13 - Renal Transplantation | Manual of Nephrology. Diagnosis and Therapy 6e

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

> Table of Contents > 13 - The Patient with Renal Transplantation

The Patient with Renal Transplantation

Eric Gibney

Chirag Parikh

Alkesh Jani

Introduction and epidemiology. The prevalence of end stage renal disease (ESRD) in the United States and developed nations continues to increase at an alarming rate. In the year 2000, there were more than 375,000 U.S. patients with ESRD. Currently, hemodialysis (HD), peritoneal dialysis (PD), and renal transplantation are the only available therapies for ESRD, with in-center HD being the most common. Comparisons of renal transplant recipients to dialysis patients awaiting kidney transplant have shown that renal transplantation, in most cases, is the ideal treatment of ESRD. Advantages include longer patient survival, less morbidity, cost savings, and improved quality of life compared with dialysis. Furthermore, substantial improvement has occurred in both short- and long-term graft survival, which can be expected to widen the advantage of transplantation over HD. The life expectancy for the average living donor kidney has now exceeded 20 years. This good news is tempered by the reality that demand for transplant kidneys far exceeds the supply of available organs. The waiting list for kidney transplants is over 56,000 as of December 2003. Currently, less than 15,000 kidney transplants are performed each year, and this number is growing less rapidly than the waiting list. Due to the high morbidity and mortality associated with ESRD, the unfortunate outcome is that many patients die before receiving a transplant.
Patient selection. Few contraindications to receiving a kidney transplant exist. However, patients should not receive a transplant if they have an active infection, ongoing active immunologic disease that led to renal failure, metastatic malignancy, inability to follow a medical regimen due to medical or psychologic reasons, or are at high operative risk due to other conditions. Although there is no definite age limit to receive a kidney transplant, the benefits of transplantation may be attenuated by comorbid conditions. Therefore, elderly patients should be screened thoroughly and counseled regarding the risks of transplantation. Human immunodeficiency virus (HIV) infection has historically been a contraindication to transplantation, but successful kidney transplantation has occurred in patients free of opportunistic infections with undetectable viral replication and sustained CD4 counts of greater than 200.
- Recipient evaluation. The goals of evaluating a potential recipient should be to identify potential barriers to transplantation, identify treatable conditions that would attenuate the risk of the operation or immunosuppression, and to explain benefits and risks. Attention is given to the cause of ESRD and its tendency to recur in renal transplants. Comorbid conditions and the effects of immunosuppression on these conditions are considered. Patient older than 50, diabetes, abnormal electrocardiogram, angina, or congestive heart failure (CHF) have been demonstrated as predictors of cardiac death and nonfatal cardiac events. Noninvasive strategies such as thallium perfusion imaging and dobuatmine stress echo have demonstrated the ability to predict cardiac events and may prevent high-risk patients from requiring angiography. Screening for malignancy should follow age-appropriate guidelines. In patients with malignancies, a 2 to 5 year remission may be required before transplantation, depending on tumor type and invasiveness. Although obesity is a risk for wound-related complications, long-term outcomes are similar to nonobese patients unless cardiovascular disease exists. Psychosocial screening is usually performed. Testing generally
  P.198
  
  includes evaluation for HIV and Hepatitis B and C. Imaging or functional evaluation of the kidneys and lower urinary tract may be necessary in certain patients. After a patient has been accepted as a candidate, ABO and human leucocyte antigen (HLA) typing is performed, along with a determination of serologic status for cytomegalovirus (CMV) and varicella. The candidate's blood is also screened with a panel reactive antibody test (PRA) for cytotoxic antibodies against common HLA antigens. A patient on the waiting list for longer than 1 year should be seen periodically to update their condition.
- Donor evaluation. Although the risks of donation are small, these risks need to be carefully explained to a potential living donor. Mortality is uncommon, but has occurred in 0.02% of donors (2 per 10,000). Infection, bleeding, and other postoperative complications occur in approximately 0.5% to 3% of patients. Progression to ESRD has occurred, but does not appear to be more common than in the general population. Mild blood pressure elevation and proteinuria may occur after donation, but the long-term consequences are currently unclear. After ABO compatibility and a negative cross match are assured, the donor evaluation process can begin. If there are multiple candidates, the donor with fewer HLA mismatches is usually selected. Donors are carefully screened for kidney disease to prevent the possibility of loss of function in the remaining kidney. Depending on severity, hypertension, proteinuria, obesity, kidney stones, and structural or functional renal disease may be contraindications to donation. Testing for latent diabetes mellitus with a glucose tolerance test may be performed if there is a family history or perceived risk for future diabetes. When recipients are affected by hereditary disorders such as polycystic kidney disease or hereditary nephritis, the condition must be ruled out before a living, related donation. If a donor is thought to be acceptable, imaging of the kidneys is performed using magnetic resonance angiography (MRA) or other modalities, allowing the team to assess for structural or vascular anomalies and suitability for laparoscopic donation. A cadaveric or deceased donor also must be evaluated. The presence of metastasis, unknown cause of death, HIV, or widespread infection precludes donation. Donors with Hepatitis C are sometimes accepted for Hepatitis C positive recipients. A combination of factors such as hypertension, advanced age, elevated creatinine, oliguria, or dependence on pressor support may exclude a donor. Pre-implantation biopsies can be performed on an individual basis when there is concern about the function of a donor kidney.
- Predictors of outcome. Recipient factors, donor factors, and donor recipient compatibility all influence long-term graft survival. Although it is difficult to eliminate confounding variables, the United States Renal Data Systems 2002 report found that recipients who are younger, have low levels of PRA, have spent less time on dialysis, and who are employed or college educated have superior graft survival. Recipients who have been transplanted preemptively also have superior long term graft survival. Race and ethnicity may affect graft survival for both donors and recipients, with non-black donor kidneys and non-black, non-Hispanic recipients of grafts having the longest graft survival. Kidneys from living related or unrelated donors survive longer on average than cadaveric kidneys. Other donor qualities that positively affect outcomes include younger age and shorter cold ischemia time. The presence of hypertension, stroke as a cause of death, older age, or terminal creatinine greater than 1.5 may qualify a kidney as an expanded criteria donor kidney due to influence on poorer graft survival. Finally, factors of donor and recipient compatibility also affect outcomes: Better HLA matching, CMV serologic status matching, and equivalent donor recipient body mass index all have positive effects on long-term graft survival.

