Kidney Disease After Heart and Lung Transplantation
Kidney disease is a commonly recognized complication of heart and lung transplantation and is associated with increased morbidity and mortality. While the spectrum of kidney disease in this population is wide-ranging, studies indicate that between 3% and 10% of these patients will ultimately develop end-stage renal disease (ESRD). This review examines the risk factors for both acute and chronic kidney injury, with a particular emphasis on the role of calcineurin inhibitor-mediated nephrotoxicity in both these settings. Against the background of current National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, we have further considered and recommended appropriate strategies for long-term management of kidney disease-related manifestations in heart and lung transplant recipients. Specific aspects addressed include retarding progressive renal injury and minimizing nephrotoxicity, as well as treatment of hypertension, hyperlipidemia and anemia. Finally, for patients in this population with advanced kidney disease, renal replacement therapy options are discussed. Based on the impact of chronic kidney disease on outcomes in both heart and lung recipients, we advocate early referral to a nephrologist for patients displaying evidence of significant renal dysfunction.
Kidney disease is a frequent and increasingly recognized complication of both heart and lung transplantation (1–6). Renal failure, both in the acute and chronic setting, increases the complexity of patient management and significantly contributes to both early and late post-transplant morbidity and mortality. Chronic kidney disease in this population is associated with a 4- to 5-fold increased risk of death after transplantation (6). Although there is no uniform definition of chronic kidney disease after heart or lung transplantation, prevalence rates range from 10 to over 90% (3,5–8). The most comprehensive assessment to date, using an estimate of kidney function, defined chronic kidney disease as a glomerular filtration rate (GFR) of 29 mL/min/1.73 M2 of body surface area or less. In that study, the 5-year risk of developing chronic kidney disease was 10.9% for recipients of heart transplants and 15.8% for recipients of lung transplants (6). By Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines applied to chronic kidney disease in the general population, this degree of renal impairment would be consistent with more severe (stage 4 or 5) dysfunction (9). In our experience, even among heart and lung transplant patients without these more advanced stages of renal disease, milder degrees of chronic kidney disease are nevertheless invariably present.
Deterioration in kidney function typically commences within the first 6 months after transplantation and progressively declines thereafter (1,2). Despite relatively limited life expectancies for heart and lung transplant recipients, at least 3–10% of these patients will ultimately go on to develop end-stage renal disease (ESRD) (4,7). In fact, recent Scientific Registry of Transplant Recipients (SRTR) analysis of 69 321 non-renal organ recipients surviving the first 3 post-transplant months revealed that 4% of patients required maintenance renal replacement therapy within a median 3 years of transplantation (6). In the future, as survival continues to improve in heart and lung transplant recipients, it is probable that the rate of development of ESRD will likewise increase in this population.
Risk Factors for Kidney Injury After Heart and Lung Transplantation
Multiple factors have been implicated in increasing the risk of progressive kidney dysfunction after heart and lung transplantation. Eligibility for non-renal organ transplantation typically requires that potential candidates have no or minimal perturbation of underlying kidney function, with sufficient reserve to undergo transplant surgery without the need for peri or post-operative dialysis. The risk factors for early post-operative acute renal failure following heart and lung transplantation are generally the same as those for non-transplant patients immediately after surgery (Table 1). Clinical situations that commonly contribute to acute renal failure in the post-heart-transplant setting are effective volume contraction due to severe left ventricular dysfunction and aggressive diuresis, acute tubular necrosis secondary to sepsis, shock and radiographic contrast, as well as nephrotoxic drugs. Less commonly, acute interstitial nephritis and atheroembolic disease occur. Unique to transplantation, however, calcineurin inhibitor exposure in the early post-transplant period represents an additional nephrotoxic insult that is usually hemodynamically mediated and reversible in the short term (10–12).
Table 1. Factors contributing to kidney injury after heart and lung transplantation
|Effective volume contraction||Calcineurin inhibitors|
| Ventricular dysfunction||Chronic effective volume contraction|
| Over-aggressive diuresis|| Ventricular dysfunction|
|Acute tubular necrosis|| Chronic diuretic use|
| Sepsis||Peri-operative acute renal failure|
| Hypotension||Increasing recipient age|
| Radiographic contrast||Diabetes mellitus|
| Nephrotoxic drugs||Hypertension|
|Acute interstitial nephritis|| Hepatitis C|
| Hepatitis B|
On a longer term basis, a multitude of retrospective studies, both single center and registry-based, have identified factors that increase the risk of developing progressive chronic kidney disease following heart and lung transplantation (6,7,13–17). Once again, most of these risk factors are similar to those that could be expected in non-transplant patients with underlying kidney disease. Included among these factors are the level of kidney function immediately pre-transplant as well as in the early post-operative period, increasing recipient age at the time of transplantation, female gender, presence of diabetes mellitus and hypertension. Hypertension occurs in the vast majority of heart and lung recipients and usually develops in the early post-transplant period. It is worth noting that pre-transplant hepatitis C virus (HCV) infection is a risk factor for chronic kidney disease in liver transplant patients, however there is insufficient data in this regard in heart and lung recipients (6). Finally, over the past two decades, the widespread use of calcineurin inhibitors has resulted in an increase in the prevalence of chronic kidney dysfunction compared to the pre-cyclosporine era (18). Comorbid conditions such as chronic left ventricular dysfunction and the requirement for drugs such as diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), may potentiate the chronic nephrotoxic effects of calcineurin inhibitors. Occasionally, protracted pre-transplant acute tubular necrosis secondary to renal hypoperfusion may be associated with persistent fibrosis and nephron loss following transplantation and may contribute to chronic kidney dysfunction.
