Adrian Covic

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

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.

Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis.

Vascular calcification (VC), which is described in the elderly and in diabetics, is frequently seen in uraemia. It is usually regarded as having little significance. We studied the roentgenological appearance of VC in a homogeneous group of 38 long-hours haemodialysis patients whose longevity on dialysis allowed sustained (10-25 years) follow-up, including annual skeletal surveys and thrice-yearly clinical examinations and biochemical profiles. We compiled a dossier of clinical and laboratory parameters from the start of dialysis to the present day. We were able to analyze the natural history of VC and to determine which clinical parameters were linked with progression. We found that VC became steadily more prevalent-at dialysis onset present in 39% of the patients, but in 92% after an average dialysis duration of 16 years, with a mean onset 9.7 years after starting dialysis. As well as becoming more prevalent, the calcification became progressively more severe in most patients. There were two patterns of VC: axial (aorta and iliac and femoral arteries), seen alone in 32% of the patients, and peripheral (digital arteries), seen alone in 3% of patients. Most patients (65%) had evidence of both types. Calcification was scored for site and severity. Patient age (r = 0.57, p < 0.001), systolic blood pressure (r = 0.54, p < 0.001), hyperparathyroidism (reduced progression after parathyroidectomy), plasma phosphate (r = 0.34, p = 0.042), and vitamin D concentrations (r = 0.53, p < 0.001) were the principal determinants of severity and rate of progression of VC in this population. There was a weak negative association between progression and serum ferritin (r = -0.33, p = 0.046). The reduced vessel compliance that results from VC is likely to be cardiovascularly deleterious. In severe cases, tissue perfusion or vascular access for haemodialysis can be compromised. VC and accelerated cardiovascular mortality are common to uraemia, diabetes, and systolic hypertension in the elderly. Better understanding of these pathological processes may permit intervention and possibly lead to a reduction in cardiovascular mortality.

A Randomized Study of Allopurinol on Endothelial Function and Estimated Glomular Filtration Rate in Asymptomatic Hyperuricemic Subjects with Normal Renal Function

BACKGROUND AND OBJECTIVES Endothelial dysfunction is an early manifestation of vascular injury and contributes to the development of atherosclerotic cardiovascular disease. Recent studies have implicated hyperuricemia as a risk factor for cardiovascular disease. We hypothesized that lowering uric acid in subjects with asymptomatic hyperuricemia with allopurinol might improve endothelial dysfunction, BP, estimated GFR (eGFR), and inflammatory markers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Subjects with asymptomatic hyperuricemia and no history of gout and 30 normouricemic control subjects were enrolled in this 4-month randomized prospective study. Thirty hyperuricemic patients received 300 mg/d allopurinol and were compared with 37 hyperuricemic patients and 30 normouricemic subjects in matched control groups. Flow-mediated dilation (FMD), eGFR, ambulatory BP monitoring, spot urine protein-creatine ratio, and highly sensitive C-reactive protein were measured at baseline and at 4 months. RESULTS Age, gender, lipid profile, eGFR, hemoglobin, glucose, and level of proteinuria were similar in hyperuricemic subjects and controls at baseline. As expected, hyperuricemic patients had higher levels of highly sensitive C-reactive protein and lower FMD compared with normouricemic patients. Allopurinol treatment resulted in a decrease in serum uric acid, a decrease in systolic BP, an increase in FMD, and an increase in eGFR compared with baseline. No significant difference was observed in the control hyperuricemic and normouricemic groups. In a multiple regression analysis, FMD levels were independently related to uric acid both before (beta = -0.55) and after (beta = -0.40) treatment. CONCLUSIONS Treatment of hyperuricemia with allopurinol improves endothelial dysfunction and eGFR in subjects with asymptomatic hyperuricemia.

Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease

BACKGROUND Chronic kidney disease (CKD) is a powerful risk factor for all-cause mortality and its most common aetiology, cardiovascular (CV) mortality. Mineral metabolism disturbances occur very early during the course of CKD but their control has been poor. A number of studies have assessed the relationship between all-cause mortality, CV mortality and events with mineral disturbances in CKD patients, but with considerable discrepancy and heterogeneity in results. Thus, a systematic review was conducted to assess methodological and clinical heterogeneity by comparing designs, analytical approaches and results of studies. METHODS Medline, EMBASE and Cochrane databases were systematically searched for articles published between January 1980 and December 2007. RESULTS Thirty-five studies were included in the review. All-cause mortality was the most commonly assessed outcome (n = 29). Data on CV mortality risk (n = 11) and CV events (congestive heart failure, stroke, myocardial infarction) (n = 4) are limited. The studies varied in populations scrutinized, exposure assessments, covariates adjusted and reference mineral levels used in risk estimation. A significant risk of mortality (all-cause, CV) and of CV events was observed with mineral disturbances. The data supported a greater mortality risk with phosphorus, followed by calcium and parathyroid hormone (PTH). The threshold associated with a significant all-cause mortality risk varied from 3.5-3.9 mg/dL (reference: 2.5-2.9) to 6.6-7.8 mg/dL (reference: 4.4-5.5) for high phosphorus, <3 mg/dL (reference: 5-7) to <5 mg/dL (reference: 5-6) for low phosphorus, 9.7-10.2 mg/dL (reference: < or =8.7) to >10.5 mg/dL (reference: 9-9.5) for high calcium, < or =8.8 mg/dL (reference: >8.8) to <9 mg/dL (reference: 9-9.5) for low calcium and >300 pg/mL (reference: 200-300) to >480 pg/mL (reference: < or =37) for PTH. Thresholds at which the CV mortality risk significantly increased were >5.5 (reference: 3.5-5.5) and >6.5 mg/dL (reference: <6.5) for phosphorus and >476.1 pg/mL (reference: <476.1) for PTH. CONCLUSIONS Serious limitations were observed in the quality and methodology across studies. In spite of enormous heterogeneity across studies, a significant mortality risk was observed with mineral disturbances in dialysis patients. Data on risk in pre-dialysis patients were less conclusive due to even more limited (numerically) evidence.

Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure

Patients with chronic kidney failure--defined as a glomerular filtration rate persistently below 15 mL/min per 1·73 m(2)--have an unacceptably high mortality rate. In developing countries, mortality results primarily from an absence of access to renal replacement therapy. Additionally, cardiovascular and non-cardiovascular mortality are several times higher in patients on dialysis or post-renal transplantation than in the general population. Mortality of patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself. Characterisation of the key pathophysiological contributors to increased mortality and cardiorenal risk staging systems are needed for the rational design of clinical trials aimed at decreasing mortality. Policy changes to improve access to renal replacement therapy should be combined with research into low-cost renal replacement therapy and optimum clinical care, which should include multifaceted approaches simultaneously targeting several of the putative contributors to increased mortality.

Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP)

1Department of Nephrology, Dialysis and Renal Transplantation, ‘A. Manzoni’ Hospital, Lecco, Italy, 2Department of Nephrology, Dialysis and Transplantation, C. I. Parhon University Hospital, University of Medicine Gr. T. Popa, Iasi, Romania, 3Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Nuremberg, Germany, 4Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Francuska, Poland and 5Nephrology Section, University Hospital, Ghent, Belgium

Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort

Background Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far. Methods We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population. Results Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R2 of the model = 0.57). Conclusions The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia.

Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability

Background. Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option. Methods. This controlled randomized, investigator-masked, multicentre trial investigated the effect of calcium acetate/magnesium carbonate (CaMg) on serum phosphorus levels compared with sevelamer hydrochloride (HCl). The study aim was to show non-inferiority of CaMg in lowering serum phosphorus levels into Kidney Disease Outcome Quality Initiative (K/DOQI) target level range after 24 weeks. Three hundred and twenty-six patients from five European countries were included. After a phosphate binder washout period, 255 patients were randomized in a 1:1 fashion. Two hundred and four patients completed the study per protocol (CaMg, N = 105; dropouts N = 18; sevelamer-HCl, N = 99; dropouts N = 34). Patient baseline characteristics were similar in both groups. Results. Serum phosphorus levels had decreased significantly with both drugs at week 25, and the study hypothesis of CaMg not being inferior to sevelamer-HCl was confirmed. The area under the curve for serum phosphorus (P = 0.0042) and the number of visits above K/DOQI (≤1.78 mmol/L, P = 0.0198) and Kidney disease: Improving global outcomes (KDIGO) targets (≤1.45 mmol/L, P = 0.0067) were significantly lower with CaMg. Ionized serum calcium did not differ between groups; total serum calcium increased in the CaMg group (treatment difference 0.0477 mmol/L; P = 0.0032) but was not associated with a higher risk of hypercalcaemia. An asymptomatic increase in serum magnesium occurred in CaMg-treated patients (treatment difference 0.2597 mmol/L, P < 0.0001). There was no difference in the number of patients with adverse events. Conclusion. CaMg was non-inferior to the comparator at controlling serum phosphorus levels at Week 25. There was no change in ionized calcium; there was minimal increase in total serum calcium and a small increase in serum magnesium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphataemia.

Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors.

Background. Management of anemia is an important factor in the care of patients with chronic kidney disease as the anemic state can confer significant morbidity and mortality. Posttransplantation anemia (PTA) has received comparatively less attention in the literature, and the prevalence and predictors of PTA vary between different studies. The purpose of this study was to investigate a large posttransplant population from 3 centres in the UK to elucidate the point prevalence of PTA, its determinants and the use of erythropoiesis stimulating agents (ESA) in these patients. Methods. All adult patients with functioning renal transplants and attending renal transplant outpatients at Guy’s, King’s College, or St. Helier Hospitals, London, as of 31/12/2004 who had a valid hemoglobin in the previous 3 months, and who were more than 3 months postengraftment, were identified. Patients’ notes and electronic patient records were obtained and a detailed cross-sectional clinical and biochemical database was constructed. The data were analyzed for the point prevalence of PTA, the prevalence of ESA use and for determinants of hemoglobin. The WHO criteria were used to define anemia and all patients on treatment with an ESA was classified as anemic irrespective of hemoglobin. Results. A total of 1,511 (947 male) patients were studied. Mean age was 48.1±13.7 years with no difference between the sexes. Mean time posttransplantation was 8.5±7.2 years and mean estimated MDRD GFR was 47.6±18.9 ml/min with a higher GFR in males (49.9±19.0 v 43.8±18.0 mL/min, P<0.0001). Mean hemoglobin in the studied population was 12.9±1.6 g/dl with a significantly higher level among males than females (mean 13.3±1.6 v 12.3±1.4 g/dl, P<0.0001). The prevalence of anemia was 45.6% with a prevalence of 44.1% among males and 48.1% amongst females. Severe anemia was present in 50 subjects (3.3% of the total cohort). One hundred and forty-five patients (9.6% of the entire cohort) were being treated with an ESA. Of these subjects, 41 did not meet WHO criteria for the definition of anemia. After multiple regression analyses, age, female sex, renal function and to a lesser extent serum ferritin and therapy with angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (both negatively associated) were predictive of hemoglobin. Conclusions. The prevalence of anemia posttransplantation was high while comparatively few patients were being treated with erythropoiesis stimulating agents. The strongest predictors of hemoglobin in this cohort of patients were age, female sex and allograft function. Medical therapy with MMF and sirolimus was associated with a high prevalence of anemia but this was likely to be the result of poorer graft function in these subjects who mostly had chronic allograft nephropathy. A large interventional prospective study with valid control groups is now needed to assess the long-term contributions of clinical and biochemical factors of renal function and to elucidate the effects of therapy on outcome.

Online haemodiafiltration: definition, dose quantification and safety revisited

The general objective assigned to the EUropean DIALlysis (EUDIAL) Working Group by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) was to enhance the quality of dialysis therapies in Europe in the broadest possible sense. Given the increasing interest in convective therapies, the Working Group has started by focusing on haemodiafiltration (HDF) therapies. Several reports suggest that those therapies potentially improve the outcomes for end-stage renal disease patients. Europe is the leader in the field, having introduced the concept of ultra-purity for water and dialysis fluids and with notified bodies of the European Community having certified water treatment systems and online HDF machines. The prevalence of online HDF-treated patients is steadily increasing in Europe, averaging 15%. A EUDIAL consensus conference was held in Paris on 13 October 2011 to revisit terminology, safety and efficacy of online HDF. This is the first report of the expert group arising from that conference.