Emmanuel A. Burdmann

International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology

Executive summary Acute kidney injury (AKI) is a major contributor to poor patient outcomes. AKI occurs in about 13·3 million people per year, 85% of whom live in the developing world, and, although no direct link between AKI and death has yet been shown, AKI is thought to contribute to about 1·7 million deaths every year. The course of AKI varies with the setting in which it occurs, and the severity and duration of AKI aff ects outcomes such as dialysis requirement, renal functional recovery, and survival. Recognition is increasing for the eff ect of AKI on patients, and the resulting societal burden from its longterm eff ects, including development of chronic kidney disease and end-stage renal disease needing dialysis or trans plantation. Few systematic eff orts to manage (prevent, diagnose, and treat) AKI have been put in place and few resources have been allocated to inform health-care professionals and the public of the importance of AKI as a preventable and treatable disease. Several factors have contributed to the paucity of information. Most importantly, there have been few population-level epidemiological studies in several regions of the world. Diffi culties in defi nition of the incidence of AKI are especially evident in searches for data from low-income and middle-income countries, where more than 85% of the world’s population resides. No nationwide data collection systems are available, and data are usually from isolated centres and probably largely underestimate the true extent of AKI because they mostly do not include patients with AKI who were not able to reach a hospital for treatment. A recent metaanalysis that included 312 cohort studies and more than 49 million patients shows a scarcity of data from Africa and large parts of southeast Asia. We did an updated meta-analysis that used the most recent KDIGO (Kidney Disease: Improving Global Outcomes) defi nitions, which confi rms the high incidence and resulting outcomes of AKI, particularly in Africa, Asia, and Latin America, for which data were previously absent. The strong relation between the severity of AKI and consequent mortality is reiterated by our fi ndings and is evident across heterogeneous populations and specifi c disease cohorts. However, large gaps remain in knowledge about the factors that aff ect the geographical variation of AKI and poor outcomes. Many diff erences exist in the aetiology, pathophysiology, and management of AKI across the world. In high-income countries, AKI develops mainly in patients in hospitals. In low-income and middle-income countries, AKI occurs mainly in the community setting in acute illness, usually in association with diarrhoeal states and dehydration, infections such as malaria, and toxins (venoms and poisons). Public health issues (eg, contaminated water, poor sanitation, endemic infections such as malaria and dengue fever, venomous snakes, and toxic traditional medicines) and socioeconomic factors (eg, availability of health-care facilities) aff ect the epidemiology of AKI. Additionally availability of trained personnel and access to diagnostic tests and dialysis aff ect practice patterns and impose barriers to care. The extent to which these factors contribute to mortality and non-recovery of renal function has not been quantifi ed. AKI is potentially preventable and treatable with timely intervention, but there continues to be a high human burden. Which specifi c factors account for the poor outcomes and to what extent variations in care delivery contribute are unclear. The ability to provide lifesaving treatments for AKI provides a compelling argument to consider therapy for AKI as much of a basic right as it is to give antiretroviral drugs to treat HIV in low-resource regions, especially because care needs only be given for a Published Online March 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60126-X

Timing of Initiation and Discontinuation of Renal Replacement Therapy in AKI: Unanswered Key Questions

Patients with acute kidney injury (AKI) often require initiation of renal replacement therapy (RRT). Currently, there is wide variation worldwide on the indications for and timing of initiation and discontinuation of RRT for AKI. Various parameters for metabolic, solute, and fluid control are generally used to guide the initiation and discontinuation of therapy; however, there are currently no standards in this field. Members of the recently established Acute Kidney Injury Network, representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI, participated in a 3-d conference in Vancouver in September 2006 to evaluate the available literature on this topic and draft consensus recommendations for research studies in this area. Key questions included the following: what are the indications for RRT, when should acute RRT support be initiated, and when should RRT be stopped? This report summarizes the available evidence and describes in detail the key questions, and some of the methods of answering them that will need to be addressed with the goal of standardizing the care of patients with AKI and improving outcomes.

Prevalence and Risk Factors for Aminoglycoside Nephrotoxicity in Intensive Care Units

