Kidney News September 2016 8#9 : Page 1

September 2016 | Vol. 8, Number 9 Urine Biomarkers May Indicate Presence of Kidney Injury in Preterm Infants By Tracy Hampton newborns have an elevated risk of devel-oping chronic kidney disease and end stage renal failure compared with term infants, and AKI may possibly contrib-ute to this risk. Although detecting AKI in new-borns is critical for their current and future health, it can be chal-lenging to achieve with current serum creatinine–based tests, in part because serum creatinine levels on postnatal day 1 reflect maternal levels, which decline over time de-pending on gestational age. Now, new research published in the Clinical Journal of the American Society of Nephrology in-dicates that several proteins are excreted differently in preterm infants with kidney injury compared with those with healthy kidneys. The biomarkers may be used to develop better diagnostics related to kid-ney health in newborns. “Having better diagnostic tests to diag-nose kidney injury can have an important impact on how we care for infants, how we prognosticate outcomes, and how we design studies to prevent and/or mitigate AKI,” said David Askenazi MD, an associ-ate professor in the University of Alabama at Birmingham’s Department of Pediatrics and director of the university’s Pediatric and Infant Center for Acute Nephrology. Using single drops of urine from 113 preterm infants (birth weight ≤1200 g and/or ≤31 weeks gestational age), Aske-nazi and his colleagues prospectively ex-amined the potential of 14 urine proteins for indicating the presence of kidney dam-age. Among the 113 infants included in the study, 28 (25%) were diagnosed with AKI. Death occurred in 13 (11.5%) in-fants. Babies with AKI had smaller birth length, were less likely to be born from mothers with preeclampsia [1/28 (4%) vs. 32/85 (38%)], and were more likely to have an umbilical artery catheter [18/28 (64%) vs. 29/85 (34%)]. The researchers found that several of the urine proteins measured during the Continued on page 2 Inside President’s Column ASN President Raymond Harris, MD, FASN, highlights 3 developments that may affect the practice of nephrology for years to come Maintenance of Certification ASN Recertification Task Force defines guiding principles and formulates initial recommendations for recertification Findings Reduced risk of kidney function decline after bariatric surgery T he field of neonatal acute kidney injury (AKI) is in its infancy, but some reports indicate that up to one-quarter of newborns in intensive care units may develop AKI, which puts them at increased risk of poor clinical outcomes and even premature death. Premature Practice Pointers Viral glomerulonephritides Policy Update Presidential candidates face off on health care After Years of Increase, CKD Prevalence Levels Off But Continued Rise in African Americans Poses Concerns By Tim O’Brien Distinguished Conversations “I hope my optimism will encourage at least one individual on the cusp of making a decision about where to go with their medical career to choose nephrology.” — Richard Glassock, MD D ata going back to the mid-1970s have suggested steady increases in the percentage of Americans with advanced chronic kidney disease (CKD). But that may be changing, as an updated data analysis finds no significant increase in CKD in the US adult population since the early 2000s, according to an updated analy-sis of population-based data. “In a reversal of prior trends, there has been no appreciable increase in the preva-lence of stage 3 and 4 CKD in the US population during the most recent decade,” concludes the new report, published by the Annals of Internal Medicine last month. It’s a welcome finding that is consistent with recent evidence of stabilization in in-cidence of end stage renal disease (ESRD). While CKD prevalence has remained sta-ble in most subgroups, the investigators strike a note of concern regarding contin-ued increase in prevalence of CKD among African Americans. Study updates nationwide data on CKD trends The study by the Centers for Disease Con-Continued on page 2

Urine Biomarkers May Indicate Presence Of Kidney Injury In Preterm Infants

Tracy Hampton

The field of neonatal acute kidney injury (AKI) is in its infancy, but some reports indicate that up to one-quarter of newborns in intensive care units may develop AKI, which puts them at increased risk of poor clinical outcomes and even premature death. Premature newborns have an elevated risk of developing chronic kidney disease and end stage renal failure compared with term infants, and AKI may possibly contribute to this risk.

