Chronic Kidney Disease in the Kidney Transplant Recipient

44 Chronic Kidney Disease in the Kidney Transplant Recipient John S. Gill, MD, FRCPC, MS, FAST, Habib Mawad, MD, FRCPC, and Olwyn Johnston, MB, MRCPI, MD, MHSc OUTLINE Introduction, 676 The Chronic Kidney Disease Classification, 676 Rationale for Including Kidney Transplant Recipients in the Chronic Kidney Disease Classification, 678 Applicability of the Chronic Kidney Disease Classification in Transplant Recipients, 678 Prevalence of Chronic Kidney Disease in Kidney Transplant Recipients, 678 Prevalence of Chronic Kidney Disease–Related Complications in Kidney Transplant Recipients, 679

INTRODUCTION There now are more than 200,000 prevalent kidney transplant recipients (KTRs) in the United States, more than double the number of patients in 2000.1 A significant proportion of prevalent KTRs will have decreased kidney function and be at risk for complications related to chronic kidney disease (CKD), including cardiovascular disease, mineral and bone disorders, metabolic acidosis, hypoalbuminemia, and anemia. Even among patients with “normal” kidney function, the burden of previous exposure to uremia and dialysis often carries through to the posttransplant period. In this chapter, we will review the current classification of CKD, potential advantages for including patients in the CKD classification, and the applicability of the CKD classification in KTRs, as well as the relevant clinical management considerations before transplantation, during the period of allograft function, and after allograft failure.

The Chronic Kidney Disease Classification The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) clinical practice guidelines published in 2002 defined CKD as either kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for ≥3 months, irrespective of cause.2 Kidney damage was defined by structural or functional abnormalities of the kidney, with or without decreased GFR, as manifested by either pathological abnormalities or markers of kidney damage (i.e., abnormalities on blood or urine tests or abnormal imaging tests). These guidelines also proposed a classification of CKD based solely on the level of GFR. Five stages of CKD were defined,

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The Predictive Value of Chronic Kidney Disease Staging for Outcomes Among Kidney Transplant Recipients, 679 Chronic Kidney Disease Management, 680 Chronic Kidney Disease Care Before Transplantation, 680 Chronic Kidney Disease Care in the Peritransplant Period, 680 Chronic Kidney Disease Care in Patients With a Functioning Allograft, 680 Chronic Kidney Disease Care in Patients With Transplant Failure, 681

and each stage had an associated action plan. The initial NKF K/DOQI CKD guidelines recommend referral to a specialist if the clinical action plan cannot be prepared, or if the prescribed evaluation or recommended treatment cannot be carried out.2 The guidelines further recommend that, in general, patients with GFR <30 mL/min/1.73 m2 be referred to a nephrologist. In the initial NKF K/DOQI CKD classification, KTRs were not specifically addressed.2 The inclusion of KTRs was subsequently emphasized in a position statement from a Kidney Disease: Improving Global Outcomes (KDIGO) initiative.3 This KDIGO position statement recommended that all KTRs be considered to have CKD, irrespective of GFR or the presence or absence of markers of kidney damage, and highlighted the inclusion of KTRs with the designation “T” to indicate transplantation. In a consensus conference on the care of KTRs, organized by the NKF and KDIGO, it was recommended that the clinical action plan in the initial NKF K/DOQI CKD classification be amended for KTRs.4 Table 44.1 summarizes both the initial NKF K/DOQI classification and the revised KDIGO classification, which included a transplant-specific clinical action plan.4 First, estimation of progression of CKD (originally recommended in patients with CKD stage ≥2) and evaluation and treatment of CKD-related complications (originally recommended in those with CKD stage ≥3) should be applied in all KTRs (CKD stage 1 to 5). The rationale for this modification is that KTRs carry the burden of preexisting CKD (i.e., hyperparathyroidism, anemia, cardiovascular disease), and consequently these complications should be addressed even if the GFR is relatively normal. Second, preparation for kidney