ABSTRACT In order to assess the prevalence of and risk factors for aminoglycoside-associated nephrotoxicity in intensive care units (ICUs), we evaluated 360 consecutive patients starting aminoglycoside therapy in an ICU. The patients had a baseline calculated glomerular filtration rate (cGFR) of ≥30 ml/min/1.73 m2. Among these patients, 209 (58%) developed aminoglycoside-associated nephrotoxicity (the acute kidney injury [AKI] group, which consisted of individuals with a decrease in cGFR of >20% from the baseline cGFR), while 151 did not (non-AKI group). Both groups had similar baseline cGFRs. The AKI group developed a lower cGFR nadir (45 ± 27 versus 79 ± 39 ml/min/1.73 m2 for the non-AKI group; P < 0.001); was older (56 ± 18 years versus 52 ± 19 years for the non-AKI group; P = 0.033); had a higher prevalence of diabetes (19.6% versus 9.3% for the non-AKI group; P = 0.007); was more frequently treated with other nephrotoxic drugs (51% versus 38% for the non-AKI group; P = 0.024); used iodinated contrast more frequently (18% versus 8% for the non-AKI group; P = 0.0054); and showed a higher prevalence of hypotension (63% versus 44% for the non-AKI group; P = 0.0003), shock (56% versus 31% for the non-AKI group; P < 0.0001), and jaundice (19% versus 8% for the non-AKI group; P = 0.0036). The mortality rate was 44.5% for the AKI group and 29.1% for the non-AKI group (P = 0.0031). A logistic regression model identified as significant (P < 0.05) the following independent factors that affected aminoglycoside-associated nephrotoxicity: a baseline cGFR of <60 ml/min/1.73 m2 (odds ratio [OR], 0.42), diabetes (OR, 2.13), treatment with other nephrotoxins (OR, 1.61) or iodinated contrast (OR, 2.13), and hypotension (OR, 1.83). In conclusion, AKI was frequent among ICU patients receiving an aminoglycoside, and it was associated with a high rate of mortality. The presence of diabetes or hypotension and the use of other nephrotoxic drugs and iodinated contrast were independent risk factors for the development of aminoglycoside-associated nephrotoxicity.

Acute kidney injury: global health alert

Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional, and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high-risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians, and other health-care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI.

Cyclosporine-induced interstitial fibrosis and arteriolar TGF-β expression with preserved renal blood flow

BACKGROUND Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by interstitial fibrosis and afferent arteriole hyalinosis. CsA lesion has been linked to maintained renal vasoconstriction and narrowing of the afferent arteriole lumen diameter, leading to preglomerular ischemia. We investigated the role of renal hemodynamics in CsA-induced transforming growth factor (TGF-beta) expression and interstitial fibrosis. METHODS Groups of rats fed a low salt diet were given CsA 5 mg/kg/day (CsA) or the vehicle (olive oil, [VH]) s.c. and had the renal blood flow (RBF), glomerular filtration rate (GFR), mean arterial pressure, renal vascular resistance, renal histologic changes, and immunohistochemical features for macrophages and TGF-beta evaluated after 1, 2, and 8 weeks of treatment. RESULTS At week 1, despite normal renal hemodynamics and MAP, there was a significant macrophage interstitial influx in CsA-treated rats (70+/-16 vs. 29+/-4 cells+/0.5 mm2, in CsA vs. VH, P=0.02) that was progressive with treatment (80+/-13 vs. 32+/-8 cells+/0.5 mm2, P=0.016 and 197+/-36 vs. 23+/-3 cells+/0.5 mm2, P=0.0002, CsA vs. VH at 2 and 8 weeks, respectively). After 2 weeks of treatment, CsA animals developed a significant interstitial fibrosis, with preserved RBF, even when it was assessed 2 hr after CsA injection. There was a significant increase in the immunostaining for TGF-beta in the juxtaglomerular arterioles in CsA-treated rats (48.6+/-3.8 vs. 35.1+/-1.1%, CsA vs. VH at 2 weeks, P<0.05 and 59.0+/-3.2 vs. 37.0+/-2.1%, CsA vs. VH at 8 weeks, P=0.0001). A significant and progressive GFR decrease followed the renal structural injury of CsA treatment. Arteriolar and glomerular anatomic injury were not found throughout the study. CONCLUSIONS Low CsA doses might generate interstitial fibrosis without any decrease in RBF or structural arteriolar lesion evidence, possibly through early macrophage influx and increased TGF-beta expression. It clearly seems that CsA-induced ischemia and tubulointerstitial injury may occur independently, suggesting that chronic CsA nephrotoxicity may be very hard to prevent or even not be preventable at all.

Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study

BACKGROUND Epidemiological data for acute kidney injury are scarce, especially in low-income countries (LICs) and lower-middle-income countries (LMICs). We aimed to assess regional differences in acute kidney injury recognition, management, and outcomes. METHODS In this multinational cross-sectional study, 322 physicians from 289 centres in 72 countries collected prospective data for paediatric and adult patients with confirmed acute kidney injury in hospital and non-hospital settings who met criteria for acute kidney injury. Signs and symptoms at presentation, comorbidities, risk factors for acute kidney injury, and process-of-care data were obtained at the start of acute kidney injury, and need for dialysis, renal recovery, and mortality recorded at 7 days, and at hospital discharge or death, whichever came earlier. We classified countries into high-income countries (HICs), upper-middle-income countries (UMICs), and combined LICs and LMICs (LLMICs) according to their 2014 gross national income per person. FINDINGS Between Sept 29 and Dec 7, 2014, data were collected from 4018 patients. 2337 (58%) patients developed community-acquired acute kidney injury, with 889 (80%) of 1118 patients in LLMICs, 815 (51%) of 1594 in UMICs, and 663 (51%) of 1241 in HICs (for HICs vs UMICs p=0.33; p<0.0001 for all other comparisons). Hypotension (1615 [40%] patients) and dehydration (1536 [38%] patients) were the most common causes of acute kidney injury. Dehydration was the most frequent cause of acute kidney injury in LLMICs (526 [46%] of 1153 vs 518 [32%] of 1605 in UMICs vs 492 [39%] of 1260 in HICs) and hypotension in HICs (564 [45%] of 1260 vs 611 [38%%] of 1605 in UMICs vs 440 [38%] of 1153 LLMICs). Mortality at 7 days was 423 (11%) of 3855, and was higher in LLMICs (129 [12%] of 1076) than in HICs (125 [10%] of 1230) and UMICs (169 [11%] of 1549). INTERPRETATION We identified common aetiological factors across all countries, which might be amenable to a standardised approach for early recognition and treatment of acute kidney injury. Study limitations include a small number of patients from outpatient settings and LICs, potentially under-representing the true burden of acute kidney injury in these areas. Additional strategies are needed to raise awareness of acute kidney injury in community health-care settings, especially in LICs. FUNDING International Society of Nephrology.

