Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes.

Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n = 166) and the CRISIS-Study (n = 889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74 ± 0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR = 1.07 [95%CI 1.00-1.15]; p = 0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p = 0.02 and p = 0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR = 1.44 [1.16-1.81]; p = 0.001) and in patients with diabetes mellitus by 16% (HR = 1.16 [1.01-1.34]; p = 0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression.

Homoarginine in patients with primary hyperparathyroidism.

BACKGROUND: Low levels of the amino acid homoarginine and parathyroid hormone (PTH) excess are both independently related to an increased risk of cardiovascular morbidity and mortality. Accumulating evidence points to a mutual interplay between homoarginine and PTH. The authors therefore aimed to investigate circulating homoarginine levels in patients with and without primary hyperparathyroidism (PHPT). METHODS: The authors performed a cross-sectional analysis of serum homoarginine levels in 59 patients with mild and severe PHPT and in 92 control persons matched for age, sex and estimated glomerular filtration rate. RESULTS: Median PTH and serum homoarginine concentrations were 99.1 (79.7-120.2) pg/mL and 1.16 (0.95-1.66) µmol/L in patients with PHPT (79.7% female; 42.4% with normocalcemia) as compared with 45.8 (36.4-53.9) pg/mL and 1.62 (1.33-2.04) µmol/L in the control group (P < 0.001 for both), respectively. The authors observed no statistically differences between cases and controls for 25-hydroxyvitamin D [25(OH)D], serum albumin, hemoglobin, waist-to-hip ratio, C-reactive protein and NT-pBNP values. Multivariate analysis of covariance revealed that patients with PHPT had significantly lower homoarginine levels than controls (P < 0.001). This difference remained significant after adjusting for multiple confounders such as 25(OH)D, body mass index, LDL cholesterol, albumin, calcium, hemoglobin, smoking status and current antihypertensive medication. The differences of homoarginine levels persisted even after exclusion of patients with estimated glomerular filtration rate <60 mL/min (P = 0.003) and 25(OH)D levels <30 ng/mL (P = 0.001), respectively. CONCLUSIONS: Patients with PHPT have lower homoarginine levels compared with matched controls irrespective of age, sex, kidney function and 25(OH)D status. Further studies are needed to evaluate whether low homoarginine accounts for higher cardiovascular risk conferred by PTH excess.

Impact of aldosterone on osteoinductive signaling and vascular calcification.

Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells. Such 'vascular osteoinduction' is characterized by expression of osteogenic transcription factors and triggered by increased phosphate concentrations. A key role in this process is assigned to cellular phosphate transporters, most notably the type III sodium-dependent phosphate transporter Pit1. Pit1 expression is stimulated by mineralocorticoid receptor activation. Therefore, aldosterone participates in the phenotypical transformation of VSMCs. In preclinical models, aldosterone antagonism reduces vascular osteoinduction. Patients with CKD suffer from hyperphosphatemia predisposing to vascular osteogenic transformation, potentially further fostered by concomitant hyperaldosteronism. Clearly, additional research is required to define the role of aldosterone in the regulation of osteogenic signaling and the consecutive vascular calcification in CKD, but more generally also other diseases associated with excessive vascular calcification and even in individuals without overt disease.

Longitudinal assessments of erythropoietin-stimulating agent responsiveness and the association with specific clinical outcomes in dialysis patients.

BACKGROUND: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. METHODS: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. RESULTS: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). CONCLUSIONS: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.

Homoarginine, kidney function and cardiovascular mortality risk.