CHAPTER 44  Chronic Kidney Disease in the Kidney Transplant Recipient

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TABLE 44.1  Stages of Chronic Kidney Disease (CKD) and Action Plan for Nontransplant CKD

(−T) and Transplant CKD (+T)

CLINICAL ACTION PLANa CKD Stage

Definition

Non-Tx CKD (−T)

Tx CKD (+T)

1

Kidney damage or post-Tx with normal or ↑ GFR(≥90 mL/min/ 1.73 m2)

2

4

Kidney damage or post-Tx with mild ↓ GFR (60–89 mL/min/1.73 m2) Moderate ↓ GFR(30–59 mL/min/ 1.73 m2) Severe ↓ GFR(15–29 mL/min/1.73 m2)

Diagnosis and treatment Treatment of comorbid conditions Slowing progression CVD risk reduction Estimating progression

5

Kidney failure(<15 mL/min/1.73 m2)

Diagnosis and treatment Treatment of comorbid conditions Slowing progression CVD risk reduction Estimating progression Evaluating and treating complications due to CKD before and after Tx Managing Tx-specific issues If evidence of CKD progression, preparation for kidney replacement therapy (patient and family education, dialysis access, preemptive Tx) Replacement (if uremia present)

3

Evaluating and treating complications Preparation for kidney replacement therapy

Replacement (if uremia present)

aIncludes

actions from preceding stages. CVD, Cardiovascular disease; GFR, glomerular filtration rate; Tx, transplant. Persistent albuminuria categories Description and range

Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012

A1

A2

A3

Normal to mildly increased

Moderately increased

Severely increased

GFR categories (ml/min/1.73 m2) Description and range

<30 mg/g <3 mg/mmol

30–300 mg/g >300 mg/g 3–30 mg/mmol >30 mg/mmol

≥90

G1

Normal or high

G2

Mildly decreased

60–89

G3a

Mildly to moderately decreased

45–59

G3b

Moderately to severely decreased

30–44

G4

Severely decreased

15–29

G5

Kidney failure

<15

Dark gray: low risk (if no other markers of kidney disease, no CKD); light gray: moderatety increased risk; light green: high risk; dark green: very high risk.

FIG. 44.1 Kidney Disease: Improving Global Outcomes Classification of Chronic Kidney Disease.  The revised Chronic Kidney Disease classification includes consideration of the etiology of disease as well as the severity of proteinuria. (From Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2013;3(1):1–150.)

replacement therapy (originally recommended in those with CKD stage ≥4) should apply only to KTRs with stage ≥4 CKD with evidence of progressive GFR decline. The rationale for this modification is the recognition that the rate of CKD progression in KTRs may differ from that in other forms of nontransplant CKD, and that KTRs can maintain a stable but low GFR for many years.5,6

In subsequent KDIGO guidelines published in 2012, stage 3 CKD was divided into stage 3a (GFR 45 to 59 mL/min/ 1.73 m2) and stage 3b (GFR 30 to 44 mL/min/1.73 m2) based on data supporting different outcomes in these subgroups.7 In addition the 2012 KDIGO guidelines recommended staging based on cause, GFR category, and albuminuria category (Fig. 44.1)7 based on evidence that proteinuria is an

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SECTION IV  Transplantation

independent predictor of mortality and progression to endstage kidney disease in transplant-naïve patients with CKD.8 Importantly, the 2012 KDIGO guidelines continued to include KTRs irrespective of the level of GFR or the presence of markers of kidney damage. The rationale for this designation is that biopsies in KTRs frequently show pathological abnormalities even in patients without decreased GFR or albuminuria, and that KTRs have an increased risk for mortality and kidney failure compared with the general population and require specialized medical care.7 It is important to note that KTRs were not included in the study cohorts that informed the recommendations to include the cause of CKD and the severity of proteinuria in the 2012 KDIGO CKD guidelines. 

