linear P-spline showed that the association did not follow a fully linear pattern with a highly significant non-linear component (p = 0.001) with an increased risk of all-cause mortality for HbA(1c) values up to 6-7%. Causes of death were associated with HbA(1c) values. The risk for CVD events, however, increased with increasing HbA(1c) values (HR = 1.24 per 1% increase, p = 0.048) but vanished after extended adjustments. CONCLUSIONS: This study considered the entire information collected on HbA(1c) over a period of more than seven years. Besides the methodological advantages our data indicate a significant inverse association between HbA(1c) levels and all-cause mortality. However, for CVD events no significant association could be found.

The association of mid-regional pro-adrenomedullin and mid-regional pro-atrial natriuretic peptide with mortality in an incident dialysis cohort.

High levels of the plasma peptides mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) are associated with clinical outcomes in the general population. Data in patients with chronic kidney disease are sparse. We therefore investigated the association of MR-proANP and MR-proADM levels with all-cause and cardiovascular (CV) mortality, CV events and peripheral arterial disease in 201 incident dialysis patients of the INVOR-Study prospectively followed for a period of up to more than 7 years. The overall mortality rate was 43%, thereof 43% due to CV events. Both baseline MR-proANP and MR-proADM were associated with higher risk of all-cause (HR = 1.44, p = 0.001 and HR = 1.32, p = 0.002, respectively) and CV mortality (HR = 1.75, p<0.001 and HR = 1.41, p = 0.007, respectively) after adjustment for age, sex, previous CV events, diabetes mellitus and time-dependent type of renal replacement therapy. We then stratified patients in high risk (both peptides in the upper tertile), intermediate risk (only one of the two peptides in the upper tertile) and low risk (none in the upper tertile). Although demographic, clinical and laboratory variables were similar among the intermediate and high risk group, to be with both parameters in the upper tertile was associated with a 3-fold higher risk for all-cause (HR = 2.87, p<0.001) and CV mortality (HR = 3.58, p = 0.001). In summary, among incident dialysis patients MR-proANP and MR-proADM were shown to be associated with all-cause and CV mortality, with the highest risk when both parameters were in the upper tertiles.

Sex-specific association of time-varying haemoglobin values with mortality in incident dialysis patients.

BACKGROUND: Previous studies in dialysis patients showed an association between haemoglobin levels and all-cause mortality, however, without addressing sex differences. METHODS: We followed up 235 incident dialysis patients of the region of Vorarlberg in a prospective cohort study applying a time-dependent Cox regression analysis using all the measured laboratory values for up to more than 7 years. In total, 12 242 haemoglobin measurements with a median of 47 (range 3-270) per patient were available to evaluate the impact of haemoglobin levels and their variability on all-cause mortality in a sex-stratified analysis. Non-linear P-splines were used to allow a flexible modelling of the association with mortality. RESULTS: We observed an inverse relationship between the increasing haemoglobin values and the decreasing risk of mortality. The linear component of the non-linear spline was highly significant for both men (P = 0.00005) and women (P = 0.0000000052). The non-linear component was also significant but less pronounced than the linear component. The inverse relationship was clear to see haemoglobin levels of up to 12-13 g/L in women, which reached a plateau for the higher values of haemoglobin. For men, an inverse trend was observed but clearly attenuated when compared to women. After adjustment for additional parameters of inflammation and malnutrition as well as diabetes, the linear component was more significant in women (P = 0.0018) than in men (P = 0.023). CONCLUSIONS: This study applied for the first time a time-dependent Cox regression analysis over a long-term observation period of several years using all available measurements. Besides the methodological advantages, our data indicate a sex-specific linear as well as non-linear effect of haemoglobin levels on all-cause mortality, which was markedly more pronounced in women.

Effect of dialysate temperature and diabetes on autonomic cardiovascular regulation during hemodialysis.

