Basic Science Helps Decode the AKI to CKD Transition

Until recently, nephrologists may have underappreciated the risks that acute kidney injury (AKI) poses to long-term kidney health. But a raft of clinical and epidemiological studies has shown that AKI greatly increases the risk of chronic kidney disease (CKD), end stage renal disease, and death (Coca SG, et al. Kidney Int 2012; 81:442–448).

“There has been a dramatic shift in our understanding of potential patient outcomes following AKI,” said David P. Basile, PhD, associate professor of medicine at Indiana University in Indianapolis, during a symposium at Kidney Week 2016.

A growing understanding of the molecular mechanisms underlying the continuum between AKI and CKD is helping nephrologists better understand why some patients with AKI never fully recover. The discoveries may one day help identify patients with AKI at risk of CKD and lead to kidney-protective AKI interventions.

Capillary loss

A rat model of what was thought to be “reversible AKI” first led Basile and his colleagues to discover permanent vascular damage that could lead to CKD. The rats undergo an ischemia reperfusion injury, and closer study revealed that not all the rats return to normal (Basile D, et al. Am J Physiol 2001; 281:F887–899).

“Renal blood vessels are permanently reduced following recovery,” he explained. “The vascular network is significantly compromised.”

Now, many investigators are studying vascular loss in AKI. Studies of tissue samples from patients with AKI have also revealed decreased peritubular vascular density and the development of fibrosis, Basile noted.

“We knew very little about what was going on with vessel loss,” Basile noted. But recent studies have shown that ischemia leads to the loss of endothelial cells then a gradual reduction of capillaries during the period after AKI when the kidney usually recovers (Ehling J, et al. J Am Soc Nephrol 2016; 27:520–532).

“While the rest of the kidney is putting itself back together, the vessels decline,” he said.

Animal studies now reveal that vascular damage contributes to the development of fibrosis, he said. This suggests there may be a window to intervene before permanent damage sets in.

“Intervention in early AKI might mitigate vascular loss,” he suggested.

Failed repair

Now, a growing body of evidence suggests that the kidney’s normal repair mechanisms may go awry and lead to an accelerated-aging like condition (Ferenbach DA and Bonventre JV. Nat Rev Nephrol 2015; 11:264–276).

Benjamin D. Humphreys, MD, PhD, chief of the division of nephrology at the Washington University School of Medicine, is one of the researchers at the cutting edge of this research. As part of the symposium, Humphreys delivered The Barry M. Brenner, MD, endowed lectureship, which recognizes the contributions of investigators like Brenner and Humphreys who have helped to nurture the careers of young nephrology investigators.

“We are interested in studying failed repair,” explained Humphreys, whose collaborator Monica Chang-Panesso, MD, presented an abstract (OR130) at Kidney Week tracing genetic factors that may inhibit kidney repair. She found that cells in the proximal tubule dedifferentiate to facilitate repair rather than relying on a population of progenitor cells.

Another collaborator, Rafael Kramann, MD, has developed a mouse model of AKI progressing to CKD. Like Basile’s rat model, Kramann’s model undergoes a loss of capillaries. The group has found that ablating kidney pericytes expressing Gli 1+, which help to regulate vascular structure and stability in the kidneys, leads to capillary loss (Kramann R. J Am Soc Neprol [published Sept. 13, 2016] pii:ASN.2016030297).

“The capillary dropout is permanent,” Humphreys said.

Already, Humphreys and his colleagues are studying experimental therapies that might prevent fibrosis. For example, they demonstrated that a small molecule that inhibits Gli2 reduces fibrosis by 60% in the AKI mouse model (Kramann R, et al. J Clin Invest 2015; 125:2935–2951).

“It is proof of principle that targeting pericytes might be a viable strategy,” said Humphreys.

Another gene of interest identified by the group is an enzyme that synthesizes retinoic acid that is up-regulated in the kidney during development. The retinoic acid may help kidney cells redifferentiate during the repair process, suggested Humphreys, and a lack of retinoic acid might contribute to failed kidney repair.

They are now studying the role of retinoic acid in human kidney organoids, which are created by coaxing stem cells into forming kidney-like structures in the laboratory. Treating the organoids with retinoic acid boosts markers of repair, but when it is absent there is capillary loss and fibrosis.

“Our data suggest that after AKI, about 80% of epithelia are able to undergo what we call successful repair, but about 20% of cells fail to repair,” said Humphreys.

In addition to highlighting his own laboratory’s research, Humphreys acknowledged the enormous contributions Brenner made to the field and urged others to follow in his footsteps as a mentor. He noted that many future department heads, division chiefs, and deans trained in Brenner’s lab. These “bright minds” were attracted there by scientific innovations made in Brenner’s lab, he said.

“It behooves all of us to support our young people to make those scientific discoveries that will improve patient care and serve to reinvigorate the field,” Humphreys said.

December 2016 (Vol 8, Issue 12)