Maarten W. Taal

Progressive Vascular Calcification over 2 Years Is Associated with Arterial Stiffening and Increased Mortality in Patients with Stages 4 and 5 Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Vascular calcification is increasingly recognized as an important component of cardiovascular disease in chronic kidney disease. The objective of this study was to investigate prospectively the determinants, cardiovascular functional consequences, and survival associated with vascular calcification over 24 mo. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 134 patients (60 on hemodialysis, 28 on peritoneal dialysis, and 46 with stage 4 chronic kidney disease) were studied. Vascular calcification of the superficial femoral artery was assessed using multislice spiral computed tomography; pulse wave velocity; all medications and time-averaged biochemical parameters were recorded at baseline and 12 and 24 mo. RESULTS A total of 101 patients remained at 24 mo. Progressive calcification was seen in 58 of 101 patients. Most (31 of 46) patients with an initial calcification score of zero did not develop calcification. The hemodialysis group demonstrated a greater degree of progression than patients who were on peritoneal dialysis or had stage 4 chronic kidney disease. Progressive calcification was associated with age, male gender, serum alkaline phosphatase, beta blockers, and lipid-lowering agents. Increases in vascular calcification correlated with increased arterial stiffness. Vascular calcification was present in 20 of 21 patients who died. Cox proportional hazard analysis identified change in calcification score, calcium intake from phosphate binders, and low albumin as risk factors for death. CONCLUSIONS Patients with stages 4 and 5 chronic kidney disease and preexisting vascular calcification exhibit significantly increased calcification over 24 mo. Rapid progression of calcification is associated with arterial stiffness and mortality.

Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation

BackgroundDonor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation. Methods and ResultsFunctioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean±SD, 9.3±0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6±0.7 days, P =0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls. ConclusionsDonor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.

A Meta-analysis of Hemodialysis Catheter Locking Solutions in the Prevention of Catheter-Related Infection

BACKGROUND Catheter-related infection (CRI) is associated with increased all-cause mortality and morbidity in hemodialysis patients and may be reduced by using antimicrobial lock solutions (ALSs). STUDY DESIGN We performed a meta-analysis of studies identified from a search conducted in February 2007 of the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, databases of ongoing trials, major renal journals, and reference lists of relevant reports. SETTING & POPULATION Patients receiving acute or long-term hemodialysis through a tunneled or nontunneled central venous catheter. SELECTION CRITERIA FOR STUDIES We included all prospective randomized studies that compared ALS with heparin. INTERVENTION Administration of antibiotic and/or antimicrobial catheter locking solution. OUTCOME MEASURES Primary outcome was CRI rate in patients using ALSs compared with those using heparin alone. We also examined effects of ALS use on mortality, adverse events, and catheter thrombosis. RESULTS 7 studies were identified with a total of 624 patients and 819 catheters (448 tunneled, 371 nontunneled). CRI was 7.72 (95% confidence interval, 5.11 to 10.33) times less likely when using ALS. There were no consistent suggestions of adverse outcomes with ALS use; in particular, rates of catheter thrombosis did not increase. There was no evidence of antibiotic resistance developing during a maximum follow-up of 12 months. LIMITATIONS The major limitation of this review is the relatively short duration of follow-up of the included studies, which does not allow complete reassurance regarding the development of antibiotic resistance. Lack of direct comparisons means that determination of the most efficient ALS is not possible. CONCLUSIONS This review confirms that antibiotic locking solutions reduce the frequency of CRI without significant side effects.

Renal risk scores: Progress and prospects

Worldwide adoption of the Kidney Disease Outcomes Quality Initiative classification for chronic kidney disease (CKD) and widespread use of the estimated glomerular filtration rate to assess renal function have identified large numbers of patients with previously undiagnosed CKD. It is clear, however, that this is a heterogeneous group and that only a small minority of such patients ever progress to end-stage renal disease. There is thus an urgent need for a simple method of risk assessment that can be applied to all patients with CKD to identify those few at greatest risk. The magnitude of baseline proteinuria has long been recognized as an important predictor of renal prognosis. Furthermore, several studies have found that change in proteinuria after initiation of antihypertensive treatment as well as achieved level of proteinuria correlate with prognosis. Thus, proteinuria has emerged as the single most important marker of renal risk. Many other factors have been identified as risk factors for CKD progression. Several attempts have been made to combine a relatively small number of risk factors into a risk score to predict renal outcomes in specific groups of patients. Validation of these risk scores as well as further studies are now required to develop a renal risk score applicable to a more general population of patients with CKD. Similar methodology could be applied to assess the important issue of the cardiovascular risk associated with CKD.

