Brenner and Rector's The Kidney, 8th ed.

CHAPTER 65. Clinical Management

Colm C. Magee   Mohammed Javeed Ansari   Edgar L. Milford



The Transplant Surgery Procedure, 2138



Currently Used Immunosuppressive Agents in Renal Transplantation, 2138



Evaluation of the Recipient Immediately Before the Transplant, 2141



Evaluation of the Recipient Immediately after the Transplant, 2142



Management of Allograft Dysfunction, 2142



Assessing Outcomes in Renal Transplantation, 2153



Medical Management of the Transplant Recipient, 2157



Transplant Issues in Specific Patient Groups, 2163



Transplantation/Immunosuppression: The Future, 2165



Conclusion, 2165


Deceased Donor Kidney Transplantation

In adult recipients, the donor kidney is transplanted into the extraperitoneal space of the right or left lower abdominal quadrant. The donor renal artery (or arteries) is usually excised in continuity with a small piece of aorta (a Carrel patch), which facilitates creation of an optimal vascular anastomosis. An end-to-side anastomosis to the external iliac, common iliac, or hypogastric artery is usually created. The renal vein or veins are usually anastomosed to the corresponding vein. The transplant ureter is either placed directly into the bladder wall using an antireflux technique or anastomosed to the recipient ureter. The latter method minimizes the risk of vesicoureteric reflux but usually requires ipsilateral nephrectomy. When there is a concern regarding the viability of the ureteric anastomosis, a temporary stent is inserted. Keeping the bladder catheter in place for up to 5 days after surgery (depending on the type of urinary anastomosis) minimizes pressure in the urinary tract. Some surgeons place drains in the perinephric area; these drains should be removed as soon as drainage volumes are insignificant.

Living Donor Kidney Transplantation

The technique for living donor kidney transplantation is similar to that described earlier except that a patch of donor aorta or vena cava cannot be used. Hence, creation of the vascular anastomoses can be more complicated. Laparoscopic, as opposed to open, retrieval of kidneys from living donors is being increasingly employed for reasons of greater donor satisfaction and faster postoperative recovery, despite initial concerns regarding a higher incidence of early allograft dysfunction. Allograft outcomes have been reported as equivalent to the open technique in adult [1] [2] but not pediatric recipients.[3]

Surgical Complications of the Transplant Procedure

Surgical complications have decreased, primarily because of improvements in surgical technique, in general medical and anesthesia care, and in immunosuppressive regimens. Major postoperative bleeding and wound infections are now relatively rare. Obesity and increased age are risk factors for postoperative complications. Urologic complications are discussed later.

Perinephric lymphoceles have been reported to occur in up to 15% of transplant recipients.[4] They are formed by drainage from locally severed lymphatic vessels. Most produce no symptoms and are noted incidentally on ultrasound. Some lymphoceles, particularly when large, can compress the ureter (causing obstruction) or the iliac veins (causing swelling and even thrombosis of the lower limb); some simply cause localized abdominal swelling. The differential diagnosis for a peritransplant fluid collection also includes seroma, hematoma, and urinoma. Often the clinical setting and the sonographic findings strongly suggest the collection is a lymphocele. Aspiration and analysis of fluid can confirm the diagnosis (but is rarely required): the fluid creatinine is equivalent to the plasma creatinine, the protein content is high and the percent of lymphocytes is high. Treatment of lymphoceles is required only if they cause complications. Percutaneous aspiration alone usually leads to recurrence. To prevent recurrence, either external drainage with subsequent injection of a sclerosing agent or internal drainage (marsupialization) is required. The latter can often be performed by laparoscopic technique.



Because the T cell plays a critical role in the rejection response, this cell is the primary target of immunosuppressive therapies. Various steps in T cell activation and replication can be targeted, and these are shown in Figure 65-1 . Many immunosuppressants, however, have additional effects on other immune cells, such as B cells and mononuclear phagocytes. In broad terms, currently used agents can be classified as (1) antibodies that target receptors on the surface of the T cell, (2) calcineurin inhibitors (CNIs), (3) glucocorticoids, (4) purine synthesis inhibitors (5) mammalian targets of rapamycin inhibitors.

FIGURE 65-1  Stages of T cell activation: multiple targets for immunosuppressive agents. Signal 1: The Ca++-dependent signal induced by T-cell receptor (TCR) stimulation results in calcineurin activation, a process inhibited by the calcineurin inhibitors (CNIs). Calcineurin dephosphorylates nuclear factor of activated T cells (NFAT) enabling it to enter the nucleus and bind to the IL-2 promotor. Glucocorticoids bind to cytoplasmic receptors, enter the nucleus, and inhibit cytokine gene transcription in both the T cell and antigen-presenting cell (APC). Glucocorticoids also inhibit NF-kB activation (not shown). Signal 2: Costimulatory signals, such as that between CD28 on the T cell and B7 on the APC, are necessary to optimize T cell transcription of the interleukin-2 (IL-2) gene, prevent T cell anergy and inhibit T cell apoptosis. Signal 3: IL-2 receptor stimulation induces the cell to enter the cell cycle and proliferate. IL-2 and related cytokines have both autocrine and paracrine effects. Signal 3 may be blocked by IL-2 receptor antibodies or by sirolimus. Further downstream, azathioprine and mycophenolate mofetil (MMF) inhibit progression into the cell cycle, by inhibiting purine and therefore DNA synthesis.


Because the risk of rejection is greatest in the early post-transplant period, maximum immunosuppression is given at this time and progressively decreased in the weeks thereafter. Current initial immunosuppression usually consists of glucocorticoids, CNIs, and mycophenolate mofetil (MMF); induction antibody preparations are sometimes added. Maintenance immunosuppression usually consists of lower doses of the first three agents. The rationale for such “triple therapy” is that adequate immunosuppression can be achieved without the need for toxic doses of any one agent. The availability of more antirejection medications has allowed more patient-specific immunosuppression. Unfortunately, accurate titration of total immunosuppressive dose is still not achievable. The properties of currently used maintenance agents are summarized in Table 65-1 .

TABLE 65-1   -- Drugs Used in Maintenance Immunosuppression


Mechanism of Action

Adverse Effects


Block synthesis of several cytokines including IL-2; multiple anti-inflammatory effects

Glucose intolerance, hypertension, hyperlipidemia, osteoporosis, osteonecrosis, myopathy, cosmetic defects; growth suppression in children


Inhibits calcineurin: synthesis of IL-2 and other molecules critical for T cell activation thereby inhibited

Nephrotoxicity (acute and chronic), hyperlipidemia, hypertension, glucose intolerance, cosmetic defects


Similar to cyclosporine although binds to different cytoplasmic protein (FKBP)

Broadly similar to cyclosporine; diabetes mellitus more common; hypertension, hyperlipidemia and cosmetic defects less common


Inhibits purine biosynthesis; lymphocyte replication therefore inhibited

Bone marrow suppression; rarely pancreatitis, hepatitis


Inhibits de novo pathway of purine biosynthesis (relatively lymphocyte selective); lymphocyte replication therefore inhibited

Bone marrow suppression, gastrointestinal upset; invasive CMV disease more common than with azathioprine


Sirolimus-FKBP complex inhibits TOR; lymphocyte proliferation to cytokines thereby inhibited

Bone marrow suppression, hyperlipidemia, interstitial pneumonitis; enhances toxicity of cyclosporine/tacrolimus


CMV, cytomegalovirus; FKBP, FK-binding protein; IL-2, interleukin-2; MMF, mycophenolate mofetil; TOR, target of rapamycin.




Antibody Preparations

These preparations bind to receptors on the T cell (and other cells), causing either depletion or down-regulation. The most commonly used preparations in the United States are now thymoglobulin and interleukin-2 (IL-2)–receptor blockers.[5]

Depleting Antibodies

Two types are currently available: polyclonal and monoclonal preparations. Both are powerful, nonspecific immunosuppressive agents. They are prescribed in two situations: (1) as induction therapy in the first week after transplant (especially in patients with delayed graft function (DGF) or at high risk of acute rejection) and (2) for reversal of severe acute rejection.

