Renal Failure in the Recipients of Nonrenal Solid Organ Transplants

The increased success and availability of transplantation of solid organs other than kidneys has resulted in a large number of patients at risk for the usual medical complications of long-term immunosuppressive therapy. Acute and chronic renal failure play a critical role in the success of these procedures. By 10 yr after transplantation among these long-term survivors, approximately 12% of heart, 2 to 7% of lung, and 4% of liver patients will have developed severe renal insufficiency. About half of these will have end-stage renal failure (ESRD) and will either be on dialysis or have received a renal transplant. The analysis of renal function in patients who were previously diabetic and who received a pancreas transplant is confounded by the presence of pretransplant diabetic renal damage. However, in these patients, too, the subsequent loss of renal function is predominantly due to their immunosuppressive therapies. The most important factor in the etiology of this renal failure is the chronic nephrotoxicity of the calcineurin inhibitor immunosuppressives (CNI), cyclosporine (CsA) (Neoral®, Sandimmune®), and tacrolimus (Prograf®). Paradoxically, it is the CNI that have made the transplantation of nonrenal organs successful. However, until we have adequate alternative immunosuppression, nephrotoxicity will remain a potential complication for patients currently receiving these transplants, and if this progresses to ESRD it will add to the number of patients waiting for kidney transplants. In nearly all patients in whom this has been studied, the pathologic findings are those of severe CNI toxicity. Cyclosporine nephrotoxicity was described soon after its introduction into clinical transplantation. One early report of clinical experience with CsA in renal, pancreas, and liver transplant recipients documented this potential nephrotoxicity (1). The most alarming reports and predictions of renal damage from the use of CsA were those of Myers et al., who in a number of reports documented the clinical course, pathology, and pathophysiology of CsA toxicity in cardiac transplant recipients (2,3,4,5). Previously, it was presumed that the drug was most damaging in the setting of renal transplantation. Other authors have reported similar findings in patients treated with CsA for autoimmune diseases (6). There have been many subsequent reports of renal failure in patients who have received nonrenal solid organ transplants (7,8,9,10,11). The frequency of perioperative renal failure is not surprising in view of the many factors that may affect renal function in these patients. These include the causes of renal failure associated with end-stage liver and heart disease, the complexity of these operations, the potential for postoperative graft dysfunction and sepsis, and the nephrotoxicity not only of the CNI, but also other therapeutic agents used to treat infection and rejection. Chronic CsA toxicity is a well described, yet poorly understood, condition. Recent studies in renal transplantation describe findings that may differentiate it from other forms of chronic interstitial nephritis and chronic renal allograft nephropathy (12,13). This understanding of the nature of CsA toxicity may allow the introduction of less toxic CNI, or provide insight into how we can minimize the damage from those CNI already in clinical use. Analysis of the impact of CsA on renal failure in these patients is complicated by a lack of good data. Most studies are descriptive and retrospective. CNI dosing and levels do not correlate well with renal damage, and reductions in dosage do not predictably halt the progression to renal failure. However, surrogate markers for acute episodes of significant toxicity and CsA exposure over time, such as trough levels and the daily dose (mg/kg) at various times after transplantation, have shown a weak correlation between higher drug exposures and the subsequent risk of a decline in renal function. In addition, most studies do not include any values, either by measurement or calculation, of the GFR or creatinine clearance (CCr). Instead, they rely on the serum creatinine concentration (SCr), which is notoriously unreliable in malnourished patients and in those with liver failure and heart failure (14). It is often not appreciated that a normal SCr does not necessarily correlate with normal renal function. Some of the apparent postoperative decline in renal function may merely reflect an increase in muscle mass in individuals who were previously severely malnourished. This is not to suggest that these patients do not have renal impairment, but rather that some of the loss of function may reflect damage already present before the introduction of cyclosporine. In patients with liver disease, the analysis of their pre- and perioperative renal function is further complicated by the impact of hepatorenal dysfunction. This is usually present to some degree by the time these patients require transplantation, even when it has not progressed to the full blown hepatorenal syndrome (HRS). None of the studies of long-term renal function in these patients has factored in the potential impact of posttransplant HRS from poor liver graft function. Only a few have segregated patients with recurrent