Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: the VitaVasK randomized controlled trial.

Background: Cardiovascular calcifications are prevented by matrix Gla protein (MGP), a vitamin K-dependent protein. Haemodialysis patients exhibit marked vitamin K deficiency. The randomized, prospective, open-label, multicentre VitaVasK trial analysed whether vitamin K1 supplementation reduces progression of coronary artery calcifications (CACs) and thoracic aortic calcifications (TACs). Methods: Patients with pre-existing CACs were randomized to continue on standard care or to additionally receive 5 mg of vitamin K1 orally thrice weekly. Hierarchically ordered primary endpoints were progression of TAC and CAC in computed tomography scans at 18 months. Linear mixed effects models with repeated measures at baseline and 12 and 18 months assessed treatment effects after adjusting for study site. Results: Of 60 randomized patients, 20 dropped out for reasons unrelated to vitamin K1, resulting in 23 control and 17 vitamin K1 patients. The trial was stopped early due to slow recruitment. At 18 months, the average TAC progression was 56% lower in the vitamin K1 compared with the control group (p = .039). CAC significantly progressed within the control group, but not within the vitamin K1 group. Average progression at 18 months was 68% lower in the vitamin K1 compared to the control group (P = .072). Vitamin K1 reduced plasma levels of pro-calcific uncarboxylated MGP by 69% at 18 months. No treatment-related adverse events were noted. Conclusion: Vitamin K1 intervention is a potent, safe and cost-effective approach to correct vitamin K deficiency and to potentially reduce cardiovascular calcification in this high-risk population.

Hospital-acquired acute kidney injury: a proposed patient safety indicator.

Patient safety, which includes adverse event reporting and routine collection of outcome measures, has become an increasingly important aspect of inpatient care worldwide. In the United States, the National Quality Forum leads the effort in developing such measures for use in payment and public reporting programs. However, choosing and prioritizing events to serve as patient safety indicators is difficult in a dynamically changing and complex healthcare environment. In this perspective, we propose that hospital-acquired acute kidney injury (HA-AKI), for example, contrast-induced and postoperative AKI, should be added to existing, more traditional measures, such as surgical site infections and patient falls. The article highlights the significance of HA-AKI as a common complication resulting from a multitude of diagnostic and therapeutic procedures, how it lends itself well to measuring patient safety, and how reporting of this complication can contribute to further improvement of patient safety and overall quality of care.

Severe symptomatic hyponatremia due to cerebral salt wasting syndrome in a patient with traumatic head injury and Dandy-Walker malformation of the brain.

Cerebral salt wasting (CSW) is an uncommon cause of hyponatremia characterized by extracellular volume depletion, high urine sodium concentration and osmolality, and low serum uric acid concentration in association with central nervous system (CNS) disease. Distinguishing CSW from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a much more common form of hyponatremia in this setting, can be challenging because both present with identical laboratory features. However, treatment of CSW and SIADH differs, making a correct diagnosis important. Here we present a case of CSW in a 75-year-old man in whom severe hyponatremia and volume depletion were discovered in the setting of traumatic head injury and Dandy-Walker malformation of the brain, a rare congenital brain malformation. Treatment with intravenous normal saline and later oral salt supplementation and fludrocortisone was successful.

Bone Biopsy Results in Chronic Kidney Disease: a Single-Center Experience.

