Endothelial function link?

To test this hypothesis, we intend to prospectively study kidney and endothelial function in a group of hyperlipidemic and non-hyperlipidemic lung allograft recipients both before and after their transplant at Cleveland Clinic. Our institution is one of the busiest lung transplant centers in the country, with more than 70 transplants performed in 2007 alone. This affords an ample population to screen for clinical inquiry.

Additionally, all patients are treated per protocol exclusively using CNI-based immunosuppression and have the same target trough concentrations for the first six months post transplant. This establishes a relatively uniform patient population and avoids the possibility of a variety of competing renal risks that might otherwise confound investigation of hyperlipidemia as an independent factor.


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Tools for accuracy

We are fortunate at Cleveland Clinic to have the ability to measure GFR using a method known as urinary clearance of iothalamate. This method is accepted as one of the most accurate assessments of renal function and eliminates bias inherent in using surrogate markers of renal function such as creatinine.

Additionally, we now have available new technology that reliably measures global endothelial function. Peripheral arterial tonometry (PAT) is a novel, simple, noninvasive technique that assesses peripheral vascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia (Am Heart J. 2003;146:168-174 and Am J Cardiol. 2002;90:756-759).

This method has been validated to correlate highly with prior established but more complex methods of endothelial function testing (J Am Coll Cardiol. 2004;44 :2137-2141). Under uniform environmental conditions, a thimble-shaped PAT probe is placed on one finger of each hand and imparts a uniform pressure on the distal surface of the phalanx, thereby unloading arterial wall tension by inhibiting venous pooling and stasis.

After the PAT signal is measured at baseline from each finger, a BP cuff placed on one arm is inflated to suprasystolic levels for five minutes, then deflated with continuous bilateral PAT signal recording. A computer calculates the RH-PAT index, i.e., the ratio of the increase in digital pulse volume during the hyperemic response as detected by the probe ipsilateral to the cuff after deflation compared with baseline (normalized to the contralateral control arm). An RH-PAT index greater than 1.6 is consistent with preserved endothelial function; an index of 1.35 or less correlates best with endothelial dysfunction.

Our hypothesis is that compared with transplant patients without hyperlipidemia, transplant patients with hyperlipidemia will exhibit evidence of more endothelial dysfunction and that the severity of the endothelial dysfunction will worsen post transplant in the setting of CNI exposure.

Additionally, we hypothesize that decline in GFR post transplant will be most significant in patients with pre-transplant hyperlipidemia and will correlate closely with decline in endothelial function.

If correct, these findings could have immediate clinical impact. First, such data will provide necessary and important mechanistic explanations of how hyperlipidemia may act as an independent predictor of CKD through the accentuation of endothelial dysfunction induced by CNI exposure post lung transplantation.

Furthermore, routine measurement of vasoreactive reserve in the pre-transplant setting may identify those at greater risk for significant postoperative renal events.

Finally, this study could serve as a basis for future interventions directed at improving endothelial function in the very early post-transplant period, and such interventions could lead to overall improvement in both short-term and long-term outcomes for lung transplant recipients.

Dr. Stephany is an associate staff member in the Department of Nephrology and Hypertension at the Glickman Urological & Kidney Institute, as well as an associate staff member in the Transplantation Center at Cleveland Clinic’s main campus in Ohio.