Immunology and pharmacotherapy

Immunology. A basic review of the mechanisms of immune recognition and response to an allograft is helpful to better understand the kidney
P.199

transplant patient as well as the pharmacologic agents used to prevent allograft rejection.
- Major histocompatibility complex (MHC). Cells in the tissues of mammals, birds, and bony fish express MHC surface molecules, which are crucial for the immune system to be able to recognize and respond to a foreign antigen. In humans, these MHC molecules are located on the short arm of chromosome 6 and encode for HLA proteins. MHC molecules serve two basic functions: they identify self from non-self, and coordinate the T-cell receptor recognition of the antigen-MHC complex. The MHC molecules are divided into two groups: class I and class II. MHC class I molecules appear on the surface of all cells and are known as HLA-A, -B, and -C. MHC class II molecules appear on antigen presenting cells (APC) and are termed HLA-DR, -DP, and -DQ. One MHC haplotype is inherited from each parent as a locus containing each of the six genetically linked HLA molecules. In kidney transplantation, only the HLA-A, -B, and -DR are determined due to their immunogenicity. A zero-antigen mismatched kidney has no mismatches in either locus for HLA A, -B, and -DR, although mismatches may be present at HLA-C, -DP, -DQ, or at other minor antigens. Although advances in immunosuppression have narrowed advantages for well-matched transplants, a two haplotype-identical transplant from a family member or a zero antigen-mismatched cadaveric transplant confers a graft survival benefit compared to transplants with lesser degrees of matching.
- Antigen-presenting cells (APCs). APCs are distributed in a ubiquitous manner in body tissues and allow T cells to recognize foreign antigens. Monocytes, macrophages, dendritic cells, and activated B cells can all serve as APCs. Either by phagocytosis or through surface immunoglobulin (B cells), APCs capture foreign antigens, degrade and process them into peptides, and express these foreign peptides on MHC class II surface molecules. Through T-cell receptor interactions and various downstream events, the T cell is then able to coordinate an immune response to this foreign antigen.
- T cells are processed in the thymus and are central to cellular immunity and allograft recognition and rejection. These properties make them a common target of drugs designed to prevent rejection. Central to the immune response is the ability of the T cell to recognize foreign antigens through a surface T-cell receptor (TCR). These receptors recognize antigens through either indirect or direct pathways. The indirect pathway involves TCR recognition of a foreign antigen that is presented by a self-MHC molecule located on an APC surface. The direct pathway refers to the ability of some T-cell populations to recognize foreign MHC that is not presented with self MHC on an APC. There are two major classes of T cells: T helper cells, which express CD4 surface molecules (CD4+), and cytotoxic T cells, which express CD8. (CD8+). CD4+ cells recognize MHC class II molecules on the surface of APCs, whereas CD8+ cells are restricted to the recognition of MHC class I. CD4+ cells are activated after the recognition of a foreign antigen (e.g., foreign MHC from a kidney transplant). They then initiate an immune response to foreign peptides by secreting cytokines important in B cell proliferation and activation and cytotoxic T-cell activation. CD8+ T cells kill cells bearing foreign antigen through the use of cytotoxic molecules such as perforins, granzymes, and Fas, which triggers apoptosis in the targeted cell.
- T-cell and APC interactions. T cells and APCs have a number of important interactions central to allograft recognition and rejection. Signal 1 is the term for initial binding of the T cell to the APC through interactions between the TCR/CD3 complex and foreign peptide expressed in MHC. Signal 1 is a calcium-dependent process and results in calcineurin activation. Although signal 1 alone will cause anergy, the addition of signal 2, also known as costimulation, will lead to an immune response.
  P.200
  
  The best understood costimulation signal is between CD28 on the T-cell surface and B7 on the APC surface. CD28/B7 activation leads to intracellular signaling, interleukin-2 (IL-2) production, and T-cell activation. Whereas B7 is expressed on resting T cells, the T-cell surface molecule cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA4) is expressed only on activated T cells. CTLA4 binds preferentially to B7 and eventually inactivates the immune response, thereby providing potent negative feedback. Another costimulatory molecule, CD40, is found on APCs and activated B cells. It binds to CD40 Ligand (CD40L) on T cells. The CD40/CD40L pathway is important in immunoglobulin production and class switching by B cells.
- B cells develop at multiple sites of the body, including the liver, spleen, and lymph nodes. In response to T-cell signals for activation and proliferation, they produce immunoglobulins. A naive B cell produces immunoglobulin M (IgM) and, after class switching, is able to produce IgG, IgA, or IgA. Depending on their class, antibodies mediate opsonization for phagocytosis or antibody-dependent cellular cytotoxicity, and can fix complement. B cells and antibodies are important in the processes of hyperacute rejection (immediate allograft destruction due to preformed antibodies), and donor-specific antibodies have been implicated in both acute humoral rejection and chronic allograft dysfunction.

Pharmacotherapy. In the past two decades, the number of immunosuppressive agents available has increased greatly. Commonly used agents, their mechanism of action, and common toxicities appear in Table 13-1. Agents can be used for induction therapy at the time of transplant, as maintenance therapy to prevent rejection of the allograft, or for the treatment of acute rejection.

Table 13-1. Commonly Used Drugs in Renal Transplantation


Class and Drugs	Mechanism	Toxicity	Indication

Calcineurin Inhibitors
Cyclosporine	Binds cyclophilin and blocks calcineurin's action	Hypertension, hyperlipidemia nephrotoxicity, neurotoxicity hirsuitism, gingival hyperplasia	M
Tacrolimus	Binds to FKBP, inhibiting calcineurin's action	PTDM, neurotoxicity side effects similar to cyclosporine	M
TOR inhibitors
Sirolimus	Binds to FKBP and inhibits mTOR effects, cytokine signaling, cell cycling, and CD28 mediated costimulation	Elevated cholesterol and triglycerides, cytopenias, acne, arthralgia, CsA toxicity, pneumonitis	M, CIW
Antiproliferatives
Azathioprine	6-MP release in vivo, interferes with DNA synthesis, cell cycling	Cytopenias, diarrhea, hepatotoxic, neoplasias	M
Mycophenolate mofetil	Inosine monophosphate dehydrogenase inhibitor, blocks de novo purine synthesis	Diarrhea, GI discomfort, cytopenias, invasive CMV	M
Corticosteroids	Multiple sites of action; cytokine production, T-cell proliferation, leucocyte traffic, others	HTN, PTDM, hyperlipidemia, obesity, infection, osteoporosis, AVN	I, M, AR
Antibody therapies
Muromonab/CD3	Mouse monoclonal Ab against CD3 on TCR	Cytokine release syndrome	I, AR
		Pulmonary edema, leucopenia
Antithymocyte Globulin	Rabbit polyclonal Ab against thymocytes	Allergic reaction, leucopenia	I, AR
ATGAM	Horse polyclonal Ab against thymocytes	Thrombocytopenia
Daclizumab	Humanized (90%) monoclonal Ab against CD-25, the alpha subunit of IL-2 receptor	Low incidence of side effects: fever, chills, allergy	I
Basiliximab	Partially humanized (75%) monoclonal Ab, same target as dacluzimab		I