BACKGROUND: Homoarginine is a novel biomarker for cardiovascular diseases. In the present large cohort study, we evaluate how homoarginine is linked to kidney function and examine the potential interaction of homoarginine and kidney function as predictors of cardiovascular outcomes. METHODS: Serum homoarginine (mean: 2.41 ± 1.05 µmol/L), cystatin C and creatinine-based estimated GFR (eGFR, mean: 86.2 ± 23.0 mL/min per 1.73 m(2)) were measured in 3037 patients (mean age: 62.8 ± 10.6 years; 31.5% women) who were referred to coronary angiography. RESULTS: Homoarginine was positively associated with eGFR (age- and gender-adjusted partial correlation coefficient: 0.20, P < 0.001); using multiple regression analysis, eGFR emerged as an independent predictor of serum homoarginine (ß = 0.10, SE 0.01, P < 0.001). Overall cardiovascular mortality was 18.5% (563 cardiovascular deaths) after 9.9 years. Multivariate Cox proportional hazard analysis revealed that compared with participants in the highest gender-specific homoarginine tertile, those in the lowest tertile were at increased risk of cardiovascular death [multivariate-adjusted HR 1.47; 95% confidence interval (95% CI) 1.15-1.87, P = 0.002]. After adjustment for confounders, both homoarginine and eGFR were associated independently with cardiovascular mortality, with a strong synergistic interaction (P for interaction 0.005). After stratifying the cohort into persons with eGFRs <60 and ≥60 mL/min per 1.73 m(2), there was a stronger association between homoarginine and cardiovascular mortality in patients within eGFR below 60 (mean: 46.5 ± 12.0 mL/min per 1.73 m(2); HR per log SD increment of homoarginine 0.78; 95% CI 0.65-0.95, P = 0.013) compared to those with eGFR values ≥60 mL/min per 1.73 m(2). Subgroup analysis revealed that homoarginine is exclusively associated with death due to heart failure in subjects with eGFR values <60 mL/min per 1.73 m(2) (HR per log SD 0.56; 95% CI 0.37-0.85; P = 0.006). CONCLUSIONS: Low homoarginine is strongly related to decreased kidney function, adverse cardiovascular events and death due to heart failure. The relationship between low homoarginine and adverse cardiovascular outcomes is most obvious when kidney function is impaired.

Vascular calcification--is aldosterone a culprit?

In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular calcification leading to growth deficit, rapid ageing and early death. The hyperphosphataemia of kl/kl mice results from excessive formation of 1,25(OH)2D3 causing excessive intestinal phosphate absorption. Further, kl/kl mice further suffer from hyperaldosteronism and compelling evidence points to an active role of mineralocorticoids in triggering osteoinductive programmes in the vasculature, thus further contributing to the development of vascular calcification. Conversely, in kl/kl mice, the mineralocorticoid receptor antagonist spironolactone decreased the vascular osteoinductive processes and reversed the excessive expression of osteogenic programmes, i.e. type III sodium-dependent phosphate transporter Pit1, tumour necrosis factor α (Tnfα), transcription factors Msx2, Cbfa1/Runx2 and osterix as well as alkaline phosphatase (Alp). In human aortic vascular smooth muscle cells (HAoSMCs), aldosterone alone similarly triggered an 'osteogenic' programme, thus increasing PIT1, TNFα, MSX2, CBFA1/RUNX2 and ALP expression as well as ALP activity and potentiated the effects of phosphate treatment. These effects were again reversed by spironolactone and in addition by PIT1 silencing. The above observations reveal that the severe vascular calcification is not only the result of high plasma phosphate concentrations, but also promoted by aldosterone-driven osteoinductive signalling. Future studies in CKD patients will be required to define the role of aldosterone and the potential impact of its inhibition by spironolactone in the pathophysiology of vascular calcification.

Bariatric surgery and the kidney-much benefit, but also potential harm.

Bariatric surgery is increasingly performed on overweight individuals. A significant benefit with respect to cardiovascular (CV) events and survival has been documented. After weight loss, reduction of albuminuria/proteinuria is almost consistently seen; small studies documented retardation of the glomerular filtration rate (GFR) loss after bariatric surgery; reduction of blood pressure (BP) is less consistent. It has been known for a long time that the frequency of oxalate stones is increased after bariatric surgery. The main renal threat of hyperoxaluria is renal oxalosis, often irreversible, causing persisting renal failure. The causes are reduced oxalate binding by calcium due to saponification of calcium causing fat malabsorption, increased permeability for oxalate because of increased permeability of colon mucosa triggered by increased bile salts and reduced colonization of the colon by oxalobacter formigenes. These mechanisms are susceptible to treatment.

Vitamin D and cancer mortality: systematic review of prospective epidemiological studies.

Accumulating evidence from experimental and epidemiological studies suggests that vitamin D deficiency might be a causal risk factor for cancer and therewith associated mortality. We performed a systematic review in Medline up to February 2012 to identify prospective studies on 25-hydroxyvitamin D (25[OH]D) and cancer mortality as well as on 25(OH)D and survival in cancer patients. Our search retrieved 13 studies on cancer-specific mortality and 20 studies on overall mortality in cancer patients. Data on 25(OH)D and cancer mortality were mainly derived from general populations. The results were inconsistent and yielded either no, inverse or positive associations. By contrast, the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality. This relationship was particularly evident in cohorts of colorectal cancer patients. In contrast, there was no indication for increased mortality risk with higher vitamin D levels in any cancer cohort. In conclusion, the relationship of vitamin D status and cancerspecific mortality is still unclear and warrants further studies. Our results provide a strong rationale to perform prospective randomized controlled studies to document a potential effect of vitamin D supplementation on survival in cancer patients.

