Global Outcomes Clinical Practice Guideline Research Articles

A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Non-dialysis-dependent Chronic Kidney Disease: an endorsement with some caveats for real-life application

Developing guidelines on a subject as broad as hypertension is difficult, especially when the guidance relates to hypertension in the chronic kidney disease (CKD) population. The Kidney Disease: Improving Global Outcomes Guideline Development Group has applied a rigorous methodology in reviewing all available evidence, and their recommendations are consistent with the evidence-based approach. As a result, the European Renal Best Practice endorses most of its recommendations. However, the Work Group feels that some additional advice could help clinicians in daily practice: (i) individualization of treatment should be taken into account, especially (cardiovascular) co-morbidities, age, gender and race; (ii) side-effects, such as postural dizziness should be monitored closely, particularly in elderly, diabetics and patients with arterial stiffness; (iii) the importance of salt restriction should not be neglected; (iv) although angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blocker (ARBs) remain a cornerstone in the management of hypertension, and especially cardiovascular protection, in some particular situations such as in advanced CKD and in patients without proteinuria, their role is less well defined; (v) as most CKD patients need more than one antihypertensive drug to achieve blood pressure control, the specific (renal) (dis)advantages of other classes than ACE-I or ARB should be taken into account.

Controversies in timing of dialysis initiation and the role of race and demographics.

Dialysis remains the predominant form of renal replacement therapy in the United States, but the optimal timing for the initiation of dialysis remains poorly defined. Not only clinical factors such as signs/symptoms of uremia, co-existing cardiovascular disease, and presence of diabetes but also key demographic characteristics including age, gender, race/ethnicity, and socioeconomics have all been considered as potential modifying factors in the decision for the timing of dialysis initiation. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of chronic kidney disease (CKD) suggests that dialysis be initiated when signs/symptoms attributable to kidney failure such as serositis, acid-base or electrolyte abnormalities, pruritus, poorly controlled volume status or blood pressure, deteriorating nutritional status despite dietary intervention, or cognitive impairment are visible or noted. These signs/symptoms typically occur when the glomerular filtration rate (GFR) is in the range of 5-10 ml/minute/1.73 m(2) , although they may occur at higher levels of GFR. We review recent data on the timing of dialysis initiation, their implications for managing patients with late-stage CKD, and the important role of considering key demographics in making patient-centered decisions for the timing of dialysis initiation.

Substantial practice variation exists in the management of childhood nephrotic syndrome

Practice variation is common for nephrotic syndrome (NS) treatment. A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS. Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4 weeks by 26 %, and 10 % prescribed 'other'. Alternate-day GC was continued for 6 weeks by 63 % of respondents and for >6 and <6 weeks by 32 and 6 %, respectively. For biopsy-confirmed minimal change disease, 65 and 46 % of respondents chose oral cyclophosphamide for frequently relapsing and steroid-dependent phenotypes, respectively; calcineurin inhibitors or mycophenolate were the second most popular choices. Kidney biopsy was 'always' performed by 16, 39, and 97 % of respondents for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Rituximab had been administered by 60 % of respondents; 22, 56, and 72 % reported that they would consider rituximab for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Most notable differences between practice and Guideline recommendations were first presentation GC duration, GC-sparing agent choices in frequently relapsing and steroid-dependent patients, and biopsy practices. There is substantial Canadian practice variation in NS treatment. Assessment of factors driving variation and strategies to implement Guideline recommendations are needed.

Treatment of idiopathic membranous nephropathy

Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.

Hemostasis in patients with acute kidney injury secondary to acute liver failure

Acute kidney injury (AKI) occurs in over half of patients with acute liver failure. Despite prolonged prothrombin times and thrombocytopenia, continuous renal replacement therapy circuits frequently develop clots during patient treatment. Here we assessed factors contributing to this by measuring coagulation parameters (standard coagulation tests, pro- and anticoagulant factors, thromboelastography, and thrombin generation) in 20 consecutive patients with acute liver failure; mean age 42 years. Within 48 h, 10 had developed stage 3 AKI and 9 required continuous renal replacement therapy, of whom 2 had frequent circuit clots. The patients with stage 3 AKI were found to have significantly lower platelet counts and levels of factor V and the natural anticoagulants antithrombin, Protein C and Protein S, but increased extrinsic pathway activation and von Willebrand factor levels. Tissue factor levels were greater in those with stage 3 AKI, as was microparticle activity. Although patients with acute liver failure and advanced AKI requiring continuous renal replacement therapy have an even more marked thrombocytopenia and more prolonged extrinsic pathway activation, this was not associated with increased bleeding. Thus, more frequent circuit clots during continuous renal replacement therapy appear to be due to a combination of increased tissue factor and microparticle release, endothelial activation, and reduction in natural anticoagulants.

RRT treatment for AKI: is more always better?

