Recent guidelines (K/DOQI) have been extensively detailed by the National Kidney Foundation and should serve as a general basis for managing all the complications of chronic kidney disease (9). Early referral to a nephrologist for implementation of the K/DOQI guidelines and pre-renal replacement therapy management should be considered to be standard of care and is strongly recommended. From a general management perspective, the poor correlation between serum creatinine and level of kidney function has become increasingly evident. The National Kidney Foundation, through the K/DOQI guidelines, have recommended that the Modification of Diet in Renal Disease (MDRD) formula for estimating GFR be applied to the serum creatinine as part of routine patient management (9). Calculators that estimate the MDRD GFR are freely available at a multitude of internet sites. For all heart and lung recipients, we recommend that an annual GFR estimation using the MDRD formula together with a urinalysis and 24-h urine protein or random urine protein/creatinine ratio be performed. Patients with an estimated GFR less than 40 mL/min, or those with proteinuria in excess of 500 mg/day (or urine protein/creatinine ratio >0.5), regardless of kidney function, should be referred for nephrological assessment. This section will focus more specifically on approaches to minimize kidney injury and retard disease progression in heart and lung recipients (Table 2). By logical extension, implementation of many of these strategies would also be expected to mitigate the risk of cardiovascular complications in this population.
Minimizing nephrotoxicity and retarding progression of renal disease
Perioperative acute renal failure
In the perioperative period, optimizing fluid management before and after transplantation is one of the essential elements required to prevent volume depletion and maintain adequate levels of renal perfusion. Attention should be given to avoidance of all potentially nephrotoxic insults including radiographic contrast. If contrast is necessary, using a smaller dye load and contrast agents with lower tonicity may be helpful. We recommend the use of either n-acetyl-cysteine or i.v. bicarbonate, both of which may attenuate the risk for contrast nephropathy when avoidance of radiocontrast is not possible (46,47). For patients who are dialysis dependent in the early post-operative period, intra-dialytic hypotension should be avoided. As it is, acute renal failure requiring dialysis after heart transplantation portends a poor outcome (48). From a dialysis treatment standpoint, there is no evidence that continuous dialysis has any advantage over intermittent dialysis in heart or lung transplantation.
Calcineurin inhibitor nephrotoxicity
Given the similar side effect profile of CyA and Tac, the choice of calcineurin inhibition for heart and lung transplantation is predominantly based on efficacy at the present time. No large-scale studies have been completed with calcineurin inhibitor avoidance or even withdrawal to assess the effectiveness of elimination of this therapy on renal functional recovery. Unfortunately, there do not appear to be therapies on the horizon that will replace the widespread use of calcineurin inhibitors any time soon. A few small and short-term case series have been reported where chronic maintenance CyA therapy has been minimized or replaced by the addition of sirolimus in heart and lung transplant patients, with mixed results (49–53). The largest of these experiences involved 31 patients where CyA was replaced by sirolimus and mycophenolate mofetil (52,53). This strategy resulted in improvement in serum creatinine with no loss of efficacy. Other small studies have found that the incidence of adverse effects was unacceptably high after conversion from CyA to sirolimus, in one case with a drop out rate of 75% (54). When the combination of sirolimus with tacrolimus was compared with CyA and MMF in 56 de novo heart transplant patients, neither arm demonstrated improved levels of arteriolopathy, patient survival or renal function (55). It is clear that more studies are necessary before any firm conclusions can be drawn regarding the effectiveness of this approach. There is also emerging data with use of MMF in a CyA-sparing capacity. In this setting, conversion of azathioprine to MMF in combination with dosage reduction of CyA has resulted in improvement in kidney function in small, single center series of heart recipients (56,57). Finally, in selective heart patients, conversion from CyA to Tac may result in reduced nephrotoxicity (21). Data with Tac-sparing or elimination therapy is not as yet available.
Calcium channel blockade (CCB) represents a non-immunosuppression strategy to mitigate acute calcineurin inhibitor-mediated nephrotoxicity in heart recipients. Similar to findings in kidney transplant patients, CCB in one study prevented the fall in GFR associated with CyA nephrotoxicity in heart recipients and was associated with enhanced renal blood flow (11). In another series, conversion of patients from ACE inhibitor based anti-hypertensive therapy to CCB was associated with an improvement in kidney function (58).
ACE inhibitors and angiotensin receptor blockers
Besides their established cardiovascular and blood pressure lowering benefits, ACE inhibition and ARBs have been extensively demonstrated to retard progressive renal injury in most non-transplant chronic kidney disease states. These drugs have been established to be safe and effective as anti-hypertensive agents in heart transplant recipients (59). In another uncontrolled series of nine heart recipients, enalapril was associated with stabilization of chronic kidney disease over 2 years of follow-up (60). In kidney transplant patients, ACE inhibitors and ARBs have been documented to slow progression of chronic allograft nephropathy and reduce circulating levels of the fibrogenic growth factor, TGF-β (61,62). As calcineurin inhibitor related kidney fibrosis is mediated through induction of TGF-β, it is likely that the effectiveness of ACE inhibitors and ARBs in retarding progressive renal injury occurs, in part, through disruption of this mechanism. In support of this, kidney biopsies from patients who had developed CyA nephropathy after heart and lung transplantation, expressed higher levels of TGF-β if the patient was not taking ACE inhibitor therapy at the time of biopsy than if they were (29). It is also plausible that ACE inhibitors and ARBs help preserve renal function by reducing hyperfiltration injury in the remaining hypertrophied, intact nephrons in recipients with calcineurin inhibitor nephropathy.