M: Maintanence, I: Induction, AR: Acute Rejection, CIW: Calcineurin Inhibitor Withdrawal, 6-MP: 6 Mercaptopurine, HTN: Hypertension, AVN: Avascular Necrosis, PTDM: Post-Transplant Diabetes Mellitus, TCR: T-cell Receptor, Ab: antibody

The calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (FK506), are a mainstay of maintenance immunosuppression. Cyclosporine and tacrolimus have similar side effects, but hyperlipidemia, hypertension, hirsutism, and gingival hyperplasia are more common with cyclosporine, and post-transplant diabetes mellitus and neurotoxicity are more common with tacrolimus. Both agents cause significant nephrotoxicity. Tacrolimus has also been advocated as the maintenance agent of choice for steroid-resistant acute rejection.
One target of rapamycin (TOR) inhibitor, sirolimus, is currently used in renal transplantation for maintenance therapy and for calcineurin inhibitor withdrawal. Important toxicities include hypertriglyceridemia, hypercholesterolemia, cytopenias, and diarrhea. Sirolimus may also increase the toxicity of cyclosporine.
The antiproliferatives, either mycophenolate mofetil (MMF) or azathioprine, can be used in combination with calcineurin inhibitors and corticosteroids for maintenance immunosuppression. MMF often causes diarrhea and gastrointestinal discomfort, can be associated with cytopenias, and may be associated with an increased risk of tissue-invasive CMV. Azathioprine, a purine analog, provides less selective lymphocyte inhibition and can be associated with cytopenias and neoplasias.
Corticosteroids are used during induction, as maintenance therapy, and for the treatment of acute rejection. Their effectiveness is complicated by a variety of well-known side effects, including hypertension, glucose intolerance, weight gain, cataracts, poor wound healing, osteoporosis, and osteonecrosis. Although corticosteroid withdrawal and avoidance have been explored (V.C.2), they remain a mainstay of current immunosuppression.
Antibody therapies are available for many indications in kidney transplantation, including acute humoral rejection, steroid-resistant acute rejection, and induction in patients with elevated PRA, repeat transplant, positive B-cell cross match, ABO incompatibility, or other situations involving high immunologic risk. Muromonab/CD3 (OKT3) is a
P.201

P.202

murine monoclonal Ab against the CD3 complex of the TCR. Given intravenously for 7 to 14 days, it is available for induction therapy and for the treatment of acute rejection. Toxicities include a cytokine release syndrome that can sometimes be complicated by capillary leak and pulmonary edema. Aseptic meningitis, serum sickness, profound immunosuppression, and lymphoproliferative disorders are less common side effects. Polyclonal antibody preparations (anti-lymphocyte globulin, anti-thymocyte globulin) are also available for induction and acute rejection. These compounds are developed by injecting human lymphoid or thymic extracts into animals (horse, rabbit, etc.) and purifying the antibodies produced. These preparations neutralize lymphocytes by multiple antibody-mediated mechanisms, with a sustained effect on proliferation. Toxicities are related to immunosuppression, heterogeneity of preparations, allergic or anaphylactoid responses to nonhuman preparations, and cytopenias. Finally, daclizumab and basiliximab are 90% and 75% humanized monoclonal antibodies to the CD25 portion of the IL-2 receptor. These agents are used for induction therapy and prevention of acute rejection. Administration has decreased the incidence of acute rejection with minimal side effects.
Drug interactions. Although it is not possible to list all possible drug interactions, it is important for the clinician to be aware of general types of interactions when initiating new therapies or witnessing unexpected toxicities. In general, interactions can result from changes in absorption, metabolism, or excretion, or through additive or synergistic toxicity with agents that have similar side effects. Agents that can decrease the absorption of immunosuppressive agents include antacids, cholestyramine, and food, and promotility agents can increase absorption. The metabolism of tacrolimus and cyclosporine occurs through cytochrome p450-3A4, so agents that affect this system can alter calcineurin-inhibitor levels or alter the metabolism of the interacting agent, thus leading to toxicity or inadequate levels. Examples of these agents include azole antifungals, calcium channel blockers, anticonvulsants, some antimicrobials, and grapefruit juice. Statin clearance may be decreased due to cytochrome p450 interactions, resulting in myopathy and rhabdomyolysis. Antimicrobials and other agents should be dosed according to renal function as in any patient, with added attention to agents that affect cyclosporine or tacrolimus metabolism. Drugs that cause synergistic or additive toxicities include allopurinol, trimethoprim-sulfamethoxazole, angiotensin converting enzyme (ACE) inhibitors or ganciclovir with azathioprine; all potentially cause myelosuppression. Also, nonsteroidal anti-inflammatory drugs (NSAIDs) and ACE inhibitors may have additive effects on glomerular hemodynamics when used with calcineurin inhibitors. Anticoagulation or antiplatelet therapies require more cautious monitoring due to frequent thrombocytopenia and multidrug therapy in many transplant patients. Although this summary is not exhaustive, cautious attention to these possibilities can prevent morbidity from drug interactions.

Transplantation
- Induction. With few exceptions, renal transplant recipients receive a brief course of high-dose steroids at the time of transplantation, followed by a taper to the initial maintenance dose. For patients at high risk for acute rejection, antibody therapy may be given during induction. These patients include those with high panel-reactive antibodies (PRA), previous transplants, African Americans, and multiple HLA-mismatches. Available antibodies therapies include anti-thymocyte globulin, muromonab/CD3 (OKT3), and IL-2 receptor antagonists (see section IV.B.5).
- Donor nephrectomy. Living donor kidneys can be harvested in either an open or laparoscopic approach, each with its own advantages and disadvantages. The left kidney is most often selected due to its longer renal vein
  P.203
  