Prevalence and associations of limited health literacy in chronic kidney disease: a systematic review

BACKGROUND Health literacy (HL) is important in chronic disease. This review aimed to evaluate the literature evidence on prevalence and associations of limited HL in chronic kidney disease (CKD). METHODS Seven databases were searched using terms for CKD and HL. Studies were included that ascertained the prevalence of limited HL using a validated tool in adults with CKD of any stage. The primary outcome was an objectively measured prevalence of limited HL in a population with CKD. The secondary outcome was associations of limited HL. Two reviewers assessed study inclusion and quality. Prevalence values were combined using a random-effect model to give overall prevalence. RESULTS Eighty-two studies were identified from searching, of which six met the inclusion criteria. The total number of people in all studies was 1405. Five studies were in dialysis or transplant populations, and all were from the USA. There was a significant heterogeneity in the prevalence of limited HL [9-32% (median 25%, inter-quartile range 16%)]. The pooled prevalence of limited HL in all studies was 22.7% (95% confidence interval 20.6-24.8%), but study heterogeneity limited the generalizability of this combined prevalence. The review identified associations between limited HL and socio-economic factors (lower education attainment, lower income), and certain process and outcome measures (lower likelihood of referral for transplant, higher mortality). CONCLUSIONS Limited HL is common among people with CKD and independently associated with socio-economic factors and health outcomes. It may represent an important determinant of inequality in CKD.

Markers of arterial stiffness are risk factors for progression to end-stage renal disease among patients with chronic kidney disease stages 4 and 5.

Background: Factors associated with chronic kidney disease (CKD) contribute to an increased risk of cardiovascular disease and death. The impact of vascular disease on CKD progression is, however, less well studied. Methods: We examined the effect of markers of vascular disease on the risk of progression to end-stage renal disease (ESRD) in 35 patients with CKD stages 4–5. Superficial femoral artery calcification was assessed by CT scan. Augmentation index (AI) and pulse wave velocity (PWV) were measured by applanation tonometry. Results: After 12.4 (5.5–28.4) months, 22/35 patients (63%) had commenced dialysis. Cox regression analysis identified baseline estimated glomerular filtration rate (hazard ratio, HR, 0.54; 95% CI 0.41–0.70; p < 0.0001), urinary protein (HR 1.84; 95% CI 1.32–2.58; p = 0.0005), PWV (HR 1.30; 95% CI 1.07–1.60; p = 0.01), AI (HR 1.08; 95% CI 1.04–1.14; p = 0.0001) and pack years of smoking (HR 1.01; 95% CI 1.00–1.03; p = 0.02) as independent risk factors for time to ESRD (–2 log likelihood = 86.7; χ2 = 30.9; p < 0.0001). Repeat analysis using AI as a categorical variable revealed an HR of 17.5 (95% CI 4.43–68.9; p < 0.0001) for time to ESRD in those with AI above versus below the median. Conclusions: We have identified two markers of arterial stiffness as independent risk factors for progression to ESRD suggesting that vascular disease may contribute to CKD progression.

Skin Autofluorescence and the Association with Renal and Cardiovascular Risk Factors in Chronic Kidney Disease Stage 3

BACKGROUND AND OBJECTIVES Tissue advanced glycation end products (AGE) accumulation is a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluorescence (SAF) correlates well with cardiovascular (CV) outcomes in diabetic, transplant, and dialysis patients, and may be a useful marker of CV risk in earlier stages of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 1707 patients with estimated GFR 59 to 30 ml/min per 1.73 m(2) were recruited from primary care practices for the Renal Risk In Derby (RRID) study. Detailed medical history was obtained, and each participant underwent clinical assessment as well as urine and serum biochemistry tests. SAF was assessed (mean of three readings) as a measure of skin AGE deposition using a cutaneous AF device (AGE Reader™, DiagnOptics, Groningen, The Netherlands). RESULTS Univariate analysis revealed significant correlations between AF readings and several potential risk factors for cardiovascular disease (CVD) and progression of CKD. SAF readings (arbitrary units) were also significantly higher among males (2.8 ± 0.7 versus 2.7 ± 0.6), diabetics (3.0 ± 0.7 versus 2.7 ± 0.6), patients with evidence of self-reported CVD (2.9 ± 0.7 versus 2.7 ± 0.6), and those with no formal educational qualifications (2.8 ± 0.6 versus 2.6 ± 0.6; P < 0.01 for all). Multivariable linear regression analysis identified hemoglobin, diabetes, age, and eGFR as the most significant independent determinants of higher SAF (standardized coefficients -0.16, 0.13, 0.12, and -0.10, respectively; R(2) = 0.17 for equation). CONCLUSION Increased SAF is independently associated with multiple CV and renal risk factors in CKD 3. Long-term follow-up will assess the value of SAF as a predictor of CV and renal risk in this population.