hepatitis C or hepatitis B, who may additionally have hepatitis-associated glomerulonephritis. The most commonly identified risk factors for the development of renal failure in recipients of nonrenal organs are impaired pre- and perioperative renal function. These patients also suffer from many of the other factors that are known to correlate with the progression of renal failure, such as hypertension, hyperlipidemia, and proteinuria. Careful preoperative management and preparation are important, as are attention to fluid management and renal function at the time of operation. Most studies correlate subsequent renal insufficiency with renal failure in this early period. The long-term management of all recipients of nonrenal transplants should include attention to the treatment of BP, using those agents most likely to reduce proteinuria, and of hyperlipidemia. When patients do reach ESRD, both cadaveric and living donor kidney transplantation have been used with successful outcomes. Factors Common to Recipients of all Nonrenal Transplants Despite the great differences between the factors leading to organ failure in the recipients of liver, heart, and lung transplantation, and the different clinical complications that result from failure of these organs, the postoperative clinical course of renal insufficiency in patients immunosuppressed with CNI is surprisingly uniform regardless of the organ transplanted. This allows a general description of renal failure in all of these groups. Subsequent sections highlight the findings peculiar to each organ group. The Course of Renal Impairment The selection process for transplantation excludes patients with severe and irreversible renal failure, unless they are accepted as candidates for combined organ transplantation. Therefore, those patients who receive nonrenal transplants usually have normal or only mildly impaired renal function at the time of transplantation. It is presumed that most of this mild renal dysfunction is reversible and that the kidneys have sufficient reserve to withstand the effects of the operation and the introduction of CNI. After the first administration of CNI, there is an acute reduction in renal perfusion caused by constriction of the afferent glomerular arteriole. However, for most patients, provided the BP and renal perfusion are well preserved, there is an immediate improvement in renal function in the postoperative period. Thereafter, there is frequently an early decline in renal function, and by 12 mo the GFR is reduced by about 50%. For most patients, renal function then stabilizes. However, Myers et al. (2,3,4,5) warned that even when the SCr remains stable, or when significant does not it is that and irreversible renal is in the of these patients. It is that we will a increase over time in the number of patients this were reported by et al. in heart and liver transplant recipients of patients progresses to Common Factors The authors of many have the factors that an increased risk of renal failure in these patients It is not surprising that similar factors affect renal function which organ is transplanted. In they are the as those that renal failure in any patients and those in patients with renal impairment, with the complication of CNI toxicity in the nonrenal transplant factors for renal patients with ESRD renal transplantation, many patients who receive nonrenal transplants are not in the preoperative period. However, patients treated with CNI, and most have a of is present in as many as of to of liver, and to of lung transplant The of is usually at a time when both dose and CsA serum levels are Most patients who will do the first but the will to increase with time in or BP are all risk factors for the progression of renal failure in patients with renal and it is that this is also for transplant The report on the and treatment of has for the management of in patients with renal disease, with and proteinuria. These for reductions in BP, and the agents for treatment in these patients, should be in all transplant patients who have hypertension, in the of the impact of on renal failure is not a usual of CNI there are reports of in patients not have any of glomerulonephritis. In has been it usually after transplantation and is associated with renal insufficiency levels of are not and there is with renal failure, this is an risk factor in these patients. When at any time after transplantation, and when renal function is preserved, this is due to a and further In recipients of liver transplantation, may be a of hepatitis-associated glomerulonephritis. patients frequently hyperlipidemia. This should be treated to reduce the risk of cardiac and other However, is an associated risk factor for the progression of renal failure, and for this it is important to this complication that there be an of and when are used with CsA have not been by clinical These agents may also reduce the risk of early graft rejection. It is that these agents be used to both and Cyclosporine all of the studies renal dysfunction have patients treated with Some of the studies have also patients on and there to be improvement the introduction of the CNI. to CNI is the to all of these patients. The used to these patients have by and by has been reported to the impact of CNI. CNI use is the most important