  and better accessibility. Laparoscopic donation rates have increased due to technical advancement and donor preferences. In general, laparoscopic donation has the advantages of a shorter hospital stay, quicker return to work, and less pain, but can come with higher costs, longer operative time, and a learning curve to decrease rates of morbidity and warm ischemia time to equal that of open nephrectomy. Cadaveric kidneys are removed together with a patch of aorta and inferior vena cava as part of a multiorgan harvesting procedure. The organs are then separated and stored in hypothermic preservation solution until implantation.
- Transplant surgery. The transplanted kidney is placed in either the right or left iliac fossa. The renal vein and artery are both connected through and end-to-side anastamosis, the donor vein usually being connected to the external iliac vein and the donor artery to either the external iliac, common iliac, or internal iliac artery. The ureter is implanted into the bladder, and the bladder mucosa is usually pulled over the ureter to create a tunnel that prevents reflux and urine leak. A ureteral stent is often placed at the time of surgery to ensure patency and prevent urine leak. Lymphatics are ligated to prevent postoperative lymphocele formation. Routine closure does not involve the use of drains except in anticoagulated patients; their presence may indicate concern for the vascular or ureterovesicular anastamosis. A Foley catheter is placed at the time of surgery and maintained for up to 5 days postoperatively. Kidney transplantation in the absence of donor ischemia or technical complications is usually accompanied by prompt urine formation.
Postoperative management
- Immediate postoperative care of the transplant recipient involves the close monitoring of urine output, fluid administration, and vital signs. Many centers use algorithms that replace the urine output with normal saline plus a small amount of hypotonic fluid to account for insensible losses. Hourly central venous pressure (CVP) measurements are often done as part of routine monitoring, with target CVP of 5 to 10 mm Hg. The brisk diuresis that can ensue in a transplant patient can cause disturbances in potassium, magnesium, calcium, and phosphorus. The effect of elevated parathyroid hormone, along with a suddenly functioning kidney, also contributes to these abnormalities. Insulin requirements may increase in diabetic patients or those without prior diabetes due to the presence of steroids, calcineurin inhibitors, and improved clearance of insulin by the transplanted kidney. An uncomplicated patient with a functioning kidney can usually ambulate by postoperative day 1 or 2, and the diet can be advanced as tolerated. By postoperative day 5, the Foley catheter can be removed, and the patient can be discharged if they are free of other complications.
- Complications can occur as a result of technical problems related to surgery, infections, disorders of renal function, or other routine postoperative complications. Surgical complications include problems with each of the aspects of the transplant: the vascular anastamoses, urologic complications, lymphocele, and wound complications.
  - Urologic complications include urine leak, obstruction, and reflux. Routine stenting at many centers may be responsible for a decrease in the incidence of urologic complications. Urine leak can occur in approximately 2% of transplants. It is usually due to ureteral necrosis caused by an interruption of blood supply, but it can be at the site of bladder implantation or the calyces. The clinical presentation is one of decreased urine output, pain, fever, abdominal tenderness, swelling, and a perinephric fluid collection by ultrasonography. Fluid aspiration reveals a high creatinine that far exceeds the plasma creatinine. The diagnosis can be confirmed through a nuclear scan demonstrating extravasation into local tissues. Temporary Foley catheterization and ureteral stenting, followed by surgical repair, is the usual management. Ureteric obstruction is usually secondary to ureteral ischemia but can be due to multiple
    P.204
    
    other factors. Imaging by ultrasound, cystogram, or other studies usually leads to a diagnosis; the obstruction can be relieved by ureteral repair, stenting, or nephrostomy. Vesicoureteral reflux into the transplanted ureter is less common since the introduction of submucosal tunneling of the ureter through the bladder.
  - Arterial or venous thrombosis are uncommon but may occur as a result of preexisting hypercoagulability or technical difficulty; these should be suspected when sudden deterioration develops in a previously functioning transplant. Although venous thrombosis can occasionally be reversed surgically or by anticoagulation, vascular thromboses most often lead to graft loss.
  - Lymphocele presents often as an asymptomatic cystic fluid collection. Lymphoceles may, however, cause graft obstruction and reduced renal function, pain, or lower extremity edema due to the compression of the femoral vein. Lymphoceles are distinguished from urine leaks when fluid aspiration yields a fluid creatinine equal to serum creatinine. The aspirated fluid should also be sent for cell count and Gram stain to rule out hematoma or abscess. Lymphoceles can be aspirated, but may require operative repair (marsupialization) if they are recurrent.
  - Wound complications may stem from the problems already described, or due to infection. Clinical suspicion is necessary, as immunosuppression both masks the symptoms and increases the risk of wound infections. Prompt drainage and antibiotic administration are central to treatment.
  - Infections in the first postoperative month are similar to those in other postoperative patients but occur frequently in immunosuppressed patients. Pneumonia, urine and wound infections, and infections related to dialysis catheters are common culprits. Infections of fluid collections (lymphocele, urinoma, hematoma) may also occur. Opportunistic and other infections are discussed in section VI.
- Maintenance immunosuppression
  - Conventional therapy. Since 1995, the available options for maintenance immunosuppression have been expanded with the introduction of MMF, tacrolimus, cyclosporine microemulsion, and sirolimus. In the United States, standard therapy consists of a calcineurin inhibitor, an antiproliferative or TOR inhibitor, and corticosteroids. The calcineurin inhibitors tacrolimus and cyclosporine have similar efficacy in patient and graft survival, but with slightly different toxicity profiles. Tacrolimus also has lowered both the incidence and severity of acute rejection in head-to-head comparisons. Our center maintains target trough levels of cyclosporine that are highest (300 ng per mL) in the first month, with gradual tapering to 200 to 250 ng per mL by 6 months and 150 to 200 ng per mL after 12 months. Similarly, target tacrolimus levels are 12 to 16 ng per mL in the first month, 8 to 12 ng per mL for months 1 through 5, and 5 to 7 ng per mL after 6 months. Target levels may need to be lower in patients receiving sirolimus; these levels are often individualized based on match, rejection history, and the presence of infection. MMF and sirolimus have largely supplanted azathioprine in clinical use, as both result in less acute rejection. Corticosteroids are the third agent used in combination regimens; they are usually tapered rapidly over the first 2 to 3 weeks post-transplant to minimize side effects. They are then gradually tapered to 5 to 10 mg daily by month 6. The availability of multiple agents has allowed clinicians to choose a regimen that best fits a patient's profile of immunologic risk and perceived susceptibility to side effects. For example, patients with second transplants or poor matching, who are at greater risk for rejection, may be placed on tacrolimus. An obese patient with a family history of diabetes but with low immunologic risk, however, may be placed on cyclosporine or chosen for a steroid withdrawal protocol in an attempt to reduce the risk of post-transplant diabetes mellitus.
  - Alternative regimens. The toxicities of corticosteroids and calcineurin inhibitors have led to interest corticosteroid withdrawal or avoidance and calcineurin inhibitor withdrawal. A meta-analysis of late steroid withdrawal, however, has been associated with acute rejection and graft loss, particularly in African Americans. In contrast, trials of early withdrawal or avoidance of steroids in low-risk patients have shown promise but lack long-term results. Until larger trials with long-term follow-up are available, steroid withdrawal remains controversial outside the realm of clinical studies. Calcineurin inhibitor withdrawal is another goal due to nephrotoxicity and other side effects. A meta-analysis of studies revealed that calcineurin-inhibitor withdrawal was again associated with an increased risk of acute rejection, especially in African-Americans. However, more recent trials with sirolimus-based regimens have allowed for calcineurin inhibitor withdrawal in low to moderate risk patients and led to Food and Drug Administration (FDA) approval for this indication. Similarly, calcineurin avoidance in sirolimus-containing regimens has been studied with relatively promising results.
Renal complications. In addition to delayed graft function, acute rejection, recurrent disease, and chronic allograft nephropathy, renal transplant patients are susceptible to renal failure from all the causes that affect the general population. In the initial 48 hours after transplantation, technical causes related to surgery or delayed graft function are most common. After 48 hours, the approach to a patient with renal dysfunction should rule out hypovolemia, medication toxicity, and obstruction, and should attempt to uncover causes of acute tubular necrosis such as hypotension, sepsis, or radiocontrast. Evaluation for acute rejection should take place if clear causes are not found.
- Delayed graft function (DGF). DGF is defined as the requirement for dialysis in the first 7 days after transplantation. It occurs in approximately 20% of cadaveric transplants but is uncommon in living donor transplants. Although technical factors or other events that affect kidney function can cause DGF, it is most commonly a result of post-ischemic ATN, caused by donor hypovolemia or hypotension, or prolonged cold or warm ischemia during harvesting and preservation. DGF adds to the cost and length of hospitalization and is associated with poorer short- and long-term graft survival. To determine the cause of graft dysfunction in the early postoperative period, a renal ultrasound should be performed to rule out technical causes, and the timing of renal biopsy, to rule out acute rejection, should be guided by the patient's immunologic risk.
- Acute rejection. Rejection refers to an immunological response by the recipient to the transplanted organ. Several types of acute rejection occur. Hyperacute rejection is rare and is caused by preformed antibodies against donor antigen, leading to immediate graft destruction after perfusion. Accelerated acute rejection usually occurs 2 to 3 days after transplant, and often is an antibody-mediated process that takes place in presensitized patients with prior transplants, transfusions, or pregnancies. Acute cellular rejection is a T-cell mediated response that may occur at any time, but is most common from 5 to 7 days post-transplant until 4 weeks after transplant, with a gradual lessening of risk in the first 6 months. Clinically, the spectrum of low-grade fever, a swollen, tender allograft, and oliguria are not seen commonly with modern immunosuppression. Thus, frequent lab monitoring and a high incidence of suspicion are necessary to diagnose acute rejection. Acute rejection typically presents as a decrease in renal function, as measured by the serum creatinine. However, rejection can occur without discernable changes in renal function, a process referred to as subclinical rejection. Some centers perform routine protocol biopsies to evaluate for subclinical rejection and other graft abnormalities. Current regimens incorporating newer agents have lowered the incidence of acute rejection in the first year to less than 20%, have improved 1 year cadaveric allograft survival to nearly 90%, and may be responsible for some of
  P.206
  