Polyclonal Antibodies

Polyclonal antibody preparations are manufactured by immunizing horses or rabbits with human lymphoid tissue. The harvested globulin fraction contains multiple antibodies directed against different leukocyte antigens. These cause nonspecific depletion of lymphocytes within hours of administration. Rabbit thymoglobulin is probably the polyclonal agent of choice.[6]

Anti-CD3 Monoclonal Antibodies

OKT3 is a mouse monoclonal antibody raised against the CD3-receptor complex on human T cells. OKT3 can cause a cytokine release syndrome, which can be minimized by avoidance of fluid overload and pretreatment with antihistamines plus steroids. It is not widely used today.[5]

Anti-CD52 Monoclonal Antibody

Alemtuzumab (Campath 1H) is a humanized antibody directed against the CD52 antigen, which is present on all blood mononuclear cells. It causes profound and long-lasting depletion of both T and B cells. It appears to be as effective an induction agent as thymoglobulin or the anti-IL2R monoclonal antibodies, although there is a paucity of data from randomized controlled trials.[7]

Nondepleting Antibodies

Anti-IL2R Monoclonal Antibodies

Unlike the polyclonals and OKT3, humanized/chimeric anti-IL2R monoclonal antibodies have the potential for more specific immunosuppression because the full IL-2 receptor is expressed only on activated T cells. Humanization or chimerization of the antibody minimizes the problem of recipient generation of antimouse antibodies (a problem with repeat courses of OKT3), thus prolonging drug half-life and efficacy. They are used for induction immunosuppression but not for treatment of acute rejection. Adverse effects of these preparations are minimal in the renal transplant setting.


Belatacept (LEA29Y) is a novel second-generation CTLA-4Ig that binds with higher affinity to B7-1/2 and prevents effective T cell activation by blocking the CD28 costimulation pathway. A multicenter trial showed equivalent rates of acute rejection but a higher glomerular filtration rate (GFR) and lower rates of chronic allograft nephropathy when compared with a cyclosporine regimen.[8]

Which Induction Antibody Should Be Used (if at All)?

The majority of recipients in the United States receive antibody induction therapy,[5] but the evidence that they improve long-term outcomes is rather weak. One meta-analysis reported that allograft outcomes were similar between anti-IL2R blockers and other induction preparations; the former had fewer adverse outcomes, however.[9]

Maintenance Immunosuppressive Agents

Calcineurin Inhibitors


Cyclosporine functions as an inhibitor of calcineurin, thereby reducing the synthesis of several critical T cell growth factors, including IL-2 (see Fig. 65-1 ). Acute rejection rates and 1-year allograft outcomes have improved significantly since its introduction. Important adverse effects include nephrotoxicity, hypertension, hyperlipidemia, glucose intolerance, hirsutism, and gum enlargement. Nephrotoxicity is troublesome because it may be difficult to distinguish from other causes of acute and chronic dysfunction.

Microemulsion formulations of cyclosporine with improved bioavailability and more consistent pharmacokinetics have replaced the standard preparation. Trough blood concentrations have traditionally been used to guide dosing; the superiority of dosing based on C2 concentrations (concentrations 2 hours after ingestion of cyclosporine) is not fully proven. [10] [11]

Tacrolimus (FK-506)

Although tacrolimus is structurally distinct from cyclosporine, its mode of action, drug interactions, and adverse effects, including nephrotoxicity, are similar. Trough blood concentrations are used to guide dosing. Its advantages over cyclosporine include lower rates of acute rejection, less hyperlipidemia, less hypertension, fewer cosmetic complications, and better reversal of refractory acute rejection. Steroid dosages can probably be lower with tacrolimus. Its disadvantages over cyclosporine include more neurotoxicity, more gastrointestinal toxicity (particularly when combined with MMF) and more diabetes mellitus. Thus, tacrolimus is often prescribed in patients at high risk of rejection or when cosmetic effects are a major concern. In general, patients on cyclosporine should be considered for conversion to tacrolimus if they have acute rejection, severe hyperlipidemia, or severe hypertension. Otherwise, the choice of cyclosporine or tacrolimus is mainly one of center preference.

The degree to which the CNIs contribute to chronic allograft dysfunction remains controversial (see later). Because both drugs are metabolized by the intestinal and hepatic cytochrome P450 systems, drugs that induce or inhibit these systems should be used with caution; more frequent monitoring of drug concentrations is required.

Purine Synthesis Inhibitors


Azathioprine is a purine analog that inhibits DNA and RNA synthesis. It thereby inhibits proliferation of cells, including T and B cells. Bone marrow suppression is the most common adverse effect, but at doses of 1 to 2 mg/kg/day, azathioprine is usually well tolerated. It has been widely used in clinical transplantation for 30 years, but its role in maintenance therapy is being superseded by MMF. Azathioprine is inactivated by xanthine oxidase, the enzyme inhibited by allopurinol. If allopurinol therapy for recurrent gout is required (a relatively common problem in transplant patients), the dosage of azathioprine must be greatly reduced to avoid life-threatening bone marrow suppression.

Mycophenolate Mofetil

MMF is a reversible inhibitor of inosine monophosphate dehydrogenase, the rate-limiting enzyme in de novo purine synthesis. Because T and B cells are mainly dependent on the de novo pathway for synthesis of guanosine nucleotides, the antiproliferative effect of MMF should be relatively lymphocyte specific. However, trials using doses of 2 to 3 g/day have not shown a lower incidence of bone marrow suppression compared with azathioprine. A pooled analysis of three trials has shown that MMF (compared with placebo or azathioprine) halved the incidence of acute rejection in the first year post-transplant from 40% to 20%.[12] Registry and trial data also suggest better long-term graft outcomes.[13] Interestingly, when MMF was compared with azathioprine on a background of cyclosporine microemulsion, a superior efficacy was not demonstrated.[14] Its principal adverse effects are nausea, vomiting, and diarrhea; these usually respond to dose reduction. Women of childbearing age should be counseled regarding the teratogenic effects of MMF and switched to azathioprine if a pregnancy is planned.

Although it is significantly more expensive than azathioprine, MMF is now the antiproliferative agent of choice in many centers. Blood concentrations are not routinely monitored, although there is evidence of interpatient variability in its pharmacokinetics. Higher doses may be required in blacks to effectively prevent acute rejection.[15]

The combination of MMF and tacrolimus is highly effective in preventing acute rejection [16] [17] but is associated with a high incidence of adverse gastrointestinal effects. This, in part, reflects the higher MMF plasma concentrations obtained when the drug is prescribed with tacrolimus rather than cyclosporine.


Glucocorticoids remain a cornerstone of immunosuppression in many patients. Their dosage is progressively decreased after transplantation to a maintenance regimen of prednisone 5 to 10 mg/day. The adverse effects of steroids are well known; of particular importance in the post-transplant setting are hyperlipidemia, hypertension, glucose intolerance, and osteoporosis.

One randomized controlled trial with relatively long follow-up showed that steroid withdrawal increased the risk of allograft rejection and loss.[18] With the availability of new, more powerful immunosuppressive agents, the desire for steroid-free, steroid-withdrawal, or steroid-minimization regimens has been rekindled.[5] Recent studies have yielded encouraging results.[19] Several caveats should be noted: long-term results are not yet available, steroid withdrawal studies often concentrate on low-risk recipients, and a commercial bias against studying optimal steroid regimens probably exists.[20]

Target of Rapamycin Inhibitors


Sirolimus (rapamycin) blocks the proliferative responses of T and B cells, as well as other cell types, to cytokines. It binds to the same intracellular protein (FK-binding protein [FKBP]) as tacrolimus, but its mechanism of action is distinct; in particular, it does not directly inhibit calcineurin.[21] Instead, the sirolimus-FKBP complex binds to and inhibits a kinase called the target of rapamycin (TOR). Target of rapamycin is central to a pathway by which receptors for growth factors control the cell cycle.[21]

The prolonged elimination half-life of sirolimus means that once-daily dosing is sufficient. Like the CNIs and many other drugs, it is metabolized through the cytochrome P450 system; thus, the potential for multiple drug interactions exists. Adverse effects of sirolimus include impaired wound healing, diarrhea, hyperlipidemia, anemia, thrombocytopenia, and interstitial pneumonitis. In one major randomized, controlled trial, sirolimus was associated with a lower incidence of acute rejection compared with azathioprine (note the use of azathioprine not MMF).[22] Creatinine clearance was lower, however, in the sirolimus-treated patients, possibly reflecting enhanced cyclosporine nephrotoxicity.

