As diabetic CKD takes toll, work on tests continues

That is what Dr. Miller and the NKDEP Laboratory Working Group are working on now.

“The focus is to collaborate with NIST [National Institute of Standards and Technology] and the renal reference laboratory at the Mayo Clinic to develop a reference measurement procedure and reference materials that can be used with a standardization scheme with the manufacturers to improve agreement among different measurement procedures,” he tells CAP TODAY. “That is still two to three years away.”

Following that is the implementation challenge among manufacturers, “which itself can take several years.”

Standardizing urine albumin is critical because “the cutpoint that is used to discriminate between low-normal and moderately elevated is fixed at a value of 30 mg/g of creatinine,” Dr. Miller says. “There is a lot of evidence that a lower cutpoint is suitable and that there should be different cutpoints for men and women. But right now, the variability among methods is too great to allow that distinction to be made. Once we standardize, we can get a more uniform assessment of patient status. Then we will be able to consider lower thresholds for identifying patients at increased risk, and identify them a little sooner and undertake treatment earlier.”

Despite the lack of standardization with urine albumin, Dr. Miller said a urine-collection controversy with regard to testing that analyte can be put to rest. Another study based on NHANES data found that just 44 percent of those showing elevated urine albumins based on urine samples collected at any time of the day were confirmed by a second sample collected at the first morning void (Saydah SH, et al. Clin Chem. 2013;59[4]:675–683). Other research has shown the first morning void sample is equivalent in accuracy to a 24-hour collection.

“This suggests that when patients go to the outpatient physician to get evaluated for their urine albumin-to-creatinine ratio, they should always come back and confirm with a first morning void sample,” Dr. Miller said.

Several speakers at the session, and a questioner from the audience, said the kidney-function tests now available are not being put to their best use by clinicians and health systems. While guidelines call for patients with diabetes to have their kidney function tested annually, or sooner if their medication is changed, Dr. Tuttle said research has found that even well-functioning health systems fail to meet that goal roughly half the time. It is unclear how well her clinical colleagues at Providence Health Care are doing in ordering this recommended testing, she said.

“The way you know how you’re doing is by measuring,” she said in an interview. Providence recently created a CKD registry that identifies those at high risk of progression, such as patients with diabetes and hypertension.

“When we are able to pull out the group with diabetes, we can ask what the rates of recommended testing are,” Dr. Tuttle adds. “We tried to align that by creating a diabetes order set, and after that point we did see an uptick in people being properly tested.” A final analysis of before-and-after improvement has not yet been conducted.

For his part, Dr. Narva drew on his experience as director of the kidney disease program for the Indian Health Service (IHS). He still serves as chief clinical consultant for nephrology for IHS and conducts a telemedicine clinic at the Zuni IHS hospital in New Mexico from his office at the NIH.

“When I started with IHS, the Am-erican-Indian population had four times the incidence rate of Caucasians for end-stage renal disease. Implementing care in a systematic way in the Indian Health Service has been associated with a decrease in the incidence rate of end-stage renal disease among diabetics of about 35 percent,” Dr. Narva said. “The incidence rate of end-stage renal disease has gone from four times the white rate to almost identical to the white rate. And that’s with a rate of spending that’s 40 percent lower than the rest of the U.S. population and with no novel therapy.”

He said that about 60 percent of patients with diabetes have been screened with a creatinine/eGFR and a urine ACR within the past 12 months. Use of ACE inhibitors to control blood pressure and avoiding nephrotoxic drugs are other elements of the evidence-based interdisciplinary approach.

Improving implementation of current testing and therapies also is at the heart of a pragmatic clinical trial launched in April and funded by the National Institutes of Health. The Improving Chronic Disease Management With Pieces, or ICD-Pieces, trial involves using pharmacist and nurse care managers to help coordinate care for patients with type 2 diabetes, CKD, and hypertension. Proper testing and use of laboratory data are key elements of the trial, Dr. Narva tells CAP TODAY. More information about the trial is available at https://bit.ly/icd-pieces.

While work proceeds to improve the use of available kidney-function tests, the limitations of those biomarkers make it harder for researchers to make progress on the therapeutic front, Dr. Tuttle said.

Aside from issues with imprecision, both eGFRcreatinine and the urine ACR are prone to “a lot of intraindividual variability day to day,” she said. “That’s particularly true in the setting where the urine albumin-to-creatinine ratio goes up with intermittent illnesses such as fever, influenza, and exacerbation of heart failure that occurs so commonly in people with diabetic kidney disease.” She estimates there is intraindividual variation in results of about 40 percent from such factors.

