Abstract
In this chapter, the management of kidney transplant recipients is reviewed, beginning in the immediate postsurgical period and through the various phases following kidney transplantation. Salient issues in the assessment of allograft function, diagnosis and management of allograft dysfunction, and the assessment and management of key complications related to immunosuppressive medications are reviewed.
Keywords
kidney transplantation, immunosuppression, chronic complications, allograft dysfunction
The management of kidney transplant recipients is complex and spans a wide range of clinical scenarios. Posttransplant care begins in the immediate postsurgical period and continues through the various phases that make up the natural history of kidney transplantation. Whereas the early phases of care focus primarily on postsurgical management, monitoring of allograft function, and optimization of immunosuppression, later phases extend this focus to include ongoing assessment and management of factors that contribute to chronic allograft dysfunction, allograft loss, and death with a functioning graft. The nuances of posttransplant care have changed significantly over time as our understanding of the natural history of transplantation has evolved. The case-mix of transplant recipients has become more complex, and new technologies to monitor transplant recipients have emerged. In this chapter, we will review the major aspects of posttransplant care through this continuum in the current era of transplantation.
Recipient and Donor Characteristics
With changes in the demographics of the population with end-stage renal disease (ESRD) and improvements in technologies and immunosuppression, kidney transplantation may benefit many patients who previously would not have been eligible. With these successes come increased challenges and complexities in posttransplant care, along with a greater need to individualize care for various subgroups of kidney transplant recipients. For instance, transplantation in older adult patients has increased significantly in the past decade, with patients 65 years of age and older accounting for 18.5% of all transplant recipients in the United States in 2016. The complexities of pre- and posttransplant care are unique in older adult recipients, because they are more likely to have a greater burden of comorbid disease and a higher risk for death with a functioning allograft. However, the risk for acute allograft rejection is lower in older transplant recipients as a result of immunosenescence, which may allow for decreased use of immunosuppression. Therefore posttransplant care must be tailored to risks and outcomes within individual populations. Also, with the advent of desensitization strategies, both human leukocyte antigen (HLA)- and ABO-incompatible transplantation are realities in our current era, but these cases require more intense follow-up, given their higher risk for rejection and allograft loss. Other high-risk recipient groups include human immunodeficiency virus (HIV)-positive recipients, repeat transplant recipients, and multiorgan transplant recipients, each of which brings unique challenges to posttransplant care.
Similarly, the characteristics of deceased donors have changed over time, further complicating early posttransplant care. In the face of increasing demand for transplantation, organs from higher risk deceased donors are routinely transplanted in selected recipients. The Kidney Donor Profile Index (KDPI) is a continuous measure (percentile) of deceased donor quality that characterizes donors according to 10 characteristics that are associated with posttransplant allograft survival. The KDPI provides a relative estimation of posttransplant allograft survival relative to the kidneys transplanted in the United States within the previous year. For example, a kidney with a KDPI of 20% is anticipated to last longer than 80% of kidneys that were transplanted (i.e., it is among the top 20% of donor kidneys in terms of expected longevity). Conversely, a kidney with a KDPI of 85% is anticipated to last longer than only 15% of kidneys that were transplanted (i.e., it is among the bottom 15% of donor kidneys in terms of expected longevity). In 2015 nearly 10% of transplant recipients received a kidney with a KDPI of 85% or greater. In addition to having an increased risk of allograft loss, recipients who receive these kidneys also have an increased risk for delayed graft function (DGF) compared with recipients who receive kidneys with lower KDPIs. These high KDPI kidneys should typically be allocated only to recipient populations that continue to derive a significant survival benefit from transplantation, such as older adult and diabetic transplant candidates.
The First Week
Most kidney transplant recipients have a hospital duration of 4 to 7 days following surgery. In the acute postoperative phase, transplant recipient care involves assessment for immediate graft function, management of potential surgical complications, and treatment of postoperative fluid and electrolyte shifts.
The details of kidney transplantation surgery vary depending on whether the kidney comes from a living donor or a deceased donor, as well as the specific anatomy of a given recipient. In general, the surgery involves engraftment in the iliac fossa with vascular anastomoses of the donor renal artery to the recipient external iliac artery and of the donor vein to the external iliac vein. Perioperative complications that may require surgical exploration and management include bleeding and thrombosis of the renal artery or vein.