Short- and medium-term data suggest sirolimus may have a useful role as a CNI-sparing agent.[23] One systematic review found that CNI withdrawal was associated with a higher risk of acute rejection but with better creatinine clearance.[24] There is growing evidence that sirolimus has important antineoplastic effects in vivo.[25]

Everolimus is a derivative of sirolimus but with a shorter half-life. As compared with MMF, everolimus was associated with more adverse effects, including higher plasma creatinine (on a background of steroids and cyclosporine).[26]


The general pretransplant work-up is reviewed in Chapter 64 .

Medical Status

The potential recipient should be evaluated to ensure that there are no new contraindications to transplant surgery and general anesthesia. This is more relevant to recipients of deceased donor allografts, for whom the date of surgery cannot be planned. Occasionally, new medical problems such as infections or unstable angina preclude or delay transplantation. A common question is whether hemodialysis, with its attendant delay of surgery and prolongation of cold ischemia time, is required. In general, preoperative hemodialysis is advisable if the plasma K is greater than 5.5 mmol/L or severe volume overload is present. A short session of 1.5 to 2 hours without anticoagulation usually suffices. Patients on peritoneal dialysis need only drain out instilled fluid before surgery; if the patient is hyperkalemic, several rapid exchanges can be performed. If there is a history of coronary artery disease, β-blockers should be administered before and after surgery.[27]

Immunologic Status

Intended recipients should be specifically asked if they have recently received a blood transfusion because this could cause a surge in alloantibodies. A pretransplant cross-match of a recent donor serum against recipient T cells must always be performed. The purpose of this is to detect antibodies against the class I human leukocyte antigens (HLAs) of the donor. For patients who are not high risk ( Table 65-2 ), an enhanced antihuman globulin lymphocytotoxicity assay is adequate screening for alloantibodies. The presence of cytotoxic donor IgG antibodies by this assay is a contraindication to immediate transplantation because of the high risk of hyperacute rejection.

TABLE 65-2   -- Factors Suggesting a Recipient Is High Risk For Acute Rejection

Previous blood transfusions, particularly if recent

Previous pregnancies, particularly if multiple

Previous allograft, particularly if rejected early

History of high PRA (>30%)

Black race


PRA, panel reactive antibody.




For immunologically high-risk patients (see Table 65-2 ), many centers also use the flow cytometry cross-match (FCXM). This can detect very low concentrations of antidonor antibodies. In high-risk patients, a negative antihuman globulin cross-match but positive FCXM against donor T cells is a relative contraindication to transplantation.

The clinical importance of an isolated positive B cell cross-match is less clear. Thus, the clinical significance of a positive cross-match depends on the particular test used and the baseline immunologic status of the potential recipient. Close consultation with the tissue-typing laboratory is essential.


The nephrologist should carefully review the donor history and the operating room notes, with particular emphasis on the following: cold and warm ischemia times, technical difficulties encountered, intraoperative fluids administered, blood pressure, and urine output. Immediate excellent urine output, which should be the norm with living donor transplants, greatly simplifies management. The management of the oligoanuric recipient can be complicated and is discussed later.


Management is discussed here under three time periods: immediate, early, and late post-transplant.

Immediate Post-transplant Period (First Week)

Patients can be divided into three groups based on allograft function in the first post-transplant week: those with DGF, those with slow graft function (SGF), and those with excellent graft function. DGF is usually defined as failure of the renal allograft to function immediately post-transplant, with the need for more than one dialysis session within a specified period, usually 1 week. Excellent allograft function implies adequate urine output and rapidly falling plasma creatinine. Management of those with excellent function (almost all living donor recipients and a highly variable percentage of deceased donor allograft recipients) is relatively straightforward. Routine imaging studies are not required. SGF defines a group of recipients with moderate early dysfunction. One definition is a plasma creatinine level of greater than 3 mg/dL and no dialysis within 1 week of transplant.[28] The causes, management, and outcomes of SGF are similar to those of DGF (see later). Interventions that simply convert DGF to SGF may have little effect on allograft outcomes; more important but difficult is achieving immediate excellent function in most allografts.[28]

Delayed Graft Function

DGF is a clinical diagnosis. Using requirements for dialysis as the sole criterion for diagnosis excludes some patients with residual native kidney function, however. Criteria for dialyzing patients post-transplant differ between centers. Recent United States Renal Database System (USRDS) data still show an approximate 22% incidence of DGF in deceased donor allografts.[29]

Table 65-3 lists the causes of DGF, considered as prerenal, intrarenal, and postrenal insults. Often there is overlap of causes, in particular between ischemia and rejection. Ischemic acute tubular necrosis (ATN) is by far the most common cause of DGF; in fact, the two terms are often used interchangeably, although they are not equivalent.

TABLE 65-3   -- Causes of DGF in Renal Transplantation


Severe hypovolemia/hypotension

Renal vessel thrombosis


Ischemic ATN

Hyperacute rejection

Accelerated or acute rejection superimposed on ATN

Acute cyclosporine/tacrolimus nephrotoxicity (± ATN)


Urinary tract obstruction/leakage


ATN, acute tubular necrosis; DGF, delayed graft function.




Risk factors for DGF include recipient factors such as male sex, black race, longer duration on dialysis, higher panel-reactive antigen (PRA) status, and greater degree of HLA mismatching; donor factors include use of deceased donor kidneys (especially if extended criteria or with cardiac death), greater donor age, longer cold ischemia time.[30] Most of these factors mediate their effects through ischemia-reperfusion injury and immunologic mechanisms. Older studies suggested that CNIs prolonged or worsened DGF; this is probably less of an issue with currently employed doses.[31]

The diagnosis of the underlying cause of DGF is based on clinical, radiologic, and sometimes histologic findings. Figure 65-2 illustrates an algorithm for the management of allograft nonfunction/oliguria immediately after surgery. Careful review of the donor history and of the retrieval and transplantation process provides clues as to the etiology of DGF. Note that interpretation of the urine output requires knowledge of the pretransplant native kidney output. Prerenal and postrenal causes (including simple problems such as urinary catheter malposition or obstruction) should be excluded. A response to a fluid challenge implicates prerenal factors. If administration of fluids and diuretics fails to improve urine output, further investigation is warranted, the urgency of which depends on the individual case. Persistent oliguria of a living donor kidney despite adequate volume expansion and high-dose loop diuretics requires immediate radiologic evaluation of renal blood flow or immediate surgical re-exploration because the cause of impaired function is much more likely to be a major surgical complication than ATN. In contrast, a deceased donor kidney at high risk of ischemic ATN (elderly donor, prolonged ischemia time, and so on) would be less urgently investigated.

FIGURE 65-2  Management of renal allograft nonfunction/oliguria immediately after transplant.


Imaging of the allograft is used to assess perfusion and to exclude urinary obstruction or leakage. Standard ultrasonography is useful because it can be quickly performed; it is inexpensive, noninvasive, and usually effective in excluding postrenal causes of renal failure. Duplex sonography is helpful in assessing renal arterial and venous blood flow but cannot reliably distinguish intrarenal causes based on changes in intrarenal vascular resistance. Isotope renography may provide additional information regarding renal perfusion and function. In rare cases, the presence of a urine leak or of urinary tract obstruction is detectable by renography but not by initial ultrasonography. Although intrarenal insults can result in typical renographic abnormalities, reliably distinguishing the causes is again not possible.

In many cases of DGF, prerenal and postrenal causes can be excluded, and the clinical and radiologic findings are consistent with an intrarenal insult. Definitive diagnosis of the underlying cause requires allograft biopsy. The decision to biopsy depends mainly on the duration of DGF and the likelihood of the underlying cause being ATN as opposed to a more allograft-threatening cause such as rejection. An algorithm for management of persistent DGF is shown in Figure 65-3 . Specific treatment of DGF depends on the underlying cause and is discussed below.

FIGURE 65-3  Algorithm for management of persistent delayed graft function. The presence of antidonor human leukocyte antigen (HLA) antibodies should prompt immediate biopsy in this setting.


Causes of Delayed Graft Function

Ischemic Acute Tubular Necrosis.