  the improvement in long-term outcomes. The diagnosis of acute rejection requires an ultrasound-guided renal biopsy, with application of the Banff criteria to grade the severity of rejection or disclose other pathology. Pathologic features are interstitial infiltration with lymphocytes, tubulitis, and endarteritis. Treatment of acute rejection is usually a 3 to 5 day course of high-dose intravenous steroids, with OKT3 or antithymocyte globulin reserved for steroid-refractory or more severe rejection. Whereas most acute rejection can be reversed, its occurrence remains a powerful predictor of long-term graft survival. Patients who do not experience acute rejection may experience graft survival that is two to three times longer than those who experience rejection episodes. The term acute humoral rejection is reserved for antibody-mediated rejection. It is distinguished by peritubular capillary staining with the complement-split product C4d, neutrophilic glomerulitis, donor-specific antibodies, and occasional fibrinoid necrosis of vessels. This process is often resistant to steroids and antibody therapies, and portends a worse prognosis than cellular rejection. It has been managed with plasmapheresis, intravenous immunoglobulin (IVIG), immunoadsorption, and tacrolimus or MMF rescue, but optimal therapy is not established.
- Recurrent disease. The diagnosis of recurrent disease is guided by the clinical scenario and knowledge of which diseases tend to recur in renal transplants. In patients with glomerulonephritis, for example, recurrent disease is the third most common cause of graft loss, after chronic allograft nephropathy and death with a functioning allograft. Recurrent nephritis may present as proteinuria, nephrotic syndrome, microscopic hematuria, and loss of function. It can be differentiated from other causes (chronic allograft dysfunction, de novo glomerular disease) through renal biopsy. In the transplanted patient, the important variables are the frequency of recurrence and frequency of graft loss due to recurrence. For example, focal and segmental glomerulosclerosis (FSGS) and type 1 membranoproliferative glomerulonephritis (MPGN) recur in 30% to 60% and 20% to 30% of patients, and commonly may lead to graft loss. Alternatively, IgA nephropathy, type II MPGN, and type 1 diabetes recur in 50%, 50% to 100%, and up to 100% of recipients respectively, but are uncommon causes of graft loss. Systemic lupus erythematosus (SLE) may also recur microscopically in renal allografts but rarely is clinically important. Oxalosis is a systemic disease that commonly causes graft loss unless concomitant liver transplant is performed, whearas cystinosis does not usually recur in allografts. Autosomal dominant polycystic kidney disease (ADPKD) does not recur in an allograft from a donor lacking the PKD mutation. Although recurrent disease caused only 3% of first graft losses in a recent European report, 48% of patients who lost one graft due to recurrence lost a second graft to recurrent disease.
- Chronic allograft nephropathy (CAN) is a syndrome that appears clinically as progressive renal failure, proteinuria, and hypertension. Pathologically, its features are tubular atrophy, interstitial fibrosis, and glomerular, vascular, and mesangial matrix changes. The etiology for this disorder is unknown, but a combination of immunologic and nonimmunologic factors have been implicated, thus explaining replacement of the term chronic rejection. Despite advances in the treatment of acute rejection and other areas of transplantation, up to 40% of grafts experience CAN, and it is the most common cause of graft loss after 1 year. The importance of immune mechanisms in the development of CAN is underscored by the reality that acute rejection episodes, anti-donor HLA antibodies, poor matching, and C4d staining all correlate with the incidence of chronic allograft nephropathy. However, important nonimmune risks also correlate with the development of CAN. These include donor age, prolonged ischemia times, size mismatching, hypertension, hyperlipidemia, proteinuria, and smoking. Some of these risks implicate low nephron dose and hyperfiltration injury as a contributing factor. The allograft response to injury may cause the release
  P.207
  