Rationale for Including Kidney Transplant Recipients in the Chronic Kidney Disease Classification

Over the past decades, there has been remarkable improvement in the 1-year graft survival rate, which is now well in excess of 90%.1 This improvement is attributed to advances in immunosuppression and reduction in acute rejection. Unfortunately, transplant survival beyond the first year has showed only modest improvement over the same period.9,10 Among 252,910 adult KTRs between 1989 and 2005 reported by the Scientific Registry of Transplant Recipients (SRTR), allograft half-life increased from 6.6 to 8.8 years in deceased donor (DD) recipients, whereas these figures barely changed for living donor (LD) recipients (11.4 to 11.9 years).11 The most significant improvement was among lower-quality DD transplant recipients, where graft half-life increased from 3 to 6.4 years during the study period.11 Based on the most recent data provided by the SRTR, 10-year graft failure for transplants in 2005 was 53% for DD transplants and 37% for LD transplants.1 Although death-censored graft survival improved over time, death with a functioning graft remained relatively constant.1 These observations suggest the need for novel strategies beyond optimization of immunosuppression to improve the long-term survival of KTRs. The potential importance of treating CKD-related complications in improving longterm allograft survival is suggested by studies demonstrating that the high levels of serum phosphate, calcium-phosphate product, fibroblast growth factor 23, and metabolic acidosis are independently associated with a greater risk for allograft loss.12,13 Similarly, the importance of optimal treatment of cardiovascular risk factors such as hypertension is emphasized by the fact that cardiovascular disease is the leading cause of death among adult KTRs. Nonetheless, controlled studies demonstrating that aggressive treatment of CKDrelated complications improves allograft or patient survival are lacking. There are a number of additional potential advantages to including KTRs in the CKD classification.14 Increased recognition of CKD may facilitate implementation of therapeutic strategies to delay progression of kidney function decline or to prevent CKD-related metabolic complications. Inclusion of KTRs in a simple severity-based kidney disease classification

schema may improve communication between clinicians, enhance public education, and facilitate research. Finally, a uniform disease classification and action plan including all patients, irrespective of the need or type of renal replacement therapy (i.e., dialysis or transplantation), may enhance the continuity of patient care. Transplant recipients have multiple care providers before, during, and after transplantation. Recent publications have shown that transplant recipients are at increased risk for death during transitions between different forms of renal replacement therapy15 (i.e., during the transition from dialysis to transplantation and the transition back to dialysis after transplant failure), suggesting that maintenance of continuity of care in these patients is a significant concern. Because aggressive CKD care should begin before transplantation and continue after allograft failure, it may be appropriate for a nontransplant physician to direct the CKD care of transplant recipients. The advantages of an integrated multidisciplinary care model in the management of CKD-related complications are well established in patients with native kidney disease. In addition to improving the proportion of patients who meet treatment targets for CKD-related complications, multidisciplinary care models have also been associated with a slower rate of decline of GFR.16-18 The effect of similar models in KTRs has yet to be evaluated. Irrespective of who assumes the responsibility for CKD care, communication between the multiple responsible care providers is essential to ensure continuity of care, and this may be enabled by the use of the CKD classification. 

APPLICABILITY OF THE CHRONIC KIDNEY DISEASE CLASSIFICATION IN TRANSPLANT RECIPIENTS Prevalence of Chronic Kidney Disease in Kidney Transplant Recipients The fact that kidney transplantation incompletely restores kidney function in most KTRs is well recognized. Fig. 44.2 shows the prevalence of CKD in 69,394 adult first KTRs between 1987 and 1997 with graft survival of at least 1 year in the United States Renal Data System (USRDS).19 GFR was estimated at 1, 3, and 5 years after the time of transplantation with an equation derived from the Modification of Diet in Renal Disease (MDRD) study,20 and patients were classified by K/DOQI CKD stage.2 At each time point, the mean GFR was approximately 50 mL/min/1.73 m2 and the prevalence of K/DOQI CKD stage 3, 4, or 5 was greater than 70%. More recent information demonstrates that although GFR at 1 year after transplantation has modestly improved in the current era, these data remain valid: Among a cohort of 189,944 adult first KTRs between 2001 and 2013 in the SRTR, the mean estimated GFR at 1 year after transplantation was 56 mL/ min/1.73 m2, and most patients would still be classified as having CKD stage 3 or greater disease.21 Given the reality of the organ shortage and the necessity to utilize DD kidneys of lower quality as well as the increasing use of kidneys from older-age living donors, we can expect that CKD will be an increasingly important issue for KTRs in the future. 

