Asymptomatic pulmonary congestion and physical functioning in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Poor physical performance is common in patients with kidney failure on dialysis (CKD-5D). Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical performance of CKD-5D patients has not been investigated in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study investigated the relationship between the physical functioning scale of the Kidney Disease Quality of Life Short Form and a validated ultrasonographic measure of lung water in a multicenter survey of 270 hemodialysis patients studied between 2009 and 2010. RESULTS: Moderate to severe lung congestion by lung ultrasonography was observed in 156 (58%) patients; among these, 60 (38%) were asymptomatic (New York Heart Association [NYHA] class I). On univariate analysis, physical functioning was inversely associated with lung water in the whole group (r=-0.22; P<0.001) and in the subgroup of asymptomatic patients (r=-0.40; P=0.002). Age (r=-0.45; P<0.001) and past cardiovascular events (r=-0.22; P=0.002) were also inversely associated with physical functioning, whereas albumin (r=0.23; P<0.001) was directly associated with the same parameter. NYHA class correlated strongly with physical functioning (r=-0.52; P<0.001). In a multiple regression analysis, both NYHA class and lung water maintained an independent association with physical functioning, whereas albumin and background cardiovascular events failed to independently relate with the same outcome. CONCLUSIONS: Symptomatic and asymptomatic lung congestion is associated with poor physical functioning in hemodialysis patients. This association is independent of NYHA, suggesting that this measurement and NYHA may have complementary value to explain the variability in physical performance in hemodialysis patients.

Long-term visit-to-visit office blood pressure variability increases the risk of adverse cardiovascular outcomes in patients with chronic kidney disease.

Long-term visit-to-visit blood pressure (BP) variability predicts a high risk for cardiovascular events in patients with essential hypertension. Whether long-term visit-to-visit BP variability holds the same predictive power in predialysis patients with chronic kidney disease (CKD) is unknown. Here we tested the relationship between long-term visit-to-visit office BP variability and a composite end point (death and incident cardiovascular events) in a cohort of 1618 patients with stage 2-5 CKD. Visit-to-visit systolic BP variability was significantly and independently related to baseline office, maximal, and average systolic BPs, age, glucose, estimated glomerular filtration rate, and albumin, and to the number of visits during the follow-up. Both the standard deviation of systolic BP (hazard ratio: 1.11, 95% confidence interval: 1.01-1.20) and the coefficient of variation of systolic BP (hazard ratio: 1.15, 95% confidence interval: 1.02-1.29) were significant predictors of the combined end point independent of peak and average systolic BP, cardiovascular comorbidities, Framingham risk factors, and CKD-related risk factors. Antihypertensive treatment (ß-blockers and sympatholytic drugs) significantly abrogated the excess risk associated with high systolic BP variability. Thus, large visit-to-visit systolic BP variability in patients with CKD predicts a higher risk of death and nonfatal cardiovascular events independent of underlying BP levels.

The fat-mass and obesity-associated gene (FTO) predicts mortality in chronic kidney disease of various severity.

BACKGROUND: Polymorphisms in the FTO (fat-mass and obesity-associated) gene have been associated with the body mass index, cancer, type 2 diabetes and hypertension. METHODS: We investigated the relationship between 17 tag single-nucleotide polymorphisms (SNPs) and all-cause mortality in three cohorts of dialysis patients (CREED-1, North Apulian and CREED-2 cohorts; n = 783) and in one cohort of stage 2-5 CKD patients (n = 757). RESULTS: We first explored the association between the 17 tag SNPs and all-cause mortality in the CREED-1 cohort and found that patients with the A allele of the FTO rs708259 polymorphism had an elevated risk of mortality (hazard ratio, HR: 1.52, 95% confidence interval (CI) 1.11-2.08; P = 0.008). Similarly, the A allele was associated with an increased risk of death also in the other two dialysis cohorts (North Apulian cohort, risk: +23%; CREED-2 cohort, risk: +21%). The elevated risk portended by this allele was even higher in the stage 2-5 CKD cohort (+97%). However, the risk of mortality associated with the A allele in the three confirmatory cohorts failed to achieve formal statistical significance. In a meta-analysis including the four cohorts (n = 1540; total deaths, n = 381), individuals with the A allele had a 42% excess risk of death (HR: 1.42, 95% CI 1.14-1.76, P = 0.002). CONCLUSION: The A allele of the FTO rs708259 polymorphism is an independent predictor of all-cause mortality in patients with CKD of various severity. These data support our hypothesis that the FTO gene may be a relevant genetic risk factor for mortality in this population.

