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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that mediates many cellular responses to tissue hypoxia, a common feature of acute kidney injury (AKI). Here we studied 241 patients with AKI and determined the relationship to adverse outcome of a non-synonymous polymorphism in the coding region of the HIF-1alpha gene where a C to T substitution occurs at position +85 in exon 12, a change known to enhance transactivation. The baseline characteristics of the patients were not different among genotype groups except for a significantly higher prevalence of shock and number of failed organs in T-allele carriers. A significant genotype-phenotype association was found for plasma levels of vascular endothelial growth factor-A but not angiopoietin-2, two downstream targets of HIF-1alpha. Compared to the CC genotype, T-allele carriers had significantly higher adjusted odds for dialysis requirement or in-hospital death; assisted mechanical ventilation or dialysis requirement; and the composite of assisted mechanical ventilation, dialysis requirement or in-hospital death. The trend for higher plasma angiopoietin-2 levels was associated with significantly higher adjusted odds for in-hospital death; dialysis requirement or in-hospital death; and the composite outcome of assisted mechanical ventilation, dialysis, or in-hospital death. Despite the limited cohort size, our study found this particular HIF-1alpha genetic variant to be associated with disease severity and adverse outcomes in AKI. Larger studies are needed to confirm these relationships.

Serum cystatin C for prediction of dialysis requirement or death in acute kidney injury: a comparative study.

BACKGROUND: Serum cystatin C has emerged as a new and potentially more reliable marker of kidney function. However, its utility and performance in patients with acute kidney injury (AKI), particularly for the prediction of dialysis requirement, is not well known. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Adult patients with AKI enrolled at 2 academic medical centers, at time of nephrology consultation. PREDICTORS: Serum cystatin C (primary predictor), serum creatinine, and serum urea nitrogen levels and 24-hour urine output measured at enrollment. OUTCOMES: The composite of dialysis requirement or in-hospital death. COVARIATES: Acute Physiology and Chronic Health Evaluation II (APACHE II) score, liver disease, sepsis, and mechanical ventilation. RESULTS: 200 participants were enrolled for this analysis. Mean age was 65 years, 55% were men, and mean APACHE II score was 20. In unadjusted analyses, increases in serum cystatin C (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.36 to 2.59), serum creatinine (OR, 1.53; 95% CI, 1.12 to 2.09), and serum urea nitrogen levels (OR, 1.84; 95% CI, 1.34 to 2.54) were associated with a higher odds (per 1-SD increase) for the composite outcome, whereas greater urine output (OR, 0.56; 95% CI, 0.39 to 0.80) was associated with lower odds. These associations persisted after adjustment for APACHE II score. The addition of serum cystatin C, serum creatinine, and serum urea nitrogen levels or urine output to a basic model entailing APACHE II score, liver disease, sepsis, and assisted mechanical ventilation improved its prediction, evidenced by increases in areas under a receiver operator characteristic curve from 0.816 to 0.829, 0.826, 0.837, and 0.836, respectively. However, there was no significant difference between each of these models. LIMITATIONS: Observational study, single serum cystatin C measurement. CONCLUSION: In patients with AKI, serum cystatin C level performs similarly to serum creatinine level, serum urea nitrogen level, and urine output for predicting dialysis requirement or in-hospital death. Larger studies are needed to confirm these findings.

Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass.

The purpose of this study was to compare the performance of six candidate urinary biomarkers, kidney injury molecule (KIM)-1, N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, cystatin C and alpha-1 microglobulin, measured 2 h following cardiopulmonary bypass (CPB) for the early detection of acute kidney injury (AKI) in a prospective cohort of patients undergoing cardiac surgery. A total of 103 subjects were enrolled; AKI developed in 13%. Urinary KIM-1 achieved the highest area under-the-receiver-operator-characteristic curve (AUC 0.78, 95% confidence interval 0.64-0.91), followed by IL-18 and NAG. Only urinary KIM-1 remained independently associated with AKI after adjustment for a preoperative AKI prediction score (Cleveland Clinic Foundation score; p = 0.02), or CPB perfusion time (p = 0.006). In this small pilot cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to explore further the role of biomarkers for early detection of AKI following cardiac surgery.

Interleukin-8 and acute kidney injury following cardiopulmonary bypass: a prospective cohort study.

BACKGROUND: Cardiopulmonary bypass (CPB) elicits an inflammatory response mediated partly by neutrophils, which are activated and recruited by interleukin-8 (IL-8). We hypothesized that acute kidney injury (AKI) following CPB might be mediated by IL-8 and examined the association of perioperative plasma IL-8 levels with AKI in a prospective cohort. METHODS: Plasma IL-8 was measured before, and 2, 24 and 48 h following CPB. Two AKI definitions, a serum creatinine increase of > or = 0.3 mg/dl or 50% (AKI Network [AKIN] stage-1) or > or = 50% alone (AKI-50%), within the first 72 h, were used. Area under the receiver operator characteristic curves (AUCs) were generated and multivariable logistic regression analyses performed. RESULTS: A total of 143 patients were enrolled. The baseline mean serum creatinine was 1.1 mg/ dl (SD = 0.3), the CPB perfusion time was 112 min (SD = 43). Twenty-nine percent of the patients developed AKIN stage-1 and 13% AKI-50%. The plasma IL-8 level 2 h after CPB was higher in AKIN stage-1 (p = 0.03) and AKI-50% (p < 0.01), and predicted AKIN stage-1 (AUC = 0.62; p = 0.02) and AKI-50% (AUC = 0.72; p < 0.01). On multivariable analysis, the 2-hour plasma IL-8 level was associated with 1.36- and 1.59-fold higher odds for AKIN stage-1 and AKI-50%, respectively (p = 0.05). CONCLUSION: Plasma IL-8 predicts the development of AKI following CPB, supporting a potential involvement for this chemokine in the pathogenesis of AKI.

Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis.

BACKGROUND: Some studies have suggested that early institution of renal replacement therapy (RRT) might be associated with improved outcomes in patients with acute renal failure (ARF). STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials and cohort comparative studies to assess the effect of early RRT on mortality in patients with ARF. SETTING & POPULATION: Hospitalized adult patients with ARF. SELECTION CRITERIA FOR STUDIES: We searched several databases for studies that compared the effect of "early" and "late" RRT initiation on mortality in patients with ARF. We included studies of various designs. INTERVENTION: Early RRT as defined in the individual studies. OUTCOMES: The primary outcome measure was the effect of early RRT on mortality stratified by study design. The pooled risk ratio (RR) for mortality was compiled using a random-effects model. Heterogeneity was evaluated by means of subgroup analysis and meta-regression. RESULTS: We identified 23 studies (5 randomized or quasi-randomized controlled trials, 1 prospective and 16 retrospective comparative cohort studies, and 1 single-arm study with a historic control group). By using meta-analysis of randomized trials, early RRT was associated with a nonsignificant 36% mortality risk reduction (RR, 0.64; 95% confidence interval, 0.40 to 1.05; P = 0.08). Conversely, in cohort studies, early RRT was associated with a statistically significant 28% mortality risk reduction (RR, 0.72; 95% confidence interval, 0.64 to 0.82; P < 0.001). The overall test for heterogeneity among cohort studies was significant (P = 0.005). Meta-regression yielded no significant associations; however, early dialysis therapy was associated more strongly with lower mortality in smaller studies (n < 100) by means of subgroup analysis. LIMITATIONS: Paucity of randomized controlled trials, use of variable definitions of early RRT, and publication bias preclude definitive conclusions. CONCLUSION: This hypothesis-generating meta-analysis suggests that early initiation of RRT in patients with ARF might be associated with improved survival, calling for an adequately powered randomized controlled trial to address this question.

Multiple organ dysfunction syndrome in children with sepsis: role of genetic factors.

This review summarizes current knowledge on the impact of genetic markers on susceptibility, severity, and outcome of acute inflammatory disorders in children, with a special focus on systemic infections. A 14-year-old child with Neisseria meningitides bacteremia, complicated by septic shock and multiple organ dysfunction, is discussed as an exemplary case, and linked to the application of genetic epidemiology and the study of common disorders in children. The current pertinent literature is comprehensively reviewed and limitations and future directions are discussed.

Protective effect of erythropoietin against radiocontrast-induced renal tubular epithelial cell injury.

BACKGROUND/AIMS: Recombinant human erythropoietin (rhEpo) has been shown to reduce tissue injury following ischemia-reperfusion. We examined whether rhEpo protects in vitro renal tubular epithelial cells against radiocontrast media-induced injury. METHODS: LLC-PK1 renal tubular epithelial cells were exposed to non-ionic radiocontrast agent iohexol (low-osmolar) or iodixanol (iso-osmolar), with or without rhEpo (200 U/ml). Following a 6-hour exposure, cells were incubated for 24 h in radiocontrast-free culture medium. Cell viability was then assessed by the MTT assay. We also assessed cell apoptosis by the TUNEL assay, and activities of caspase-3, caspase-8, and caspase-9 were determined by a luminescence assay. RESULTS: rhEpo improved viability of iohexol-treated LLC-PK1 cells by 27 +/- 6% (88.1 +/- 1.5 vs. 70.8 +/- 3.3%, p = 0.008). Similarly, rhEpo improved the viability of iodixanol-treated LLC-PK1 cells by 26 +/- 4% (82.5 +/- 2.1vs. 65.7 +/- 1.7%, p = 0.028). rhEpo also decreased apoptosis rates of iohexol-treated LLC-PK1 cells (6.4 +/- 0.9/1,000 cells vs. 14.8 +/- 2.4/1,000 cells, p = 0.028), and iodixanol-treated LLC-PK1 cells (8.0 +/- 1.2/1,000 cells vs. 13.5 +/- 1.9/1,000 cells, p = 0.028). In iohexol-treated LLC-PK1 cells, rhEpo attenuated activation of caspase-3 (p = 0.003), caspase-8 (p = 0.033) and caspase-9 (p = 0.055). CONCLUSION: rhEpo attenuates in vitro renal tubular epithelial cell injury induced by low- and iso-osmolar radiocontrast media, possibly by reduction of caspases activation and apoptosis rates.