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CHAPTER 44  Chronic Kidney Disease in the Kidney Transplant Recipient 3.5

49  19

49  19 Stage 5 Stage 4

80%

Stage 3 Stage 2

60%

Stage 1

40%

20%

Mean number of complications

100%

GFR (mean  SD) 50  17

3.0 2.5 2.0 1.5 1.0 0.5 0.0

0% 1 yr n  60,816

3 yrs n  37,857

5 yrs n  20,761

FIG. 44.2 Glomerular filtration rate and prevalence of chronic kidney disease in patients with functioning transplants. Mean ± standard deviation (SD) of estimated glomerular filtration rate (GFR) (mL/min/1.73 m2) and prevalence of Kidney Disease Outcomes Quality Initiative (K/DOQI) chronic kidney disease stages among adult first transplant recipients in the United States between 1987 and 1997 at 1, 3, and 5 years after transplantation. (Adapted from Gill J, Mix C, Pereira BJG: Glomerular filtration rate and the prevalence of chronic kidney disease in transplant recipients. Am J Transplant. 2002;2(Supplement 3):417.)

Prevalence of Chronic Kidney Disease–Related Complications in Kidney Transplant Recipients

As in patients with native kidney disease, the prevalence of CKD-related complications including anemia, hypertension, hyperphosphatemia, hypoalbuminemia, and acidosis increases with declining GFR in transplant recipients. Fig. 44.3 shows the mean number of CKD complications per patient in a stable kidney transplant population at a single Canadian center.22 Similar findings have recently been reported in patient cohorts from the United Kingdom23 and Spain.24 

The Predictive Value of Chronic Kidney Disease Staging for Outcomes Among Kidney Transplant Recipients

The association of CKD stage based on GFR estimation at 1 year after transplantation with long-term allograft survival was evaluated in over 13,000 KTRs.25 Compared with stage 2 disease, increasing CKD stage was associated with a progressively higher risk for all-cause graft failure. However, patients with CKD stage 1 disease were also at higher risk for all-cause graft failure (hazard ratio [HR], 1.41 [1.13 to 1.75], P = 0.002), which may be due to serum creatinine–based associations independent of kidney function. The association of CKD stage with death-censored graft failure was stronger and showed a more consistent dose-response pattern than did the association with death with a functioning allograft.25 Although proteinuria has been associated with decreased kidney allograft survival and with increased risk for cardiovascular events and death in KTRs,26 the predictive value of the

1

2 3 4 Chronic kidney disease stage

5

FIG. 44.3  The mean number of chronic kidney disease (CKD) complications per patient by CKD stage.  The complications included hypertension (blood pressure ≥140/90 mmHg), serum calcium <8.5 mg/dL, serum phosphorus >4.5 mg/dL, hemoglobin <11 g/dL, serum albumin <3.5 g/dL, low-density lipoproteins >100 mg/dL, and total CO2 <22 mEq/L. (Adapted from Karthikeyan V, Karpinski J, Nair RC, Knoll G: The burden of chronic kidney disease in renal transplant recipients. Am J Transplant. 2004;4(2):262-269.)