With regard to eGFR what is most important to clinicians is not a single reported number but how that number varies with time, Dr. Tuttle said. As an estimate, after all, there is only an 80 to 90 percent chance that a given eGFR will be within 30 percent of the patient’s measured GFR.

“We just need to know these are ballpark estimates,” she said. “What’s still important is the ballpark they’re in and whether they’re progressing.”

As mentioned earlier, diabetic patients will see their GFR spike before falling. However, eGFRs above 60 are not reliable.

“There’s a stage of hyperfiltration before decline and we can’t detect that,” Dr. Tuttle said. “There’s a lot of debate about what that means, but I think most experts would agree that patients with higher GFRs are the highest-risk patients, paradoxically, for long-term GFR loss, and we are not able to detect them by clinical methods at this time.”

On the therapeutic front, Dr. Tuttle painted a resolute portrait.

“We have not had a new, approved therapy for diabetic kidney disease in 15 years,” she said. “The last approval was for ARBs [angiotensin II receptor blockers] in type 2 diabetes characterized by macroalbuminuria. There is tremendous preclinical and experimental science that’s pointed us in many mechanistic directions. But for various reasons, there has been a failure in clinical translation.”

She showed a slide listing more than three dozen novel therapies that have been investigated (“that’s all I could fit on here,” Dr. Tuttle said). Many are still under study, while others were terminated for safety, regulatory, or business reasons.

“To me, what that list looks like is a Jackson Pollock painting,” she said. “It’s kind of pretty in its own way, but I’m not sure where we’re going.”

The lack of biomarkers for diagnosis, prognosis, and action have proved to be a major barrier in translation research, she said. That having been said, Dr. Tuttle presented research that she and her colleagues have done on the JAK/STAT signal transduction pathway where inflammation is overexpressed in humans with diabetic kidney disease. And if it is overexpressed in mice, they “develop a very human-looking form of diabetic kidney disease,” she said.

Partnering with Eli Lilly, which already markets the JAK1/2-inhibitor baricitinib for treatment of rheumatoid arthritis, the researchers did a phase two clinical trial with 129 patients with type 2 diabetes, median macroalbuminuria of 1,800 mg/g, and eGFR of 57. Four-mg doses of the drug appeared to be effective over three months, reducing the urine ACR, at the median, by about 0.3-fold from baseline while the ACR among patients taking placebo rose. The results could lead to a phase three trial, Dr. Tuttle said.

Another inflammatory pathway in diabetes that Dr. Tuttle and her colleagues are investigating is serum amyloid A. Plasma levels of SAA are higher in patients with DKD, and the kidney tissue of those with type 1 and type 2 diabetes shows obvious immunohistochemical staining due to the kidney disease (Anderberg RJ, et al. Lab Invest. 2015;95[3]:250–262). A paper recently published in the Journal of Diabetes and Its Complications (Dieter BP, et al. Published online ahead of print July 27, 2016. doi:10.1016/j.jdiacomp.2016.07.018) shows that patients in the highest third of SAA levels—more than 1 mg/mL—have three times the risk of death and end-stage renal disease when compared with patients in the lowest third of SAA levels of 0.55 mg/mL or lower.

Those findings suggest that SAA could have prognostic value, while correlation of higher SAA blood levels and lower eGFR independent of other DKD risk factors could offer predictive value. Last, Dr. Tuttle said, SAA could be actionable because JAK2 regulates SAA expression in the kidney.

“That’s just a preview,” Dr. Tuttle said. “Other people have their favorite biomarkers. But I think that it gives us hope that maybe some day we’ll go beyond albuminuria and eGFR not only to risk-stratify people but to identify patients who are at high risk where we can predict a certain therapeutic response and we can use those actionable biomarkers to measure whether or not the patient is improving and whether we’re hitting the target as a result of our therapy.”

David Sacks, MB, ChB, FRCPath, senior investigator at the National Institutes of Health and chief of clinical chemistry at NIH Clinical Center, convened and moderated the AACC panel discussion. He described Dr. Tuttle’s presentation as “very interesting,” while noting that “some of her stuff is in a very preliminary stage and is not going to be translated into patient care in the next few years.”

“What she’s doing is what’s necessary, often, to understand the pathophysiology of disease, in order to comprehend where the breakdown is and what’s causing the problem,” Dr. Sacks added. “Once you understand what is disrupted and what goes awry in disease, then you can try to fix the problem. . . . I look at it as a piece of the jigsaw puzzle. Other people are identifying other pieces. Then someone will presumably put everything together, but it’s going to take a long time.” 

Kevin B. O’Reilly is CAP TODAY senior editor.