Online conductivity monitoring: Validation and usefulness in a clinical trial of reduced dialysate conductivity

Relatively low dialysate conductivity (Cndi) may improve outcomes by reducing the overall sodium burden in dialysis patients. Excess sodium removal, however, could lead to hemodynamic instability. We performed a randomized controlled trial of reduction of Cndi. For the study, 28 patients were randomized to maintenance of Cndi at 13.6 mS/cm (equivalent to 135 mmol/L of Na+) or serial reduction of Cndi in steps of 0.2 mS/cm, guided by symptoms and blood pressure. Sodium removal estimated from pre- and postplasma concentrations correlated well with removal measured by conductivity monitoring as ionic mass balance (R2 0.66, p < 0.0001). Of the 16 patients randomized to reduction of Cndi, 6 achieved Cndi 13.4 mS/cm, 6 achieved 13.2 mS/cm, and 4 achieved 13.0 mS/cm. No episodes of disequilibrium occurred. Interdialytic weight gain was reduced from 2.34 ± 0.10 kg to 1.57 ± 0.11 kg (p < 0.0001). Predialysis systolic blood pressure fell from 144 ± 3 mm Hg to 137 ± 4 mm Hg (p < 0.05). The reduction in convective sodium removal was balanced by an increase in diffusive sodium removal (95 ± 9 mmol cf. 175 ± 14 mmol, p < 0.0001). Reduction in Cndi monitored by IMB is safe and practical and leads to improved interdialytic weight gains and blood pressure control, while avoiding excessive sodium removal.

Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor.

Although considerable improvement in the prognosis of diabetic nephropathy has been achieved in recent years due to intensive insulin and angiotensin-converting enzyme inhibitor treatment, these approaches do not provide complete protection against progression of diabetic nephropathy. An urgent need for additional novel therapies to prevent or further slow the progression of diabetic nephropathy motivated us to provide an up-to-date review with particular emphasis on the potential role of two growth factors - transforming growth factor-β and connective tissue growth factor - in the pathogenesis of diabetic nephropathy. The most intensively studied to date, transforming growth factor-β appears to play a central role in the pathogenesis of diabetic nephropathy. Recently, attention has focused on connective tissue growth factor, which mimics the biological activity of transforming growth factor-β in profibrotic tissue formation. Thus, acting as a downstream mediator of the profibrotic activity of transforming growth factor-β, connective tissue growth factor may constitute a more specific target for future antifibrotic therapies.

Tissue-Advanced Glycation End Product Concentration in Dialysis Patients

BACKGROUND AND OBJECTIVES Tissue-advanced glycation end products (AGE) are a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluoresence (AF) correlates well with cardiovascular outcomes in hemodialysis (HD) patients. This study aimed to measure and compare tissue AGE levels in HD and peritoneal dialysis (PD) patients and to evaluate the impact of systemic PD glucose exposure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Tissue AGE were measured in 115 established dialysis patients (62 HD and 53 PD) using a cutaneous AF device (AGE Reader; DiagnOptics). Values were compared with an age-matched non-chronic kidney disease database. Review of all previous PD solution delivery/prescription data determined PD glucose exposure. RESULTS PD patients were similar in age to HD patients but had a shorter dialysis vintage. There were no differences in ischemic heart disease or smoking history, statin or angiotensin-converting enzyme inhibitor (ACEi) use, lipids, biochemistry, or prevalence of diabetes. More than 90% of both groups had met current dialysis adequacy targets. Skin AF values in PD and HD patients were similar and strongly correlated with historical PD glucose exposure. Skin AF correlated with age in both groups but with dialysis vintage only in PD patients CONCLUSIONS Cumulative metabolic stress and transient hyperglycemia results in grossly elevated levels of tissue AGE in dialysis patients. In PD patients, this high level of AGE deposition is associated with historical glucose exposure. This observation provides a previously unappreciated potential link between PD exposure to glucose and systemic cardiovascular disease.