Exposure of pregnant rats to cigarette-smoke condensate causes glomerular abnormalities in offspring.

BACKGROUND: Higher blood pressure and albuminuria are found in offspring of mothers who smoke during pregnancy. Whether or not kidney development is affected by maternal smoking is unknown. METHODS: Sprague-Dawley rats were randomly allocated to twice-daily cigarette smoke and nicotine condensate (1 mg/kg) or vehicle at day 10 of pregnancy until delivery. RESULTS: Exposed offspring did not differ from control offspring with respect to body weight, kidney weight, albuminuria, and creatinine clearance. Both male and female offspring had higher tail-plethysmographic blood pressures and lower mean glomerular volume, podocyte, mesangial-cell, and endothelial-cell number, compared to control offspring. CONCLUSIONS: The data document that prenatal exposure to cigarette-smoke condensate containing nicotine influences normal kidney development and could predispose to higher blood pressures later in life.

Hyperparathyroidism in patients with primary aldosteronism: cross-sectional and interventional data from the GECOH study.

CONTEXT: Experimental studies suggest that aldosterone induces hypercalciuria and might contribute to hyperparathyroidism. OBJECTIVE: We aimed to test for differences in PTH levels and parameters of calcium and vitamin D metabolism in patients with primary aldosteronism (PA) compared with patients with essential hypertension (EH) and to evaluate the impact of PA treatment on these laboratory values. DESIGN, SETTING, AND PARTICIPANTS: The Graz Endocrine Causes of Hypertension study includes hypertensive patients referred for screening for endocrine hypertension at a tertiary care center in Graz, Austria. MAIN OUTCOME MEASURES: Differences in PTH levels between patients with PA and EH. RESULTS: Among 192 patients, we identified 10 patients with PA and 182 with EH. PTH levels (mean ± sd in picograms per milliliter) were significantly higher in PA patients compared with EH (67.8 ± 26.9 vs. 46.5 ± 20.9; P = 0.002). After treatment of PA with either adrenal surgery (n = 5) or mineralocorticoid receptor antagonists (n = 5), PTH concentrations decreased to 43.9 ± 14.9 (P = 0.023). Serum 25-hydroxyvitamin D concentrations were similar in both groups. Compared with EH, serum calcium concentrations were significantly lower (2.35 ± 0.10 vs. 2.26 ± 0.10 mmol/liter; P = 0.013), and there was a nonsignificant trend toward an increased spot urine calcium to creatinine ratio in PA [median (interquartile range) 0.19 (0.11-0.31) vs. 0.33 (0.12-0.53); P = 0.094]. CONCLUSIONS: Our results suggest that PA contributes to secondary hyperparathyroidism. Further studies are warranted to evaluate whether PTH has implications for PA diagnostics and whether mineralocorticoid receptor antagonists have a general impact on PTH and calcium metabolism.

Wasting and sudden cardiac death in hemodialysis patients: a post hoc analysis of 4D (Die Deutsche Diabetes Dialyse Studie).