Ischemic ATN is the most common cause of DGF in deceased donor kidney recipients. At multiple steps during the surgical transplantation procedure, the allograft is at risk of ischemia-reperfusion injury ( Table 65-4 ).[32]

TABLE 65-4   -- Causes of Ischemic Damage to the Deceased Donor Renal Allograft



Preharvest donor state



Shock syndromes



Endogenous and exogenous catecholamines



? Brain injury



Nephrotoxic drugs



Organ procurement surgery






Trauma to renal vessels



Organ transport and storage



Prolonged storage (cold ischemia time)



Pulsatile perfusion injury



Transplantation of recipient



Prolonged second warm ischemia time



Trauma to renal vessels






Postoperative period






Acute heart failure (MI)



? Hemodialysis


MI, myocardial infarction.




There are no clinical or radiologic features unique to transplant ATN. As is the case with acute kidney injury (AKI) in native kidneys, transplant ATN should be a diagnosis of exclusion. Several of the risk factors identified in Table 65-4 may be present. Radiologic studies confirm intact allograft perfusion and are consistent with an intrarenal insult (a high resistive index by duplex or slow clearance of radiotracer by renography). Histology, if available, shows tubule cell damage and necrosis. Patchy interstitial mononuclear cell infiltrates, but not tubulitis, may be present. The natural history of uncomplicated ATN is spontaneous resolution. Usually, improvements in urine output begin from 5 to 10 days after transplant, but ATN may persist for weeks.

Management of the patient during this period is supportive, including dialysis as needed and avoidance of fluid overload. Glucose/insulin and high-dose diuretics may be useful in controlling hyperkalemia and thus postponing dialysis. Sorbitol-based ion exchange resins should be used with caution in the early postoperative period because of the risk of colonic perforation. When hemodialysis is required, minimal anticoagulation should be used to reduce the risk of postsurgical bleeding. Intradialytic hypotension must be avoided. In general, peritoneal dialysis is best minimized in the first week after transplant because of the risk of peritonitis or leakage of dialysis fluid into the wound area.

A major concern in the management of the patient with post-transplant ATN is that the diagnosis of new surgical or medical complications involving the allograft is difficult. Rejection, for example, may be easily missed. In fact, acute rejection occurs more frequently in allografts with delayed as opposed to immediate function. The postulated mechanism is that ischemia-reperfusion injury increases the immunogenicity of the allograft, thereby predisposing to acute rejection. Experimental animal models have demonstrated that ischemic ATN is associated with increased expression/production within the renal parenchyma of class I and II major histocompatibility complex (MHC) molecules, costimulatory molecules, proinflammatory cytokines and adhesion molecules.[32] Such an altered local milieu could amplify alloimmune responses. Therefore, a high degree of suspicion for additional complications related to the allograft must be maintained. The possibility of accelerated acute rejection must be considered, particularly in the high-risk recipient. We recommend a low threshold for performing core kidney biopsies in patients with DGF ( Fig. 65-4 ). Radiologic evaluation of the graft should also be repeated to detect new urinary or vascular complications.

FIGURE 65-4  Algorithm for management of allograft dysfunction in early post-transplant period.


In cases in which DGF is expected, antilymphocyte antibody preparations are often used. These have the potential benefit of avoiding CNI nephrotoxicity, which might prolong ATN while reducing the chances of occult rejection. Recipients are weaned from antibody therapy onto a CNI when allograft function improves. In fact, there is little evidence to support this delayed CNI strategy.[31] Data from our own institution suggest that intraoperative thymoglobulin shortens the duration of DGF, possibly by blockade of multiple receptors on human leukocytes.[33] The advantages and disadvantages of antibody therapy in the setting of DGF are summarized in Table 65-5 .

TABLE 65-5   -- Advantages and Disadvantages of Using Various Induction Regimens in the Setting of DGF




IL-2R Blockers

Effectiveness in preventing early acute cellular rejection




Increased risk of opportunistic infection




Increased risk of neoplasia




Cytokine release syndrome




Sensitization, affecting future use of product









DGF, delayed graft failure; IL-2R, interleukin-2R.




Hyperacute Rejection.

Hyperacute rejection is now a rare cause of immediate nonfunction. It is caused by preformed recipient antibodies reacting with antigens on the endothelium of the allograft, activating the complement and coagulation cascades. These antibodies are usually directed against antigens of the ABO blood group system or against HLA class I antigens. Anti-HLA class I antibodies are formed in response to previous transplantation, blood transfusion, or pregnancy. Less commonly, hyperacute rejection is caused by antibodies directed against donor HLA class II antigens or endothelial or monocyte antigens (the last two are not detected in the standard cross-match). In classic hyperacute rejection, cyanosis and mottling of the kidney and anuria occur minutes after the vascular anastomosis is established. Disseminated intravascular coagulopathy may occur. Histology shows widespread small vessel endothelial damage and thrombosis, usually with neutrophil polymorphs incorporated into the thrombus. There is no effective treatment; transplant nephrectomy is indicated. Screening for recipient-donor ABO or class I HLA incompatibility (the presence of the latter is often referred to as a “positive T cell cross-match”) has ensured that hyperacute rejection is now uncommon. Rare cases occur because of clerical errors or due to the presence of the other preformed antibodies described earlier that are not detected by routine screening methods.

Recently, desensitization protocols (to remove or neutralize anti-HLA antibodies and make the cross-match negative) have been described. Typically these involve either (1) high-dose immunoglobulin G (IgG) or (2) plasmapheresis plus low-dose IgG.[34] Short- and medium-term allograft outcomes have been relatively good, but these protocols are expensive and limited to specialist centers.

Accelerated Rejection Superimposed on Acute Tubular Necrosis.

Accelerated acute rejection refers to rejection episodes occurring roughly 2 to 5 days after transplant. It is usually mediated by the humoral immune system. The cause is thought to be pretransplant sensitization of the recipient to donor alloantigens. Titers of alloantibody are too low to give a positive pretransplant lymphocytotoxicity cross-match, but presumably antibody production occurs rapidly after transplant. Patients who have a negative pretransplant lymphocytotoxicity cross-match but a positive FCXM are at greater risk of developing this form of rejection.

Accelerated acute rejection may be superimposed on ischemic ATN, in which case there may be no signs of rejection, or it may occur in an initially functioning allograft. Diagnosis is made by renal biopsy and cross-match findings. Histology usually shows evidence of predominantly antibody rather than cell-mediated immune damage. The diagnosis and management of these two forms of rejection are discussed in detail below.

Acute Cyclosporine or Tacrolimus Nephrotoxicity Superimposed on Acute Tubular Necrosis.

Cyclosporine or tacrolimus, especially in high doses, causes an acute reversible decrease in GFR by renal vasoconstriction, particularly of the afferent glomerular arteriole. Potentially, such vasomotor effects could exacerbate ischemic ATN. The clinical significance of these effects at currently employed doses of CNIs is unclear. Nevertheless, this is one reason antilymphocyte antibodies are substituted for CNIs in the setting of DGF (see earlier).

Vascular and Urologic Complications of Surgery.

Renal vessel thrombosis, urinary leaks, and obstruction are rarer but important causes of DGF. These complications may also cause allograft dysfunction in the early postoperative period and are discussed later in this chapter.

Outcome and Significance of Delayed Graft Function

In most cases, recovery of renal function is sufficient to become independent of dialysis. There is no recovery in less than 5% of cases, resulting in primary nonfunction. The majority of studies suggest that DGF has a negative impact on long-term renal allograft survival.[32] Patients with DGF require longer hospitalization and more investigations, and are at higher risk of occult rejection. Postoperative fluid and electrolyte management is more difficult.

Therefore, use of measures to limit the incidence and duration of DGF are very worthwhile. Obvious strategies include optimization of the hemodynamic status of the donor and recipient. Management of the potential deceased donor is a somewhat neglected area of study.[35] Intraoperative mean arterial pressure should be maintained greater than 70 mm Hg in the recipient. Monitoring of central venous pressure may be helpful. Meticulous surgical technique, rapid transport of retrieved allografts and use of optimum preservation solutions are also of obvious extreme importance.

Whether machine perfusion of deceased donor allografts is more effective than simple cold storage in preventing DGF and improving long-term function remains controversial. It is certainly more expensive and complex. Prospective, controlled trials in which one kidney from each donor is allocated to machine perfusion and the other to cold storage (thus controlling for donor factors) have yielded conflicting results. [36] [37] There is some evidence that machine perfusion of donor-with-cardiac death (DCD) allografts lowers the incidence of DGF.