Assessment of graft function involves quantifying urine output (keeping the preoperative urine output of the recipient in mind) and following serum chemistries every 12 to 24 hours. Immediate graft function is denoted by a rapid drop in serum creatinine levels and urine output in excess of 100 mL/hour; this is expected in all living donor kidney transplant recipients and in most recipients of deceased donor kidneys. Immediate graft function is less likely in recipients of higher KDPI kidneys and in cases with prolonged cold ischemic times (>24 hours).
DGF is typically denoted as the requirement for dialysis within the first week posttransplant and occurs in less than 5% of living donor transplant recipients. Conversely, DGF is seen in more than 30% of recipients of deceased donor kidneys with a KDPI ≥85%. In addition to donor factors, the duration of cold ischemic time and warm ischemic time is an important predictor of DGF. Dialysis is performed based on volume status and metabolic parameters, and either hemodialysis or peritoneal dialysis may be used, depending on the patient’s baseline dialysis modality. In the case of peritoneal dialysis, it is important to confirm that the peritoneum was not breached during the surgery before resumption of dialysis.
Although the cause of DGF is usually acute ischemia-reperfusion injury, alternate causes (including vascular thrombosis and early acute rejection) need to be considered. Therefore a Doppler kidney ultrasound to assess for blood flow in the allograft is recommended within hours of a clinical change in allograft function. Elevated resistive indices may suggest either tubular injury or rejection; thus the baseline risk for rejection and duration of DGF should be considered in assessing the cause of early graft dysfunction. If rejection is suspected or DGF persists beyond 1 week, an allograft biopsy should be performed. In cases of prolonged DGF, serial biopsies should be considered to rule out immune-mediated injury.
Reduced exposure to calcineurin inhibitors (CNIs) in the setting of DGF is recommended to avoid further tubular injury associated with CNI nephrotoxicity, but this must be balanced with the risk for rejection. The use of induction immunosuppressive agents is recommended if CNIs are to be reduced or avoided in the setting of DGF. There are few data to support a uniform approach to immunosuppression in the setting of DGF, but some centers prefer to use T lymphocyte–depleting antibodies (thymoglobulin) for induction, along with immediate initiation of an antimetabolite (mycophenolate) and corticosteroids, with delayed introduction of CNI only once there is evidence of graft function. A number of novel therapeutic agents are currently being studied to minimize the risk of DGF in kidney transplantation. QPI-1002 (formerly I5NP) is an intravenously administered synthetic small interfering ribonucleic acid (siRNA) that is currently in a phase 3 clinical trial to prevent DGF. The agent is designed to temporarily inhibit the expression of the proapoptotic gene p53 in order to allow proximal tubular cells the opportunity to repair ischemia reperfusion-associated cellular damage.
The majority of DGF cases recover within the first 2 to 3 weeks, but numerous studies have demonstrated inferior allograft survival in patients who have developed DGF, although it remains unclear how much of this is directly attributable to cold ischemia–induced DGF versus baseline donor and recipient factors that may independently contribute to both an increased risk of DGF and allograft loss. Importantly, although DGF appears to be associated with an increased risk of allograft loss, the survival benefit of transplantation is retained even among recipients who develop DGF and largely irrespective of the KDPI of the transplanted kidney.
Fluid and electrolyte management is a key component of early postoperative care. Hemodynamic extremes of hypotension and volume overload should be avoided in all patients and, particularly, in older adult patients and in those with compromised cardiac function. Electrolyte shifts, including hypercalcemia and hypophosphatemia associated with secondary hyperparathyroidism and hypomagnesemia associated with diuretic use, may be seen early posttransplantation and should be managed accordingly.
Outpatient Care
Following discharge from the hospital, transplant recipients are closely followed by the transplant center. The frequency of monitoring is greatest during the first 3 months, as the risk for rejection is highest during this period. Many centers follow patients twice weekly during the first month posttransplant and then weekly for the remainder of the first 3 months, with the frequency of visits gradually reduced to every 4 to 8 weeks by the end of the first year.
Routine posttransplant monitoring includes a follow-up history and physical examination, along with measurement of serum chemistries, a complete blood count, liver enzymes, whole blood CNI levels, and urinalysis. Spot albumin-to-creatinine ratios are also periodically monitored. Preemptive viral screening and monitoring are indicated at a high frequency (weekly) for the first 3 to 6 months, depending on the patient’s risk for infection, and should continue at a lower frequency for the duration of the first year posttransplantation. Testing beyond the first year should be tailored to each patient’s risk.