Besides these potentially renal-sparing advantages of ACE inhibitors and ARBs, other documented renal benefits in heart transplant recipients include enhanced sodium excretion, as well as uricosuria that was associated with a lowering of plasma uric acid levels (63–65). These are desirable therapeutic effects given that volume overload and gout are both well-recognized complications in this patient population.
An extensive review of anti-hypertensive therapy is beyond the scope of this review and updated guidelines have recently been published by the Joint National Commission VII (JNC VII) (66). Given the strong relationship between blood pressure and progressive kidney failure, we recommend that the guidelines be closely followed and that hypertension be vigorously treated to target levels as outlined by JNC VII. Certainly, all the commonly used anti-hypertensive agents appear to be safe in the heart and lung transplant populations and most patients require a multi-drug regimen. Close multi-disciplinary collaboration may on occasion, be necessary between the transplant team and the kidney consultants in order to tailor the blood pressure lowering regimen to specific patient needs. As discussed in the previous section, certain therapies may have benefits on mitigating calcineurin inhibitor-mediated nephrotoxicity. From an immunosuppressive standpoint, it is highly likely that minimization, avoidance or withdrawal of either calcineurin inhibitors or steroids in the future will, at the very least, greatly ease the ability to treat post-transplant hypertension.
Cardiovascular disease is the leading cause of death among patients with chronic kidney disease and ESRD. A proactive and aggressive approach to reduction of all cardiovascular risk factors is therefore warranted. Lipid management should be in keeping with the recently published recommendations of the 3rd National Cholesterol Education Program (67). Additional non-cardiac indications to use lipid-lowering therapy include the documented benefits of statin therapy in lowering acute rejection rates (68) and delaying progression of chronic kidney disease (39). In incorporating lipid-lowering therapy into routine post-transplant clinical practice, it is important to appreciate that CyA may substantially increase the bioavailability of statins (69–71). It has been very recently demonstrated that this interaction is not observed between tacrolimus and atorvastatin, an effect that likely holds true for the other statin drugs as well (71). We would recommend that starting doses of statins should, therefore, be lower in transplant patients receiving CyA as compared to tacrolimus. In addition, one should appreciate that with the statins, the risk of myopathy rises as renal function declines. In patients who develop myopathy, the statin agent should be stopped until the side effects resolve. These patients can be considered for a second trial of these agents later, but typically switching to a different member of this class and starting at a lower dose. The use of fibrates, especially Tricor, has been associated with a reversible decline in renal function in renal transplant patients taking calcineurin inhibitors that may be related to glomerular hemodynamics (72,73). The experience with the newer agent ezetimibe in transplant patients is limited, but appears to be generally well tolerated (74). In a single report in a heart transplant patients taking CyA, the response to ezetimibe was supratherapeutic, suggesting that lower starting doses of ezetimibe should be used (75).
Renal replacement therapy
As recipients of heart and lung transplants experience greater longevity, it is almost a foregone conclusion that rates of ESRD will continue to increase in the future. Current SRTR data demonstrates that kidney transplantation should be the treatment of choice for non-renal organ recipients with ESRD as it is associated with a significantly lower risk of death than maintenance dialysis (6). Because of the dismal outcome for heart and lung recipients on dialysis, patients should be referred early for kidney transplantation and where possible, living donation encouraged. A lengthy wait for a deceased donor organ could well result in the demise of the patient prior to receiving the kidney, particularly if dialysis becomes necessary in the interim. Determination of eligibility for subsequent kidney transplantation would be based on standard transplant center evaluation criteria. However, in the case of prior heart and lung recipients, certain factors may need to be weighed more heavily in evaluating their suitability for a kidney transplant. Such factors would include overall comorbidity and well-being, level of non-renal transplant organ function, anticipated lifespan, as well as impact of further increasing future immunosuppressive burden. Based on superior patient and renal allograft outcomes observed with transplantation prior to starting dialysis in primary kidney recipients (78,79), this pre-emptive approach would be recommended in lung and heart recipients for whom kidney transplantation has become subsequently indicated.
For patients not deemed suitable kidney transplant candidates or for those without potential living kidney donors, dialysis represents an alternative therapy. Only very few single-center, small studies have evaluated dialysis outcomes in heart and lung recipients. Both hemodialysis (HD) and peritoneal dialysis (PD) have been performed on a chronic maintenance basis. PD has often been reserved for the most unstable patients from a cardiovascular standpoint. In this context, Bernardini et al. found that patient survival rates for heart and lung recipients were worse for PD than HD (80). A second study of 17 patients demonstrated an increased risk of PD peritonitis and higher mortality rate in transplant recipients compared to non-transplant patients on PD (48). In contrast, a cohort of heart transplant patients on HD had similar survival to their non-transplant HD counterparts (81).