The benefits and risks of induction therapy with antilymphocyte antibody preparations in the setting of DGF have been discussed earlier. Calcium channel blockers have been shown in experimental models to prevent ischemic injury and attenuate CNI-mediated renal vasoconstriction. These properties suggested that their administration to recipients or to the donor before organ retrieval might reduce the incidence and duration of ischemic ATN. Unfortunately, studies have not provided definitive answers. Perioperative administration of dopamine to the recipient is of no benefit. Atrial natriuretic peptide has been of limited benefit in the setting of nontransplant ATN and therefore is unlikely to find use in the transplant situation. Attempts to prevent neutrophil-mediated reperfusion injury and adhesion molecule interaction have been of limited benefit. Other strategies under investigation include the use of trimetazidine and bioflavinoids in the preservation solutions. [38] [39] Unfortunately, DGF from ATN is likely to remain a significant problem.

A national system that preferentially allocates deceased donor kidneys to zero HLA-mismatched recipients will result in prolongation of cold ischemia time in some cases. This is because of inevitable delays with matching of organs to recipients and transport of organs. Such a system operates in many countries, including the United States. Overall, national sharing of HLA-matched organs does have a benefit on allograft outcomes. [40] [41] Matas and Delmonico[42] and others[43] have recently advised several measures that should reduce cold ischemia times. These include faster identification of potential recipients and establishment of a list of patients in each transplant region who would quickly accept expanded criteria donor (ECD) kidneys.

Early Post-transplant Period (First Six Months)

Table 65-6 shows the causes of allograft dysfunction during the early post-transplant period. There is obviously some overlap in the causes of delayed and early allograft dysfunction. Despite its known limitations, the primary measure of early and late transplant function remains the plasma creatinine. It is worthwhile to immediately recheck the plasma creatinine to confirm any increase and to determine its trend. Again, prerenal and postrenal failure should be systematically excluded.

TABLE 65-6   -- Causes of Allograft Dysfunction in the Early Postoperative Period



Renal vessel thrombosis

Drugs: ACE inhibitors, NSAIDs

Transplant renal artery stenosis


Acute rejection

Acute CNI nephrotoxicity

CNI induced thrombotic microangiopathy

Recurrence of primary disease

Acute pyelonephritis

Acute interstitial nephritis


Urinary tract obstruction/leakage


ACE, angiotensin-converting enzyme; NSAIDS, nonsteroidal anti-inflammatory drugs; CNI, calcineuin inhibitor.




Prerenal Dysfunction in the Early Post-transplant Period

Hypovolemia and Drugs

Hypovolemia may develop secondary to excessive diuresis from the transplanted kidney or from diarrhea. Diarrhea is a common adverse effect of the MMF plus tacrolimus combination. Patients accustomed to fluid restriction on dialysis may have difficulty maintaining adequate fluid intake. Angiotensin-converting enzyme inhibitors (ACE-Is) and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in the early post-transplant period because of the risk of functional prerenal failure; this risk is probably enhanced by the renal vasoconstrictive effects of CNIs.

Renal Vessel Thrombosis

Transplant renal artery or renal vein thrombosis usually occurs in the first 72 hours but may be delayed for up to 10 weeks. Acute vascular thrombosis is the most common cause of allograft loss in the first week. Although poor surgical technique is a factor in some cases, there is now greater appreciation of the role of hypercoagulable states.[44] Risk factors for renal vessel thrombosis are shown in Table 65-7 .

TABLE 65-7   -- Risk Factors for Renal Vessel Thrombosis

Risk Factor


Pediatric recipient

Especially if <6 years; reflects technical difficulties

Pediatric donor

Especially if <6 years; reflects technical difficulties

History of thromboembolism or multiple unexplained access thromboses

Should always be sought in the pretransplant evaluation

Antiphospholipid antibody syndrome and other thrombophilic states

The presence of antiphospholipid antibodies or laboratory abnormalities alone do not necessarily increase risk




Renal artery thrombosis presents with abrupt onset of anuria (unless there is a native urine output) and rapidly rising plasma creatinine, but often little localized graft pain or discomfort. Duplex studies show absent arterial and venous blood flow. Renography or magnetic resonance (MR) angiography shows absent perfusion of the transplanted kidney. Removal of the infarcted kidney is indicated.

Renal vein thrombosis also manifests with anuria and rapidly increasing plasma creatinine. Pain, tenderness, swelling in the graft, and hematuria are more pronounced than in renal artery thrombosis. Severe complications such as embolization or graft rupture and hemorrhage may occur. Duplex studies show absent renal venous blood flow and characteristic highly abnormal renal arterial signals. MR venography demonstrates thrombus in the vein. Transplant nephrectomy is usually indicated. If the venous thrombosis extends beyond the renal vein, anticoagulation is necessary to reduce the risk of embolization. There are reports of salvaging renal function after early diagnosis of renal vessel thrombosis and its treatment with thrombolysis or thrombectomy. In almost all cases, however, infarction occurs too quickly to make this treatment worthwhile. Furthermore, thrombolysis is relatively contraindicated in the early post-transplant period because of the high risk of graft-related bleeding.

Meticulous surgical technique and avoidance of hypovolemia can minimize the incidence of this devastating complication. Patients with a history of recurrent thrombosis or a history of thrombosis plus a positive thrombophilia test should receive unfractionated heparin immediately after transplant; warfarin should then be continued for a minimum of 3 months. The presence of antiphospholipid antibodies alone (with no history of thrombosis) does not warrant such aggressive anticoagulation. These antibodies are often found in end-stage renal disease (ESRD) patients without pathologic sequelae.

Intrarenal Dysfunction in the Early Post-transplant Period

Acute Rejection

Most cases of acute rejection occur in the first 6 months, but this complication may occur at any time. With ongoing improvements in immunosuppression, the incidence of acute rejection continues to decrease; in the United States, it is now less than 15% in the first 6 months.[45]

With current immunosuppression regimens, symptoms and signs of acute rejection are rarely pronounced, but low-grade fever, oliguria, and graft pain or tenderness may occur. Note that a raised plasma creatinine level may be a relatively late marker of pathologic changes occurring within the allograft, hence, the interest in developing markers of early immune system activation that precedes rejection. Imaging studies are usually abnormal in acute rejection, but the changes are not specific enough to exclude other causes. Definitive diagnosis requires biopsy, but when there is a high likelihood of uncomplicated acute cellular rejection (ACR), empiric treatment is sometimes instituted. Acute rejection is presumed to involve cellular and humoral immune mechanisms, but evidence of cell-mediated responses has traditionally predominated on most biopsies. Differences between ACR and acute antibody-mediated rejection (AMR) are summarized in Table 65-8 .

TABLE 65-8   -- Differences Between Pure Forms (There Can Be Overlap) of Acute Cellular Rejection (ACR) and Acute Antibody-Mediated Rejection (AMR)



Acute AMR

Clinical onset

>5 days

>3 days

Donor specific antibody in serum

Usually absent





Neutrophil polymorphs in glomerular and peritubular capillaries



C4d staining of peritubular capillaries



Primary therapy

Pulse steroids

Plasmapheresis, IgG, pulse steroids


IgG, immunoglobulin G; MMF, mycophenolate mofetil.




Acute Cellular Rejection.

The Modified-Banff classification ( Table 65-9 ) is a widely used schema for classifying rejection. The classic histologic findings in acute ACR are (1) edema and mononuclear cell infiltration of the interstitium, mainly with T cells but also with some macrophages and plasma cells, and (2) tubulitis (infiltration of tubule epithelium by lymphocytes). Vascular involvement (endothelialitis) is frequently a focal process and may be easily missed on biopsy (hence, the need for adequate tissue). Here, mononuclear cells undermine endothelium, and the endothelial cells are swollen and detached. Endothelialitis reflects more severe rejection.

TABLE 65-9   -- Modified-Banff Classification of Renal Allograft Pathology






Antibody-mediated rejection






Type I: C4d+, ATN



Type II: C4d+, capillaritis



Type III: C4d+, arteritis



Chronic active



Glomerular double contours and/or peritubular capillary basement membrane multilayering and/or interstitial fibrosis/tubular atrophy and/or fibrous intimal thickening in arteries, C4d+



Borderline changes (“suspicious” for acute rejection). Foci of mild tubulitis only.



T-cell mediated rejection






Type I: moderate or severe tubulitis



Type II: mild, moderate or severe intimal arteritis



Type III: transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells.