Although detecting AKI in newborns is critical for their current and future health, it can be challenging to achieve with current serum creatinine–based tests, in part because serum creatinine levels on postnatal day 1 reflect maternal levels, which decline over time depending on gestational age. Now, new research published in the Clinical Journal of the American Society of Nephrology indicates that several proteins are excreted differently in preterm infants with kidney injury compared with those with healthy kidneys. The biomarkers may be used to develop better diagnostics related to kidney health in newborns.

“Having better diagnostic tests to diagnose kidney injury can have an important impact on how we care for infants, how we prognosticate outcomes, and how we design studies to prevent and/or mitigate AKI,” said David Askenazi MD, an associate professor in the University of Alabama at Birmingham’s Department of Pediatrics and director of the university’s Pediatric and Infant Center for Acute Nephrology.

Using single drops of urine from 113 preterm infants (birth weight =1200 g and/or =31 weeks gestational age), Askenazi and his colleagues prospectively examined the potential of 14 urine proteins for indicating the presence of kidney damage. Among the 113 infants included in the study, 28 (25%) were diagnosed with AKI. Death occurred in 13 (11.5%) infants. Babies with AKI had smaller birth length, were less likely to be born from mothers with preeclampsia [1/28 (4%) vs. 32/85 (38%)], and were more likely to have an umbilical artery catheter [18/28 (64%) vs. 29/85 (34%)].

The researchers found that several of the urine proteins measured during the first 4 postnatal days were good candidates for further investigation. Compared with those without AKI, those with AKI had 2. 0 times higher median levels for cystatin C, 1.8 times higher neutrophil gelatinase– associated lipocalin (NGAL), 1.7 times higher clusterin, 1.7 times higher osteopontin, and 3.7 times higher alpha glutathione S-transferase (a-GST). On the other hand, those with AKI had 1.4 times lower median epithelial growth factor (EGF) and 1.6 times lower median uromodulin than those without AKI.

Of the biomarkers that were significantly different between patients with and without AKI, all had fair discriminative capability, with the highest being uromodulin, followed by a-GST and EGF. The biomarkers with the lowest discriminative ability were clusterin and albumin.

Maximum biomarker values (or minimum for uromodulin and EGF) occurred before the diagnosis of AKI by serum creatinine criteria in 44% to 66% of infants for any given biomarker. This percentage was elevated to 78% to 85% for any given biomarker when evaluating the timing of biomarker maximum/minimum on the day before or the day of AKI diagnosis.

Although other studies have suggested that urine kidney injury molecule-1 (KIM-1) can be an early marker of AKI in premature infants, the marker was not significantly associated with serum creatinine elevation in this study. “This could be due to differences in tubular development in premature infants, or it could be that the reasons for elevation of serum creatinine were different in our cohort compared to others,” the authors wrote.

The researchers also noted that their work previously found a protective association between AKI and preeclampsia in premature infants, which was again present in this study. They explained that it is possible that preeclampsia alters the physiology of the premature kidney in a way that reduces its susceptibility to develop AKI, for example by causing episodes of ischemia pre-conditioning. Studies with larger cohorts are underway to address some of the study’s remaining questions and limitations.

“The burgeoning field of AKI urinary biomarkers has largely ignored one of the most vulnerable populations, namely verylow- birth–weight infants. This study has examined 14 multiplexed biomarkers in a relatively large cohort, confirming the results of previous smaller studies examining only a single biomarker,” said Prasad Devarajan, MD, FAAP, who was not involved with the study and is the director of the Division of Nephrology and Hypertension at Cincinnati Children’s Hospital Medical Center. “If validated in larger multicenter cohorts, these findings hold promise for the development of biomarker panels to predict neonatal AKI and its adverse outcomes, as well as to design clinical trials guided by biomarker changes.”

Additional research is needed to determine whether the candidate biomarkers predict significant clinical outcomes, including the development of chronic kidney disease, and whether interventions guided by the biomarkers can impact these outcomes. ____

Study co-authors include Rajesh Koralkar, MPH, Neha Patil, MD, Brian Halloran, MS, Namasivayam Ambalavanan, MD, and Russell Griffin, PhD.