BACKGROUND/AIMS: Although bone histology remains the diagnostic standard in renal osteodystrophy (ROD), biomarkers are used more commonly. Data comparing bone biopsy results and biomarkers of bone metabolism remain sparse. METHODS: This is a single-center retrospective analysis of bone biopsy results (105) stratified by renal function, compared with intact parathyroid hormone (iPTH), bone-specific alkaline phosphatase (BAP) and other biomarkers. We tested associations with high-turnover ostitis fibrosa (OF) and mixed uremic osteodystrophy (MUO), i.e. classes I and III according to Delling's classification. RESULTS: 37% of patients had CKD stage 3-5 not on dialysis (CKD NOD) and 50% CKD stage 5 requiring haemodialysis (CKD 5D). iPTH was significantly higher in CKD 5D with high-turnover ROD, 26 (18) versus 8 (9) pmol/l (p< 0.001). BAP showed no association. In CKD NOD, high-turnover ROD was associated with elevated iPTH, 32 (44) versus 8 (11) pmol/l (p=0.001), and BAP, 39 (32) versus 16 (7) U/l (p=0.01). iPTH achieved receiver operator characteristic (ROC) areas under the curve (AUC) of 0.83 (P=0.003) and 0.91 (P=0.019) for high-turnover ROD among CKD 5D and CKD NOD patients, respectively. An iPTH cutoff of 12.8 (CKD 5D) and 13.5 pmol/l (CKD NOD) reached sensitivities and specificities of 0.83, 0.91 and 1.00, 0.91, respectively. In CKD NOD, BAP achieved an AUC of 0.93 (P=0.013) and with a cutoff at 19.8 U/l a sensitivity and specificity of 1.00, 0.91, respectively. CONCLUSION: In CKD 5D patients, high-turnover ROD was associated with elevated iPTH at a low cutoff but not with BAP. The same diagnosis in CKD NOD was associated both with iPTH and BAP.

Association of Preoperative Urinary Uromodulin with AKI after Cardiac Surgery.

BACKGROUND AND OBJECTIVES: AKI is a serious complication after cardiac surgery. Although high urinary concentrations of the tubular protein uromodulin, a marker of tubular health, are associated with less AKI in animal models, its relationship in humans is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis of a prospective cohort study of 218 adults undergoing on-pump cardiac surgery between 2004 and 2011 was conducted. Multivariable logistic and linear regression analyses were used to evaluate the associations of preoperative urinary uromodulin-to-creatinine ratio with postoperative AKI (defined as a rise in serum creatinine of >0.3 mg/dl or >1.5 times baseline); severe AKI (doubling of creatinine or need for dialysis) and peak postoperative serum creatinine over the first 72 hours. RESULTS: Mean age was 68 years, 27% were women, 95% were white, and the median uromodulin-to-creatinine ratio was 10.0 µg/g. AKI developed in 64 (29%) patients. Lower urinary uromodulin-to-creatinine ratio was associated with higher odds for AKI (odds ratio, 1.49 per 1-SD lower uromodulin; 95% confidence interval, 1.04 to 2.13), which was marginally attenuated after multivariable adjustment (odds ratio, 1.43; 95% confidence interval, 0.99 to 2.07). The lowest uromodulin-to-creatinine ratio quartile was also associated with higher odds for AKI relative to the highest quartile (odds ratio, 2.94; 95% confidence interval, 1.19 to 7.26), which was slightly attenuated after multivariable adjustment (odds ratio, 2.43; 95% confidence interval, 0.91 to 6.48). A uromodulin-to-creatinine ratio below the median was associated with higher adjusted odds for severe AKI, although this did not reach statistical significance (odds ratio, 4.03; 95% confidence interval, 0.87 to 18.70). Each 1-SD lower uromodulin-to-creatinine ratio was associated with a higher adjusted mean peak serum creatinine (0.07 mg/dl per SD; 95% confidence interval, 0.02 to 0.13). CONCLUSIONS: Lower uromodulin-to-creatinine ratio is associated with higher odds of AKI and higher peak serum creatinine after cardiac surgery. Additional studies are needed to confirm these preliminary results.

Treating hyperphosphatemia - current and advancing drugs.

INTRODUCTION: Hyperphosphatemia is a hallmark of advanced chronic kidney disease (CKD) and associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causal relationship between hyperphosphatemia and mortality as well as cardiovascular complications, especially including vascular, valvular and soft-tissue calcifications. Thus, appropriate phosphate lowering is considered to play a major role in health and longevity of CKD patients. In this respect, phosphate binders are the most powerful therapeutic option, while dietary phosphate restriction and intensified dialysis are valuable supportive approaches. AREAS COVERED: Pubmed was the primary research platform. This search focused on novel phosphate lowering compounds, including iron-containing binders and phosphate transport inhibitors, which have just become available or are in the approval process. Further, additional reports on effective strategies to counteract the adverse consequences of resistant hyperphosphatemia were also collected. EXPERT OPINION: New iron-containing drugs may offer advantages, including iron supplementation, low pill burden and high efficacy. Phosphate transport inhibitors possess a high potential as add-on compounds in patients with insufficient phosphate binder therapy. One unsolved question remains at what CKD stage to start therapeutically counteracting phosphate retention.