Immunosuppression
Immunosuppression after transplantation consists of induction therapy followed by lifelong maintenance immunotherapy. Chapter 62 provides greater details on specific induction and maintenance agents, including their side-effect profiles. Induction therapy is administered at the time of transplantation and includes intravenous methylprednisolone, along with either an anti-CD25 antibody (basiliximab) or a T lymphocyte–depleting antibody (the polyclonal antibody thymoglobulin). Alemtuzumab is a monoclonal antibody used in the management of chronic lymphocytic leukemia that results in potent lymphocyte depletion and is increasingly used as an induction agent in kidney transplantation.
Maintenance immunosuppression typically consists of triple immunosuppressive therapy with a CNI, an antimetabolite, and low-dose corticosteroids. Until the early 2000s, azathioprine was the preferred posttransplantation antimetabolite; however, mycophenolic acid (MPA) agents more selectively target lymphocytes, resulting in superior efficacy in preventing acute rejection and increased patient tolerability. Rapamycin has been studied as an alternative to CNIs or for use in combination with CNIs. Although concerns regarding wound healing and nephrotoxicity have minimized the use of rapamycin as a primary de novo immunosuppressant agent after transplantation, data suggesting a reduced risk for malignancies with the use of rapamycin have renewed interest in this agent, particularly for patients with recurrent skin cancers posttransplant. Belatacept is an intravenously administered costimulatory blocker that binds CD80 and CD86 on the surface of antigen-presenting cells to inhibit T-cell activation and promote anergy and apoptosis. While long-term outcomes comparing this agent with cyclosporine have been very promising, the optimal indication and immunosuppressive cocktail within which this agent should be used still remains uncertain and will likely be refined in the coming years.
Immunosuppressive Protocols
The majority of transplant recipients are maintained on triple immunosuppressive therapy, including CNI, MPA, and corticosteroids. Low rates of acute rejection and growing concern with the adverse effects of these agents, including chronic CNI nephrotoxicity, have led to strategies to minimize immunosuppressive exposure. Minimization of CNI and corticosteroid exposure has been most frequently studied, but the merits of immunosuppression minimization with the increasingly recognized importance of chronic immune-mediated injury are debatable in the current era.
Posttransplant corticosteroid exposure has been reduced significantly, with prednisone doses rapidly tapered to 5 to 10 mg daily within the first 4 to 6 weeks after surgery. Late withdrawal of corticosteroids has been largely abandoned in the face of numerous studies demonstrating an increased risk for rejection when corticosteroids are withdrawn beyond 3 to 6 months posttransplant. Early corticosteroid withdrawal or avoidance strategies, however, are associated with largely favorable outcomes. A meta-analysis of 34 studies, including 5637 patients receiving steroid withdrawal or avoidance regimens, found that steroid avoidance reduced the risk for hyperlipidemia, hypertension, and new-onset diabetes after transplantation (NODAT). Woodle and colleagues conducted a multicenter randomized controlled trial of early corticosteroid withdrawal (within 7 days) compared with low-dose maintenance corticosteroids in a CNI- and MPA-based regimen. The early steroid withdrawal group had an increased rate of biopsy-proven acute rejection and chronic allograft nephropathy, but no difference was found in the composite primary endpoint of death, graft loss, or severe acute rejection through 5 years. When examined separately, graft and patient survival also did not differ. Although steroid exposure should be minimized whenever possible, corticosteroid avoidance or early withdrawal should be reserved for patients at low risk for rejection and only with careful and frequent posttransplant monitoring.
Long-Term Drug Dosing and Monitoring
Because of inter- and intrapatient variability in the bioavailability and absorption of CNI, routine whole-blood drug-level monitoring is essential. Trough levels of CNI correlate well with drug exposure and clinical events, particularly for tacrolimus. However, evidence exists that peak drug levels (2 hours after dose) of cyclosporine correlate better with drug exposure and clinical events, including acute rejection. As a result, certain centers have adopted peak level, or “C2” monitoring, for cyclosporine. Although specific therapeutic targets may vary depending on concomitant immunosuppression, levels are typically kept highest in the first month after transplant, with a gradual reduction over the next 6 months. In interpreting drug levels, it is important to remember that different labs may use different assays, resulting in different results.