The MAURO study: baseline characteristics and compliance with guidelines targets.

BACKGROUND: The Multiple Intervention and Audit in Renal Diseases to Optimize Care (MAURO) study was a cluster randomized controlled trial in 22 renal clinics which aimed to assess the efficacy of a multimodal quality improvement intervention to increase compliance with guideline recommendations for prevention of chronic kidney disease (CKD) progression and cardiovascular (CV) complications. The trial aimed to test whether this multimodal intervention improved adherence to recommended targets for a series of surrogate indicators relevant to blood pressure (BP) control, sodium intake, proteinuria, dyslipidemia, anemia and calcium-phosphate alterations. The trial also tested whether the same intervention slowed CKD progression and prevented CV complications in CKD patients. METHOD: Twenty-two renal clinics were randomized to 2 arms: an intervention arm applying a multimethod quality improvement intervention and a control arm providing standard care. Surrogate indicators were measured to evaluate blood pressure (BP) control, sodium intake, proteinuria, dyslipidemia, anemia and calcium-phosphate alterations. RESULTS: Notwithstanding the fact that the vast majority of patients enrolled in this study (95%) were being treated with antihypertensive drugs, BP goals at baseline (specific for proteinuria level and diabetes) were met only in 45% of nonproteinuric patients and in just 14% and 18% of proteinuric and diabetic patients, respectively. The use of diuretics in hypertensive patients was less than what was needed, and about 80% of patients showed a salt excretion >100 mmol/24 hours. Total and low-density lipoprotein cholesterol levels were out of target in over 40% of patients, but only about 60% of these were on statins. A large majority of CKD patients were obese or overweight. The proportion of smokers was relatively small (13%), and 37% of patients had quit smoking, indicating patients' awareness of the health risks of smoking. CONCLUSIONS: In our cohort, management of modifiable risk factors for CKD progression and CV disease could be substantially improved.

Heart rate, age and the risk of progression to kidney failure in patients with CKD.

BACKGROUND AND METHODS: Since heart rate (HR) is a cardiovascular risk factor and a marker of sympathetic activity, we tested the predictive value of HR for progression to kidney failure in a well characterized cohort of 759 patients with stage 2-5 CKD followed up for 29 ± 11 months. RESULTS: Overall, a total of 244 patients had renal events. In an unadjusted analysis by age tertiles the predictive value of HR for renal events was apparent only in patients in the third age tertile (older than 68 years) but not in those in the first two tertiles indicating effect modification by age of the HR--progression to kidney failure relationship. In a multiple Cox regression model adjusting for potential confounders, a 5 beats/min increase in HR entailed a 16% risk excess (Hazard Ratio = 1.16, P = .004) for renal events in patients in the third age tertile but no excess risk for the same events in patients in the first two tertiles. A statistically significant interaction (P<.001) was also found between age and the risk for renal events associated with proteinuria. CONCLUSIONS: Heart rate is an independent age-dependent effect modifier for progression to kidney failure in CKD patients. This observation generates the hypothesis that high sympathetic activity is a relevant risk factor for adverse renal outcomes in elderly patients with CKD.

Pro-inflammatory cytokines and bone fractures in CKD patients. An exploratory single centre study.