Patients with ischaemic, mixed and nephrotoxic acute tubular necrosis in the intensive care unit – a homogeneous population?

IntroductionAcute tubular necrosis (ATN) is usually studied as a single entity, without distinguishing between ischaemic, nephrotoxic and mixed aetiologies. In the present study we evaluated the characteristics and outcomes of patients with ATN by aetiological group.MethodWe conducted a retrospective comparison of clinical features, mortality rates and risk factors for mortality for the three types of ATN in patients admitted to the general intensive care unit of a university hospital between 1997 and 2000.ResultsOf 593 patients with acute renal failure, 524 (88%) were classified as having ATN. Their mean age was 58 years, 68% were male and 52% were surgical patients. The overall mortality rate was 62%. A total of 265 patients (51%) had ischaemic ATN, 201 (38%) had mixed ATN, and 58 (11%) had nephrotoxic ATN. There were no differences among groups in terms of age, sex, APACHE II score and reason for ICU admission. Multiple organ failure was more frequent among patients with ischaemic (46%) and mixed ATN (55%) than in those with nephrotoxic ATN (7%; P < 0.0001). The complications of acute renal failure (such as, gastrointestinal bleeding, acidosis, oliguria and hypervolaemia) were more prevalent in ischaemic and mixed ATN patients. Mortality was higher for ischaemic (66%; P = 0.001) and mixed ATN (63%; P = 0.0001) than for nephrotoxic ATN (38%). When ischaemic ATN patients, mixed ATN patients and all patients combined were analyzed by multivariate logistic regression, the independent factors for mortality identified were different except for oliguria, which was the only variable universally associated with death (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.64–5.49 [P = 0.0003] for ischaemic ATN; OR 1.96, 95% CI 1.04–3.68 [P = 0.036] for mixed ATN; and OR 2.53, 95% CI 1.60–3.76 [P < 0.001] for all patients combined]).ConclusionThe frequency of isolated nephrotoxic ATN was low, with ischaemic and mixed ATN accounting for almost 90% of cases. The three forms of ATN exhibited different clinical characteristics. Mortality was strikingly higher in ischaemic and mixed ATN than in nephrotoxic ATN. Although the type of ATN was not an independent predictor of death, the independent factors related to mortality were different for ischaemic, mixed and all patients combined. These data indicate that the three types of ATN represent different patient populations, which should be taken into consideration in future studies.

Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Experience

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Switch from calcineurin inhibitors to sirolimus- induced renal recovery in heart transplant recipients in the midterm follow-up

Background. Calcineurin inhibitor (CI)-based immunosuppression has prolonged the survival of heart transplant recipients. However, CI-induced renal injury remains as a major problem in these patients. Sirolimus is an immunosuppressant with no significant impact on renal function. A limited number of recent papers have showed that the switch from CI to sirolimus improved renal function in late follow-up of heart transplant patients with CI-related nephrotoxicity. Methods. Ten heart transplant recipients with CI-induced nephrotoxicity (creatinine 3.9±1.8 mg/dl) at a median of 701 (465 to 1325) days posttransplant had CI switched to sirolimus (target though levels 10 to 14 ng/ml) while mycophenolate mofetil (MMF, 3g/day) was maintained and adjusted according to white blood cell count. Results. This maneuver caused a marked decrease in serum creatinine (P<0.00001) at 30 (1.2±0.4 mg/dl), 90 (1.3±0.4 mg/dl) and 180 (1.3±0.4 mg/dl) days postconversion and a significant decrease in serum potassium levels (5.1±0.5 at baseline vs. 3.9±0.3 at 180 days, P<0.00005). After the drugs switch no changes in hemoglobin levels, white blood cell count, platelets count, blood glucose and glutamic oxaloacetic transaminase plasma levels were observed. Total cholesterol increased from 242±28 to 290±117 mg/dl (P>0.05) after 90 days and decreased to 216±58 mg/dl at day 180 (P>0.05) after statins dose adjustment. Rejection and infection rates were not modified by sirolimus. Conclusions. Conversion to a sirolimus-based immunosuppression regimen associated with MMF allowed striking renal function recovery in heart transplant recipients with calcineurin inhibitor-induced renal impairment at midterm follow-up.

The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology

Abstract Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1–9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.