Chronic active



“Chronic allograft arteriopathy” (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neo-intima)



Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology



Other: Changes not considered to be due to rejection

Adapted from Solez K, Colvin RB, Racusen LC, et al: Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy. Am J Transplant 7:518–526, 2007.

ATN, acute tubular necrosis.





Focal infiltrates of mononuclear cells without endothelialitis or tubulitis may occur in the presence of stable allograft function; treatment is not required. Conversely, histologic evidence of rejection can also be seen in the presence of stable allograft function, and there is evidence to support its treatment.[46] The presence of eosinophils in the infiltrate suggests severe rejection, but allergic interstitial nephritis should also be considered. Note that polyoma virus infection may also cause tubulointerstitial nephritis.

Uncomplicated ACR is generally treated with a short course of high-dose steroids. Typically, 500 to 1000 mg/day of methylprednisolone is given intravenously for 3 to 5 days. There is a 60% to 70% response rate to this regimen. After completion of pulse therapy, the maintenance oral steroid dose can be resumed immediately, although some centers prefer to taper back to the maintenance dose. An episode of acute rejection implies that prior immunosuppression has been inadequate. The patient's compliance with prescribed medications should be reviewed. If there are no contraindications, baseline immunosuppression should be increased or changed, at least in the short term. OKT3 and the polyclonals are highly effective in treating first rejection episodes but because of cost and toxicity, these agents are usually reserved for steroid-resistant cases or when there is severe rejection on the initial biopsy.

Steroid-resistant ACR, defined somewhat arbitrarily as failure of improvement in urine output or plasma creatinine within 5 days of starting pulse treatment, is usually treated with depleting antibodies. If steroid treatment was based on an empiric rather than a histologic diagnosis, allograft biopsy should be performed to confirm this diagnosis before starting treatment with these agents. At least a partial response to OKT3/polyclonals in these situations is common. One randomized, controlled trial has shown rabbit thymoglobulin to be more effective than ATG as primary therapy for acute rejection[47]; thymoglobulin has also largely replaced OKT3 in this setting.[5]

Refractory Acute Cellular Rejection.

Refractory ACR is generally defined as ACR resistant to a course of OKT3/polyclonals. By definition, the patient has already received aggressive immunosuppression; the risks and benefits of further amplifying immunosuppression should be very carefully considered. Renal histology is helpful in this regard. Therapeutic options include (1) continuing maintenance immunosuppression in the hope that renal function will slowly improve, (2) repeating a course of anti-lymphocyte antibody therapy or (3) switching from cyclosporine to tacrolimus if not already done.[48] Uncontrolled trials of refractory rejection report a 70% response to tacrolimus “rescue” therapy.[49] If there is a component of acute AMR, this can be treated as discussed below.

Acute Antibody-Mediated Rejection.

Acute AMR is increasingly recognized as a cause of allograft dysfunction and is now seen in 12% to 37% of biopsies done for acute rejection. This probably reflects better diagnostic tools (in particular, the C4d stain and improvements in tissue typing[50]), more awareness of acute AMR, better prevention of ACR, and more transplantation across HLA or ABO incompatibilities.[34] Diagnosis of acute AMR requires allograft dysfunction and at least two of the following: (1) neutrophil polymorphs or mononuclear cells or thrombi in capillaries, (2) diffusely positive staining of peritubular capillaries for C4d, (3) serologic evidence of antibody against donor HLA or ABO antigens.[51] Acute AMR typically occurs early after transplantation but can also occur late, especially in the setting of reduced immunosuppression or noncompliance. Acute AMR may occur alone or with ACR.

Until recently, the prognosis of acute AMR was considered poor. Now, good short- and medium-term outcomes have been reported with protocols that typically include the following: pulse steroids, tacrolimus, MMF, plasmapheresis, or high-dose IgG.[52] Rituximab is sometimes used as an adjunct in severe cases, although randomized controlled trials are lacking.

Significance of Acute Rejection

Although acute rejection is frequently reversed (at least as assessed by plasma creatinine), retrospective studies show that it is strongly associated with the development of chronic rejection and poorer allograft survival. Poorer allograft outcome also correlates with the severity of rejection, the number of rejection episodes, and with resistance to steroid therapy. Whatever the outcome is in terms of allograft function, treatment involves exposing the patient to supplemental immunosuppression and its attendant risks. Reducing the incidence of acute rejection has been a major goal in renal transplantation.

Acute Calcineurin Inhibitor Nephrotoxicity.

The CNIs, especially in high doses, cause an acute reversible decrease in GFR by renal vasoconstriction, particularly of the afferent glomerular arteriole. This is manifested clinically as dose and blood concentration-dependent acute reversible increases in plasma creatinine. Because acute CNI nephrotoxicity is mainly vasomotor/prerenal, histologic changes in this setting may be unimpressive. Histology may show tubule cell vacuolization; more prolonged toxicity is associated with hyaline thickening of arterioles[53]; these changes are not specific. Acute CNI nephrotoxicity responds to dosage reduction.

Distinguishing Acute Calcineurin Inhibitor Nephrotoxicity and Acute Rejection.

Distinguishing acute CNI nephrotoxicity and acute rejection clinically can be difficult. Low and high blood concentrations in the presence of rising creatinine suggest but do not imply rejection and drug nephrotoxicity, respectively. Both syndromes can coexist. Indicators of a diagnosis of acute CNI nephrotoxicity are severe tremor (neurotoxicity), a moderate increase in plasma creatinine (<25% over baseline), and high trough blood CNI concentrations (e.g., cyclosporine > 350ng/mL or tacrolimus levels > 20ng/mL). Indicators of a diagnosis of acute rejection are low-grade fever, allograft pain and tenderness (although with current drug regimens these symptoms or signs are uncommon), rapid, non-plateauing increases in plasma creatinine and low drug concentrations. Fever and symptoms localized to the allograft do not occur with CNI toxicity but by no means imply rejection; acute pyelonephritis must also be considered.

The threshold for biopsy depends on the individual patient and center practice. An algorithm for this setting is shown in Figure 65-4 . One common strategy is to institute a trial of therapy and, if the clinical response to this is unsatisfactory, to proceed to biopsy within 48 to 96 hours. For example, if acute CNI nephrotoxicity were suspected, the CNI dose would be reduced, which should improve renal function within 24 to 48 hours, were this diagnosis correct. A presumptive diagnosis of acute rejection would mean empiric treatment with a steroid pulse. Lack of response after several days of antirejection treatment because of resistant rejection or another cause would be diagnosed by biopsy. The threshold for biopsy is lower in high-risk patients: those who are highly sensitized, have previously rejected an allograft, or are at high risk of early recurrent primary renal disease (see later). In our center, we aim to minimize the use of empiric steroid pulses; with rapid biopsy and processing of tissue, basic histology is available within 5 to 6 hours. A delay of 6 hours in initiating specific therapy should not be detrimental to the graft. In addition to determining the degree and type of rejection in the allograft, histology also occasionally reveals unexpected pathology such as thrombotic microangiopathy (TMA) or polyomavirus infection. Biopsy results alone should not dictate management; rather, the constellation of clinical and histologic findings should be used to shape a treatment plan.

Immune Monitoring.

It has been suggested that measuring the serum or urine concentrations of cytokines, IL-2 receptor, adhesion molecules, or other inflammatory markers such as complement and acute-phase proteins could be useful in diagnosing acute rejection. A serum or urine marker with high positive and negative predictive values might obviate the need for biopsy or aid the follow-up of treated rejection. Quantification of mRNA transcripts of perforin and granzyme B in urinary cells was found to be useful in predicting the presence or development of acute rejection.[54] More recently, the same group has reported that levels of FOXP3 mRNA in urinary cells predicted the reversibility of acute rejection and identified patients at high risk for graft loss after an episode of acute rejection.[55] Methods to monitor cellular and humoral immune responses in CAN have also been described.[56]

There are several concerns with regard to the applicability of these assays to clinical practice. First, these markers have not been validated in large-scale, multicenter human studies. Second, they cannot diagnose vessel involvement by rejection. Finally, infections could mimic acute rejection by elevating levels of inflammatory and immunologic markers. Thus, core kidney biopsy with appropriate histology remains the “gold standard” for diagnosing intrarenal causes of allograft dysfunction.