BACKGROUND: Pro-inflammatory cytokines play a key role in bone remodeling. Inflammation is highly prevalent in CKD-5D patients, but the relationship between pro-inflammatory cytokines and fractures in CKD-5D patients is unclear. We studied the relationship between inflammatory cytokines and incident bone fractures in a cohort of CKD-5D patients. METHODS: In 100 CKD-5D patients (66 on HD, 34 on CAPD; males:63, females:37; mean age: 61 ± 15; median dialysis vintage: 43 months) belonging to a single renal Unit, we measured at enrolment bone metabolic parameters (intact PTH, bone and total alkaline phosphatase, calcium, phosphate) and inflammatory cytokines (TNF-α, IL-6, CRP). Patients were followed-up until the first non traumatic fracture. RESULTS: During follow-up (median: 74 months; range 0.5 -84.0) 18 patients experienced fractures. On categorical analysis these patients compared to those without fractures had significantly higher intact PTH (median: 319 pg/ml IQ range: 95-741 vs 135 pg/ml IQ: 53-346; p = 0.04) and TNF-α levels (median: 12 pg/ml IQ: 6.4-13.4 vs 7.8 pg/ml IQ: 4.6-11; p = 0.02). Both TNF-α (HR for 5 pg/ml increase in TNF-α: 1.62 95% CI: 1.05-2.50; p = 0.03) and intact PTH (HR for 100 pg/ml increase in PTH: 1.15 95% CI: 1.04-1.27; p = 0.005) predicted bone fractures on univariate Cox's regression analysis. In restricted (bivariate) models adjusting for previous fractures, age, sex and other risk factors both PTH and TNF-α maintained an independent association with incident fractures. CONCLUSIONS: In our bivariate analyses TNF-α was significantly associated with incident fractures. Analyses in larger cohorts and with adequate number of events are needed to firmly establish the TNF α -fracture link emerged in the present study.

Pulmonary congestion and physical functioning in peritoneal dialysis patients.

PURPOSE: Decline in physical function is commonly observed in patients with kidney failure on dialysis. Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical functioning of these patients has not been investigated. METHODS: In 51 peritoneal dialysis (PD) patients, we investigated the cross-sectional association between the physical functioning scale of the Kidney Disease Quality of Life Short Form (KDQOL-SF: Rand Corporation, Santa Monica, CA, USA) and an ultrasonographic measure of lung water recently validated in dialysis patients. The relationship between physical functioning and lung water was also analyzed taking into account the severity of dyspnea measured using the New York Heart Association (NYHA) classification currently used to grade the severity of heart failure. RESULTS: Evidence of moderate-to-severe lung congestion was evident in 20 patients, and this alteration was asymptomatic (that is, NHYHA class I) in 11 patients (55%). On univariate analysis, physical functioning was inversely associated with lung water (r = -0.48, p < 0.001), age (r = -0.44, p = 0.001), previous cardiovascular events (r = -0.46, p = 0.001), and fibrinogen (r = -0.34, p = 0.02). Physical functioning was directly associated with blood pressure, the strongest association being with diastolic blood pressure (r = 0.38, p = 0.006). The NYHA class correlated inversely with physical functioning (r = -0.51, p < 0.001). In multiple regression analysis, only lung water and fibrinogen remained independent correlates of physical functioning. The NYHA class failed to maintain its independent association. CONCLUSIONS: This cross-sectional study supports the hypothesis that symptomatic and asymptomatic lung congestion is a relevant factor in the poor physical functioning of patients on PD.

Chest ultrasound and hidden lung congestion in peritoneal dialysis patients.

BACKGROUND: Chest ultrasound (US) is a non-invasive well-validated technique for estimating extravascular lung water (LW) in patients with heart diseases and in end-stage renal disease. We systematically applied this technique to the whole peritoneal dialysis (PD) population of five dialysis units. METHODS: We studied the cross-sectional association between LW, echocardiographic parameters, clinical [pedal oedema, New York Heart Association (NYHA) class] and bioelectrical impedance analysis (BIA) markers of volume status in 88 PD patients. RESULTS: Moderate to severe lung congestion was evident in 41 (46%) patients. Ejection fraction was the echocardiographic parameter with the strongest independent association with LW (r = -0.40 P = 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r = 0.21 P = 0.05). Among patients with severe lung congestion, only 27% had pedal oedema and the majority (57%) had no dyspnoea (NYHA Class I). Similarly, the prevalence of patients with BIA, evidence of volume excess was small (11%) and not significantly different (P = 0.79) from that observed in patients with mild or no congestion (9%). CONCLUSIONS: In PD patients, LW by chest US reveals moderate to severe lung congestion in a significant proportion of asymptomatic patients. Intervention studies are necessary to prove the usefulness of chest US for optimizing the control of fluid excess in PD patients.

