World Study Finds Differences in Acute Kidney Injury Characteristics, Outcomes

As ‘0by25’ Gets Moving, New Data on Global Burden of AKI

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Acute kidney injury (AKI) is a global problem affecting patients all over the world—but it’s not the same everywhere. A prospective, worldwide comparison of AKI patients revealed significant differences in patient characteristics, treatment, and outcomes between developed and emerging countries, according to a study in the Clinical Journal of the American Society of Nephrology.

Led by Ravindra Mehta, MD, of the University of California, San Diego, and Josée Bouchard, MD, of the University of Montreal, the researchers analyzed data on the characteristics, treatment patterns, and clinical outcomes in a worldwide sample of intensive care unit (ICU) patients with AKI. Patients were treated at nine ICUs in developed countries: the United States, Canada, Ireland, and Greece; and five ICUs in emerging countries: China, Brazil, and India. “This is very helpful in terms of giving at least a glimpse of what the broader issues are in terms of this highly prevalent disease,” Mehta said.

The results appear as the world nephrology community gears up for the “0by25” Initiative—a global project with the ambitious goal of eliminating preventable deaths from AKI within the next decade. Mehta is program director of the initiative.

“This immense and vanguard effort, led by Dr. Mehta, and many collaborators worldwide, will focus on establishing that AKI is a contributor to the global burden of disease, increasing awareness in the world, and developing an infrastructure for education, training and care delivery, said Mark D. Okusa, MD, FASN, of the University of Virginia School of Medicine. “Through the collaborative efforts of the global community, AKI outcomes will be markedly improved and the outlook will be much brighter.

World differences in AKI—emerging versus developed countries

Data for the CJASN study were drawn from an ongoing web-based database created by the UAB-UCSD O’Brien Core Center for Acute Kidney Injury ( Supported by The National Institute of Diabetes and Digestive and Kidney Diseases, the O’Brien Center is one of eight interdisciplinary centers of excellence in AKI-related research.

From 2008 to 2012, a total of 6647 patients were screened for inclusion. Acute kidney injury was defined by the modified AKIN creatinine criterion of 0.3 mg/dL or less within 48 hours. Of these, 1275 developed AKI within seven days after ICU admission—a rate of 19.2 percent. The incidence was similar for patients in developed and emerging countries: 19.1 versus 19.9 percent, respectively. About 62 percent of cases in developed countries were de novo AKI (without known chronic kidney disease), compared to 46 percent in emerging countries.

Complete data were available for 745 consenting patients. Bouchard and colleagues compared differences in the causes, risk factors, and course of AKI for patients from emerging versus developed countries.

The results showed some noteworthy differences in the causes of AKI: patients in emerging countries were more likely to have glomerulonephritis and acute interstitial nephritis, while those in developed countries had higher reported rates of prerenal AKI, sepsis, and acute tubular necrosis.

While the data on causes have some important limitations, the findings are consistent with differences in the exposures leading to AKI, according to Mehta. For example, patients in developing countries may be more likely to have envenomation from snake bites, or toxicity related to indigenous drugs or misuse of medications.

But the variation may also reflect differences in medical care and resources—for example, patient monitoring after septic exposures or use of contrast agents. Limited access to diagnostic testing might also be a significant contributor. “Most people in the developing world have to pay for every lab test,” Mehta said. “And if they don’t have the resources, then the lab tests may not be done or frequency of the lab tests goes down.”

He also noted that the information on causes came from case report forms asking what was documented as the potential reason for AKI. “We don’t have a clear explanation as to why there are differences or what they represent in the general population—other than simply saying that they exist and are likely conditioned by the different settings.”

Differences in AKI severity, treatment, and outcomes

Patients in developed countries tended to have less severe AKI. However, this difference became nonsignificant after exclusion of patients with chronic kidney disease.

Patients in developed countries actually received dialysis less often: about 16 percent, compared to 30 percent in emerging countries. Dialysis was also started later in developed countries, 2 versus 0 days. The duration of dialysis was similar between the two groups.

Crude hospital mortality was 22 percent overall, but substantially higher in developed countries: 28 percent, compared to 18 percent in emerging countries.

On logistic regression analysis accounting for a wide range of patient and clinical characteristics, however, residence in an emerging country was associated with more than a twofold increase in hospital mortality: odds ratio 2.32. “Unfortunately, we do not know the exact reason(s) underlying this finding,” said Bouchard. “Some of the risk factors for mortality, like a higher cumulative fluid balance, were significant in developed countries only, while the use of vasopressors was significant in emerging countries only.

“Are these related to differences in the timing, type, and amount of fluids or vasopressors used? There may also be differences in access to general and specialized care and possible confounding factors which may explain this result.” Other independent risk factors for death were older age, use of mechanical ventilation, higher APACHE score, and stage 3 AKI with renal replacement therapy.

Seventy-two percent of survivors in developed countries recovered renal function, while only 52 percent of survivors in emerging countries did so. Six percent of survivors in developed countries were dialysis dependent at hospital discharge, compared to nearly 19 percent in emerging countries.