Disclosures: All authors declare no real or perceived conflicts of interest that could affect the study design, collection, analysis and interpretation of data, writing of the report, or the decision to submit for publication. Askenazi is a speaker for the Acute Kidney Injury (AKI) foundation, Baxter, and BTG. He received a career development award from ASN. That support was critical to gathering of the data for this work.

The article, entitled “Acute Kidney Injury Urine Biomarkers in Very Low Birth Weight Infants,” is available online at cjasn.asnjournals.org/content/early/2016/07/27/CJN.13381215.abstract.

Read the full article at http://onlinedigeditions.com/article/Urine+Biomarkers+May+Indicate+Presence+Of+Kidney+Injury+In+Preterm+Infants/2580829/336403/article.html.

After Years Of Increase, CKD Prevalence Levels Off But Continued Rise In African Americans Poses Concerns

Tim O’Brien

Data going back to the mid-1970s have suggested steady increases in the percentage of Americans with advanced chronic kidney disease (CKD). But that may be changing, as an updated data analysis finds no significant increase in CKD in the US adult population since the early 2000s, according to an updated analysis of population-based data.

“In a reversal of prior trends, there has been no appreciable increase in the prevalence of stage 3 and 4 CKD in the US population during the most recent decade,” concludes the new report, published by the Annals of Internal Medicine last month.

It’s a welcome finding that is consistent with recent evidence of stabilization in incidence of end stage renal disease (ESRD). While CKD prevalence has remained stable in most subgroups, the investigators strike a note of concern regarding continued increase in prevalence of CKD among African Americans.

Study updates nationwide data on CKD trends

The study by the Centers for Disease Control and Prevention’s Chronic Kidney Disease Surveillance Team analyzed trends in CKD prevalence among US adults. The CKD Surveillance System provides a centralized source of data for use in tracking the full scope of kidney disease, including risk factors, impact on population health, and the healthcare system’s capacity for managing CKD. In addition to the CDC, the CKD Surveillance System is supported by research teams at the University of California, San Francisco, led by Neil Powe, MD, MPH, MBA; and the University of Michigan, Ann Arbor, led by Rajiv Saran, MD.

The CKD Surveillance Team analyzed National Health and Nutrition Examination Survey (NHANES) data from 1988 to 1994, and every two years from 1999 to 2012. Stage 3 or 4 CKD was defined as an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2. The eGFR estimates were derived from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, using calibrated serum creatinine measurements.

The study was supported by the Centers for Disease Control and Prevention and the National Institutes of Health. In addition, lead author Daniel Murphy, MD— previously a UCSF medical student, now a resident at the University of Minnesota— received support from the American Society of Nephrology Foundation for Kidney Research Student Scholar Grant Program.

The results suggest a steady increase in the percentage of Americans with CKD from the late 1980s through the early 2000s. The crude prevalence of stage 3 or 4 CKD rose from 4.8% in 1988–94, to 5. 3% in 1999–2000, to 6.4% in 2001–02, to 6.9% in 2003–04.

Since then, there has been no further change in CKD prevalence. From NHANES 2005–06 to 2011–12, the figures have remained in the range of 6.4% to 6.9%.

While prevalence leveled off across age groups, estimates were substantially higher in older Americans. In 2011–12, the figures were 3.8% in participants aged 40 to 64 years, 21.7% in those aged 65 to 79, and 51.1% in those aged 80 years and older. The pattern was similar for participants with and without diabetes—peak prevalences were about 19% and 5%, respectively.

In non-Hispanic white participants, the figures followed the overall population trend: peaking at about 8% in 2005–06 and remaining stable thereafter.

However, there was evidence of a continued increase in prevalence among non- Hispanic blacks: from 3.7% in 1988–94, to 4.9% in 2003–04, to 6.2% in 2011–12. All of these patterns—including the persistent rise in CKD among non-Hispanic blacks—persisted in adjusted analyses.