Atypical case of AL amyloidosis with urinary erythrocyte casts.

We present the case of a 73-year-old man who developed an acute, severe febrile illness with multiorgan dysfunction, featuring renal failure, nephrotic-range proteinuria, microhematuria, and a skin rash. Numerous erythrocyte casts were found on urine microscopy. Typically, the finding of urinary erythrocyte casts indicates the presence of an underlying glomerular inflammatory disease. However, on renal biopsy, only amyloid light-chain (AL) amyloidosis and tubular injury were the predominant findings with no signs of glomerular or vascular inflammation. Photomicrographs of urinary sediment as well as renal biopsy histopathology of the presented case are shown. The unusual combination of findings, is then discussed in light of the existing literature on renal amyloidosis as well as erythrocyte casts in conditions other than glomerulonephritis.

Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury.

BACKGROUND: Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). METHODS: We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, α-GST, and π-GST) markers, in 262 hospitalized adults. RESULTS: In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM-1 level (p = 0.03), and the AA genotype group tended to have a higher urinary π-GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. CONCLUSIONS: The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships.

Urinary α- and π-glutathione s-transferases for early detection of acute kidney injury following cardiopulmonary bypass.

CONTEXT: Urinary α-GST and π-GST are renal tubular leakage markers. OBJECTIVE: To evaluate the performance characteristics of these markers for the early detection of acute kidney injury (AKI). MATERIALS AND METHODS: Multicenter prospective cohort study of 252 adults undergoing cardiopulmonary bypass (CPB). RESULTS: AKI developed in 72 patients. The 2 h post-CPB π-GST level modestly predicted the development of AKI, including higher stages of severity, whereas α-GST did not. DISCUSSION: Small number of events and absence of subsequent post-operative biomarker measurements. CONCLUSIONS: Among adults undergoing CPB, urinary π-GST outperformed α-GST for predicting AKI, but neither marker displayed good discrimination.

FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease.

For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.

Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury-related outcomes.

Myeloperoxidase (MPO) is a lysosomal enzyme that may be involved in oxidative stress-mediated kidney injury. Using a two-step approach, we measured the association of four polymorphisms across the length of the MPO gene with systemic markers of oxidative stress: plasma MPO and urinary 15-F(2t)-isoprostane levels. Adverse outcomes were measured in a primary cohort of 262 adults hospitalized with acute kidney injury, and a secondary cohort of 277 adults undergoing cardiac surgery with cardiopulmonary bypass and at risk for postoperative acute kidney injury. Dominant and haplotype multivariable logistic regression analyses found a genotype-phenotype association in the primary cohort between rs2243828, rs7208693, rs2071409, and rs2759 MPO polymorphisms and both markers of oxidative stress. In adjusted analyses, all four polymorphic allele groups had 2-3-fold higher odds for composite outcomes of dialysis or in-hospital death or a composite of dialysis, assisted mechanical ventilation, or in-hospital death. The MPO T-G-A-T haplotype copy-number was associated with lower plasma MPO levels and lower adjusted odds for the composite outcomes. Significant but less consistent associations were found in the secondary cohort. In summary, our two-step genetic association study identified several polymorphisms spanning the entire MPO gene locus and a common haplotype marker for patients at risk for acute kidney injury.

Urinary α-GST and π-GST for prediction of dialysis requirement or in-hospital death in established acute kidney injury.

CONTEXT: Urinary α-glutathione S-transferase (α-GST) and π-glutathione S-transferase (π-GST) are promising proximal and distal tubular leakage markers for early detection of acute kidney injury (AKI). OBJECTIVE: To examine the performance of these markers for predicting the composite of dialysis requirement or in-hospital death in patients with an established diagnosis of AKI. MATERIALS AND METHODS: Prospective cohort study of 245 adults with AKI. A single urinary α-GST and π-GST measurement was obtained at time of nephrology consultation. RESULTS: Overall, urinary π-GST performed better than α-GST for prediction of dialysis requirement (AUC 0.59 vs. 0.56), and the composite outcome (AUC 0.58 vs. 0.56). In subgroup analyses, π-GST displayed better discrimination for prediction of dialysis requirement in patients with baseline eGFR <60 mL/min/1.73 m(2) (AUC 0.61) and oliguria (AUC 0.72). Similarly, α-GST performed better in patients with stage-1 (AUC 0.66) and stage-2 AKI (AUC 0.80). CONCLUSIONS: In patients with an established diagnosis of AKI, a single urinary π-GST measurement performed better than α-GST at predicting dialysis requirement or death, but neither marker had good prognostic discrimination.