  of proinflammatory and profibrotic growth factors and cytokines, such as transforming growth factor beta (TGF- ), platelet derived growth factor (PDGF), and others, worsening the cascade of CAN. Premature senescence (aging) has also been implicated. Although calcineurin-inhibitor induced nephrotoxicity has similar effects on renal function, there are conflicting results on their use and the risk of CAN. Treatment of CAN is not currently well-defined; control of blood pressure and lipids are advocated, and ACE-inhibition appears safe and helpful in retrospective analysis. Immunosuppressive strategies are not generally effective, but trials of novel regimens aimed at preventing CAN are ongoing.
Medical care of the transplanted patient. The success of renal transplantation and the growing population of transplant recipients are unfortunately accompanied by the complications from comorbid diseases and side effects of long-term immunosuppression. Patients often die with functioning grafts due to cardiovascular disease, infections, and malignancy, and these and other conditions contribute to a spectrum of common disorders in transplantation.
- Infectious diseases. In the transplanted patient, typical signs and symptoms of infection may be absent, and coinfections are common, thus necessitating increased scrutiny. Infections after renal transplantation occur in patterns that are important to recognize. Immediately after transplant, patients are at risk for common postoperative infections: wound infections, pneumonia, line, and urinary infections. The first 6 months after transplant is marked by a risk of opportunistic infections due to more intense immunosuppression, especially after antibody induction. For this reason, patients usually receive prophylaxis against Pneumocystis carinii pneumonia (PCP) for at least 6 months, and for cytomegalovirus (CMV) for 3 to 6 months if they are at risk (see section VII.A.2). Some centers provide prophylaxis for fungal infections. After 6 months, the risk of opportunistic infections is lower but remains present, and patients remain at risk for more frequent and severe infections by community-acquired pathogens.
  - Immunosuppression during infection. No clear guidelines exist for decreasing immunosuppression during infection. Furthermore, many infections carry an increased risk of acute rejection due to upregulation of immune surveillance and activity. In general, mild infections treated with appropriate antimicrobials, can be managed without a change in immunosuppression. However, more severe infections may require decreasing or stopping antiproliferative medications (sirolimus, MMF, azathioprine) and reducing calcineurin-inhibitor dosing. Severe or life-threatening infections should include attention to the requirement for stress-doses of corticosteroids, which are often adequate to decrease the risk of rejection during an illness. Reduction of immunosuppression is best done with careful monitoring of graft function along with the consultation of transplant physicians.
  - Cytomegalovirus (CMV) is a human herpes virus that is common in the general population but usually does not lead to serious morbidity without immunosuppression. A potential organ recipient who has not been exposed to CMV is at risk for a primary infection if transplanted with a CMV⁺ organ, and a recipient who has been exposed before transplant is at risk for reactivation or superinfection, especially if receiving antibody induction. Thus, the risk of CMV infection is tied to the serologic status of the donor and recipient, with rates as high as 50% to 70% in Donor⁺/Recipient^- patients not receiving prophylaxis, and 20% to 30% in patients who were exposed prior to transplant. CMV infection is uncommon in Donor^-/Recipient^- transplants. Therefore, Donor⁺/Recipient^- patients and Recipient⁺ patients who receive antibody therapies should receive prophylaxis for CMV for 3 to 6 months. Options for oral agents include ganciclovir, valganciclovir, and valacyclovir. CMV infection leads to morbidity related directly to infection, but also increases the risk of acute rejection, graft loss, and death. Clinically,
    P.208
    
    the disease often presents as low-grade fever, leucopenia and/or thrombocytopenia, and malaise. Tissue invasion can occur in 5% to 15% of infections, with syndromes of pneumonitis, hepatitis, esophagitis, and diarrhea being most common. PCR-based testing is the most sensitive diagnostic technique, but other options exist, including biopsy of affected tissues. Standard therapy is intravenous ganciclovir, a nucleoside analog, although ganciclovir-resistance can develop.
  - BK virus nephropathy (BKV nephropathy, polyomavirus). Human BK virus is a polyoma virus that is present as a latent infection in most of the population and has tropism for the genitourinary tract. During immunosuppression, the virus can reactivate. In renal transplant patients, BK virus most commonly causes a syndrome of decreased renal function and interstitial nephritis that appears clinically and pathologically similar to acute rejection. Ureteral stenosis and ulceration may also occur, and infection is a risk for allograft loss. When BKV nephropathy is present, decoy cells are usually shed in the urine, and polymerase chain reaction (PCR)-based testing usually demonstrates viuria and viremia. Immunohistochemical techniques and the presence of viral inclusions can be used to confirm the diagnosis through renal biopsy. It is important to suspect BKV nephropathy when presumed acute rejection does not respond to steroids or occurs after 6 months, because increasing the intensity of immunosuppression may lead to graft loss. Lessening the intensity of immunosuppression may stabilize graft function, but increases the risk of acute rejection. IVIG therapy may have advantages because it can theoretically improve both acute rejection and viral infection. Cidofovir may have activity against the virus, but it can cause severe nephrotoxicity, thus underscoring the importance of finding new antiviral agents.
  - Hepatitis B and C. Although the incidence of Hepatitis B in patients with ESRD has been declining due to immunization, isolation techniques, and the screening of transfused blood, Hepatitis C infections are relatively common, affecting up to 7% of recent U.S. cadaveric transplant recipients. No consensus has been formed on the management or outcome of either disease in respect to renal transplant. For Hepatitis B, patients with antigenemia usually receive evaluation and liver biopsy prior to transplant, because antiviral therapies may be more effective before transplantation. For Hepatitis C, the effect on outcomes and management are somewhat controversial. Data suggest that Hepatitis C infection increases the risk of graft loss, death, and post-transplant diabetes mellitus, and that donor seropositivity may also affect graft loss and death. Although many patients have mild, indolent disease, there are reports of rapid progression to cirrhosis and liver failure after renal transplantation. A complicating factor is that interferon therapy may increase the risk of acute rejection. Thus, decisions about the timing and treatment of Hepatitis C should be considered prior to transplantation, and post-transplant interferon therapy should only be undertaken with careful monitoring and collaboration among caregivers.
  - Other infections. Urinary infections are common after renal transplantation, and pyelonephritis of the transplanted kidney can lead to decreased renal function. Pulmonary infections from both common and uncommon pathogens are the most common cause of tissue-invasive infection. Although the list of pathogens affecting patients is too long to mention, differential diagnosis should include fungal diseases such as Cryptococcus, Candida, and endemic fungi, mycobacterial disease, Nocardia, P. carinii, viral pathogens, and others.
  - Immunization. Potential transplant recipients should receive immunization against influenza, pneumococcus, Hepatitis B, and varicella if they are seronegative. After transplant, many centers wait 6 months before any immunizations because of theoretical risks of stimulating the immune system and increasing the risk of rejection. Also, the vaccines may
    P.209
    