BACKGROUND: Wasting is common in hemodialysis patients and often is accompanied by cardiovascular disease and inflammation. The cardiovascular risk profile meaningfully changes with the progression of kidney disease, and little is known about the impact of wasting on specific clinical outcomes. This study examined the effects of wasting on the various components of cardiovascular outcome and deaths caused by infection in hemodialysis patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,255 hemodialysis patients from 178 centers participating in Die Deutsche Diabetes Dialyse Studie (4D) in 1998-2004. PREDICTOR: Moderate wasting was defined as body mass index, albumin, and creatinine values less than the median (26.7 kg/m(2), 3.8 g/dL, and 6.8 mg/dL, respectively) and C-reactive protein level less than the median (5 mg/L) at baseline. Severe wasting was defined as body mass index, albumin, and creatinine levels less than the median and C-reactive protein level greater than the median at baseline. OUTCOMES & MEASUREMENTS: Risks of sudden cardiac death (SCD), myocardial infarction (MI), stroke, combined cardiovascular events, deaths due to infection, and all-cause mortality were determined using Cox regression analyses during a median of 4 years of follow-up. RESULTS: 196 patients had wasting (severe, n = 109; and moderate, n = 87). Overall, 617 patients died (160 of SCD and 128 of infectious deaths). Furthermore, 469 patients experienced a cardiovascular event, with MI and stroke occurring in 200 and 103 patients, respectively. Compared with patients without wasting (n = 1,059), patients with severe wasting had significantly increased risks of SCD (adjusted HR, 1.8; 95% CI, 1.1-3.1), all-cause mortality (adjusted HR, 1.8; 95% CI, 1.4-2.4), and deaths due to infection (adjusted HR, 2.3; 95% CI, 1.2-4.3). In contrast, MI was not affected. The increased risk of cardiovascular events (adjusted HR, 1.5; 95% CI, 1.0-2.1) was explained mainly by the effect of wasting on SCD. LIMITATIONS: Selective patient cohort. CONCLUSIONS: Wasting was associated strongly with SCD, but not MI, in diabetic hemodialysis patients. Nonatherosclerotic cardiac disease potentially has a major role to account for the increased cardiovascular events in patients with wasting, suggesting the need for novel treatment strategies.

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring.

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.

High-dose enalapril treatment reverses myocardial fibrosis in experimental uremic cardiomyopathy.

AIMS: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. METHODS: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR. RESULTS: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.57±0.43% in SNX vs 1.50±0.43% in sham, p<0.05) and a significantly lower capillary length density (4532±355 mm/mm(3) in SNX vs 5023±624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63±0.25%, p<0.05), but not capillary reduction (3908±486 mm/mm(3)) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. CONCLUSIONS: The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX.

Creatinina sérica, cistatina C e proteína ß-traço no estadiamento disgnóstico e na predição da progressão da doença renal crônica não diabética / Serum creatinine, cystatin C, and ß-trace protein in diagnostic staging and predicting progression of primary nondiabetic chronic kidney disease

HISTÓRICO: A redução da função renal basal é um fator de risco bem definido para a progressão da doença renal crônica (DRC). Avaliamos a taxa de filtração glomerular (TFG) medida e os marcadores séricos creatinina, cistatina C e proteína χ-traço (PBT) para a acurácia diagnóstica na definição do estágio da lesão renal e como preditores do risco de progressão da DRC. MÉTODOS: Dosamos as concentrações dos marcadores em 227 pacientes com DRC primária não diabética e com vários graus de lesão renal e seguimos 177 pacientes prospectivamente por até sete anos para avaliar a progressão da DRC. RESULTADOS: No início, creatinina, cistatina C e PBT se correlacionaram fortemente com a TFG medida pela depuração do ioexol. As concentrações dos três marcadores aumentaram progressivamente com a diminuição da TFG, e seus desempenhos diagnósticos para a detecção até mesmo de discretas deteriorações da função renal (TFG < 90 ml/min/1,73 m2) foram similares. Sessenta e cinco pacientes tiveram progressão da DRC, definida como duplicação da creatinina inicial e/ou falência renal terminal durante o seguimento prospectivo. Esses pacientes eram mais velhos e tinham, inicialmente, menor TFG e valores mais altos de creatinina, cistatina C e PBT (todos p < 0,001) comparados com os pacientes que não alcançaram o endpoint renal pré-definido. As análises de regressão de risco proporcional de Cox revelaram que os três marcadores de depuração eram igualmente fortes preditores da progressão da DRC, mesmo após os ajustes para idade, sexo, TFG e proteinúria. CONCLUSÃO: O desempenho diagnóstico da creatinina sérica, da cistatina C ou da PBT na detecção até mesmo de discretos graus de deterioração da função renal é boa, e esses marcadores fornecem previsão do risco de progressão da doença renal em pacientes com DRC.