2012 KDIGO CKD classification that recommends consideration of the cause of CKD and the level of kidney function and proteinuria has not been rigorously evaluated in KTRs. Furthermore, the cause of decreased kidney allograft function is frequently uncertain, multifactorial, and/or due to complex pathogenic processes that are incompletely understood from a mechanistic perspective, and therefore the prognostic value of the current CKD classification in KTRs remains unclear. Previous work has shown that although kidney allograft function at 1 year after transplantation is independently associated with outcomes including allograft failure and patient death,25,27-29 GFR at 1 year has limited predictive value for long-term outcomes in individual patients. Previous work has also shown a disconnect between the level of kidney function achieved at 1 year after transplantation and the subsequent decline in kidney function.5 This has precluded the use of early measures of kidney allograft function as a surrogate for outcomes in clinical trials.30 In contrast, the stability of kidney function may hold more promise for use as surrogate outcome in clinical trials in KTRs. A recent study using data from the Australia and New Zealand Dialysis and Transplant Registry31 evaluated different surrogate endpoints in 7949 adult first KTRs from 1995 to 2009 with graft survival of at least 3 years. A decline in GFR ≥30% between years 1 and 3 after transplant was found to be superior to all other surrogates, including 1-year GFR.31 The advantages of using a ≥30% decline in GFR over 2 years compared with doubling of serum creatinine as a surrogate were recently demonstrated in transplant-naïve CKD cohorts as part of a workshop sponsored by the NKF and the US Food and Drug Administration (FDA).32,33 Further work is needed to advance stability of kidney allograft function and/or measures of proteinuria as surrogate endpoints for clinical trials. 

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SECTION IV  Transplantation

CHRONIC KIDNEY DISEASE MANAGEMENT Chronic Kidney Disease Care Before Transplantation The clinical manifestations of CKD in a given transplant recipient will depend on the duration and burden of CKD before transplantation and the level of kidney function achieved after transplantation. Exposure to immunosuppressive medications after transplantation may exacerbate CKD-related complications such as hypertension, diabetes, dyslipidemia, and anemia. Early recognition and treatment of CKD-related complications, maximization of allograft function, and minimization of immunosuppressive-related side effects should decrease the effect of CKD in transplant recipients. Aggressive CKD care should begin before transplantation, because the preexisting burden of CKD present at the time of transplantation will not necessarily be undone by the provision of a functional allograft. In contrast, many of the complications of CKD, such as hypertension, dyslipidemia, anemia, and malnutrition, can be minimized by early detection and treatment before transplantation.34 Prolonged exposure to dialysis before transplantation has been associated with reduced allograft survival,35,36 and preemptive transplant recipients have an allograft survival advantage.37,38 The reasons underlying these associations are somewhat uncertain; however, a lower burden of CKD complications in patients with no or limited dialysis exposure is a plausible explanation.39 Reducing dialysis exposure through LD transplantation and preemptive transplantation should be encouraged. 

Chronic Kidney Disease Care in the Peritransplant Period

Transplant recipients are at increased risk for mortality in the peritransplant period compared with wait-listed patients who remain on dialysis. Data from the USRDS and Medicare claims were used to describe the incidence of cardiovascular morbidity and mortality after transplantation.40 There was a marked increase in the rate of all cardiovascular events (death, myocardial infarction, congestive heart failure, coronary revascularization, and stroke) during the early posttransplant period. The estimated probability of myocardial infarction, cardiac arrest, and congestive heart failure in DD transplant recipients in the first posttransplant month was 1.2%, 1.1%, and 5.2%, respectively. Approximately 5% of first KTRs will die within the first posttransplant year.40 The majority of deaths are due to cardiac causes and comorbid disease (diabetes, peripheral vascular disease, angina), and patients with a longer duration of CKD are at increased risk. These deaths could be regarded as failures of CKD management rather than as failures of transplantation because they result from the accumulated burden of CKD before transplantation that might have been prevented by aggressive pretransplant CKD care. Posttransplant factors including the incidence of acute rejection and delayed graft function may contribute to the excess morbidity and mortality in the peritransplant period.41,42 Whether more rigorous attention to volume status, standardization of the use of dialysis, and immunosuppression in the setting of delayed graft function would reduce peritransplant morbidity and mortality

merits further study. Ideally, patients who consent to accept lower-quality DD kidneys should undergo transplantation rapidly, allowing for close wait-list surveillance and optimal management of comorbid conditions, which may also help reduce the risk for perioperative morbidity and mortality.43 