BACKGROUND/AIMS: Lowering dialysate temperature to increase intradialytic hemodynamic stability may interfere with the ultrafiltration-dependent intradialytic autonomic cardiovascular regulation. The present study aimed to investigate hemodynamic and autonomic responses depending on dialysate temperature and the presence of diabetes. METHODS: Seventeen (8 diabetic, 9 non-diabetic) hypotension-resistant patients were alternately treated at dialysate temperatures of 37 and 35 degrees C. Hemodynamic parameters, heart rate variability (HRV) and baroreceptor reflex sensitivity (BRRS) were measured noninvasively. Power spectral analysis of HRV was used to evaluate cardiac sympathetic and parasympathetic activity. RESULTS: In contrast to diabetic patients who showed an overall reduced autonomic activity and a blunted autonomic response, in non-diabetic patients cardiac sympathetic activity increased during dialysis (p < 0.05) resulting in a shift in sympathovagal balance towards sympathetic predominance. This response was not altered by dialysate temperature. Significant decreases in stroke volume and cardiac output were found in both patient groups. Total peripheral resistance increased in diabetic (p < 0.05) and in non-diabetic patients (p < 0.01) at both dialysate temperatures. No differences in BRRS were determined. CONCLUSION: The presence of diabetes has great impact on the cardiovascular autonomic regulation during hemodialysis. Varying the dialysate temperature does not influence cardiovascular autonomic regulation in hemodynamically stable diabetic and non-diabetic patients.

Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.

The kidney is one of the organs most prominently affected by aging. This can be seen by a loss of renal mass which is caused by a decrease in the number of nephrons resulting in hyperfiltration, hypertrophy and elevations in glomerular pressure. The factors influencing aging of the kidney are not fully elucidated. Epidemiological, experimental and interventional studies resulted in inconsistent results and have not firmly established whether uric acid levels affect progression of Chronic Kidney Disease (CKD). Therefore, we analyzed whether uric acid levels predict the progression of CKD in the Mild to Moderate Kidney Disease Study comprising at baseline 227 Caucasian patients aged 18-65 years with primary non-diabetic CKD of various degrees of renal impairment. Of them, 177 completed a prospective follow-up of 7 years. Primary endpoint was progression of CKD defined as doubling of baseline serum creatinine and/or terminal renal failure. Patients who reached a progression endpoint (n =6 5) were significantly older, had higher baseline serum creatinine and protein excretion rates as well as lower Glomerular Filtration Rate (GFR). Uric acid levels were only higher in patients with progression of disease when patients with uric acid-lowering drugs were excluded from the analysis. Cox regression analysis revealed that increasing uric acid levels predict disease progression only when the analysis was not adjusted for baseline kidney function parameters. As soon as we adjusted the analysis for GFR and proteinuria this association completely vanished. In summary, our prospective 7 year follow-up study in patients with non-diabetic primary CKD did not support uric acid as an independent predictor for CKD progression.

Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study.

It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.

Cigarette smoking and chronic allograft nephropathy.

BACKGROUND: Smoking has been demonstrated to decrease patient and graft survival after kidney transplantation. Data on histological changes associated with smoking in renal allografts are lacking. METHODS: Smoking habits before and after renal transplantation were evaluated by questionnaire in 279 patients. A transplant biopsy was performed more than 1 year after transplantation in 76 of them. Histological changes were classified according to Banff 97 criteria. Linear regression analysis and proportional odds models for histological changes including the factors age, gender, diabetes, body mass index, donor age, time since transplantation, history of acute rejection and smoking status were calculated. RESULTS: Overall 22% of patients continued smoking after transplantation, with the proportion decreasing from 38% of those transplanted before 1990 to 13% of those transplanted after 2000. Serum creatinine was non-significantly higher in smokers (2.3 +/- 2.7 mg/dl vs 1.8 +/- 1.4 mg/dl, P = 0.21). A renal biopsy was performed in 24% of non-smokers and 39% of smokers (P = 0.02), and smokers were biopsied on average 1.5 years earlier. Among biopsied patients current smokers tended to suffer more often from diabetes (25.0% vs 13.5%, P = 0.33), to develop transplant failure (33.3% vs 21.2%, P = 0.25) or experience a cardiovascular event (29.2% vs 15.4%, P = 0.16). The frequency of acute rejection was comparable between smokers and non-smokers (25.0% vs 34.6%, P = 0.40). Glomerular sclerosis was associated with diabetes (P = 0.03). Severity of vascular intimal fibrous thickening was associated with current smoking (P = 0.004), whereas the degree of arteriolar hyalinosis (P < 0.001) and chronic/sclerosing nephropathy (P = 0.05) were associated with time since transplantation. CONCLUSIONS: The number of patients who continue cigarette smoking after renal transplantation has decreased in recent years. The main allograft lesion associated with smoking is fibrous intimal thickening of small arteries.

