New Insight into CNI Nephropathy

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Brian Stephany, MD
Brian Stephany, MD
Endothelial dysfunction may have a role in hyperlipidemia-linked calcineurin inhibitor nephropathy.

The Achilles heel of solid organ transplantation is progressive CKD. Although transplant-associated renal dysfunction is often multifactorial, calcineurin inhibitor (CNI) nephrotoxicity is thought to be a major contributor. Chronic allograft nephropathy is the most common cause of late renal allograft loss, due in large part to CNI toxicity.

Similarly, heart, liver, and lung transplant patients experience native CKD at rates as high as 20% within five years (N Engl J Med. 2003;349:931-940) in the setting of chronic CNI exposure. Acutely, CNIs induce kidney damage by causing renal hypoperfusion, which results in reduced glomerular filtration rate (GFR).

Mechanistic studies of CNI-treated subjects have demonstrated an imbalance of endothelium-derived constricting and relaxing factors favoring relative vasoconstriction (J Lab Clin Med. 1995;125:113-119 and J Cardiovasc Pharmacol. 2007;50:399-405).

Support for this theory is demonstrated by in vitro studies showing that exposure to CNIs caused vasoconstriction of isolated rat renal arteries only in the presence of intact endothelium (J Auton Pharmacol. 2001; 21:205-210). This alteration in renal hemodynamics can be reversible upon discontinuation of the CNI. With chronic exposure, however, the reduction in renal blood flow, in addition to other direct toxic CNI effects on resident renal cells, ultimately leads to progressive irreversible kidney damage.

Given the lack of major advances in effective “kidney-friendly” immunosuppression, progressive CKD is nearly inevitable in the current era of solid organ transplantation. Thus, we and other researchers are seeking to identify novel factors that could help clinicians better stratify a patient's risk of CNI-induced CKD. These factors might also serve as targets that could be modified to reduce the deleterious effects of CNIs following solid organ transplantation.

Hyperlipidemia

In the non-transplant population, the presence of hyperlipidemia has been shown to independently associate with—and likely induce and potentiate—kidney disease. For example, epidemiologic data from the Physician's Health Study and the Atherosclerosis Risk in Communities Study (Kidney Int. 2000;58:293-301) show that aberrations in baseline lipid profiles in apparently healthy men independently predict renal dysfunction after a mean follow-up of 14 and three years, respectively.

Similarly, diabetic patients enrolled in the Early Treatment Diabetic Retinopathy Study who had dyslipidemia at time of study entry had a significantly higher risk of progressing to end-stage renal disease after controlling for other known risk factors (Kidney Int. 2004;66:1173-1179).

Finally, post hoc analysis of nondiabetic CKD patients in the Modification of Diet in Renal Disease Study found an independent association between more rapid loss of kidney function and dyslipidemia (Kidney Int. 1997;51:1908-1919).

However, few data exist regarding the association between hyperlipidemia and kidney disease in transplant patients. To investigate this, we looked at the records of all patients who received lung transplants at Cleveland Clinic dating back to 1997.

In some regard, lung transplant patients tend to be ideal subjects for the study of transplant-related kidney disease because immunologic injury to the lungs, in the absence of multisystem organ failure, does not directly impact renal function. Immunologic injury associated with kidney, cardiac, or liver allografts, however, has a definite effect on kidney function via renal interstitial inflammation, cardiorenal physiology, and hepatorenal physiology mechanisms, respectively.

Controlling for other factors known to influence progression of kidney disease in lung transplant patients, we identified the presence of hyperlipidemia very early in the transplant course as an independent predictor of faster CKD progression over a mean follow-up of 2.4 years.

Additionally, we also showed that the pace of kidney function decline within the first post-transplant month was faster in hyperlipidemic recipients. Knowing that changes in kidney function early after transplant are more likely reflective of the endothelium-dependent hemodynamic alterations induced by CNIs, we hypothesize that the presence of hyperlipidemia either induces—or is at least a marker of—endothelial dysfunction that exacerbates the renal hypoperfusion caused by CNI therapy. 

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