risk factor in these patients, there are with to how this renal function. daily dose trough levels correlate well with the exposure to the for drug This was in the of patients who were treated with than for those treated with either or the other the of has resulted in a for patients with trough for such as of the drug or drug at times after transplantation, it is to a weak correlation with exposure and the subsequent progression to renal failure. Most transplant the dose of CNI to levels that are presumed to provide adequate toxicity. However, there is correlation between and and when the serum creatinine it is usual for the CNI dose to be to as a as to minimize further Renal on these patients that CNI toxicity is the most of and the decline in kidney function. were in all of the There are and The most is that of interstitial by This is often associated with an by with and The of and with some These were described in patients in studies the in patients receiving only and These findings are to those described in patients receiving CsA for the treatment of autoimmune diseases The only frequently in nonrenal transplant patients is that of This is frequently in patients with proteinuria, and may rather reflect the of The glomerular and have been described in these patients, and reflect the of of Renal The most important in this is the presence of the HRS and the of glomerular most commonly at the time of transplantation. the introduction of liver transplantation, the of ESRD due to HRS was There is some in the analysis of patients with liver and of renal failure, as not all the nature of the large number of these patients will have episodes of renal dysfunction. The in most of is HRS by by by or by and renal In patients with is less likely to to of SCr than is the use of It is that renal function in the HRS is impaired by by in the of and which to an in glomerular and a in the studies have shown a correlation with preoperative renal dysfunction and both postoperative and long-term renal insufficiency. For documented renal function in of patients before transplantation, and in after transplantation in the management of these patients have reduced the of postoperative acute renal failure. The of of the to some of the reduction in renal has with success In a of the of and and et al., that of patients with failure and of patients with pretransplant renal insufficiency or on was reduced for those patients receiving dialysis at the time of transplantation, they received a liver or transplant. These suggest that some severely patients should not be as candidates for transplantation report from the of that renal failure, and the for are significant risk factors the in liver recipients CsA toxicity is associated with further in renal an acute in This in the GFR has been documented in liver transplant in whom it after the introduction of This is by administration of CNI. The in GFR was documented in than patients with the use of clearance The GFR by of transplantation, but for than yr has documented long-term in liver transplant decline with to the preoperative GFR was documented in other studies in patients with stable, long-term renal function renal function in liver transplant patients treated with of early CNI administration in these patients is by the that the The of a number of studies in which the immunosuppressive was first for use in liver transplantation, reduction in nephrotoxicity et al. the use of CsA and tacrolimus and less in renal and in patients treated with tacrolimus transplant patients with renal function at the time of transplantation experience a decline in renal function of to by mo reported that only of liver transplant recipients a normal SCr by mo after transplantation In et al. that nearly of patients reduced renal function at yr The SCr from at yr to at In patients at 4% developed The time to the of ESRD was about after the of ESRD was reduced to a of of the patients with severe renal insufficiency Renal CsA nephrotoxicity in all but who In patients, there were with a The clinical and of patients on CsA and tacrolimus were in this and that of et al. risk factor analysis for the development of severe renal insufficiency at yr identified an SCr at mo and at yr as However, the of an SCr was There was a weak between higher CsA trough levels at mo and subsequent severe renal insufficiency when the were by with severe renal insufficiency at yr were into the first with early and the with renal failure, on the SCr was than at The risk factors for early dysfunction a for renal and of the CsA levels were not a In those in whom renal dysfunction developed than risk factors were a higher daily CsA dose at and a higher CsA dose at analysis of a reduction in CsA dose at the time that renal dysfunction was in with the One of the most for is to a combined transplant in patients with organ failure. There is adequate to the to which renal is only a of the HRS or acute or in there is renal The usual of renal function such as the and SCr and are all unreliable in this The presence of a associated with a renal such as kidney disease, and the presence of the of renal failure. The presence of may be a of or may result from to impaired It is important to about renal function before the decline in liver function and to use and Renal should be when By the