Showing papers in "Nephrology Dialysis Transplantation in 2012"

A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: Part 1: definitions, conservative management and contrast-induced nephropathy

Abstract: The broad clinical syndrome of acute kidney injury (AKI) encompasses various aetiologies, including specific kidney diseases (e.g. acute interstitial nephritis), non-specific conditions (e.g. renal ischaemia) as well as extrarenal pathology (e.g. post-renal obstruction). AKI is a serious condition that affects kidney structure and function acutely, but also in the long term. Recent epidemiological evidence supports the notion that even mild, reversible AKI conveys the risk of persistent tissue damage, and severe AKI can be accompanied by an irreversible decline of kidney function and progression to end-stage kidney failure [1–3]. The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI [4] were designed to systematically compile information on this topic by experts in the field. These guidelines are based on the systematic review of relevant trials published before February 2011. Nevertheless, for many sections of the guidelines, appropriate supporting evidence is lacking in the literature. As a consequence, variations in practice will inevitably occur when clinicians take into account the needs of individual patients, available resources and limitations unique to a region, an institution or type of practice. Therefore, in line with its philosophy [5], the European Renal Best Practice (ERBP) wanted to issue a position statement on these guidelines. A working group was established to produce guidance from the European nephrology perspective, based on the compiled evidence as presented, with an update of the literature up to March 2012, following the methodology as explained in the ERBP instructions to authors [6]. The present document will deal with the diagnosis and prevention of AKI, and contrast-induced nephropathy (CIN) (Sections 1–4 of the KDIGO document), and other chapters will be discussed in a separate position statement. As a general rule, we will only mention those guideline statements of the KDIGO document that we have amended, even when the change is small. If a KDIGO recommendation is not repeated, it can be considered as endorsed by ERBP as is, unless specifically stated otherwise.

Therapeutic potential of mesenchymal stem cell-derived microvesicles

Abstract: Several studies have demonstrated that mesenchymal stem cells have the capacity to reverse acute and chronic kidney injury in different experimental models by paracrine mechanisms. This paracrine action may be accounted for, at least in part, by microvesicles (MVs) released from mesenchymal stem cells, resulting in a horizontal transfer of mRNA, microRNA and proteins. MVs, released as exosomes from the endosomal compartment, or as shedding vesicles from the cell surface, are now recognized as being an integral component of the intercellular microenvironment. By acting as vehicles for information transfer, MVs play a pivotal role in cell-to-cell communication. This exchange of information between the injured cells and stem cells has the potential to be bi-directional. Thus, MVs may either transfer transcripts from injured cells to stem cells, resulting in reprogramming of their phenotype to acquire specific features of the tissue, or conversely, transcripts could be transferred from stem cells to injured cells, restraining tissue injury and inducing cell cycle re-entry of resident cells, leading to tissue self-repair. Upon administration with a therapeutic regimen, MVs mimic the effect of mesenchymal stem cells in various experimental models by inhibiting apoptosis and stimulating cell proliferation. In this review, we discuss whether MVs released from mesenchymal stem cells have the potential to be exploited in novel therapeutic approaches in regenerative medicine to repair damaged tissues, as an alternative to stem cell-based therapy.

Estimating the financial cost of chronic kidney disease to the NHS in England

Abstract: Background. Chronic kidney disease (CKD) is a major challenge for health care systems around the world, and the prevalence rates appear to be increasing. We estimate the costs of CKD in a universal health care system. Methods. Economic modelling was used to estimate the annual cost of Stages 3–5 CKD to the National Health Service (NHS) in England, including CKD-related prescribing and care, renal replacement therapy (RRT), and excess strokes, myocardial infarctions (MIs) and Methicillin-Resistant Staphylococcus Aureus (MRSA) infections in people with CKD. Results. The cost of CKD to the English NHS in 2009–10 is estimated at £1.44 to £1.45 billion, which is ∼1.3% of all NHS spending in that year. More than half this sum was spent on RRT, which was provided for 2% of the CKD population. The economic model estimates that ∼7000 excess strokes and 12 000 excess MIs occurred in the CKD population in 2009–10, relative to an age- and gender-matched population without CKD. The cost of excess strokes and MIs is estimated at £174–£178 million. Conclusions. The financial impact of CKD is large, with particularly high costs relating to RRT and cardiovascular complications. It is hoped that these detailed cost estimates will be useful in analysing the cost-effectiveness of treatments for CKD.

Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment

Abstract: Primary hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver–kidney transplantation.

Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population

Abstract: Background. We sought to identify the long-term renal survival rate and related risk factors of progression to renal failure in Chinese adult patients with IgA nephropathy (IgAN) and to quantify the effects of proteinuria during the follow-up on outcome in patients with IgAN. Methods. Patients with biopsy-proven primary IgAN in the Nanjing Glomerulonephritis Registry were studied. Renal survival and the relationships between clinical parameters and renal outcomes were assessed. Results. One thousand one hundred and fifty-five patients were enrolled in this study. The 10-, 15- and 20-year cumulative renal survival rates, calculated by Kaplan–Meier method, were 83, 74 and 64%, respectively. At the time of biopsy, proteinuria >1.0 g/day [hazard ratio (HR) 3.2, P 1.0 g/day were associated with a 9.4-fold risk than patients with TA-P <1.0 g/day (P < 0.001) and 46.5-fold risk than those with TA-P <0.5 g/day (P < 0.001). Moreover, patients who achieved TA-P <0.5 g/day benefit much more than those with TA-P between 0.5 and 1.0 g/day (HR 13.1, P < 0.001). Conclusions. Thirty-six percent of Chinese adult patients with IgAN progress to end stage renal disease within 20 years. Five clinical features—higher proteinuria, hypertension, impaired renal function, hypoproteinemia and hyperuricemia—are independent predictors of an unfavorable renal outcome. The basic goal of anti-proteinuric therapy for Chinese patients is to lower proteinuria <1.0 g/day and the optimal goal is to lower proteinuria to <0.5 g/day.

Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients—a single-center cohort study

Abstract: Background. In chronic kidney disease stage 5D, diagnostic usefulness of bone mineral density (BMD) in predicting fracture has not been established because of variable results in previous studies. The reason for this may be the heterogeneity of underlying pathogenesis of the fracture. Methods. BMD was measured annually and serum biochemistry monthly for 485 hemodialyzed patients from April 2003 to March 2008, and all fractures were recorded. Results. Forty-six new episodes of any type of fracture and 29 cases of prevalent spine fracture were recorded. Serum bone-specific alkaline phosphatase (b-AP) was a very useful surrogate marker for any type of incident fracture risk [area under curve (AUC) ¼ 0.766, P 300 pg/mL (HR ¼ 5.88, P < 0.0001) compared with 150–300 pg/mL. Receiver-operating characteristic analysis demonstrated a significant predictive power for incident of any type of fracture by BMD at the total hip (AUC ¼ 0.760, P < 0.0001) and other hip regions in females in the lower PTH group (PTH < 204 pg/mL). BMDs at every site but whole body or lumbar spine had significant power to discriminate prevalent spine fracture regardless of gender or PTH. Conclusions. Hemodialyzed patients with low or high PTH or increased b-AP had a high fracture risk. BMD by Dual Energy X-ray Absorptiometry (DEXA), especially at the total hip region, was useful to predict any type of incident of fracture for females with low PTH or to discriminate prevalent spine fracture for every patient.

Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation

Abstract: Background. Inflammation is a constant feature and a major mediator of the progression of chronic kidney disease (CKD) and its numerous complications. There is increasing evidence pointing to the impairment of intestinal barrier function and its contribution to the prevailing inflammation in advanced CKD. Under normal condition, the intestinal epithelium and its apical tight junction prevent entry of the luminal microorganisms, harmful microbial by-products and other noxious contents in the host’s internal milieu. This study was designed to test the hypothesis that impaired intestinal barrier function in uremia must be due to disruption of the intestinal tight junction complex. Methods. Sprague–Dawley (SD) rats were randomized to undergo 5/6 nephrectomy (CKD) or sham-operation (control) and observed for 8 weeks. In a separate experiment, SD rats were rendered uremic by addition of 0.7% adenine to their food for 2 weeks and observed for an additional 2 weeks. Rats consuming a regular diet served as controls. The animals were then euthanized and their colons were removed and processed for expression of the key constituents of the tight junction complex using real-time polymerase chain reaction, western blot analysis and immunohistological examinations. Results. The CKD groups showed elevated plasma urea and creatinine, reduced creatinine clearance, thickened colonic wall and heavy infiltration of mononuclear leukocytes in the lamina propria. This was associated with marked reductions in protein expressions of claudin-1 (70–90%), occludin (50–70%) and ZO-1 (80–90%) in the colonic mucosa in both CKD models compared with the corresponding controls. The reduction in the abundance of the given proteins was confirmed by immunohistological examinations. In contrast, messenger RNA abundance of occludin, claudin-1 and ZO-1 was either unchanged or elevated pointing to the post-transcriptional/post-translational modification as a cause of the observed depletion of the tight junction proteins. Conclusion. The study revealed, for the first time, that uremia results in depletion of the key protein constituents of the colonic tight junction, a phenomenon which can account for the impaired intestinal barrier function and contribute to the systemic inflammation in CKD.

Hemodialysis and peritoneal dialysis are associated with similar outcomes for end-stage renal disease treatment in Canada

Abstract: Background. There were 35 265 patients receiving renal replacement therapy in Canada at the end of 2007 with 11.0% of patients on peritoneal dialysis (PD) and 48.9% on hemodialysis (HD) and a remaining 40.1% living with a functioning kidney transplant. There are no contemporary studies examining PD survival relative to HD in Canada. The objective was to compare survival outcomes for incident patients starting on PD as compared to HD in Canada. Methods. Using data from the Canadian Organ Replacement Register, the Cox proportional hazards (PH) model was employed to study survival outcomes for patients initiating PD as compared to HD in Canada from 1991 to 2004 with follow-up to 31 December 2007. Comparisons of outcomes were made between three successive calendar periods: 1991–95, 1996–2000 and 2001–04 with the relative risk of death of incident patients calculated using an intent-to-treat (ITT) analysis with proportional and non-PH models using a piecewise exponential survival model to compare adjusted mortality rates. Results. In the ITT analysis, overall survival for the entire study period favored PD in the first 18 months and HD after 36 months. However, for the 2001–04 cohort, survival favored PD for the first 2 years and thereafter PD and HD were similar. Among female patients >65 years with diabetes, PD had a 27% higher mortality rate. Conclusion. Overall, HD and PD are associated with similar outcomes for end-stage renal disease treatment in Canada.

Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis

Abstract: Background The reported incidence, prevalence and outcomes of atrial fibrillation (AF) in patients with end-stage renal disease (ESRD) are variable. The risks and benefits of warfarin anticoagulation need to be defined as the risk of bleeding in ESRD patients may overwhelm the benefits of embolic stroke prevention. We undertook a systematic literature review to clarify these issues. Methods A literature search was undertaken using Medline and EMBASE from 1990 to September 2011. Studies that reported incidence, prevalence or selected outcomes in ESRD patients with AF were included. Cross-sectional, cohort and randomized controlled trials with >25 participants were included. The lists of authors and abstracts from the search were reviewed by two investigators to determine the manuscripts for full text review. Data were abstracted to a form designed specifically for this study. The quality of the studies was assessed using the Newcastle-Ottawa scale. Event rates were calculated using a random-effects model. Results Twenty-five studies met our inclusion criteria. The prevalence of AF was 11.6% and the overall incidence was 2.7/100 patient-years. The risk of mortality and stroke was increased in ESRD patients with AF at 26.9 and 5.2/100 patient-years versus 13.4 and 1.9/100 patient-years compared with ESRD patients without AF. The majority of studies do not support a protective effect for warfarin in ESRD patients with AF. Conclusions The incidence and prevalence of AF in ESRD patients are higher than in the general population and are associated with an increased risk of stroke and mortality. An appropriately designed randomized controlled trial is required to determine whether anticoagulation is an appropriate therapeutic strategy in patients with end-stage renal disease and atrial fibrillation.

Factors that influence the decision to be an organ donor: a systematic review of the qualitative literature

Abstract: Background. Transplantation is the treatment of choice for organ failure, but a worldwide shortage of suitable organs exists. We conducted a systematic review of qualitative studies that explored community attitudes towards living and deceased solid organ donation to inform strategies to improve organ donation rates. Methods. Medline, Embase, PsycINFO and EconLIT were searched. Qualitative studies that explored community attitudes towards living and deceased solid organ donation were included. A thematic synthesis of the results and conclusions reported by primary authors was performed. Results. Eighteen studies involving 1019 participants were identified. Eight themes emerged. The decision to be an organ donor was influenced by (i) relational ties; (ii) religious beliefs; (iii) cultural influences; (iv) family influences; (v) body integrity; (vi) previous interactions with the health care system—medical mistrust, validity of brain death and fear of early organ retrieval; (vii) the individual’s knowledge about the organ donation process and (viii) major reservations about the process of donation, even in those who support organ donation. Conclusions. This review of qualitative studies highlights that seemingly intractable factors, such as religion and culture, are often tied in with more complex issues such as a distrust of the medical system, misunderstandings about religious stances and ignorance about the donation process. Intervention that could be considered includes culturally appropriate strategies to engage minority groups, especially through religious or cultural leaders, and more comprehensively available information about the donation process and its positive outcomes.

Survival analysis and causes of mortality in patients with lupus nephritis

Abstract: Background. This study aimed to define the causes and associated risks of death compared with the local general population in Chinese patients with lupus nephritis in the recent era. Methods. The records of all lupus nephritis patients followed in a single centre during 1968–2008 were reviewed. The causes of death were identified, the survival curves constructed and the standardized mortality ratios (SMRs) of potential risk factors were calculated with reference to the local general population. Results. Two hundred and thirty systemic lupus erythematosus patients with history of renal involvement (predominantly Class III/IV lupus nephritis with or without membranous features) were included. The follow-up was 4076.6 person-years (mean 17.7 6 8.9 years). Twenty-four patients (10.4%) died, and 85% of the deaths occurred after 10 years of follow-up. The 5-, 10-, and 20-year survival rates were 98.6, 98.2 and 90.5%, respectively. The leading causes of death were infection (50.0%), cardiovascular disease (20.8%) and malignancy (12.5%). The renal survival rates at 5, 10 and 20 years were 99.5, 98.0 and 89.7%, respectively. The SMR in patients with renal involvement, end-stage renal disease (ESRD), malignancy or cardiovascular disease was 5.9, 26.1, 12.9 and 13.6, respectively. Conclusions. Lupus nephritis is associated with a 6-fold increase in mortality compared with the general population. Lupus patients who develop ESRD have a 26-fold excess in the risk of death, which is more than twice the risk associated with malignancy or cardiovascular disease in these patients.