Acute kidney injury (AKI) is an increasingly common condition, occurring in up to 25% of critically ill patients admitted to the intensive care unit (ICU) [1]. It is associated with significant morbidity and up to 60% in-hospital mortality in its most severe form, necessitating renal replacement therapy (RRT) [2]. In the absence of effective pharmacological therapy, the treatment of patients with AKI is predominantly supportive, managing haemodynamic and volume status, correcting electrolyte and acid–base disturbances, providing adequate nutrition and adjusting drug doses. In patients with sustained, severe renal failure, RRT is indicated for the management of volume overload, hyperkalaemia, acidosis and symptoms of uraemia while awaiting the recovery of kidney function. Most clinicians are convinced that RRT is life saving and not starting RRT will lead to death in severely ill AKI patients, but data are lacking to support this opinion. Conservative treatment for AKI has only been considered as the treatment option for less severe patients. In recent years, several controlled studies [3–7] and metaanalysis [8–10 ]s howed similar benefit with continuous and intermittent dialysis modalities. Critics of the published studies, however, pointed to different shortcomings in these studies [11, 12]. However, hard data remain absent or conflictive regarding when to start dialytic therapy and what constitutes the appropriate dose [13]. In 2011, the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for AKI was developed, aiming to assist practitioners caring for adults and children at risk for or with AKI [14]. They recommend to initiate RRT emergently when life-threatening changes in fluid, electrolyte and acid–base balance exist. Continuous RRT (CRRT) and intermittent RRT (IRRT) are considered as complementary therapies, but they suggest using CRRT, rather than standard IRRT, for haemodynamically unstable patients. The dose of RRT to be delivered should be prescribed before starting each session of RRT. KDIGO recommend delivering a Kt/V of 3.9/week when using IRRT or extended RRT and an effluent volume of 20–25 mL/kg/h for CRRT. This will usually require a higher prescription of effluent volume. Numerous modalities of RRT can be used in the treatment of patients with AKI. These include various modalities of intermittent haemodialysis (IHD), of CRRT, ‘hybrid’ modalities such as sustained low-efficiency dialysis (SLED), that combine aspects of both conventional IHD and CRRT, and peritoneal dialysis. Although there are many arguments favouring the use of continuous therapies in critically ill patients with AKI [15], the predominance of current evidence does not support a benefit of CRRT compared with IRRT. Nonetheless, the use of CRRT versus IRRT remains a subject of ongoing controversy, in particular because studies of modality must

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.

Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1-18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.

Hypertension after kidney transplantation

Hypertension after kidney transplantation

Current status of renal and urinary proteomics: ready for routine clinical application?

4. Newsome BB, Warnock DG, McClellan WM et al. Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med 2008; 168: 609–616 5. Coca SG, Yusuf B, Shlipak MG et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009; 53: 961–973 6. Warnock DG. Towards a definition and classification of acute kidney injury. J Am Soc Nephrol 2005; 16: 3149–3150 7. Morcos SK, Thomsen HS, Webb JA. Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol 1999; 9: 1602–1613 8. DuBose TD Jr, Warnock DG, Mehta RL et al. Acute renal failure in the 21st century: recommendations for management and outcomes assessment. Am J Kidney Dis 1997; 29: 793–799 9. American Society of Nephrology. American Society of Nephrology Renal Research Report. J Am Soc Nephrol 2005; 16: 1886–1903 10. Kellum JA, Mehta RL, Ronco C. Acute dialysis quality initiative (ADQI). Contrib Nephrol 2001; 258–265 11. Kellum JA, Bellomo R, Ronco C et al. The 3rd International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI). Int J Artif Organs 2005; 28: 441–444 12. Bellomo R, Kellum JA, Ronco C. Defining acute renal failure: physiological principles. Intensive Care Med 2004; 30: 33–37 13. Bellomo R, Ronco C, Kellum JA et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212 14. Mehta RL, Kellum JA, Shah SV et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31 15. Zoltan E, Pickering J. Outcome definitions in non-dialysis intervention and prevention trials in acute kidney injury (AKI). Nephrol Dial Transplant 2009; 25: 107–118 16. Coca SG, Parikh CR. Urinary biomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol 2008; 3: 481– 490 17. Eknoyan G, Lameire N, Barsoum R et al. The burden of kidney disease: improving global outcomes. Kidney Int 2004; 66: 1310– 1314 18. KDIGO. Clinical practice guidelines. Kidney disease: improving global outcomes clinical practice guidelines on acute kidney injury 2009. http://www.kdigo.org/clinical_practice_guidelines_3.php (October 20, 2009, date last accessed)

Medical Care of Kidney Transplant Recipients after the First Posttransplant Year

Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded-criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease, infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions, and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Outcomes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the contemporary aspects of care for these patients.

411 Pharmacodynamic evaluation of the mTOR inhibitor AP23573 in phase 1 clinical trials

The pharmacology of the sirolimus and their use in renal transplant recipients are discussed here. In majority of the transplant centers, sirolimus whole-blood concentrations are measured by enzyme-linked immunoassays and high-performance liquid chromatography (HPLC) with ultraviolet or mass spectrometry detection. HPLC measures the parent drug and is very accurate but time-consuming. The recommended time for collection is 1 h prior to the next oral dose. Because of metabolic interactions, sirolimus should be given 4 h after cyclosporine, whereas sirolimus and Tacrolimus can be given simultaneously. The target sirolimus levels should be 5–15 ng/mL depending on immunologic risk, time of conversion and other immunosuppressive drugs. Sirolimus trough concentrations >15 ng/mL have been correlated with side effects such as hypertriglyceridemia, thrombocytopenia, and leukopenia. The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for the care of kidney transplant recipients suggest monitoring sirolimus levels (2C). KDIGO recommend that if sirolimus is used, they should not be started until graft function is established and surgical wounds are healed (1B). KDIGO recommend that the combined use of sirolimus and calcineurin inhibitor (CNI) should be avoided, because they potentiate nephrotoxicity, particularly if used in the early period following transplantation. Conversion from CNI to sirolimus is generally not recommended when proteinuria >800 mg/day, acute rejection during the 3 months before conversion, estimated GFR < 40 mL/min, acute Banff 2A at any time post-transplant and dyslipidemia despite lipid lowering agents.