it is to that renal failure is In patients with renal function after liver transplantation, and these patients should receive only a liver transplant. to yr after transplantation, the long-term and graft is usually reported as similar in patients with and However, in to of patients with HRS progressed to ESRD, with only of recipients HRS In a report of patients at of an dialysis after transplantation, and an developed reversible episodes of renal dysfunction. The of patients with HRS preoperative dialysis was than that of the as a which the for these patients when they liver transplantation. When patients presumed to have HRS or require dialysis for than before liver transplantation, it is likely that they will renal and that their renal function will not these we a transplant The impact of renal failure on the and of liver transplantation has combined transplantation. There is an acute of organs for kidney transplantation, and this should only be when there is a that kidney function is irreversible and impaired by other than HRS or The at which combined transplants are as a function of all liver transplants from about to as as at different liver transplant In reports on combined transplant patients, the causes of renal failure in the combined renal and patients with renal failure from CNI The and graft in this combined is when the patients are before transplantation. et al. patients who received combined transplants at and graft was for of 2 patients, and for patients, but for the patients at yr was only This that this is not necessarily in patients with severe failure organ does not this into should be to to patients with HRS who require to the for of renal failure in patients receiving significant number of patients with liver failure to hepatitis or C of hepatitis in the liver By the time this of patients the at which they are for a liver many will have mild and an in the These can result both from CNI treatment and in some patients from or However, they may only have and a kidney may this The of liver transplantation with or kidney transplantation is There is currently treatment for hepatitis but in patients with hepatitis B, treatment with has been shown to the risk of of diabetic patients transplants, a number of patients receive transplants. The from the of has renal function in the patients and a of patients that was not first described the findings at the time of for transplantation, both normal renal function. those patients who receiving CNI, renal function and not The was and that at yr was patients with pancreas but on CsA a decline in the from a similar to This decline over the first 12 In these patients, the of the decline in renal function with the daily CsA dose 12 after transplantation. of the pancreas transplant recipients developed hypertension, to of 10 In of the kidneys of the pancreas there were of CNI toxicity. of the patients a kidney transplant when they developed This reported on the 10 yr of of the patients. the diabetic glomerular the SCr to the findings in liver transplantation, there are a number of reports the pathology, and clinical course of renal dysfunction cardiac transplantation. In many patients, there is a in renal function over the first By yr after transplantation, et al. that few patients will have a normal GFR have reported a of at by measurement of the about yr after transplantation and in most patients for many Myers et al. in a of reports suggest that this apparent is by of and and that damage will in patients treated with CNI (2,3,4,5). et al. have provided for this in studies that renal reserve that even in cardiac transplant patients with a GFR of the renal reserve was only of that of The at in has that of patients yr or will ESRD, and already a SCr These are to those reported from other In to patients receiving liver transplants, it has been to risk factors that a poor renal in an analysis of cardiac transplant the factors that with renal insufficiency were and renal function at the time of transplantation. In addition, this of patients severe hypertension, higher and This with is important, as it is known from renal transplantation that kidneys from do less well after transplantation, they the effects of CNI less In this of it will be important to immunosuppressive that minimize exposure to CNI. The correlation with CNI exposure in this of transplant recipients is than in any other receiving nonrenal transplants. Some authors have that the CNI dose in patients with renal failure the risk of et al. have the to which of cardiac function, and renal for this decline in renal function that the cardiac even in patients with renal function. further the use of a by renal perfusion before transplantation, reduce the of renal failure in the immediate postoperative period. of an was associated with a preoperative SCr with patients not on an This improvement impact on long-term renal function, and by mo after transplantation the an This was present at 2 yr The of kidneys in patients from severe heart failure has been with that of cardiac transplant recipients who been for at 2 The heart failure by that the of renal in the cardiac transplant renal were caused by after transplantation The transplant glomerular and or in of These are findings of cyclosporine toxicity It is of that many cardiac transplant