Hospital-acquired acute kidney injury: an analysis of nadir-to-peak serum creatinine increments stratified by baseline estimated GFR.

BACKGROUND AND OBJECTIVES: Serum creatinine (sCr) increments currently used to define acute kidney injury (AKI) do not take into consideration the baseline level of kidney function. The objective of this study was to establish whether baseline estimated GFR (eGFR) provides additional risk stratification to sCr-based increments for defining AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 29,645 adults hospitalized at an acute care facility were analyzed. Hospital-acquired AKI was defined by calculating the difference between the nadir and subsequent peak sCr. RESULTS: Different thresholds of nadir-to-peak sCr were found to be independently associated with increased in-hospital mortality according to baseline eGFR strata. A nadir-to-peak sCr minimum threshold of ≥0.2, ≥0.3, and ≥0.5 mg/dl was required to be independently associated with increased in-hospital mortality among patients with baseline eGFR ≥60 ml/min per 1.73 m² (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.13 to 2.47), 30 to 59 ml/min per 1.73 m² (OR 2.69; 95% CI, 1.82 to 3.97), and <30 ml/min per 1.73 m² (OR 2.15; 95% CI 1.02 to 4.51), respectively. There was a significant interaction between the nadir-to-peak sCr and baseline eGFR for in-hospital mortality (P < 0.001). Using these thresholds, survivors of AKI episodes had an increased hospital length of stay and were more likely to be discharged to a facility rather than home. Sensitivity analyses showed a significant interaction between baseline eGFR strata and relative increases in sCr, as well as absolute and relative decreases in eGFR for in-hospital mortality (P < 0.001). Conclusions This study suggests that future sCr-based definitions of AKI should take into consideration baseline eGFR.

Vitamin D, chronic kidney disease and survival: a pluripotent hormone or just another bone drug?

It is now about 40 years ago that the mechanism of renal 1-α-hydroxylation of vitamin D was discovered and characterized. After this seminal observation, the key role of the active vitamin D derivative 1, 25-(OH)2-vitamin D (calcitriol) in calcium homeostasis and bone mineralization, and its specific role in the course of chronic kidney disease (CKD) and renal osteopathy, was unraveled step by step, while the precursor 25-OH-vitamin D (calcidiol) was gradually ignored. Calcitriol and its synthetic analogue alfa-calcidol became the first-line standard drug to tackle secondary hyperparathyroidism (sHPT) in CKD. Potential side-effects, including hypercalcemia, hyperphosphatemia, and vascular calcification, were partly abrogated by developing less calcemic substances such as paricalcitol or maxacalcitol. Thus, TIME Magazine surprised when nominating vitamin D, with regard to its newly discovered pleiotropic actions, as one of the "top medical breakthroughs" in the December issue of 2007. This vote was driven by novel and spectacular insights into the pivotal regulatory role of vitamin D with regard to autoimmune diseases, immune defense, cancer development and progression, and cardiovascular function and disease. More than 30 cell types express the vitamin D receptor (VDR), and more than ten organs in addition to the kidney are capable of paracrine 1-α-hydroxylation. More than 200 genes are under the control of calcitriol. A MEDLINE search performed in December 2009 focusing on the keywords "vitamin D-and-kidney-and-2009" yielded 523 hits. This review intends to give a subjective and CKD-related update on novel biological and clinical insights with relevance to the steroid hormone vitamin D.

CYBA Gene Polymorphisms and Adverse Outcomes in Acute Kidney Injury: A Prospective Cohort Study.