A secondary outcome evaluated the complete spectrum of CKD stages (1 to 5), including individuals with eGFR of 60 mL/ min/1.73 m2 or higher who had a marker of kidney damage (urine-to-creatinine ratio of 30 mg/g or higher). The results showed a similar pattern: starting in the early 2000s, overall crude prevalence remained stable at about 14%, while the adjusted prevalence decreased slightly.

As in the main analysis, the prevalence of CKD (all stages) continues to increase among the non-Hispanic black population, although there was no statistically significant interaction. Similar patterns also prevailed in a sensitivity analysis using the Modification of Diet in Renal Disease (MDRD) Study equation to calculate eGFR.

Stabilization is consistent with trends in ESRD

Because nearly all cases of ESRD are preceded by CKD, reducing the prevalence of CKD would seem to be a critical step toward reducing the number of cases of ESRD. After decades of increases, the incidence of ESRD has decreased since the early 2000s. According to the 2015 US Renal Data System report, the adjusted incidence rate of ESRD decreased from 386 cases per million persons per year in 2003 to 351 per million in 2013. “There is no room for complacency however,” added Saran, who is Director of the USRDS Coordinating Center. “Falling mortality rates in the general population could affect future prevalence of CKD in an aging population or in specific subgroups, and should continue to be monitored closely along with intensive efforts at prevention, earlier detection, and management.”

Previous reports have suggested continued increases in the prevalence of CKD— by up to 5% per year. However, these studies have not incorporated data from more recent years.

Of course the analysis of NHANES data can’t explain why CKD prevalence has flattened out—but recent improvements in medical management seem likely to play a role, according to an accompanying editorial by Linda F. Fried, MD, MPH, and Paul M. Palevsky, MD, of the University of Pittsburgh. “One can speculate that it is related to improvements in blood pressure and glycemic control among high-risk persons and increased use of medications blocking the renin-angiotensin system in patients with proteinuria,” Drs. Fried and Palevsky write. “If so, this would support intensified efforts to increase awareness and treatment of persons with CKD.”

“When you’re trying to decrease ESRD, the first thing you want to do is decrease the prevalence of earlier stages of the disease in addition to slowing progression of disease,” Powe commented. “This reversal of the trend of rising CKD rates should ultimately mean less end stage renal failure and its morbid consequences and excess mortality. The kidney disease community should be commended for this scientific progress.” The researchers note evidence of similar trends in CKD from other countries, notably including England.

“For nephrologists, it’s exciting to have these data supporting the effectiveness of our interventions to prevent and slow the progression of CKD,” commented Chi-yuan Hsu, MD, of UCSF—along with Powe, one of the study’s senior authors. “Our efforts are paying off in terms of combating kidney disease in the population.”

Meanwhile, the apparent continued increase in CKD prevalence among African Americans is a major concern. “This is the group with the highest risk of developing end stage kidney disease, and needing to have kidney replacement therapy,” Powe said. “African Americans have two to three times the risk of developing end stage kidney failure than any other racial or ethnic group. Genetics, quality of care and environmental factors together probably play a role.”

The new finding occurs against the backdrop of known racial differences in the progression from CKD to ESRD, as well as recent data on the genetic factors (i. e., APOL1 gene variants) contributing to racial differences in CKD risk. Ongoing research is needed—particularly in light of recent data showing that, while ESRD incidence remains higher in the black population, it has decreased much faster than in whites. The CKD Surveillance Team calls for “careful monitoring” of CKD in the African American population, as well as studies to understand the pathophysiology of advanced CKD in blacks.

“These findings highlight the importance of getting all eligible patients into proper treatment for their conditions,” Hsu said. “As nephrologists, we have a real opportunity to promote better CKD awareness and care among internists and primary care physicians who really provide most of the care antecedent to development of CKD, as well as much of the care given to diagnosed CKD patients.”

Read the full article at http://onlinedigeditions.com/article/After+Years+Of+Increase%2C+CKD+Prevalence+Levels+Off+But+Continued+Rise+In+African+Americans+Poses+Concerns/2580838/336403/article.html.

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