    be less effective during this period. The oral polio, typhoid, varicella, yellow fever, and bacillus Calmette-Guerin (BCG) vaccines are live vaccines that are contraindicated after renal transplant due to their ability to cause disease in immunocompromised hosts. However, the live measles-mumps-rubella (MMR) vaccine can be given after 6 months if indicated. Vaccination for influenza, pneumococcus, Hepatitis A and B, and tetanus/diphtheria should be given as indicated.
- Cardiovascular disease is the most common cause of death in patients with a functioning allograft. Ischemic coronary artery disease, congestive heart failure (CHF), and left ventricular hypertrophy are all more common in patients with kidney disease than in the general population, and cerebrovascular disease is another important cause of morbidity and mortality. Thus, efforts at improving outcomes after renal transplantation have been appropriately shifted to focus on cardiovascular risks. Efforts at preventing cardiovascular events begin with pre-transplant evaluation, risk-stratification, and intervention when necessary. After renal transplant, attention is given to the modification of existing risk factors and a careful evaluation and treatment of new symptoms or disease.
  - Hypertension. Since the introduction of calcineurin inhibitors, hypertension has been present in 70% to 90% of patients after renal transplant. Hypertension not only represents a modifiable cardiovascular risk factor, but also is correlated with graft loss, especially in African-Americans. Clinicians should aim for a target blood pressure below 130/80 mm Hg, as indicated by current recommendations for patients with chronic kidney disease. The choice of agents after renal transplantation is controversial and complicated by the interpretation of fluctuations in renal function that occur with diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). In general, beta-blockers and dihydropyridine calcium channel blockers are used in the early post-transplant period due to their lack of drug interactions and effects on renal function. Many patients require diuretics because of salt retention due to corticosteroids, calcineurin inhibitors, and other blood pressure medication. ACE inhibitors and ARBs are often avoided early after transplantation due to effects on renal hemodynamics and serum creatinine. These agents appear to be safe and effective in patients with chronic allograft nephropathy, however, and may be an important addition to attenuate hypertension and cardiovascular risk.
  - Hyperlipidemia. Lipid abnormalities occur in at least 50% of transplant patients and represent an important modifiable cardiovascular risk factor. Hypertriglyceridemia, high low-density lipoprotein (LDL), and low high-density lipoprotein (HDL) often occur as part of a metabolic syndrome that is common after transplantation. Corticosteroids, calcineurin inhibitors, and sirolimus may all play important roles in worsening lipid profiles. Despite concerns about rhabdomyolysis due to drug interactions, we now have prospective data from randomized, controlled trials indicating that statins (specifically, fluvastatin) prevent cardiac death and nonfatal myocardial infarction after renal transplantation without effects on graft survival. Other therapies such as niacin, fibrates, and binding resins have been used as well. As always, attention to drug interactions must be given, especially regarding the risk of rhabdomyolysis (statins, fibrates, calcineurin inhibitors) and decreased or enhanced absorption (binding resins, ezetimibe).
  - Diabetes mellitus
    - Background. Diabetes is a major independent risk factor for cardiovascular disease, is present in 30% to 40% of patients prior to transplant, and develops after transplant in 2.5% to 20% of nondiabetic patients. Complications from diabetes have important effects on patient outcomes, leading to cardiovascular and infectious morbidity, renal allograft loss and decreased function, as well as decreased patient
      P.210
      
      survival. In patients with diabetes preceding transplant, control may be worsened by corticosteroids, calcineurin inhibitors, and the decreased half-life of endogenous and exogenous insulin due to improved kidney function. The rigorous control of diabetes is likely to decrease diabetic complications, based on accumulated evidence in other populations. A target glycosylated hemoglobin target of 6.5 to 7.0 is likely to be associated with improved outcomes.
    - Post transplant diabetes mellitus (PTDM) also called new onset diabetes after transplantation, complicates a substantial percentage of renal transplants and is associated with poorer patient outcomes. Risks for PTDM include increasing age, obesity, family history of diabetes, African-American or Hispanic race or ethnicity, Hepatitis C infection, and abnormal glucose tolerance. Corticosteroids have well-known adverse effects on insulin resistance, and calcineurin inhibitors are diabetogenic, likely due to a combination of beta cell toxicity and the promotion of insulin resistance. The definition of PTDM has varied in the past, but consensus has established that it should be defined similarly to the general population: a fasting glucose of greater than 126 mg per dL, symptoms of diabetes with any glucose above 200 mg per dL, or a 2-hour oral glucose tolerance test value above 200 mg per dL. Fasting plasma glucose should be routinely monitored after transplant, because the incidence of PTDM is high. Prevention of diabetes through weight loss and exercise in patients at risk should be attempted, and treatment of new onset diabetes should follow established guidelines.
  - Other cardiovascular risk factors. Smoking is obviously an important modifiable cardiovascular risk factor, and evidence is accumulating that smoking also influences deterioration of renal function and is a risk for graft loss. At any stage in the transplant process, counseling, formal smoking cessation programs, and pharmacologic agents should be offered to encourage smoking cessation.
    
    Anemia is present in many patients both before and after transplant, and may be underrecognized and undertreated. Anemia is correlated with left ventricular hypertrophy and cardiovascular disease; therefore, diagnosis and treatment based on cause is probably appropriate.
    