Importance of normohydration for the long-term survival of haemodialysis patients

Abstract: Background Fluid overload and hypertension are among the most important risk factors for haemodialysis (HD) patients. The aim of this study was to analyse the impact of fluid overload for the survival of HD patients by using a selected reference population from Tassin. Methods A positively selected HD population (n = 50) from Tassin (Lyon-France) was used as a reference for fluid status and all-cause mortality. This population was compared to one dialysis centre from Giessen (Germany) which was separated into a non-hyperhydrated (n = 123) and a hyperhydrated (n = 35) patient group. The hydration status (ΔHS) of all patients was objectively measured with whole-body bioimpedance spectroscopy in 2003. All-cause mortality was analysed after a 6.5-year follow-up. Results Most of the reference patients from Tassin were normohydrated (ΔHS = 0.25 ± 1.15 L) at the start of the HD session. The hydration status of the Tassin patients was not different to the non-hyperhydrated Giessen patients (ΔHS = 0.8 ± 1.1 L) but significantly lower than in the hyperhydrated Giessen group (ΔHS = 3.5 ± 1.2 L). Multivariate adjusted all-cause mortality was significantly increased in the hyperhydrated patient group (hazard ratio = 3.41)- no difference in mortality could be observed between the Tassin and the non-hyperhydrated group from Giessen-even considering the fact that Tassin patients presented a significantly lower blood pressure. Conclusions Fluid overload has a very high predictive value for all-cause mortality and seems to be one of the major killers in the HD population. Patients might strongly benefit from active management of fluid overload.

Barriers to exercise participation among dialysis patients

Abstract: Background. Physical inactivity is a strong predictor of mortality in patients with end-stage renal disease and is associated with poor physical functioning. Patients with end-stage renal disease are inactive even compared to sedentary individuals without kidney disease. We sought to identify patient barriers to physical activity. Methods. Adult patients on hemodialysis in the San Francisco Bay Area were recruited and asked to complete a study survey composed of questions about self-reported level of physical functioning, physical activity participation, patient physical activity preference and barriers to physical activity. Univariate and multivariable linear regression analyses were performed to study the association between barriers to physical activity and participation in physical activity. Results. A total of 100 patients participated in the study, the majority of whom were male (73%), with a mean age of 60 6 15 years. Twenty-seven percent identified themselves as white, 30% black and 21% Hispanic. The majority of participants strongly agreed that a sedentary lifestyle was a health risk (98%) and that increasing exercise was a benefit (98%). However, 92% of participants reported at least one barrier to physical activity. The most commonly reported barriers were fatigue on dialysis days and non-dialysis days (67 and 40%, respectively) and shortness of breath (48%). In multivariate analysis, a greater number of reported barriers was associated with lower levels of physical activity (P < 0.02). Post-dialysis fatigue was not associated with differences in activity level in multivariate analysis. Lack of motivation was associated with less physical activity. Endorsement of too many medical problems and not having enough time on dialysis days were also associated with less activity in adjusted analysis. Conclusion. We have identified a number of barriers to physical activity that can be addressed in studies aimed at increasing levels of physical activity. Inconsistent with nephrologists’ reported assumptions, dialysis patients were interested in physical activity.

Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic–uraemic syndrome: an analysis of the German STEC-HUS registry

Abstract: BACKGROUND May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases. METHODS To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). RESULTS Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. CONCLUSIONS Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury

Abstract: Background. Acute kidney injury (AKI) after cardiac surgery is a common and serious condition carrying significant costs. During cardiopulmonary bypass (CPB) surgery, modifiable factors may contribute to post-operative AKI. Their avoidance might be a potential target for nephroprotection. Methods. The objective of the present study was to identify and determine whether intraoperative hypotension, anaemia, or their combination, red blood cell transfusion or vasopressor use are independent risk factors for postoperative AKI defined by the RIFLE (renal Risk, Injury, Failure, Loss of renal function and End-stage renal disease) classification and other thresholds using a mixed logistic multivariate model. Results. We analysed 381 468 mean arterial pressure (MAP) measurements from 920 consecutive on-pump cardiac surgery patients. Overall, 19.5% developed AKI which was associated with an 8.2-fold increase in-hospital mortality. Haemoglobin concentration was an independent risk factor for AKI {odds ratio [OR] 1.16 per g/dL decrease [95% confidence interval (CI) 1.05–1.31]; P ¼ 0.018} with systemic arterial oxygen saturation and pressure values not adding further strength to such an association. MAP alone or vasopressor administration was not independently associated with AKI but volume of red blood cell transfusion was, with its effect being apparent at a haemoglobin level of > 8g /dL (>5 mmol/L). In patients with severe anaemia ( 75th percentile of area under the curve MAP 8 g/dL (>5 mmol/L) may help decrease AKI in patients undergoing cardiac surgery and represent targets for future controlled interventions.

Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension

Abstract: Glomerular hyperfiltration is a characteristic functional abnormality in insulin-dependent diabetes mellitus and occurs in the large majority of young Type 1 diabetic patients. Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Glomerular filtration rate (GFR) then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure. Experimental and clinical studies have shown that glomerular hyperfiltration can occur also in hypertension. However, whether hyperfiltration occurs also in early stages of hyperglycaemia and high blood pressure, such as in pre-diabetes and pre-hypertension, is not well known. In this issue of the Journal, Okada and Coll studied a large Japanese population showing that in pre-diabetic and pre-hypertensive subjects, the prevalence of hyperfiltration is proportional to the level of glucose and blood pressure, respectively. One main problem with the diagnosis of hyperfiltration is that no generally accepted definition is available due to the strong inverse correlation of GFR with age. To overcome this limitation, Okada et al. calculated the upper normal limit of GFR in a large healthy Japanese sample divided into 10-year age groups, providing ageand sex-specific reference values. For hyperfiltration to develop, the concomitant action of a variety of pathogenetic factors are needed including increased body mass index, hyperinsulinaemia, activation of the sympathetic nervous system, hyperleptinaemia, increased oxidative stress, inflammatory cytokines, etc. Another mechanism accounting for increased GFR in obese persons is increased NaCl intake. In addition, a significant role of increased Na reabsorption in the pathophysiology of glomerular hyperfiltration in obesity and hypertension has been described. Pharmacological agents with action on the renin–angiotensin system are effective in reducing glomerular hypertension which accounts for their efficacy in preventing progression of microalbuminuria in diabetes and hypertension. According to current guidelines, only low GFR and microalbuminuria or proteinuria should be considered as markers of renal dysfunction. Due to the strong association between hyperfiltration and risk of microalbuminuria found in diabetes and hypertension, hyperfiltration should be regarded as a precursor of nephropathy in these clinical conditions. More extensive use of markers of early organ damage may help clinicians to reach a more timely decision about the initiation of treatment and thus delay cardiovascular complications. Hyperglycaemia and high blood pressure in people with hyperfiltration should be treated earlier to prevent the progression of renal dysfunction to chronic kidney disease. Increased GFR, also called hyperfiltration, is a proposed mechanism for renal injury in several clinical conditions. According to the Brenner theory [1], low nephron number at birth explains why some individuals are prone to developing progressive renal damage later in life when other risk factors become operative. At the single-nephron level, hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Increased glomerular capillary hydraulic pressure may be due to changes in systemic arterial pressure and/or changes in efferent and afferent arteriolar resistances. In the absence of therapeutic interventions, GFR then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure (Figure 1). Human models of renal injury are in keeping with this pathogenetic view. Glomerular hyperfiltration has been observed in patients with unilateral renal agenesis [2], congenitally reduced nephron number [3] and acquired reduction in renal mass [4]. These individuals are prone to developing proteinuria early in life in association with glomerular sclerosis. It is suggested that this model of renal injury may apply to the early diabetic or hypertensive kidney.

Serum free p -cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients—a prospective cohort study

Abstract: Background The mortality rate of elderly hemodialysis (HD) patients is high. Serum p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are associated with cardiovascular (CV) disease and mortality in renal patients. The association between such biomarkers and mortality in elderly HD patients has a high clinical value but remains unclear. Methods This prospective cohort study investigated the association of serum IS and PCS with all-cause and CV mortality in elderly HD patients. Multivariate Cox regression analysis was used to estimate the risk of all-cause and CV mortality in this prospective cohort. Results Of 112 patients, 45 deaths (18 CV deaths) were identified after a mean follow-up of 33.2 months. The cumulative and CV survival of patients with lower free PCS was significantly better than high free PCS patients. In multivariate Cox regression analysis, serum free PCS was associated with all-cause and CV mortality after various adjustments, including age, gender and diabetes status (Model 1), albumin (Model 2), Ca × P product and intact parathyroid hormone (Model 3), hemoglobin and high-sensitivity C-reactive protein (Model 4) and hierarchically selected covariates (age, diabetes status and albumin, Model 5). Conclusion Serum free PCS levels may help in predicting risk of all-cause and CV mortality in elderly HD patients beyond traditional and uremia related risk factors.

Thrombotic microangiopathy and associated renal disorders

Abstract: Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation Furthermore, recent developments are challenging established management protocols This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS

Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD

Abstract: BACKGROUND Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. METHODS We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-α], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. RESULTS Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R(2) = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. CONCLUSION Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD.

Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury

Abstract: Background. Patients with acute kidney injury (AKI) requiring initiation of renal replacement therapy (RRT) have poor short- and long-term outcomes, including the development of dialysis dependence. Currently, little is known about what factors may predict renal recovery in this population. Methods. We conducted a single-center, retrospective analysis of 170 hospitalized adult patients with AKI attributed to acute tubular necrosis who required inpatient initiation of RRT. Data collection included patient characteristics, laboratory data, details of hospital course and degree of fluid overload at RRT initiation. The primary outcome was recovery of renal function to dialysis independence. Results. Within 1 year of RRT initiation, 35.9% (61/170) of patients reached the primary end point of renal recovery. The median (interquartile range) duration of RRT was 11 (3–33) days and 83.6% (51/61) recovered prior to hospital discharge. Recovering patients had significantly less fluid overload at the time of RRT initiation compared to non-recovering patients (3.5 versus 9.3%, P ¼ 0.004). In multivariate Cox proportional hazard regression analysis, a rise in percent fluid overload at dialysis initiation remained a significant negative predictor of renal recovery (hazard ratio 0.97, 95% confidence interval 0.95–1.00, P ¼ 0.024). Conclusions. In patients with AKI, a higher degree of fluid overload at RRT initiation predicts worse renal recovery at 1 year. Clinical trials are needed to determine whether interventions targeting fluid overload may improve patient and renal outcomes.