Chronic Kidney Disease Care in Patients With a Functioning Allograft

Cardiovascular disease is one of the most important threats to long-term patient survival after transplantation. The management of cardiovascular disease in transplant recipients will continue to be an important component of posttransplant CKD care because of the increasing age and burden of CKD in these patients. Comprehensive reviews of posttransplant cardiovascular disease as well as treatment guidelines for cardiovascular risk reduction are available (see Chapter 39), and therefore a detailed discussion of these issues is not provided here.44-46 There is significant interest in the effect of immunosuppressive agents on the development and progression of cardiovascular disease. For example, new-onset diabetes mellitus after transplantation (NODAT) is now recognized as a common immunosuppression-related complication47 that is associated with an increased risk for graft loss, with the risk being comparable to that of acute rejection.48 Randomized studies of early steroid withdrawal showed surprisingly little effect on NODAT.49,50 However, a modest decrease in NODAT was observed in patients randomized to receive cyclosporine rather than tacrolimus.51 In the BENEFIT trial, KTRs randomized to treatment with belatacept had better metabolic and cardiovascular risk profiles compared with those randomized to cyclosporine (i.e., less NODAT, lower blood pressure, and lower serum lipids).52,53 The mean 5-year GFR was also significantly higher.53 At 7 years posttransplantation, there was a 43% reduction in the risk for death and graft loss compared with cyclosporine, despite a greater incidence of acute rejection.54 A comparison of the specific causes of death in the trial revealed a trend in favor of fewer cardiovascular events in the belatacept-treated group.54,55 In summary, the choice of immunosuppression continues to be determined by center-specific protocols that are dominated by considerations of immune risk rather than cardiovascular risk. Although there are important differences between immunosuppressive drugs that may mitigate the risk for posttransplant cardiovascular disease, early and aggressive treatment of cardiovascular risk factors is likely the most important strategy to minimize the risk for cardiovascular disease after transplantation. The level of kidney function achieved after transplantation has been associated with both patient and allograft survival and with the development of hospitalized heart disease.28,56 Because of these associations, it is important that an accurate assessment of allograft function be made. A key component of CKD care in transplant recipients is recognition of the fact that patients who are typically thought of as having “good graft function” actually have significantly impaired kidney transplant function and are at risk for the complications of CKD. Serum creatinine alone is not an accurate index of kidney function, and an estimate of the GFR is the preferred measure of kidney function. There are a number of prediction equations available to estimate kidney function in transplant