Acute Thrombotic Microangiopathy

Acute TMA after renal transplantation is a rare but serious complication.[57] Causes include CNIs, OKT3, acute AMR (additional pathologic findings are present, however[58]), viral infections such as cytomegalorvirus (CMV) and recurrence of primary disease (see later). The presence of hepatitis C and anticardiolipin antibodies increases the risk.[59] Onset is usually in the early post-transplant period. The classic laboratory findings are increasing plasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis. and low haptoglobin level. The hematologic features of TMA may be easily missed, however. For example, other drugs such as thymoglobulin or MMF can depress platelet and red blood cell counts, although by different mechanisms. Allograft biopsy shows damaged endothelium and, in severe cases, thrombosis of glomerular capillaries and arterioles.

In severe cases, the long-term prognosis for the allograft is often poor. Early diagnosis of TMA is essential to salvage renal function. There are no controlled trials of therapy for TMA after transplant. Suggested measures are cessation of CNIs and other implicated drugs, and control of any hypertension present. The benefit of plasma exchange is unclear.

Acute Pyelonephritis

Urinary tract infections (UTIs) may occur at any period but are most frequent shortly after transplantation because of catheterization, stenting and aggressive immunosuppression. Other risk factors for UTI are anatomic abnormalities and neurogenic bladder. Fortunately, acute pyelonephritis is less common since the widespread use of prophylactic sulfamethoxazole-trimethoprim (SMX-TMP). Fever, allograft pain and tenderness, and leukocytosis count are usually more pronounced in acute pyelonephritis than in acute rejection. Diagnosis requires urine culture, but empiric antibiotic treatment should be started immediately. The most commonly implicated microorganisms are gram-negative bacilli, coagulase-negative staphylococci, and enterococci. Renal function usually returns to baseline quickly with antimicrobial therapy and volume expansion. Recurrent pyelonephritis requires investigation to exclude underlying urologic abnormalities.

Acute Allergic Interstitial Nephritis

Distinguishing acute allergic interstitial nephritis and ACR is very difficult. In fact, the pathogenesis is somewhat similar in both cases, involving mainly cell-mediated immunity. Fever and rash after ingestion of a new drug favor the former. These clinical features are rarely seen, however. Mononuclear cell and eosinophil infiltration of the transplanted kidney may occur with either condition, but endothelialitis implicates rejection. Polyomavirus infection must also be considered in the differential diagnosis. Both acute allergic interstitial nephritis and ACR usually respond to steroids; of course, the suspected drugs must be stopped. SMX-TMP is probably the drug most likely implicated in causing allergic interstitial nephritis in renal transplant patients.

Early Recurrence of Primary Disease

Several renal diseases may recur early and cause acute allograft dysfunction (diseases that recur later are discussed below) (see Table 64-3 in Chapter 64 ). These may be classified into three groups: (1) glomerulonephritides, (2) metabolic diseases such as primary oxalosis, and (3) systemic diseases such as hemolytic-uremic syndrome/thrombotic thrombocytopenia purpura (HUS/TTP). Primary focal segmental glomerulosclerosis (FSGS) is considered in more detail in the following section because of its relatively high frequency of recurrence and its propensity to cause severe graft injury.

Primary Focal Segmental Glomerulosclerosis.

Primary FSGS has a reported recurrence rate of about 30% and causes graft loss in a high percentage of such cases (familial FSGS rarely recurs). Risk factors for recurrence include white recipient, younger recipient, rapidly progressive FSGS in the recipient's native kidneys, and recurrence of disease in a previous allograft. Most cases become manifest (as proteinuria) hours to weeks after transplant. This rapidity of recurrence suggests the presence of a pathogenic circulating plasma factor.[60] Patients with FSGS should be monitored after transplantation for new-onset proteinuria. Early biopsy is indicated in those who develop proteinuria; this may not show FSGS lesions per se, but electron microscopy demonstrates diffuse effacement of foot processes. Treatment options include plasmapheresis or immunoadsorption, high-dose CNIs, ACE-Is, high-dose glucocorticoids, and cyclophosphamide, but controlled studies are lacking. Those at high risk of recurrence should probably be offered deceased rather than living donor kidneys.

Antiglomerular Basement Membrane Disease.

Before transplantation, patients with ESRD due to anti-glomerular basement membrane (GBM) disease should generally be on dialysis for at least 6 months and have negative anti-GBM serology. If these criteria are fulfilled, post-transplant recurrence is rare. De novo anti-GBM disease can occur in recipients with Alport syndrome (see later).

De Novo Glomerulonephritis.

De novo anti-GBM disease may rarely arise in the early post-transplant period in allografts transplanted into recipients with Alport syndrome. Here, the recipient with abnormal type IV collagen produces antibodies against the previously “unseen” normal a chain in the basement membrane of the transplanted kidney. Patients with allograft dysfunction should be treated with plasmapheresis and cyclophosphamide. Those with only immunofluorescence evidence of recurrence (i.e., linear staining of GBMs by IgG) do not require therapy.[61]

Hemolytic-Uremic Syndrome/Thrombotic Thrombocytopenia Purpura.

The causes of TMA after renal transplant have been discussed earlier. Recurrence of classic (diarrhea-associated) HUS/TTP is uncommon. However, transplantation should still be deferred until the disease is quiescent for at least 6 months. In contrast, recurrence of atypical (non-diarrhea-associated) HUS/TTP, particularly if inherited, is common. Certain genetic disorders of complement regulation (such as of Factor H) are associated with high risks of severe recurrence, so it is very useful to define these risks, if possible, before proceeding with transplant.[62] In general, the prognosis for the allograft is poor if there is recurrence.

Postrenal Dysfunction in the Early Post-transplant Period

The incidence of serious early post-transplant urologic complications has decreased significantly over the last 20 years. Nevertheless, postrenal causes must always be considered in the differential diagnosis of acute allograft dysfunction. Most urologic complications are secondary to technical factors at the time of transplant and manifest themselves in the early postoperative period, but immunologic factors may play a role in some cases.

Urine Leaks

Urine leaks usually occur in the first few weeks. Leaks may occur at the level of the renal calyx, ureter, or bladder. Causes include infarction of the ureter due to perioperative disruption of its blood supply and breakdown of the ureterovesical anastomosis. Severe obstruction may also result in rupture of the urinary tract with leakage. Clinical features include abdominal pain and swelling; the plasma urea and creatinine levels increase due to resorption of solutes across the peritoneal membrane. If a perirenal drain is being used, however, a urine leak may present with high-volume drainage of fluid. Ultrasound may demonstrate a fluid collection (urinoma); aspiration of fluid from the collection (or from the drain bag) by sterile technique allows comparison of the fluid and plasma creatinine. When renal excretory function is good, the creatinine concentration in the urinoma greatly exceeds that in the plasma.

In cases in which ultrasound diagnosis is difficult, renal scintigraphy may be useful in demonstrating extravasation of tracer from the urinary system, provided there is adequate renal function. Rough localization of the site of the leak is sometimes possible by this technique. Antegrade pyelography allows precise diagnosis and localization of proximal urinary leaks. Cystography is the best test to demonstrate a bladder leak.

The clinical features may mimic those of acute rejection. Whenever urine leakage is suspected, a bladder catheter should be immediately inserted to decompress the urinary tract. Selected patients may do well with a bladder catheter or endourologic treatment. Many cases, however, require urgent surgical exploration and repair. The type of repair depends on the level of the leak and the viability of involved tissues.

Urinary Tract Obstruction

Urinary tract obstruction can cause allograft dysfunction at any time after transplantation but is most common in the early postoperative period. The main intrinsic causes are poor implantation of the ureter into the bladder, intraluminal blood clots or slough material, and fibrosis of the ureter due to ischemia or rejection. The main extrinsic cause is an enlarged prostate in elderly men (causing bladder outlet obstruction); less common is compression by a lymphocele or other fluid collection. Rarely, calculi cause transplant urinary tract obstruction.