BACKGROUND: NADPH oxidase is an important enzyme involved in the generation of reactive oxygen species in acute kidney injury (AKI). Its key subunit, p22(phox), is encoded by the highly polymorphic CYBA gene. METHODS: We examined the associations of CYBA gene polymorphisms across the CYBA locus (rs8854, rs3794624, rs4673, rs4782390, and rs1049255) with dialysis requirement or in-hospital death in 256 hospitalized adults with AKI. Dominant and haplotype multivariable logistic regression analyses were performed, adjusted for sex, race, age, and severity of illness. RESULTS: The baseline characteristics of the patients were not different among genotype groups with the exception of a lower prevalence of sepsis and shock in the CYBA rs8854 A-allele group; a higher prevalence of shock in the CYBA rs4782390 T-allele group, and a higher APACHE II score in the CYBA rs1049255 G-allele group. The CYBA rs8854 A-allele had an adjusted odds ratio (OR) of 0.41 (95% confidence interval, CI, 0.18-0.96) for the outcome of dialysis requirement or in-hospital death. The CYBA rs4673 T-allele and rs1049255 G-allele had unadjusted ORs of 1.69 (95% CI 1.03-2.79) and 1.66 (95% CI 1.01-2.73) for the composite outcome, respectively, which became non-significant after multivariable adjustment. The remaining 2 polymorphisms were not associated with the outcomes of interest. Finally, the presence of the CYBA A-A-G-G haplotype (generated from rs4782390, rs4673, rs3794624, and rs8854, all in Hardy-Weinberg equilibrium) was associated with an elevated OR of 1.81 (95% CI 1.07-3.08) for dialysis requirement or in-hospital death, which was attenuated after multivariable adjustment (OR 1.80; 95% CI 0.99-3.29). CONCLUSION: This study identifies several polymorphisms spanning the entire CYBA gene locus and a common haplotype as risk markers for dialysis requirement or in-hospital death in patients with AKI. Additional studies are needed to validate these findings.

Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CS/CPB) is associated with increased risk for postoperative complications causing substantial morbidity and mortality. To identify the molecular mechanisms underlying CS/CPB-induced pathophysiology we employed an integrative systems biology approach using the whole blood transcriptome as the sentinel organ. METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was isolated and globin mRNA depleted from whole blood samples prospectively collected from 10 patients at time points prior (0), 2 and 24 hours following CS/CPB. Genome-wide transcriptional analysis revealed differential expression of 610 genes after CS/CPB (p<0.01). Among the 375 CS/CPB-upregulated genes, we found a gene-regulatory network consisting of 50 genes, reminiscent of activation of a coordinated genetic program triggered by CS/CPB. Intriguingly, the highly connected hub nodes of the identified network included key sensors of ischemia-reperfusion (HIF-1alpha and C/EBPbeta). Activation of this network initiated a concerted inflammatory response via upregulation of TLR-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, HGF/HGFR, CalgranulinA/B, and coagulation factors F5/F12 among others. Differential regulation of 13 candidate genes including novel, not hitherto CS/CBP-associated genes, such as PTX3, PGK1 and Resistin, was confirmed using real-time quantitative RT-PCR. In support of the mRNA data, differential expression of MMP9, MIP1alpha and MIP1beta plasma proteins was further confirmed in 34 additional patients. CONCLUSIONS: Analysis of blood transcriptome uncovered critical signaling pathways governing the CS/CPB-induced pathophysiology. The molecular signaling underlying ischemia reperfusion and inflammatory response is highly intertwined and includes pro-inflammatory as well as cardioprotective elements. The herein identified candidate genes and pathways may provide promising prognostic biomarker and therapeutic targets.

Plasma cystatin C and acute kidney injury after cardiopulmonary bypass.

BACKGROUND AND OBJECTIVES: Little is known about the performance of plasma cystatin C (CysC) in patients undergoing cardiopulmonary bypass (CPB) and its utility in the early diagnosis of acute kidney injury (AKI). In this post hoc analysis, the goal was to determine whether plasma cystatin C, measured 2 hours after the conclusion of CPB, is a reliable marker of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma CysC was measured in 150 patients undergoing CPB at the following times: preoperatively, 2 hours after the conclusion of CPB, postoperative day 1, and postoperative day 2. Plasma CysC levels were related to the development of AKI as defined by an increase in serum creatinine of >or=50% or >or=0.3 mg/dl from baseline up to 3 days postoperative. Mixed linear models were used to evaluate the relationship of serial plasma CysC values with AKI. The discriminatory capacity of plasma CysC was estimated using receiver operating characteristic curves. Logistic regression was utilized to assess the adjusted relationship between plasma CysC and subsequent AKI. RESULTS: AKI developed in 47 (31.3%) patients. Plasma CysC was higher at all times among patients who developed AKI compared with those who did not (P < 0.0001). The discriminatory capacity of plasma CysC measured preoperatively and 2 hours after the conclusion of CPB was modest. CONCLUSIONS: Serial measures of plasma CysC are highly correlated with the development of AKI. However, the discriminatory capacity of plasma CysC as an early marker of AKI remains limited.

Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case-control pilot study.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality. OBJECTIVE: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB. METHODS: In a nested case-control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls. RESULTS: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1beta, 2 h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1alpha, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI. CONCLUSION: Biomarkers associated with AKI following CPB may merit further study.

Effect of intra-dialytic, low-intensity strength training on functional capacity in adult haemodialysis patients: a randomized pilot trial.

BACKGROUND: Kidney failure is associated with muscle wasting and physical impairment. Moderate- to high-intensity strength training improves physical performance, nutritional status and quality of life in people with chronic kidney disease and in dialysis patients. However, the effect of low-intensity strength training has not been well documented, thus representing the objective of this pilot study. METHODS: Fifty participants (mean +/- SD, age 69 +/- 13 years) receiving long-term haemodialysis (3.7 +/- 4.2 years) were randomized to intra-dialytic low-intensity strength training or stretching (attention-control) exercises twice weekly for a total of 48 exercise sessions. The primary study outcome was physical performance assessed by the Short Physical Performance Battery score (SPPB) after 36 sessions, if available, or carried forward from 24 sessions. Secondary outcomes included lower body strength, body composition and quality of life. Measurements were obtained at baseline and at completion of 24 (mid), 36 (post) and 48 (final) exercise sessions. RESULTS: Baseline median (IQR) SPPB score was 6.0 (5.0), with 57% of the participants having SPPB scores below 7. Exercise adherence was 89 +/- 15%. The primary outcome could be computed in 44 participants. SPPB improved in the strength training group compared to the attention-control group [21.1% (43.1%) vs. 0.2% (38.4%), respectively, P = 0.03]. Similarly, strength training participants exhibited significant improvements from baseline compared to the control group in knee extensor strength, leisure-time physical activity and self-reported physical function and activities of daily living (ADL) disability; all P < 0.02. Adverse events were common but not related to study participation. CONCLUSIONS: Intra-dialytic, low-intensity progressive strength training was safe and effective among maintenance dialysis patients. Further studies are needed to establish the generalizability of this strength training program in dialysis patients.

Phenylethanolamine N-methyltransferase gene polymorphisms and adverse outcomes in acute kidney injury.

BACKGROUND/AIMS: The catecholaminergic pathway is important in the physical stress response; however, its role is not well understood in acute kidney injury (AKI). We studied single nucleotide polymorphisms (SNPs) of phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholaminergic pathway, and their association with adverse outcomes in AKI. METHODS: We performed a case-control study of 961 Caucasian subjects (194 with AKI and 767 controls). The PNMT promoter G-161A (rs876493) and coding A+1543G (rs5638) SNPs were genotyped and haplotypes generated. The outcomes of interest were the development of AKI, in-hospital mortality, dialysis requirement, oliguria, and hemodynamic shock. Urine catecholamines were measured in cases to explore genotype-phenotype correlations. RESULTS: The PNMT +1543 G allele was associated with AKI [odds ratio (OR) 2.19, 95% confidence interval (CI): 1.04-4.60]. For AKI cases, each PNMT -161 A allele was associated with lower mortality (OR 0.58, 95% CI: 0.35-0.99) and hemodynamic shock (OR 0.63, 95% CI: 0.40-1.00). The PNMT +1543 G allele was associated with oliguria (OR 3.35, 95% CI: 1.13-9.95). Urine adrenaline was associated with increased hemodynamic shock and mortality, but was lowest in PNMT -161 A/A carriers. CONCLUSION: In Caucasians, PNMT SNPs are associated with the development of AKI, disease severity, and in-hospital mortality. The adrenergic pathway provides another area of focus in the study of AKI.