CHAPTER 44  Chronic Kidney Disease in the Kidney Transplant Recipient recipients, and a review of the accuracy and limitations of these equations is beyond the scope of this discussion. The latest KDIGO guidelines recommend the use of the Chronic Kidney Disease–Epidemiologic Prognosis Initiative (CKD-EPI) equation in adult patients.7 The CKD-EPI equation uses the same four variables as the MDRD equation (i.e., gender, race, age, and serum creatinine) but has been shown to perform better, especially at higher GFR.57 In the transplant setting, the superiority of CKD-EPI over MDRD is less clear.58-62 In a recent study performed in 3622 solid organ transplant recipients, including 53% adult KTRs, the CKD-EPI and MDRD equations performed similarly.63 Although both the CKD-EPI and the MDRD equations performed better than all other creatinine-based equations, both the CKD-EPI and the MDRD equations misestimated true GFR by more than 30% in 1 of 5 patients in the study.63,64 The use of cystatin C as an alternative or a complement to creatinine may improve the accuracy and precision of the estimation of GFR in KTRs. Cystatin C–based equations have been shown to perform better than creatininebased equations in some59 but not all studies.65 The level of kidney function achieved after transplantation is determined largely by donor and immunological factors. Because the mean level of kidney function established after 1 year of transplantation is only about 56 mL/min/1.73 m2,21 preservation of kidney function is an important aspect of CKD management in transplant recipients. Recent studies of administrative data sets as well as experience in single centers have described the change in kidney function after transplantation.66-68 Of importance is the observation that transplant recipients have a mean rate of kidney function decline that is slower than that in patients with native kidney disease with similar levels of kidney function.69 This is surprising given the fact that KTRs are at increased risk for kidney failure. There have been secular improvements in the rate of kidney function decline after transplantation over the last decade,6,68 but the reasons for this improvement have remained somewhat uncertain in these reports. It would appear that there are only relatively small differences in the rate of kidney function decline between patients treated with cyclosporine and tacrolimus-based maintenance immunosuppressive regimens.70 In contrast, calcineurin-free maintenance immunosuppressive regimens using belatacept have shown stability in kidney allograft function compared with cyclosporine-based regimens. In the latest analysis of the BENEFIT trial, the mean GFR for KTRs treated with belatacept increased at an approximate rate of +1.35 mL/min/1.73 m2 per year over the first 7 years after transplantation.54 In comparison, among KTRs treated with cyclosporine, there was a decline in GFR at a rate of −1.04 mL/min/1.73 m2 per year.54 Because tacrolimus is used in the vast majority of new transplant recipients, robust studies comparing belataceptand tacrolimus-based maintenance regimens are needed. Proteinuria and hypertension are associated with a loss of kidney function in KTRs. Although renin-angiotensin system (RAS) blockade has been proven effective at lowering blood pressure and proteinuria in KTRs, its role in preservation of kidney transplant function remains unclear.71,72 A recent metaanalysis of existing trials failed to show that RAS blockade

681

improves clinical outcomes in KTRs.73 Evidence regarding the role of anemia in the progression of kidney function decline is relatively sparse.74 Although associations between anemia and adverse graft outcomes have been reported in observational studies, correction of anemia to preserve allograft function and survival is not recommended. Further studies are needed to determine the optimal blood pressure and the role of proteinuria and other modifiable CKD factors in the rate of kidney function decline after transplantation. In the absence of direct evidence in KTRs, treatment of these factors based on their established role in the progression of native kidney disease is justified, especially because many of these factors also increase the risk for cardiovascular disease. 

Chronic Kidney Disease Care in Patients With Transplant Failure

Patients with transplant failure now make up about 15% of the waiting list in the United States.1 A number of studies have demonstrated that patients with transplant failure who return to dialysis are at increased risk for death compared with patients who maintain transplant function,15,75 and that their mortality is higher than that of transplant-naïve patients initiating dialysis for the first time.76 The survival of transplant failure patients who initiate hemodialysis and peritoneal dialysis is similar.77 Older patients and those with comorbid conditions such as peripheral vascular disease and diabetes have a higher risk for mortality after transplant failure.15,78 Surprisingly, however, survival after transplant failure is not significantly affected by transplant-related factors such as acute rejection, antibody induction, donor source, duration of graft survival, and the maximum attained GFR during transplantation.78 Repeat transplantation is associated with a survival benefit in transplant failure patients compared with treatment with dialysis.79 Preemptive repeat transplantation is associated with a lower risk for allograft failure from any cause including death, and death with a functioning graft but a similar risk for death-censored graft loss compared with nonpreemptive repeat transplantation.80 The benefits of preemptive transplantation were evident in patients with first transplant survival ≥1 year; however, there was a 34% increased risk for death-censored graft loss in preemptive recipients when first transplant survival was <1 year.80 When preemptive repeat transplantation is not possible, planning for dialysis should be undertaken in a timely fashion and include optimization of CKD parameters and vascular access creation if hemodialysis is chosen. The optimal timing of dialysis initiation after transplant failure remains uncertain. Despite being known to physicians with knowledge of CKD, recipients of failed transplant in the United States initiate dialysis with levels of hematocrit, albumin, erythropoietin use, and residual renal function that are suboptimal and similar to those in the general incident dialysis population.81 In addition, based on recent data from the USRDS, the rate of central venous catheter use in patients with allograft failure initiating dialysis was about 65%.82 Recent studies have demonstrated a higher rate of sepsis after dialysis initiation in transplant failure patients compared with nontransplant failure patients.83 The role of continued immunosuppression and temporary vascular