    Homocysteine is increased in renal transplant patients and is also correlated with cardiovascular events. It is not yet clear if lowering homocysteine levels with high-dose B-vitamins and folic acid will lead to decreased events.
- Malignancy is an important complication of immunosuppression, probably due to effects on immune surveillance of abnormal tumor cell populations and viral-mediated cancers. The intensity of immunosuppression, including exposure to antilymphocyte antibodies, is an important factor in determining the risk for malignancy. Nonmelanoma skin cancers, especially squamous cell carcinomas, have a particularly high incidence and aggressiveness in transplant patients compared with the general population. Human papilloma virus (HPV) has been partially implicated in these cancers. Thus, patients with transplants are counseled to avoid the sun, use protective sunscreens and clothing, and see a dermatologist at least once yearly. After skin cancers, post-transplant lymphoproliferative disorders (PTLD) are the next most common malignancy. These lymphomas are associated with Epstein Barr virus (EBV) infection and usually contain EBV DNA. Risks are increased after T-cell depleting antibody therapies. These malignancies are often managed with a reduction in immunosuppression and antiviral treatment, but aggressive tumors, particularly when monoclonal, may require systemic chemotherapy. Similarly, women are at increased risk of cervical squamous cell carcinomas related to HPV infection; they require yearly Pap smears, with increased frequency of surveillance and attention if there are any abnormalities. Vulvar, perineal, and anogenital cancers are
  P.211
  
  also more frequent after transplantation. Hepatitis B and C may lead to hepatocellular carcinoma, and Kaposi's sarcoma, caused by human herpes virus 8, is another viral-mediated cancer that affects transplant patients. Solid tumors, such as breast, lung, and colon cancer are approximately twice as common in transplant patients than the general population. Given the risks of malignancy in transplantation, age-appropriate screening should occur prior to placement on the waiting list, and should continue for the patient's lifetime.
- Bone disease
  - Preexisting bone disease. The clinical picture after renal transplantation is often complicated by the presence of preexisting bone disease. Most commonly, secondary hyperparathyroidism leads to osteitis fibrosa, imparting a risk of bone loss and fracture. Other causes of preexisting bone disease include adynamic (low-turnover) bone disease, aluminum related osteomalacia, and ₂-microglobulin ( ₂M)-associated arthropathy. Furthermore, diabetic patients have decreased in bone mineral density compared to other populations. While aluminum and ₂M-related bone disease are no longer common, many patients will undergo transplant with established bone loss and increased fracture risk.
  - Post-transplant bone disease. It is well established that up to 9% of bone density is lost in the first 6 to 12 months after transplantation. Furthermore, osteopenia and osteoporosis are present in a substantial number of transplanted patients after long-term follow-up. Renal transplant patients carry an increased risk of fracture of 3% to 4% per year for the first 3 years after transplant, declining somewhat after that time. Fracture risk is increased in men and women and is particularly increased in older women. Many factors contribute to the milieu that supports bone loss. Steroids are known to induce osteopenia and osteoporosis through effects on calcium absorption and excretion, aggravation of secondary hyperparathyroidism, hypogonadism, and effects on bone turnover. Cyclosporine, secondary hyperparathyroidism, renal phosphate wasting, uremia, and gonadal hormones are other contributing factors to bone loss. Another syndrome affecting transplant patients is avascular osteonecrosis, especially of the femoral head, which is associated with steroid use. Patients present with bone pain but may be asymptomatic. Often patients require operative intervention, including replacement of the affected joint.
  - Management. The timing and frequency of measuring bone mineral density is not well-defined, but should be performed at some established interval due to the risk of fractures. The control of secondary hyperparathyroidism before transplant is important. After transplant, calcium and vitamin D supplements are recommended unless hypercalcemia is present. Parathyroidectomy is usually reserved for patients with symptomatic or persistent hypercalcemia or with persistent (longer than 1 to 2 years) hyperparathyroidism. Trials of bisphosphonates have been shown to reduce bone loss, especially when given immediately after transplant, but indications are not defined and concerns remain regarding the promotion of adynamic bone disease. Weight-bearing exercise is a low-cost intervention that should be recommended for all patients.
- Hematologic disease. Hematologic disorders are common after transplantation and have multifactorial origins. Anemia and post-transplant erythrocytosis are common. Leucopenia and thrombocytopenia often are seen as complications of antiproliferative medication, CMV or other viral infections, or any of a number of primary diseases.
  - Anemia is all too common after renal transplantation, occurring in 30% to 40% of patients in some series. Furthermore, it has been correlated with an increased risk of cardiovascular events and death and thus may be an important prognostic factor. It is more common in the early post-transplant period, but it is also present in high frequency in patients with
    P.212
    
    decreased renal function. An obvious factor involved in the presence of anemia is the decreased renal production of erythropoietin (EPO), especially when graft function is impaired. Iron deficiency, ACE inhibitors, ARBs, MMF, and azathioprine have also been associated with anemia after transplantation. Recurrent or de novo hemolytic uremic syndrome (HUS) can be a dramatic cause of anemia and graft loss and may be associated with calcineurin inhibitors and other medications. Although prospective data is needed, it seems prudent to correct anemia depending on the underlying etiology, including administration of EPO to those with impaired renal function.
  - Post-transplant erythrocytosis (PTE), defined as a hematocrit above 51%, occurs in 10% to 15% of renal transplant patients. The etiology of the disorder is not clear, but EPO and non-EPO dependent mechanisms have been implicated. It is more common in smokers, those without acute rejection episodes, and patients with diabetes. This condition can usually be managed by treatment with ACE inhibitors or ARBs. Occasionally, phlebotomy may be necessary if the hematocrit cannot be lowered below 56% to 60%.
- Pregnancy. Years of experience in renal transplantation have allowed some understanding of pregnancy after transplantation. Most women are counseled to avoid pregnancy for some period after the transplant, usually 6 months to 2 years. Fertility is improved after transplantation, and attention to contraception should be given. Intrauterine devices (IUDs) should be avoided, but other contraception options can be used unless there are specific contraindications. In mothers at high risk for primary CMV infection, pregnancy should probably be delayed until an antibody response has occurred and viremia has cleared. Renal function, if normal at the time of conception, is probably not adversely affected during pregnancy. However, the risk of a pregnancy-related deterioration in renal function is increased when renal insufficiency is present. Glucose intolerance may also complicate pregnancy, leading to gestational diabetes or increased insulin requirements in those with diabetes. Immunosuppression should be maintained at levels similar to nonpregnant women, but levels should be checked frequently, because changes in pharmacokinetics are unpredictable. Prednisone is unlikely to be teratogenic, and calcineurin inhibitors and azathioprine have minimal to small risks. Animal data indicate that MMF may be teratogenic, and MMF has limited experience in pregnancy. Sirolimus has similar limited experience in pregnancy. Fetal outcomes after renal transplantation include a significant risk of pre-term delivery (50%) and growth restriction (40%), but these outcomes may be more closely related to renal impairment than the transplant per se. After delivery, breast feeding may not be recommended in patients taking calcineurin inhibitors, but discussion of the risks and benefits should occur on an individual basis.