Residence in an emerging country was also associated with nearly a threefold increase in the risk of discharge without renal recovery: odds ratio 2.91. Stage 3 AKI with renal replacement therapy was also an independent risk factor for lack of renal recovery.

The findings provide “a novel assessment of commonalities and difference in the natural history and management of mild to severe AKI”—but interpretation of those differences is far from clear-cut. For example, while the increases in AKI severity and higher use of renal replacement therapy in emerging countries may partly reflect lower baseline kidney function, there are also substantial differences in treatment patterns, including lower use of vasopressors and mechanical ventilation in emerging countries.

For patients with more severe AKI, access to high-tech care is almost certainly a contributor to the higher survival rate in developed countries. Bouchard, Mehta, and colleagues noted that in their cohort, some AKI patients in India and China had to pay for their dialysis therapy. Other patients in countries with limited resources may not have had access to optimal treatment, owing to poor prognosis or lack of resources. In these countries, the convenience sample was limited to patients from large urban centers—many more patients in outlying areas likely receive no specialized care.

Although the study focused on the ICU population, it provides new insights into the entire spectrum of the disease—including milder cases of AKI tracked forward over time. “You can see that there are obvious differences in outcomes from AKI, and what are the factors that influence how these patients are managed,” said Mehta. “And to some extent, that represents not only the inherent population differences in emerging and developed countries—but also the fact that the resources available in each setting influence how AKI patients are managed and what ultimately happens to them.”

The new research begins to address major gaps in knowledge of the worldwide burden of AKI and regional variations in its causes and treatment, Okusa said. “This paper by Bouchard et al. is highly informative, timely, focuses on the global nature of AKI and is a harbinger of a wealth of information to follow. [It] provides a glimpse into the disparities and variations in global AKI.

“However, since these studies were done in academic centers worldwide, these data likely represent an underestimate of the magnitude of variations, given that access to care may be a much greater problem in emerging countries,” Okusa said. “In emerging countries there is likely a greater degree of avoidable causes of death due to access of care, lack of resources to diagnose and treat AKI and need for greater education. By addressing these issues AKI can be largely prevented or mostly treated.”

Growing body of evidence on global burden of AKI

The results help to set the stage for the International Society of Nephrology’s 0by25 initiative, with its ambitious goal of “Zero preventable deaths from AKI by 2025”—focusing on understanding AKI and intervening to prevent adverse outcomes in low- to middle-income countries.

The study by Bouchard et al. is not a part of the 0by25 initiative—data collection began several years earlier. “But in the context of 0by25, the whole idea is that many of these cases—in poor and rich countries alike—are potentially survivable, if appropriately targeted and treated,” Mehta said. He targeted three areas that must be assessed and understood in developing effective interventions to prevent AKI deaths:

  • Environmental exposures and risks. A major goal will be to identify the environmental factors and risks that contribute to preventable mortality from AKI in low- to middle-income countries. “So for example if you don’t have access to water, sanitation, or hygiene, to what extent does that contribute to diarrheal illnesses, which in turn contribute to downstream events?” asked Mehta. “Or endemic malaria or leptospirosis—how do those things contribute?”

  • Failed recognition or inadequate resources. Failed or delayed recognition of sudden declines in kidney function is a critical contributor: “It occurs daily even in our hospitals here in the developed countries,” said Mehta, giving the example of a small rise in creatinine that is not recognized and doesn’t translate into action.

  • Lack of resources. Lack of necessary health care resources is of course a critical factor affecting the risk of death from more severe AKI. Many poor countries simply do not have dialysis facilities. In others, access is limited by cost or distance.

Addressing these factors will require understanding how they contribute to the burden of AKI on the regional as well as global level. A major 0by25 initiative is the Global AKI Snapshot—a prospective, cross-sectional study assessing the incidence of AKI in a wide range of settings worldwide. Over a 10-week period between September and December last year, “contributing nephrologists and other physicians were asked to pick one day on which they were asked to record information on any person they saw who met criteria for AKI,” Mehta said. “Then we also asked them to tell us seven days later what happened to those patients.”

Data on more than 4000 adults and children with AKI were contributed by over 320 participating centers in more than 72 countries. Data analysis is ongoing, with a final report expected to be published later this year. Some preliminary findings were presented at the ISN World Congress of Nephrology in March.

The data are “pretty striking” in demonstrating the etiologic factors contributing to AKI, according to Mehta. “Dehydration and hypotension and shock emerge as major factors across all settings, but there are differences across countries. So we have a rich data set that we are exploring further.”

Building on those findings, 0by25 investigators are now in the planning phases to implement a prospective pilot study aimed at further understanding and acting to reduce the burden of AKI in low- to middle-income countries. Teams will travel to three target regions—Africa, Asia, and Latin America—in a demonstration project to track patients with AKI, starting at the community health level. The pilot study will also include initial interventions to identify high risk patients and carry out specific interventions to improve AKI management and outcomes. Project implementation is planned for late 2015 or early 2016.