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SECTION IV  Transplantation

Failed transplant

Signs/symptoms of rejection or systemic inflammation: nephrectomy

No symptoms

Not repeat transplant candidates: taper and discontinue immunosuppression

Repeat transplant candidate

Re-transplant in < 1 year: maintain immunosuppression

Re-transplant > 1 year: taper immunosuppression

FIG. 44.4  Suggested management of transplant failure patients.  The speed of immunosuppressant drug tapering will vary depending on risk of rejection and patient tolerance of immunosuppressant medications (see text for details). (Adapted from Gill JS: Managing patients with a failed kidney transplant: how can we do better? Curr Opin Nephrol Hypertens. 2011;20(6):616-621.)

access was not specifically assessed but may have contributed to the higher rate of sepsis in the transplant failure group. These findings demonstrate that there are significant opportunities to improve the CKD management of transplant recipients and that there is a need for increased awareness of CKD among the medical professionals involved in the care of these patients. Management of immunosuppression after transplant failure is dependent on the patient’s suitability for repeat transplantation.84 There is no consensus on the optimal management of immunosuppression after transplant failure.84-87 In patients who are not repeat transplant candidates, immunosuppression should generally be tapered with the long-term objective of complete withdrawal or long-term treatment with minimal doses of corticosteroids to avoid adrenal insufficiency.84 Some nephrologists may continue immunosuppression with the goal of preserving residual renal function.86 To date, no study has formally evaluated the effect of maintenance of residual allograft function on outcomes in patients with kidney transplant failure. The rate at which immunosuppression is tapered in transplant failure patients is also an area of uncertainty. The key considerations are avoiding acute rejection that would require therapeutic nephrectomy and/or manifest more subtly as fatigue, weight loss, and resistance to erythropoietic-stimulating agents.84,88,89 In addition to factors noted with close patient monitoring, clinical and laboratory factors that may indicate the need for a slower pace of tapering include early transplant failure and rejection as the mechanism of transplant failure, as well as the patient’s pretransplant and current level of sensitization against anti–human leukocyte antigen antibodies. Nephrectomy traditionally has been

reserved for patients with acute symptoms related to rejection of the failed allograft. Although observational data have suggested that nephrectomy is associated with improved survival in transplant failure patients who return to dialysis, these findings may be confounded by other factors, and the role of elective nephrectomy in the management of transplant failure patients warrants further study.90,91 In patients who are repeat transplant candidates, the timing of repeat transplantation is a key consideration. In general, some degree of immunosuppression should be continued to avoid allosensitization. In transplant candidates who are not expected to undergo repeat transplantation rapidly (i.e., within 1 year of transplant failure), an individualized approach is recommended. In general, patients who are at relatively low risk for sensitization or the development of symptoms in the failed allograft and who have prolonged waiting times for repeat transplantation may be suitable for tapering of immunosuppressive medications over a period of 6 months to a year.84 Whether such patients should completely discontinue all drugs or be maintained on low-dose prednisone is unknown. Patients thought to be at higher risk for sensitization and/or rejection in the retained allograft may require ongoing immunosuppressive medications for longer time periods. The amount of immunosuppressant medication required would be determined empirically with ongoing monitoring for signs or symptoms suggestive of inadequate immunosuppression and for drug-related complications. Fig. 44.4 summarizes a suggested management approach.84 A full list of references is available at www.expertsonsult.com.

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