Calcineurin Inhibition and Nephrotoxicity
Calcineurin inhibitor-mediated nephrotoxicity is commonly observed in heart and lung transplantation and may manifest as both acute and chronic renal failure (4). In fact, earlier reports described the deterioration in renal function in heart transplant recipients as a biphasic phenomenon, with a rapid decline through 24 months and a slower decline thereafter (1). This progressive decline occurred despite decreasing levels of CyA through the post-operative course (1).
Acute calcineurin inhibitor nephrotoxicity
Most of the published literature pertaining to calcineurin inhibition in heart and lung transplantation involves CyA. Acute injury is usually reversible and appears to be mediated by direct vasoconstriction of the afferent and efferent renal arterioles, resulting in a decrease in renal blood flow and GFR (10). CyA increases levels of the potent vasoconstrictor, endothelin, in the circulation and also impairs the endothelial production of vasodilatory nitric oxide (19,20). Studies comparing patient cohorts treated with CyA to those treated in the pre-CyA era have demonstrated that this calcineurin inhibitor was associated with a substantial reduction of the GFR (18). The serum creatinine was greatest in the cohorts receiving the highest doses of CyA. Other investigators, by examining CyA pharmacokinetics and renal hemodynamic parameters measured simultaneously, have demonstrated that the peak acute nephrotoxicity occurred 2–4 h after the maximal blood CyA concentration and returned to baseline as the CyA concentration approached its trough level (11).
There is far less published information on acute renal injury associated with Tac in heart and lung transplant recipients. A small case series in heart recipients and a prospective, randomized crossover study comparing calcineurin nephrotoxicity in normal subjects have suggested that Tac had a less unfavorable effect on acute renovascular hemodynamics than CyA (21,22). In support of this, Pratschke et al. have reported that 13 of 19 stable liver recipients converted from CyA to TAC for nephrotoxicity experienced a 25% improvement in serum creatinine (23).
Chronic calcineurin inhibitor nephrotoxicity
Chronic CyA-associated nephropathy is a well-described clinical entity, though it is poorly understood. CyA exposure over time, defined in terms of serial trough levels and daily dosage, has shown a weak correlation with risk of progressive kidney dysfunction at higher levels of exposure (4). Renal hemodynamic studies in CyA-treated patients have revealed decreased GFR in association with reduced renal blood flow, increased renal vascular resistance and elevated mean arterial pressure (18,22). Serial investigation of these physiological parameters at 36 and 48 months post-transplant demonstrated no improvement in GFR, as well as progressively increasing renal vascular resistance and urinary albumin excretion rates (18). These processes culminate in glomerular ischemic collapse, increasing glomerulosclerosis and afferent arteriolopathy (18). Progressive renal functional deterioration occurs as a consequence of hyperfiltration injury in the remaining intact nephrons and may ultimately result in ESRD (18).
Given the relative paucity of published clinical studies evaluating tacrolimus in heart and lung transplantation, available data comparing the chronic nephrotoxicity of this drug to CyA remains contradictory. Some studies have demonstrated no difference between the two calcineurin inhibitors (24), while other investigators suggest that Tac may be associated with a decreased severity of renal dysfunction (5). The recently published SRTR non-renal transplant study demonstrated that the risk of chronic kidney disease was higher among liver transplant recipients treated with CyA though could not demonstrate a difference among recipients of other types of transplants (6). Randomized, prospective clinical trials comparing safety and efficacy of the calcineurin inhibitors will be required to lay this issue to rest one way or another.
The majority of patients with chronic calcineurin inhibitor nephropathy are asymptomatic, with the only substantive clinical findings being hypertension and an abnormal creatinine or creatinine clearance. The urine sediment is typically bland with a paucity of cellular elements and contains small amounts of protein in the urine. Although nephrotic range proteinuria has rarely been attributed to chronic CyA nephrotoxicity (25), the presence of this abnormality should warrant consideration of another diagnostic etiology. In light of the well-recognized association between calcineurin inhibitor nephropathy and chronic kidney disease, renal biopsies are not routinely utilized in the evaluation of impaired renal function unless other specifically treatable causes are being entertained. In fact, several investigators have performed kidney biopsies in CyA-treated heart and lung recipients to determine the etiology of chronic kidney disease and have confirmed that calcineurin inhibitor-related renal injury is the commonest finding (18,26–28).