A case–control study of calciphylaxis in Japanese end-stage renal disease patients

Abstract: Background. Calciphylaxis, also called calcific uremic arteriolopathy, is a rare and often fatal complication of endstage renal disease and is characterized by painful skin ulceration, necrosis, medial calcification and intimal proliferation of small arteries. Studies in western countries have reported incidences ranging from 1 to 4% in chronic hemodialysis patients. Since no systematic studies of calciphylaxis have ever been performed in Japan, we conducted a nationwide survey and a case–control study to identify the characteristics of calciphylaxis in the Japanese dialysis population. Methods. Firstly, we sent a questionnaire to 3760 hemodialysis centers in Japan, asking whether calciphylaxis cases had been encountered in the past, and detailed clinical data regarding each case were then collected from the centers. In addition, two control dialysis patients matched for age and duration of hemodialysis to each calciphylaxis case were identified at the participating centers, and their data were analyzed to identify risk factors for calciphylaxis. Results. Responses to the questionnaire were obtained from 1838 centers (48.3%), and 151 centers reported that a total of 249 cases had been encountered. Sixty-four centers agreed to participate in the case–control study, and detailed clinical data in regard to 67 cases were obtained. In 28 of the 67 cases, a definite diagnosis of calciphylaxis was made by our study group based on the clinical characteristics and skin biopsy findings. A univariate logistic regression model comparing them with 56-matched controls identified warfarin therapy [odds ratio (OR) 11.4, 95% confidence interval (CI)] 2.7–48.1, P ¼ 0.0009], each 1 g/dL decline in serum albumin level (OR 19.8, 95% CI 4.4–89.5, P ¼ 0.0001), each 100 mg/dL increment in plasma glucose level (OR 3.74, 95% CI 1.08–12.9, P ¼ 0.037) and each 1 mg/dL increment in adjusted serum calcium level (OR 3.2, 95% CI 1.63–6.30, P ¼ 0.0008) at the time of diagnosis as significantly associated with calciphylaxis, but no significant associations were found with female gender, vitamin D analog therapy, serum phosphate level, adjusted calcium–phosphate products or serum alkaline–phosphatase level. Warfarin therapy and lower serum albumin levels were still significant risk factors after a multivariate logistic regression model analysis. Conclusion. The results of this study showed that warfarin therapy and lower serum albumin levels are significant and strong risk factors for the development of calciphylaxis in chronic hemodialysis patients in Japan.

The pathogenic role of the renal proximal tubular cell in diabetic nephropathy

Abstract: A growing body of evidence indicates that the renal proximal tubular epithelial cell (PTEC) plays an important role in the pathogenesis of diabetic nephropathy (DN). Microalbuminuria that intensifies over time to overt proteinuria, a hallmark of DN, is already known to activate the PTEC to induce tubulointerstitial inflammation. In addition to proteins, a number of diabetic substrates including high glucose per se, advanced glycation end-products and their carbonyl intermediates, angiotensin II, and ultrafiltered growth factors activate a number of signaling pathways including nuclear factor kappa B, protein kinase C, extracellular signal-regulated kinase 1/2, p38, signal transducer and activator of transcription-1 and the generation of reactive oxygen species, to culminate in tubular cell hypertrophy and the accumulation in the interstitium of a repertoire of chemokines, cytokines, growth factors and adhesion molecules capable of orchestrating further inflammation and fibrosis. More recently, the kallikrein-kinin system (KKS) and toll-like receptors (TLRs) in PTECs have been implicated in this process. While in vitro data suggest that the KKS contributes to the progression of DN, there are conflicting in vivo results on its precise role, which may in part be strain-dependent. On the other hand, there are both in vitro and in vivo data to suggest a role for both TLR2 and TLR4 in DN. In this review, we offer a critical appraisal of the events linking the participation of the PTEC to the pathogenesis of DN, which we believe may be collectively termed diabetic tubulopathy.

Genetic causes and mechanisms of distal renal tubular acidosis

Abstract: The primary or hereditary forms of distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in impaired acid excretion. Dysfunction of intercalated cells in the collecting tubules accounts for all the known genetic causes of dRTA. These cells secrete protons into the tubular lumen through H(+)-ATPases functionally coupled to the basolateral anion exchanger 1 (AE1). The substrate for both transporters is provided by the catalytic activity of the cytosolic carbonic anhydrase II (CA II), an enzyme which is also present in the proximal tubular cells and osteoclasts. Mutations in ATP6V1B1, encoding the B-subtype unit of the apical H(+) ATPase, and ATP6V0A4, encoding the a-subtype unit, lead to the loss of function of the apical H(+) ATPase and are usually responsible for patients with autosomal recessive dRTA often associated with early or late sensorineural deafness. Mutations in the gene encoding the cytosolic CA II are associated with the autosomal recessive syndrome of osteopetrosis, mixed distal and proximal RTA and cerebral calcification. Mutations in the AE1, the gene that encodes the Cl(-)/HCO(3)(-) exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Several studies have shown trafficking defects in the mutant protein rather than the lack of function as the major mechanism underlying the pathogenesis of dRTA from AE1 mutations.