Prevalence of decreased glomerular filtration rate in patients seeking non-nephrological medical care--an evaluation using IDMS-traceable creatinine based MDRD as well as Mayo Clinic quadratic equation estimates.

BACKGROUND: Data on the prevalence of decreased glomerular filtration rate in Europe are limited. Most of the available studies did not employ laboratory methods providing creatinine concentrations traceable to the reference method, i.e. isotope dilution mass spectrometry (IDMS). METHODS: We therefore conducted a cross-sectional study in the principality of Liechtenstein consecutively enrolling adult patients seeking non-nephrological medical care from whom serum samples were referred for renal function assessment. All measurements were done in one central laboratory. The estimated glomerular filtration rate (eGFR) was calculated based on the determination of IDMS-traceable creatinine by a kinetic Jaffe method (Roche Diagnostics, Switzerland) by means of the MDRD and Mayo Clinic quadratic equations. We further estimated the incidence of end stage renal disease during the next 5 years. RESULTS: For 43% (n=9378) of the entire population>or=25 years renal function assessment was available. An eGFR indicating chronic kidney disease (CKD) stages 3-5 was found in 4.93% when using the MDRD equation and in 3.98 % when using the Mayo Clinic quadratic equation. The two equations had a very good agreement in classifying patients to have an eGFR consistent with CKD stages 3-5 (Cohen's kappa 0.887). Further calculations suggested that among patients aged 80 or younger, annually 42 per 100,000 are going to develop an eGFR<15 ml/min/1.73 m2 over the next 5 years. CONCLUSIONS: 4-5% of patients seeking non-nephrological medical advice have an eGFR consistent with CKD stages 3-5, and a considerable number of subjects is expected to develop end stage renal disease over a 5 year period. In order to obtain comparable kidney function estimates among different institutions it is not only important to use standardized methods to measure creatinine but rather to employ standardized methods to calculate a GFR estimate.

Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria.

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells.

Carotid plaques and their predictive value for cardiovascular disease and all-cause mortality in hemodialysis patients considering renal transplantation: a decade follow-up.

BACKGROUND: Carotid plaque formation is very common in dialysis patients. The prognostic value of plaques, both calcified and noncalcified, rarely was investigated prospectively in these patients. By using a carotid plaque score, this study aims to determine the risk for combined cardiovascular disease (CVD) events and all-cause mortality in 165 hemodialysis patients in a long-term follow-up considering phases of renal transplantation. METHODS: Baseline carotid ultrasonography was performed in 165 hemodialysis patients to screen for carotid plaques. Patients subsequently were followed up for a period up to 13 years (average, 86 months). Because of biases associated with renal transplantation, 3 methods of multivariate analysis were compared by using Cox proportional hazards regression models. RESULTS: Plaques were present in 107 of 165 patients (65%). During the observation period, 50 patients (30%) experienced a combined CVD event, 95 patients (58%) died, and 79 patients (48%) underwent at least 1 renal transplantation. Mean plaque score differed significantly between patients who reached an end point and those who did not (CVD events, 3.1 +/- 2.7 versus 2.0 +/- 2.4; P = 0.01; all-cause mortality, 3.5 +/- 2.6 versus 0.9 +/- 1.3; P < 0.001). Plaque score entered all 3 tested Cox regression models for CVD events and all-cause mortality. The lowest statistical power was associated with censoring at the time of renal transplantation. Not considering transplantation at all neglected a major change in risk. CONCLUSION: We identified carotid plaque score and treatment modality as highly significant predictors for CVD events and all-cause mortality.

Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study.

It has not been established firmly whether dyslipidemia contributes independently to the progression of kidney disease. Lipid and lipoprotein parameters, including levels of total, HDL, and LDL cholesterol; triglycerides; lipoprotein(a); apolipoprotein A-IV; and the apolipoprotein E and A-IV polymorphisms, were assessed in 177 patients who had mostly mild to moderate renal insufficiency and were followed prospectively for up to 7 yr. Progression of kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy. In univariate analysis, patients who reached a progression end point (n = 65) were significantly older and had higher serum creatinine and proteinuria as well as lower GFR and hemoglobin levels. In addition, baseline apolipoprotein A-IV and triglyceride concentrations were higher and HDL cholesterol levels were lower. Multivariate Cox regression analysis revealed that baseline GFR (hazard ratio 0.714; 95% confidence interval [CI] 0.627 to 0.814 for an increment of 10 ml/min per 1.73 m(2); P < 0.0001) and serum apolipoprotein A-IV concentrations (hazard ratio 1.062; 95% CI 1.018 to 1.108 for an increment of 1 mg/dl; P = 0.006) were significant predictors of disease progression. Patients with apolipoprotein A-IV levels above the median had a significantly faster progression (P < 0.0001), and their mean follow-up time to a progression end point was 53.7 mo (95% CI 47.6 to 59.8) as compared with 70.0 mo (95% CI 64.6 to 75.4) in patients with apolipoprotein A-IV levels below the median. For the apolipoprotein E polymorphism, only the genotype epsilon2/epsilon4 was associated with an increased risk for progression. In summary, this prospective study in patients with nondiabetic primary kidney disease demonstrated that apolipoprotein A-IV concentration is a novel independent predictor of progression.

Proteinuria and hemoglobin levels in patients with primary glomerular disease.

BACKGROUND: Anemia in association with nephrotic syndrome has been described in small patient series and case reports. Whether nephrotic patients develop anemia has not been formally investigated. METHODS: We undertook a retrospective cross-sectional study of patients with biopsy-proven primary glomerular disease, various degrees of proteinuria, and creatinine levels less than 2 mg/dL (< 177 micromol/L). In addition to proteinuria, values for hemoglobin (Hb), age, body mass index (BMI), serum albumin and protein, and estimated glomerular filtration rate (eGFR) were derived from patient charts. RESULTS: We studied 297 patients, 187 men and 110 women, aged between 16 and 81 years. Univariate analysis showed no correlation between Hb level and proteinuria in either sex. Stratification of women and men into quartiles according to proteinuria showed no differences in Hb levels among the 4 groups. Three of 52 non-nephrotic women (6%) were anemic (Hb < 12 g/dL [< 120 g/L]) compared with 11 of 58 nephrotic women (19%; P = 0.047). Multiple regression analysis of all patients showed Hb level to have a correlation with sex (P < 0.001), BMI (P < 0.001), and eGFR (P = 0.005); negative correlation with age (P = 0.028); and borderline negative correlation with proteinuria (P = 0.054). In women, BMI showed a positive correlation with Hb level (P = 0.030). Proteinuria did not reach statistical significance (P = 0.093). In men, BMI (P = 0.001) and eGFR (P = 0.013) were associated positively and age (P = 0.031) was associated negatively with Hb level. CONCLUSION: These results indicate that nephrotic syndrome is not associated with anemia in men, but with a tendency to decrease Hb levels in women.