Visceral leishmaniasis reactivation in transplant patients: a minireview with report of a new case.

An updated review of cases of reactivated visceral leishmaniasis (VL) in transplant patients is presented, with a new report of a kidney transplant patient who had VL caused by reactivation of a dormant infection contracted 21 years previously. Close to the time of disease reactivation, the patient had a primary varicella-zoster infection.

Ranolazine can markedly increase tacrolimus blood levels.

We report the case of a renal transplant patient on tacrolimus who developed a fully reversible renal failure and a doubling in serum tacrolimus closely associated with initiation of ranolazine (Ranexa) treatment, a new anti-angina drug recently introduced in Europe.

Hypokalaemia with paralysis: don't forget the thyroid.

The authors report the case of a 33-year-old Italian man who had three episodes of hypokalaemia with paralysis linked to hyperthyroidism. Because of its low prevalence in western populations, the diagnosis of thyrotoxic hypokalaemic periodic paralysis can be easily missed in non-Asian countries.

Severe hyponatraemia during sepsis and marijuana addiction.

The authors report a 29-year-old kidney transplant patient who presented, four episodes of severe hyponatraemia associated with sepsis from 2006 to 2010. He was a long-term user of marijuana. The association between severe recurrent hyponatraemia during sepsis and marijuana addiction might not be casual, since experimental data show that vasopressin release induced by sepsis is modulated by the endocannabinoid system.

Noncardiogenic pulmonary edema induced by hydrochlorothiazide.

We report the case of a 74-year-old woman with pulmonary edema induced by hydrochlorothiazide. We missed the diagnosis in the first episode, and it was only upon unintentional hydrochlorothiazide rechallenge that we correctly identified the cause of the pulmonary edema.

Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis.

BACKGROUND: Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied. METHODS: We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free tri-iodothyronine (fT3) in a cohort of 41 CAPD patients (mean age, 66 years; M, 26; F, 15) without heart failure and inter-current illnesses. RESULTS: CAPD patients had lower fT3 levels (2.7 +/- 0.8 pg/ml) than healthy subjects (3.7 +/- 1.0 pg/ml, P < 0.001) of similar age. Free T3 levels were directly related to those of serum albumin (r = 0.52, P = 0.001) and inversely to IL-6 (r = -0.30, P = 0.05) and CRP (r = -0.54, P < 0.001). Age (r = -0.61, P < 0.001), haemoglobin levels (r = 0.32, P = 0.05) and diastolic blood pressure (r = 0.50, P = 0.001) were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3. During the follow-up (2.8 +/- 1.7 years) 27 patients died. Plasma fT3 levels were lower in patients who died (2.5 +/- 0.8 pg/ml) compared with survivors (3.3 +/- 0.5 pg/ml P = 0.001). In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors. CONCLUSIONS: The relationship between fT3, CRP and serum albumin suggests that inflammation-malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients.

Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections.

BACKGROUND AND METHODS: The endogenous inhibitor of nitric oxide synthase (NOs) asymmetrical dimethyl-arginine (ADMA) has been implicated as a possible modulator of inducible NOs during acute inflammation. We examined the evolution in the plasma concentration of ADMA measured at the clinical outset of acute inflammation and after its resolution in a series of 17 patients with acute bacterial infections. RESULTS: During the acute phase of inflammation/infection, patients displayed very high levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin and nitrotyrosine. Simultaneous plasma ADMA concentration was similar to that in healthy subjects while symmetric dimethyl-arginine (SDMA) levels were substantially increased and directly related with creatinine. When infection resolved, ADMA rose from 0.62 +/- 0.23 to 0.80 +/- 0.18 micromol/l (+29%, P = 0.01) while SDMA remained unmodified. ADMA changes were independent on concomitant risk factor changes and inversely related with baseline systolic and diastolic pressure. Changes in the ADMA/SDMA ratio were compatible with the hypothesis that inflammatory cytokines activate ADMA degradation. CONCLUSIONS: Resolution of acute inflammation is characterized by an increase in the plasma concentration of ADMA. The results imply that ADMA suppression may actually serve to stimulate NO synthesis or that in this situation plasma ADMA levels may not reflect the inhibitory potential of this methylarginine at the cellular level.

