Acute kidney injury (AKI) following revascularization for chronic limb ischemia is associated not only with increased risk of developing chronic kidney disease (CKD) but also with higher long-term mortality, according to a retrospective study published online December 8, 2014, ahead of print in the Journal of Vascular Surgery. 

“Our results suggest that even a small increase in serum creatinine [SCr]… is associated with worse outcomes in incident CKD and mortality. Therefore, trying to avoid factors that can cause AKI to improve long-term outcomes is imperative,” the authors say.

Nader D. Nader, MD, PhD, and colleagues from the University at Buffalo, the State University of New York (Buffalo, NY), reviewed data on 717 patients with PAD who underwent 875 endovascular or surgical revascularizations and were enrolled in the VA Western New York Healthcare System database between 2001 and 2009. Mean age was 66.2 years, 99% were men, and 89% were Caucasian. Mean BMI was 29.3 kg/m² and 46% had diabetes, 74% hypertension, 55.4% CAD, and 26.5% chronic obstructive pulmonary disease (COPD).

AKI developed in 86 patients (12%). Most had stage 1 (SCr increase ≥ 0.3 mg/dL or 50-200% from baseline; 77.9%) or stage 2 (SCr increase more than twofold from baseline; 8%) AKI. Postrevascularization AKI was more likely to be associated with older age, diabetes, low HDL cholesterol levels, CAD, and preoperative CKD (eGFR < 60 mL/min).

Mortality, CKD Increased With AKI

Over a median follow-up of 42 months, 401 patients (56%) died, including 73% of those who developed AKI and 3.6% of those who did not. Mortality risk during the 5-year period after revascularization was more than twice as high in patients with perioperative AKI than those who did not experience the complication (OR 2.09; 95% CI 1.34-3.26; P < .0001) or whose kidney function after revascularization was unknown (OR 2.33; 95% CI 1.47-3.70; P < .0001). Patients who died during follow-up were more likely to have a history of diabetes, stroke, CAD, or CKD and to have low serum albumin, lower HDL, or higher LDL cholesterol levels.

To analyze the effect of postoperative AKI on long-term development of CKD, the researchers excluded patients with underlying CKD whose SCr levels were unavailable after 3 months of follow-up. Among this cohort (n = 350), 52 patients developed CKD—42.9% of those with AKI vs 9.3% of those who did not have AKI or whose AKI status was unknown (P = .01).

Among the factors that predicted increased risk of mortality on multivariable analysis were:

• Older age
• Diabetes
• Moderate to severe CKD
• COPD
• AKI

Use of aspirin, clopidogrel, and statins was associated with reduced mortality risk.

For CKD, only AKI increased the risk and only use of ACE inhibitors/angiotensin receptor blockers decreased it.

Possible Mechanisms Behind Long-term Impact

According to the authors, several mechanisms may explain why critical limb ischemia patients with AKI after revascularization are more likely to develop persistent and progressive renal injury. Possibilities include:

• Perioperative renal hypoperfusion and ischemic injury in the setting of underlying vascular disease
• Contrast use
• Drug toxicity (eg, from antibiotics)
• Embolization

In addition, they note, “[t]hese patients may already have an underlying poor renal reserve that is unmasked by an episode of AKI in a stressful situation. Their renal function may return to baseline, once the acute stress is over, before they eventually develop CKD.”

Delayed CKD development after recovery from AKI may be due to persistent underlying vascular damage. Moreover, the investigators say, experimental studies have shown that AKI can induce tissue injury—possibility permanent—in other organs such as the heart and lungs.

The authors acknowledge that the study cohort consists mostly of older men with multiple comorbidities and so may not be reflective of the general population.

Strategies to Prevent or Curb the Impact of Renal Injury

Identification of AKI survivors with diabetes, hypertension, and lower HDL and serum albumin levels—who seem to be at highest risk for progression to CKD—“represents an important opportunity to improve care and outcomes in this population,” Dr. Nader and colleagues say.

Also needed, they note, are strategies to minimize renal failure after vascular procedures, such as:

• Avoiding dehydration, diuretic, and ACE inhibitor medications on the day of surgery
• Using isotonic contrast and as low a volume as possible
• Avoiding nonsteroidal anti-inflammatory drugs for long-term postoperative pain
• Early diagnosis and treatment of sepsis with appropriate antibiotics

In a telephone interview with TCTMD, Richard Solomon, MD, of the University of Vermont (Burlington, VT), said the current paper adds to a growing repertoire of studies showing an association between in-hospital AKI and subsequent development of CKD and increased mortality. “The more we see this in different patient cohorts, the stronger we believe the association is,” he said.

But he emphasized that it remains an association. “When you look at the patients who develop AKI, they are clearly sicker,” he noted. “They have a lot of factors that put them at risk for long-term adverse events.”

In addition, Dr. Solomon noted, the current findings do not address the proximate cause of AKI and whether it is the same in all patients.

Clinical Challenges

From a clinical standpoint, better tools are needed to diagnose AKI early, Dr. Solomon asserted. “Relying on changes in serum creatinine identifies patients too late. We need validated biomarkers to diagnose AKI within hours, much [like how] cardiologists have troponin to identify myocardial injury. Unfortunately, he observed, management of AKI is “currently a wasteland—we don’t have good strategies.”

AKI presents other clinical pitfalls as well, Dr. Solomon said. If patients recover from the acute episode, clinicians may forgo surveillance. On the other hand, if AKI persists, research has shown that physicians are far less likely to prescribe prophylactic therapies such as statins and beta-blockers.

“That is another downstream consequence of having AKI that may in part explain why the outcomes are so bad,” Dr. Solomon said. It is also an argument for referring anyone who experiences in-hospital AKI to a nephrologist for follow-up, he added.

With regard to periprocedural measures that might help forestall AKI in the first place, Dr. Solomon said he doubted they were widely followed, in part because as yet there are no randomized data supporting use of, for example, therapeutic volume expansion or statins in the PAD population.

But the main clinical message, Dr. Solomon said, is the need for aggressive therapies to prevent the progression of AKI to CKD and minimize the resulting cardiovascular risk.

Source:
Arora P, Davari-Farid S, Pourafkari L, et al. The effect of acute kidney injury after revascularization on the development of chronic kidney disease and mortality in patients with chronic limb ischemia. J Vasc Surg. 2014;Epub ahead of print.

Disclosures:

Drs. Nader and Solomon report no relevant conflicts of interest.

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