Chronic calcineurin inhibitor nephrotoxicity is characterized histopathologically by widespread changes involving all aspects of the kidney. The most common structural change is that of interstitial fibrosis, that may have the pathognomonic striped pattern (‘striped fibrosis’), although other abnormalities include afferent arteriolar hyalinosis, tubular atrophy and ischemic glomerular collapse and sclerosis. In recent years, much attention has been given to the role of transforming growth factor-β (TGF-β), a fibrogenic cytokine, in the promotion of fibrosis observed in calcineurin inhibitor nephropathy. TGF-β expression is induced in renal tissue by CyA in heart transplant recipients (29). In the absence of specific data in heart and lung transplant patients, extrapolation from studies involving protocol biopsies in kidney recipients suggests that renal expression of TGF-β is similar in patients regardless of whether they are receiving CyA or Tac as their calcineurin inhibitor (30).
Besides the manifestations of chronic calcineurin inhibitor nephrotoxicity described above, thrombotic microangiopathy represents an additional complication of these immunosuppressive agents that may be associated with kidney dysfunction. Thrombotic microangiopathy has been described in heart and lung recipients with both CyA and Tac (28,31,32). Several case series have indicated that reduction in dosage of the offending agent may often result in resolution of the condition. It should be noted that similar pathological changes have been observed with sirolimus in kidney transplant patients (33).
Complications of Chronic Kidney Disease
Chronic kidney disease at all stages is an important risk factor for cardiovascular morbidity and mortality (34,35). Moreover, the risk of cardiovascular complications escalates with progressively worsening levels of kidney function (34,35). The increased risk of death observed in heart and lung recipients with chronic kidney disease is likely directly attributable to this above inverse relationship.
Hypertension, both systolic and diastolic, is commonly observed in heart and lung transplant patients, occurring in at least 90% of cardiac and 70% of lung recipients (4,36). Calcineurin inhibition is an important contributor to the development of hypertension after heart and lung transplantation and CyA appears to be more significantly associated with this complication than Tac (22,37). Steroids also cause blood pressure elevation, particularly in the early post-transplant period when higher doses are being used. Ishani et al. have recently demonstrated that diastolic blood pressure elevation is an independent predictor of progressive chronic kidney disease after lung or heart-lung transplantation (5). This effect of blood pressure on progressive kidney disease confirms similar findings previously observed in non-transplant patients (38).
Hyperlipidemia is a common complication of immunosuppression after transplantation. Besides being an important risk factor for cardiovascular disease and mortality, hyperlipidemia is a recognized risk factor for progression of chronic kidney disease (39).
There is a paucity of information regarding chronic anemia after heart and lung transplantation, particularly as it relates to chronic kidney disease. However, prevalence rates of anemia of up to 65% have been reported, with one study reporting severe anemia (hemoglobin <100 g/L) in 31% of patients (40–42). One recent investigation has demonstrated that anemia is closely associated with impaired kidney function in this population, although it could not link this hematological abnormality to reduced patient survival (43). Besides the common association of chronic kidney disease with anemia, a multitude of other factors have been implicated including anti-metabolite immunosuppression (azathioprine and mycophenolate), sirolimus, iron deficiency, dyshemopoiesis, relative erythropoietin deficiency and other comorbid conditions (40–42,44). Given the strong association between anemia and morbidity and mortality in non-transplant patients with chronic kidney disease (45), it is probable that a similar relationship exists in recipients of non-renal organs with chronic kidney dysfunction as well.
Treatment of Kidney Disease in Heart and Lung Transplant Recipients
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
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).
Anemia becomes increasingly common as kidney function declines. Anemia is also a strong predictor of reduced mortality and increased morbidity in patients with underlying heart disease (76). Although there is a paucity of data specific to anemia following heart and lung transplantation, we recommend that K/DOQI guidelines for iron and anemia management should still be followed, with a target hemoglobin on therapy of 11–12.5 mg/dL (77).
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).
Improving immunosuppression, in particular the advent of calcineurin inhibition, over the past 25 years has resulted in superior transplant outcomes in heart and lung transplantation. The trade-off for this immunological success has been continued proliferation of chronic kidney disease in this population, evolving to increasing ESRD rates. ESRD brings with it a host of metabolic, hematological and cardiovascular complications, all of which result in an excessive risk of mortality. While kidney transplantation is the treatment of choice for ESRD in this population, future efforts should be directed to mitigating calcineurin inhibitor-mediated nephrotoxicity through minimization and elimination regimens. For patients displaying any evidence of chronic kidney disease, early referral to a nephrologist is strongly recommended.
This manuscript is a work product of an AST committee.