Fibrinogen and calcium x phosphate product are predictors of cardiovascular events in the CAPD population.

OBJECTIVE: Plasma fibrinogen (Fib) and calcium x phosphate product have emerged as cardiovascular (CV) event predictors in hemodialysis (HD) patients, but their role in peritoneal dialysis (PD) is less studied. DESIGN AND SUBJECTS: We investigated whether Fib and calcium x phosphate product predict CV events in a prospective cohort study of 47 continuous ambulatory PD (CAPD) patients (mean follow-up 34.6 months). RESULTS: During the follow-up, 29 patients experienced CV events, which were fatal in 11 of them. Plasma Fib was markedly elevated in the entire population studied (median 612 mg/dL inter-quartile range (IQ): 566-718 mg/dL). On univariate analysis, Fib was higher (p=0.02) in those patients who had fatal or non-fatal CV events (median 654 mg/dL, IQ: 577-801) than in event-free patients (median 579 mg/dL, IQ: 532-629). Patients with incident CV events also tended to have higher calcium x phosphate product (51.6 +/- 12.8 vs. 43.8 +/- 13.9 mg2/dL2, p=0.06). On multivariate Cox's regression analyses, including traditional risk factors and history of previous CV events, Fib (hazard ratio (HR) associated with 100 mg/dL increase in plasma Fib 1.29 95% confidence interval (CI) 1.03-1.63 (p=0.03)) and calcium x phosphate product (HR associated with a 5 mg2/dL2 increase 1.25 95% CI 1.05-1.49 (p=0.01)) emerged as independent CV event predictors. CONCLUSIONS: Calcium x phosphate product and Fib are CV event predictors in CAPD patients.

Clinical epidemiology of major nontraditional risk factors in peritoneal dialysis patients.

BACKGROUND: End-stage renal disease (ESRD) is a situation with a cardiovascular (CV) risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, in chronic kidney disease (CKD), nontraditional risk factors play an increasingly important role, being perhaps dominant in ESRD patients. OBJECTIVE: We review the role inflammation [C-reactive protein (CRP)], hyperhomocysteinemia, high plasma norepinephrine, and accumulation of the endogenous inhibitor of the nitric oxide synthase asymmetric dimethylarginine (ADMA) in the high all-cause and CV mortality of patients on continuous ambulatory peritoneal dialysis (CAPD). RESULTS: The association between CRP and clinical outcomes in patients on peritoneal dialysis (PD) was examined in six studies totaling 692 subjects. The largest of these studies in Caucasians indicates that the independent risk of CV events in patients in the top CRP quartile is about five times higher than in the bottom quartile. Seven prospective studies, including over 1000 hemodialysis and 176 CAPD patients, reported both positive and negative associations between homocysteine and mortality and/or CV events. Because homocysteine circulates bound to albumin, negative associations--rather than negating the vasculotoxicity of homocysteine--most likely reflect the very deleterious effects of malnutrition. Plasma norepinephrine is higher in CAPD than in hemodialysis patients, and multivariate analyses suggest the difference quantitatively entails a 16% higher risk of incident CV events. Likewise, ADMA is more elevated in CAPD patients and such an elevation corresponds to a 15% increase in risk. CONCLUSION: Nontraditional risk factors are far more prevalent in ESRD patients than in the general population. ADMA and norepinephrine may play a greater role in CV risk in CAPD than in hemodialysis patients.

Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients.

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.