Routine therapeutic drug level monitoring is not recommended for MPA, because trough levels do not correlate well with clinical efficacy, and the repeat measurements required to appropriately calculate the area under the curve are labor intensive and not feasible for routine measurement. Target doses (2 g daily for mycophenolate mofetil and 1440 mg daily for mycophenolate sodium, typically in divided doses) are based on clinical trials demonstrating efficacy at these doses. Transient dose reduction or temporary discontinuation of MPA is recommended in cases of significant diarrheal symptoms or profound leukopenia. However, full doses should be resumed after resolution of symptoms, if tolerated, because prolonged dose reductions or discontinuations are associated with inferior allograft survival.
Nonadherence to immunosuppressive medications after kidney transplantation significantly increases the risk of acute and chronic immune-mediated allograft dysfunction and allograft loss. Therefore assessment and management of nonadherence are important aspects of immunosuppressive management. An assessment of patient-level risk factors for nonadherence (including young age, a history of nonadherence to other therapies, psychiatric/psychological disorders, substance abuse, cognitive impairment) should be completed, and mechanisms to monitor adherence should be implemented before transplantation. Tools to optimize adherence should be explored, including increased education and support to promote adherence, tailoring the immunosuppressive regimen, or consideration of once-daily formulations of medications when available, blister packaging of medications, and increased frequency of follow-up. Importantly, these interventions require frequent reassessment and evaluation in the early and late posttransplant setting.
Adverse Effects and Drug Interactions
Adverse effects of immunosuppressant medications should be assessed during each follow-up visit. Significant effects of corticosteroids include cataracts, bone loss and fractures, avascular necrosis, hypertension, weight gain, dyslipidemia, glucose intolerance, mood lability, and acne. MPAs may confer bone marrow toxicity (leukopenia, anemia), gastric reflux, diarrhea, and pancreatitis. Calcineurin inhibitors may cause acute and chronic nephrotoxicity, although the impact of CNIs on chronic graft function is being increasingly questioned. Other significant effects of CNIs include hypomagnesemia, hyperkalemia, hyperuricemia, neurotoxicity (e.g., tremor), and, rarely, thrombotic microangiopathy. Tacrolimus is more strongly associated with NODAT than cyclosporine, whereas cyclosporine is more commonly associated with cosmetic changes, including gingival hyperplasia and hirsutism.
The narrow therapeutic and toxic window for CNIs, in addition to the high potential for altered metabolism from interference of the cytochrome 450 (CYP450) mechanism, mandates careful examination and recognition of potential drug interactions. Common CYP450 drug inhibitors (which will increase CNI levels) and inducers (which will lower CNI levels) are outlined in Table 61.1 . New drugs should be introduced with care, and drug levels should be carefully monitored, when indicated. MPA is not metabolized via the CYP450 enzyme pathway, and there are fewer drug interactions compared with CNI; however, any drugs that may potentiate leukopenia should not be used in conjunction with these agents.
| Increase CNI Level (Inhibits Enzyme) a | Decrease CNI Level (Stimulates Enzyme) a |
|---|---|
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a Listed drugs interact with the calcineurin inhibitors, cyclosporine, and tacrolimus because they are metabolized by the cytochrome P450 CYP3A4 isoenzyme.
Allograft Dysfunction
The immune response to an allograft involves (1) recognition of foreign antigens, (2) activation of recipient lymphocytes, and (3) effector mechanisms leading to rejection of the allograft. The human major histocompatibility complex (MHC) is a cluster of genes on chromosome 6 that encodes HLA, in addition to other agents critical in controlling the immune response; MHC is the key factor in the initiation of the immune response to an allograft. The HLA antigens are the major barriers to transplantation, and allogeneic donor HLA antigens are the main targets of the immune system in rejection of the graft. However, the role of non-HLA antigens in inciting an immune response and subsequent rejection is increasingly being realized.
Acute Allograft Dysfunction
A 15% to 20% increase in serum creatinine from baseline suggests graft dysfunction and warrants a thorough evaluation, including an assessment of risk factors for acute kidney injury, an ultrasound of the allograft, and often an allograft biopsy. Nonimmune causes of allograft dysfunction should be ruled out, including CNI nephrotoxicity, acute interstitial nephritis, pyelonephritis, ischemic injury, recurrent native kidney disease, and BK nephropathy. Supratherapeutic CNI levels and the presence of isometric tubular vacuolization or arteriolar hyalinosis on biopsy ( Fig. 61.1 ) strongly suggest acute CNI nephrotoxicity, although an allograft biopsy is not usually required for diagnosis because a reduction in CNI dose will quickly improve kidney function. Recurrent native kidney disease rates vary, depending on the original cause of ESRD, and require allograft biopsy for diagnosis. BK polyomavirus nephropathy may cause graft injury with a high risk for subsequent graft loss, but a histologic diagnosis is often difficult.