recipients with severe and renal insufficiency a and as renal insufficiency The renal function of patients by the at the from the of was in all patients for than yr these patients, received a and a lung transplant. In patients for than the SCr was patients ESRD, of whom received a successful living donor kidney Renal function after lung et al. reported an analysis of the renal function of lung transplant recipients for a of with a of mo after transplantation. The SCr increased from a of at the time of transplantation to at mo and at after transplantation this patients SCr and There was between CsA dosage and in renal function even patients with SCr a higher CsA dose at In these patients, renal function to decline even after the CsA were In patients who a renal the findings were those of CNI have described reductions in the GFR of to 2 yr of lung transplantation et al. the factors of a long-term decline in renal function. There were factors that with a decline in GFR from before transplantation to and to by These were the causes of and perioperative renal function. with or chronic than those with in whom renal function In those SCr the decline in renal function has been to renal constriction at the time of transplantation Other that of lung transplant patients developed the first were to correlate the degree of with the of renal failure The findings in reports of the in recipients of lung transplants are similar to those described for other described for all other organs, the decline in renal function is et al. from reported on transplant recipients There was a decline over the first with a increase in the SCr from to Thereafter, there was a and by mo the SCr was these patients, SCr and The time to ESRD was similar to the of progression in other organ groups. In this there was correlation with CsA or CsA levels and the decline in renal function. Renal in with Nonrenal Transplants of the that renal function in the recipients of nonrenal organ transplants describe the use of renal transplantation in patients who This has been described as as successful as renal transplantation The of renal failure in these has not been for the some of the of this a was to for to patients who received a renal transplant after they received any other solid organ transplant. The the of the of the and the renal and the of renal allograft failure. The the from to These the number of kidney transplants that have experience at and that at the the that renal transplantation is a successful of treatment for ESRD after nonrenal renal transplantation after nonrenal of Renal The decline in renal function in these patients is the result of the perioperative to renal function, and subsequent CNI therapy. In the preoperative the management of these patients be similar to that of patients with known renal and all factors should be or The of adequate and renal perfusion be in and have already reduced the of early postoperative renal failure and the for When CNI should be until renal function has in patients with or renal from heart failure or The use of CNI should be When dialysis is be to and in patients already on CNI. It is that some patients will early renal dysfunction. will be to long-term CNI and be at risk for chronic renal The factors that correlate with progression of renal failure in patients with renal have been described in in It is likely that attention to similar risk factors will reduce the of decline in the function of the kidneys of patients immunosuppressed with CNI for solid organs other than However, the use of the which do not to reduce to the degree as other in patients not on CNI, may be in these patients may be in the afferent caused by CNI. and have reported an improvement in the in a of heart transplant recipients treatment was from to et al. also reported a of the use of in heart and lung transplant recipients Other studies have documented from the use of with and has been shown to all patients with renal insufficiency and should be for use in these patients as The pathophysiology of CNI toxicity and the caused by both to factors that may be by should be when using or as these can an in CsA levels by of CsA The treatment of was in the on risk It is that with the introduction of and the and it will be to or reduce the use of CNI in the immediate postoperative period. The do not have the severe the risk of renal dysfunction and with and other In the immediate postoperative some transplant CNI in patients with HRS who receive liver transplants, until the to have and renal function is about the use of CNI allow for the potential increase in graft loss from as a of the the introduction of CNI has a increase in nonrenal transplantation. This success has been at the of a number of complications in all transplant These include hypertension, and if not patients treated with CNI will a reduction in renal function. Some of this reduction in GFR is reversible if the CNI are early However, this is and for most patients it is to minimize the pre- and perioperative factors known to increase the risk of renal insufficiency. often in heart and lung transplant recipients than in those receiving a liver, will to ESRD and require dialysis or kidney transplantation. time of these patients may ESRD from chronic CNI The and other reported transplantation as an treatment for