INTRODUCTION: Impaired baseline kidney function is a well-defined risk factor for progression of chronic kidney disease (CKD). We evaluated measured glomerular filtration rate (GFR) and the serum markers creatinine, cystatin C, and χ-trace protein (BTP) for diagnostic accuracy in defining the stage of kidney impairment and as risk predictors of CKD progression. METHODS: We measured serum marker concentrations in 227 patients with primary nondiabetic CKD and various degrees of renal impairment and followed 177 patients prospectively for up to seven years to assess progression of CKD. RESULTS: At baseline, creatinine, cystatin C, and BTP were strongly correlated with GFR as measured by iohexol clearance. Concentrations of all three markers increased progressively with decreasing GFR, and their diagnostic performance for the detection of even minor deteriorations of renal function (GFR < 90 ml À min-1 À (1.73 m²)-1) was similar. Sixty-five patients experienced progression of CKD, defined as doubling of baseline creatinine and/or terminal renal failure during prospective follow-up. These patients were older and had a lower GFR and higher serum creatinine, cystatin C, and BTP values at baseline (all p < 0.001) compared with the patients who did not reach a predefined renal endpoint. Cox proportional hazard regression analysis revealed that all three clearance markers were equally strong predictors of CKD progression, even after adjustment for age, sex, GFR, and proteinuria. CONCLUSION: The diagnostic performance of serum creatinine, cystatin C, or BTP for detecting even minor degrees of deterioration of renal function is good, and these markers provide reliable risk prediction for progression of kidney disease in patients with CKD.

Association of plasma aldosterone with cardiovascular mortality in patients with low estimated GFR: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

BACKGROUND: We have previously shown that plasma aldosterone levels within the physiologic reference range predicted increased all-cause and cardiovascular disease (CVD) mortality in patients referred for coronary angiography. Decreased kidney function is associated with a marked increase in CVD mortality that is not explained fully by known cardiovascular risk factors. We hypothesized that level of kidney function might modify the association between plasma aldosterone level and CVD mortality. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,153 patients (mean age, 62.7 ± 10.6 years; 30.1% women) free of primary kidney disease at baseline were referred for coronary angiography in a tertiary-care center in Southwest Germany between 1997 and 2000. PREDICTORS: Plasma aldosterone level, determined using radioimmunoassay. Tertiles of estimated glomerular filtration rate (eGFR) based on creatinine and cystatin C levels. OUTCOMES & MEASUREMENTS: CVD mortality and sudden cardiac death events at 7.75 years. RESULTS: At baseline, median plasma aldosterone concentration was 79.0 (25th-75th percentile, 48.0-124.0) pg/mL. Mean eGFR was 83.8 ± 20.1 (SD) mL/min/1.73 m(2), and mean eGFRs in tertiles 1-3 were 61.9 ± 13.0, 84.7 ± 4.4, and 104.7 ± 10.3 mL/min/1.73 m(2), respectively. After a median follow-up of 7.75 years, 454 (14.4%) patients died of cardiovascular causes and 179 (5.7%) died suddenly. Multivariate Cox proportional hazard analyses showed increased risks of CVD mortality (HR per 50-pg/mL increment in plasma aldosterone concentration, 1.08; 95% CI, 1.03-1.12; P = 0.001) and sudden cardiac death (HR, 1.11; 95% CI, 1.06-1.15; P < 0.001). In tertiles 1-3 of eGFR, adjusted HRs per 50-pg/mL increment in plasma aldosterone concentration for CVD mortality were 1.10 (95% CI, 1.05-1.14; P < 0.001), 1.00 (95% CI, 0.83-1.16; P = 0.8), and 0.97 (95% CI, 0.75-1.26; P = 0.8), respectively (product term for interaction, P = 0.001), and for sudden cardiac death were 1.13 (95% CI, 1.08-1.17; P < 0.001), 0.99 (95% CI, 0.75-1.29; P = 0.9), and 0.90 (95% CI, 0.60-1.34; P = 0.5), respectively (product term for interaction, P < 0.001). LIMITATIONS: No urinary analysis was performed to assess dietary salt intake and proteinuria. CONCLUSIONS: Our findings suggest that the association of higher plasma aldosterone concentration with overall CVD mortality and sudden cardiac death is stronger for patients with lower kidney function.

Symmetrical and asymmetrical dimethylarginine as predictors for mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study.

BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. The clinical role of its structural isomer symmetrical dimethylarginine (SDMA) remains largely unclear. METHODS: We measured SDMA and ADMA in 3229 patients undergoing coronary angiography at baseline (1997-2000) and recorded total and cardiovascular mortality during a median follow-up time of 7.7 years. We investigated associations of SDMA with cardiovascular risk factors and mortality and compared its role as a cardiovascular risk factor with ADMA, which predicted mortality in previous analyses of our study. RESULTS: In linear regression analyses including common cardiovascular risk factors as covariates, SDMA and ADMA were significantly associated with cystatin C, N-terminal pro-B-type natriuretic peptide, New York Heart Association classification, and homocysteine. The regression coefficients were higher for SDMA than for ADMA. In Cox proportional-hazards models adjusted for cardiovascular risk factors, the hazard ratios (HRs) (with 95% CI) in the second, third, and fourth SDMA quartile compared to the lowest quartile were 0.77 (0.60-0.99), 0.99 (0.78-1.25), and 1.51 (1.20-1.91) for total mortality and 0.92 (0.68-1.25), 0.93 (0.68-1.26), and 1.54 (1.14-2.01) for cardiovascular mortality. The same calculations for ADMA quartiles revealed HRs of 1.05 (0.83-1.32), 1.19 (0.95-1.50), and 1.61 (1.30-1.99) for total mortality and HR of 1.00 (0.74-1.34), 1.26 (0.95-1.68), and 1.54 (1.18-2.02) for cardiovascular mortality. CONCLUSIONS: Serum concentrations of SDMA are independently associated with increased cardiovascular and all-cause mortality in patients undergoing coronary angiography. The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2 methylarginine metabolites.

Is there an obesity-metabolic syndrome related glomerulopathy?

PURPOSE OF REVIEW: There is an increasing evidence for a specific form of focal segmental glomerulosclerosis (FSGS) related to obesity. Its prevalence has progressively increased in past decades. This form of FSGS represents the tip of an iceberg: a much broader spectrum of renal malfunction is linked to visceral obesity, which is closely connected to, but not completely identical with, the concept of 'metabolic syndrome'. RECENT FINDINGS: The obesity-associated FSGS (obFSGS) is characterized by massive proteinuria and glomerular lesions which are similar to but less pronounced than in idiopathic FSGS, but the long-term prognosis is still dubious. The patholophysiology underlying obesity-associated renal pathology includes insulin resistance and salt sensitivity of blood pressure (BP); more recently adiponectin deficiency, hyperaldosteronism and many other pathogenetic factors have been identified. The abnormalities of renal structure in obese and morbidly obese individuals include increased kidney weight, glomerulomegaly, disorder of podocytes, mesangial expansion and more recently also abnormalities of the renal interstitium. This is accompanied by functional abnormalities, that is renal hyperperfusion, increased filtration fraction and albuminuria. Both obesity and metabolic syndrome have been identified as powerful predictors of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This correlation is not fully explained by associated hypertension and prediabetes/diabetes. SUMMARY: The link between progressive kidney disease and visceral obesity is of enormous public health importance. Apart from causing obFSGS, obesity aggravates most primary kidney diseases. Beyond standard therapy and weight loss, bariatric surgery has recently emerged as a successful intervention for obFSGS.

Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice.

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 µg/kg) or paricalcitol (0.1 µg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 µm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-ß1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-ß expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

Serum creatinine, cystatin C, and beta-trace protein in diagnostic staging and predicting progression of primary nondiabetic chronic kidney disease.

BACKGROUND: Impaired baseline kidney function is a well-defined risk factor for progression of chronic kidney disease (CKD). We evaluated measured glomerular filtration rate (GFR) and the serum markers creatinine, cystatin C, and beta-trace protein (BTP) for diagnostic accuracy in defining the stage of kidney impairment and as risk predictors of CKD progression. METHODS: We measured serum marker concentrations in 227 patients with primary nondiabetic CKD and various degrees of renal impairment and followed 177 patients prospectively for up to 7 years to assess progression of CKD. RESULTS: At baseline, creatinine, cystatin C, and BTP were strongly correlated with GFR as measured by iohexol clearance. Concentrations of all 3 markers increased progressively with decreasing GFR, and their diagnostic performance for the detection of even minor deteriorations of renal function (GFR <90 mL x min(-1) x (1.73 m(2))(-1)) was similar. Sixty-five patients experienced progression of CKD, defined as doubling of baseline creatinine and/or terminal renal failure during prospective follow-up. These patients were older and had a lower GFR and higher serum creatinine, cystatin C, and BTP values at baseline (all P < 0.001) compared with the patients who did not reach a predefined renal endpoint. Cox proportional hazard regression analysis revealed that all 3 clearance markers were equally strong predictors of CKD progression, even after adjustment for age, sex, GFR, and proteinuria. CONCLUSIONS: The diagnostic performance of serum creatinine, cystatin C, or BTP for detecting even minor degrees of deterioration of renal function is good, and these markers provide reliable risk prediction for progression of kidney disease in patients with CKD.