The Banff classification, originally published in 1993 and subsequently revised in multiple iterations, was instrumental in standardizing criteria for allograft pathology, including those for acute rejection ( Box 61.1 ). The glomeruli, tubules, interstitium, and vessels should be examined for the presence of inflammation and lymphocyte infiltration. Interstitial inflammation with lymphocytes is scored from absent (i0) to severe (i3). Tubulitis is the definitive aspect of acute cellular rejection and is quantified from mild (t1) to severe (t3). Vessel wall infiltration, or arteritis, represents a greater severity of rejection (grade II) and ranges from mild/moderate (v1) to severe (v2). Although lymphocyte infiltration in the glomeruli may accompany acute rejection, it is not a criterion of rejection.
- 1.
Normal
- 2.
Antibody-mediated changes (may coincide with categories 3, 4, and 5)
Acute/active AMR: all three features must be present
- 1.
Histologic evidence of tissue injury (one or more): microvascular inflammation ( g >0 and/or ptc >0); intimal or transmural arteritis ( v >0); acute thrombotic microangiopathy; ATN without other cause
- 2.
Evidence of antibody interaction with vascular endothelium (one or more): C4d staining in peritubular capillaries; moderate-severe microvascular inflammation ( g + ptc ≥2); validated molecular markers for AMR
- 3.
Serologic evidence for donor-specific antibodies (HLA or non-HLA)
- 1.
Chronic active AMR: all three features must be present
- 1.
Chronic tissue injury (one or more): transplant glomerulopathy (by light microscopy or by EM alone); severe peritubular capillary basement membrane multilayering; unexplained new arterial intimal fibrosis
- 2.
Evidence of antibody interaction with vascular endothelium (one or more): C4d staining in peritubular capillaries; moderate-severe microvascular inflammation ( g + ptc ≥2); validated molecular markers for AMR
- 3.
Serologic evidence for DSAs (HLA or non-HLA)
- 1.
C4d staining without evidence of rejection (require all three):
- 1.
C4d staining in peritubular capillaries
- 2.
No acute or chronic microvascular inflammation, intimal or transmural arteritis, thrombotic microangiopathy, or unexplained ATN
- 3.
No acute T-cell mediated rejection or borderline changes
- 1.
- 3.
Borderline changes
Suspicious for acute T-cell–mediated rejection. No intimal arteritis, but foci of tubulitis (t1, t2, or t3) with minor interstitial inflammation (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis (t1, i1, or greater)
- 4.
T-cell–mediated rejection (TCMR; may coincide with 2, 5, and 6)
Acute T-cell–mediated rejection (type/grade)
- 1.
Significant interstitial infiltration (i2; >25% of parenchyma affected) and foci of moderate tubulitis (t2; >4 mononuclear cells/tubular cross section or group of 10 tubular cells)
- 2.
Significant interstitial infiltration (i2; >25% of parenchyma affected) and foci of severe tubulitis (t3; >10 mononuclear cells/tubular cross section or group of 10 tubular cells)
- 3.
Mild to moderate intimal arteritis (v1)
- 4.
Severe intimal arteritis comprising >25% of the luminal area (v2)
- 5.
Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle
- 1.
Chronic active T-cell–mediated rejection
Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration)
- 5.
Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology (grade)
- 1.
Mild interstitial fibrosis (ci1) and tubular atrophy (ct1); <25% of cortical area affected
- 2.
Moderate interstitial fibrosis (ci2) and tubular atrophy (ct2); 26%–50% of cortical area affected
- 3.
Severe interstitial fibrosis (ci3) and tubular atrophy (ct3); >50% of cortical area affected
- 1.
- 6.
Other: changes not considered to be due to rejection—acute and/or chronic (may coincide with categories 2, 3, 4, and 5)
AMR , Antibody-mediated rejection; ATN , acute tubular necrosis; C4d+ , activated complement component C4d; cg , glomerulopathy; ci , interstitial fibrosis; ct , tubular atrophy; EM , electron microscopy; g , glomerulitis; i , interstitial infiltration; ptc , peritubular capillaritis; t , tubulitis; v , vessel wall infiltration or arteritis.
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