Longer dialysis session length is associated with better intermediate outcomes and survival among patients on in-center three times per week hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

Abstract: Background Longer dialysis session length (treatment time, TT) has been associated with better survival among hemodialysis (HD) patients. The impact of TT on clinical markers that may contribute to this survival advantage is not well known. Methods Using data from the international Dialysis Outcomes and Practice Patterns Study, we assessed the association of TT with clinical outcomes using both standard regression analyses and instrumental variable approaches. The study included 37,414 patients on in-center HD three times per week with prescribed TT from 120 to 420 min. Results Facility mean TT ranged from 214 min in the USA to 256 min in Australia-New Zealand. Accounting for country effects, mortality risk was lower for patients with longer TT {hazard ratio for every 30 min: all-cause mortality: 0.94 [95% confidence interval (CI): 0.92-0.97], cardiovascular mortality: 0.95 (95% CI: 0.91-0.98) and sudden death: 0.93 (95% CI: 0.88-0.98)}. Patients with longer TT had lower pre- and post-dialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin (for the same erythropoietin dose), serum albumin and potassium and lower serum phosphorus and white blood cell counts. Similar associations were found using the instrumental variable approach, although the positive associations of TT with weight loss and potassium were lost. Conclusions Favorable levels of a variety of clinical markers may contribute to the better survival of patients receiving longer TT. These findings support longer TT prescription in the setting of in-center, three times per week HD.

Physical activity and energy expenditure in haemodialysis patients: an international survey

Abstract: Background. The assessment of physical activity and energy expenditure is relevant to the care of maintenance haemodialysis (MHD) patients. In the current study, we aimed to evaluate measurements of physical activity and energy expenditure in MHD patients from different centres and countries and explored the predictors of physical activity in these patients. Methods. In this cross-sectional multicentre study, 134 MHD patients from four countries (France, Switzerland, Sweden and Brazil) were included. The physical activity was evaluated for 5.0 6 1.4 days (mean 6 SD) by a multisensory device (SenseWear Armband) and comprised the assessment of number of steps per day, activity-related energy expenditure (activity-related EE) and physical activity level (PAL). Results. The number of steps per day, activity-related EE and PAL from the MHD patients were compatible with a sedentary lifestyle. In addition, all parameters were significantly lower in dialysis days when compared to non-dialysis days (P < 0.001). The multivariate regression analysis revealed that diabetes and higher body mass index (BMI) predicted a lower PAL and older age and diabetes predicted a reduced number of steps. Conclusions. The physical activity parameters of MHD patients were compatible with a sedentary lifestyle. This inactivity was worsened by aging, diabetes and higher BMI. Our results indicate that MHD patients should be encouraged by the health care team to increase their physical activity.

Red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy

Abstract: Background. A potential independent association was recently demonstrated between high red blood cell distribution width (RDW) and the risk of all-cause mortality in patients with cardiovascular disease, although the mechanism remains unclear. However, there have been no reports on the relationship between RDW and mortality in acute kidney injury (AKI) patients treated with continuous renal replacement therapy (CRRT). In this study, we assessed whether RDW was associated with mortality in AKI patients on CRRT treatment in the intensive care unit (ICU). Methods. We enrolled 470 patients with AKI who were treated with CRRT at the Yonsei University Medical Center ICU from August 2007 to September 2009 in this study. We performed a retrospective analysis of demographic, biochemical parameters and patient outcomes. Following CRRT treatment, 28-day all-cause mortality was evaluated. Results. At the initiation of CRRT treatment, RDW level was significantly correlated with white blood cell count, hemoglobin (Hb) and total cholesterol. Patients with high RDW levels exhibited significantly higher 28-day mortality rates than patients with low RDW levels (P < 0.01). Baseline RDW level, Sequential Organ Failure Assessment (SOFA) score, low mean arterial pressure (MAP) and low cholesterol levels were independent risk factors for mortality. In multivariate Cox proportional hazard analyses, RDW at CRRT initiation was an independent predictor for 28-day all-cause mortality after adjusting for age, gender, MAP, Hb, albumin, total cholesterol, C-reactive protein and SOFA score. Conclusion. Our study demonstrates that RDW could be an additive predictor for all-cause mortality in AKI patients on CRRT treatment in the ICU.

Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea

Abstract: Background. In both healthy male subjects and men with heart failure, the severity of obstructive sleep apnea (OSA) is related to the amount of fluid displaced from their legs into the neck overnight. Whether overnight rostral fluid shift contributes to the pathogenesis of OSA in patients with end-stage renal disease (ESRD) is unknown. We hypothesized that the change in neck circumference (NC) and severity of OSA are related to the extent of overnight change in leg fluid volume (LFV) in patients with ESRD. Methods. We studied 26 patients with ESRD (14 men) on conventional hemodialysis. All subjects underwent polysomnography. LFV was measured by bioelectric impedance at bedtime and repeated in the next morning on awakening. Results. Our cohort’s overall apnea–hypopnea index was 22.8 6 26.8 episodes/h of sleep. Their overnight change in LFV was � 243 6 278 mL. The change in LFV correlated with apnea–hypopnea time (AHT) (P ¼ 0.001) and NC (P ¼ 0.0016). Other independent factors associated with AHT included age (P ¼ 0.005), baseline neck (P ¼ 0.0002), sitting time (P ¼ 0.008) and male gender. Stepwise multiple regression analysis revealed that age, change in LFV and male gender remained independent related to AHT. Conclusions. Nocturnal rostral fluid shift is associated with the severity of OSA in ESRD. Prospective evaluation of the effect of reducing fluid overload and severity of OSA in ESRD patients warrants further examination.

Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner

Abstract: Background. Vascular calcification (VC), mainly due to elevated phosphate levels, is one major problem in patients suffering from chronic kidney disease. In clinical studies, an inverse relationship between serum magnesium and VC has been reported. However, there is only few information about the influence of magnesium on calcification on a cellular level available. Therefore, we investigated the effect of magnesium on calcification induced by b-glycerophosphate (BGP) in bovine vascular smooth muscle cells (BVSMCs). Methods. BVSMCs were incubated with calcification media for 14 days while simultaneously increasing the magnesium concentration. Calcium deposition, transdifferentiation of cells and apoptosis were measured applying quantification of calcium, von Kossa and Alizarin red staining, real-time reverse transcription–polymerase chain reaction and annexin V staining, respectively. Results. Calcium deposition in the cells dramatically increased with addition of BGP and could be mostly prevented by co-incubation with magnesium. Higher magnesium levels led to inhibition of BGP-induced alkaline phosphatase activity as well as to a decreased expression of genes associated with the process of transdifferentiation of BVSMCs into osteoblast-like cells. Furthermore, estimated calcium entry into the cells decreased with increasing magnesium concentrations in the media. In addition, higher magnesium concentrations prevented cell damage (apoptosis) induced by BGP as well as progression of already established calcification. Conclusions. Higher magnesium levels prevented BVSMC calcification, inhibited expression of osteogenic proteins, apoptosis and further progression of already established calcification. Thus, magnesium is influencing molecular processes associated with VC and may have the potential to play a role for VC also in clinical situations.

Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: low and oscillating shear stress locates the sites of stenosis

Abstract: Background. Despite recent clinical and technological advancements, the vascular access (VA) for haemodialysis still has significant early failure rates after arteriovenous fistula (AVF) creation. VA failure is mainly related to the haemodynamic conditions that trigger the phenomena of vascular wall disease such as intimal hyperplasia (IH) or atherosclerosis. Methods. We performed transient computational fluid dynamics simulations within idealized three-dimensional models of ‘end-to-side’ and ‘end-to-end’ radio-cephalic anastomosis, using non-Newtonian blood and previously measured flows and division ratio in subjects requiring primary access procedure as boundary conditions. Results. The numerical simulations allowed full characterization of blood flow inside the AVF and of patterns of haemodynamic shear stress, known to be the major determinant of vascular remodelling and disease. Wall shear stress was low and oscillating in zones where flow stagnation occurs on the artery floor and on the inner wall of the juxta-anastomotic vein. Conclusions. Zones of low and oscillatory shear stress were located in the same sites where luminal reduction was documented in previous experimental studies on sites stenosis distribution in AVF. We conclude that even when exposed to high flow rates, there are spot regions along the AVF exposed to athero-prone shear stress that favour vessel stenosis by triggering IH.

Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients

Abstract: Background. Sclerostin is a soluble inhibitor of osteoblast function. Sclerostin is downregulated by the parathyroid hormone (PTH). Here, it was investigated whether sclerostin levels are influenced by intact (i) PTH and whether sclerostin is associated with bone turnover, microarchitecture and mass in dialysis patients. Methods. Seventy-six haemodialysis patients and 45 healthy controls were included in this cross-sectional study. Sclerostin, Dickkopf-1 (DKK-1), intact parathyroid hormone (iPTH), vitamin D and markers of bone turnover were analysed. A subset of 37 dialysis patients had measurements of bone mineral density (BMD) using dual-energy X-ray absorptiometry and bone microarchitecture using high-resolution peripheral quantitative computed tomography. Results. Dialysis patients had significantly higher sclerostin levels than controls (1257 pg/mL versus 415 pg/mL, P < 0.001). Significant correlations were found between sclerostin and gender (R ¼ 0.41), iPTH (R ¼� 0.28), 25-hydroxy-cholecalciferol (R ¼ 0.27) and calcium (R ¼ 0.25). Gender and iPTH remained significantly associated with sclerostin in a multivariate analysis. Sclerostin serum levels were positively associated with BMD at the lumbar spine (R ¼ 0.46), femoral neck (R ¼ 0.36) and distal radius (R ¼ 0.42) and correlated positively mainly with trabecular structures such as trabecular density and number at the radius and tibia in dialysis patients. DKK-1 was related neither to bone measures nor to serologic parameters. Conclusions. Considering that sclerostin is an inhibitor of bone formation, the observed positive correlations of serum sclerostin with BMD and bone volume were unexpected. Whether its increase in dialysis patients has direct pathogenetic relevance or is only a secondary phenomenon remains to be seen.