Typical clinical features are rising plasma creatinine without localizing symptoms (unless there is prostate related obstruction). In severe cases, high pressure within the urinary tract may result in rupture and leakage (see earlier). Ultrasound usually demonstrates hydronephrosis. Because some dilation of the transplant urinary collecting system is often seen in the early postoperative period, serial scans showing worsening hydronephrosis may be needed to confirm the diagnosis. Renal scintiscan with diuretic washout is useful in equivocal cases. Percutaneous antegrade pyelography is the best radiologic technique for determining the site of obstruction and can be combined with interventional endourologic techniques. In expert hands, endourologic techniques (e.g., balloon dilation, stenting) may be effective in treating ureteric stenosis and stricture. More complicated cases require open surgical repair. Extrinsic compression requires specific intervention such as draining of the lymphocele. Obstruction in the early postoperative period due to an enlarged prostate should be managed with bladder catheter drainage and drugs such as tamsulosin.

Late Post-transplant Period

Late Acute Allograft Dysfunction

The causes and evaluation of late (>6 months post-transplant) acute allograft dysfunction are broadly similar to those of early acute dysfunction. Acute prerenal failure may occur at any time, and the causes are similar to those seen with native kidneys, such as shock syndromes and ACE-I or NSAID hemodynamic effects. Urinary tract obstruction must also be considered in the differential diagnosis. At this point, the causes of obstruction are similar to those associated with native kidney disease, including stones, bladder outlet obstruction and neoplasia. Ureteric obstruction due to BK virus infection has also been described. Several causes of late acute allograft dysfunction are reviewed in more detail below.

Late Acute Rejection

With standard immunosuppressive protocols, acute rejection is uncommon after the first 6 months. Late acute rejection should alert the physician to prescription of inadequate immunosuppression or patient noncompliance.[63]Cessation of steroids or CNIs by the physician, although sometimes appropriate, can lead to late acute rejection; therefore, plasma creatinine must be carefully monitored when these drugs are stopped. Late acute rejection usually has a large cellular component, but there may be superimposed acute AMR (C4d staining should be routinely performed).

In general, treatment is the same as for early acute rejec-tion (whether ACR or acute AMR or both), as discussed above. Unfortunately, complete reversibility is difficult, and registry data show that late acute rejection has a more negative impact on allograft survival than early acute rejection or DGF.

Risk factors for noncompliance include adolescence, more immunosuppressant adverse effects, lower socioeconomic status, minority status, and psychological stress or illness.[64] Transplant physicians should be alert to the possibilities of poor compliance in all their patients. Interventions that might reduce this problem include reiteration of the permanent risk of rejection and the importance of daily intake of antirejection medications, simplification of the drug regimen, and social worker assistance with high-risk cases.

Late Acute Calcineurin Inhibitor Nephrotoxicity

Although lower doses of CNIs are generally prescribed after the first 6 to 12 months, acute CNI toxicity may occur at any time after transplant. Intake of medications that impair metabolism of the CNIs ( Table 65-10 ) may induce acute deterioration in renal function, but this should be reversible with appropriate drug adjustment.

TABLE 65-10   -- Commonly Used Drugs That May Induce Acute Renal Failure in Renal Transplant Recipients





Functional prerenal failure; rarely interstitial nephritis

Avoid in renal transplant patients

Acyclovir, foscarnet (high dose)

Crystal deposition in tubules causing obstruction and damage; also ATN

Hydration prevents crystal deposition


Functional prerenal failure—particularly if hypovolemia or renal artery stenosis present

Monitor renal function carefully after starting these drugs; avoid in early post-transplant period


High dose TMP impairs tubular secretion of creatinine (no effect on GFR); rarely interstitial nephritis

In general, drug is well tolerated in transplant recipients


Proximal and distal tubular damage; cumulative dose effect

Lysosomal preparation is less nephrotoxic but very expensive


Immune stimulating effects promote acute rejection; other nephrotoxic effects reported

Risk/benefit of using interferon-alfa must be determined for individual patient

Erythromycin, verapamil, diltiazem, ketoconazole

Inhibit metabolism of CsA/tacrolimus

Monitor CsA/tacrolimus concentrations carefully

Statins, e.g., simvastatin

Concentrations increased with concomitant CsA therapy, increasing risk of rhabdomyolysis

Use lowest dose initially; monitor CK


Hemodynamic effects; other effects

Hydration and use of minimum volume nonionic contrast media reduce risk of contrast nephropathy; no data on acetylcysteine but worth trying


ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ATN, acute tubular necrosis; CK, creatine kinase; CsA, cyclosporine; SMX-TMP, sulfamethoxazole-trimethoprim.




Transplant Renal Artery Stenosis

Transplant renal artery stenosis can arise at any time after transplantation. The reported incidence varies widely.[65] Luminal narrowing of more than 70% is probably required to render a stenosis functionally significant. The stenosis may occur in the donor or recipient artery or at the anastomotic site. Stenosis of the recipient iliac artery may also compromise renal arterial flow. Causes include operative trauma to these vessels, atherosclerosis of the recipient vessels, and possibly immunologic factors. Features suggestive of functionally significant stenoses include resistant hypertension; fluctuating plasma creatinine, especially with hypovolemia or ACE inhibition; peripheral vascular disease; and new bruits over the allograft.[65]

The “gold standard” for diagnosis is renal angiography, but this is invasive. Both MR angiography and duplex sonography (in experienced hands) are highly sensitive in diagnosing transplant renal artery stenosis and are adequate screening tests.[65] MR angiography has the advantage of better imaging the iliac arteries and identifying anatomy before angioplasty. Mild cases are often treated conservatively with antihypertensives, aspirin, and so on. Percutaneous transluminal angioplasty (PTA) has been the treatment of choice for more severe cases. In most series, PTA was technically successful with few major complications. Early reports suggest stenting reduces recurrence. Surgical repair is reserved for severe cases, not amenable to PTA/stenting. Measures used to minimize contrast nephropathy are discussed later.

Infections Causing Late Acute Allograft Dysfunction

Human Polyomavirus Infection.

The polyomaviruses are DNA viruses, the best known of which are the BK virus, JC virus, and SV40 virus. Many healthy adults have serologic evidence of past (usually subclinical) exposure. Over the last 10 years, BK virus has been increasingly recognized as an important cause of renal allograft dysfunction and loss. This probably reflects more recognition and reporting of the disease but also the effects of more powerful maintenance immunosuppression regimens incorporating MMF and tacrolimus.

Replication of BK virus, with shedding of infected uroepithelial cells (decoy cells) into the urine occurs in more than one third of renal transplant recipients.[66] The clinical features associated with such replication include none (most common), acute and chronic allograft dysfunction, and hemorrhagic cystitis. The allograft dysfunction is usually due to interstitial nephritis, although ureteric stenosis has been described.

Diagnosis of polyomavirus interstitial nephritis obviously requires allograft biopsy. Because the histopathologic changes may be patchy, two cores are recommended for analysis.[67] The presence of intranuclear tubule cell inclusions by light microscopy should raise suspicion; diagnosis is confirmed by immunohistochemistry. It is difficult to distinguish viral infection alone from infection plus superimposed rejection.

The most important therapy for established BK virus nephritis is major reduction in immunosuppression to augment host mechanisms of viral clearance. Other therapies that have been reported in small series to be effective include leflunomide, low-dose cidofovir (high doses are nephrotoxic), IgG, and fluoroquinolones.[68]

Many transplant centers now screen all new transplant recipients for subclinical infection, the idea being to reduce immunosuppression before severe nephritis occurs. Protocols are still evolving. Some involve testing the urine every 3 months by light microscopy for decoy (infected) cells or by polymerase chain reaction (PCR) quantification of viral load. Other protocols involve blood PCR quantification of viral load or a combination of urine and blood testing. Positive screening tests trigger reduction in immunosuppression and, if the creatinine is increased, an allograft biopsy. Brennan and colleagues[66] have also reported a protocol of monitoring for viruria and viremia; rates of acute rejection, graft loss, and virus nephritis were very low.

Hepatitis C.

The management of progressive hepatitis C virus (HCV) disease in renal transplant recipients remains unsatisfactory. Reduction in immunosuppression is the first step, and this obviously increases the risk of rejection. Treatment with interferon-alfa may induce temporary remission but the rate of relapse is high. Furthermore, the risk of provoking acute allograft dysfunction or loss with this drug via rejection or other mechanisms is high.[69]

Both membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy are more commonly seen in HCV-positive compared with HCV-negative renal transplant recipients. The MPGN form can be associated with cryoglobulinemia, although severe systemic vasculitis is rare. An association of TMA with anticardiolipin antibodies in HCV-positive patients has also been reported.[59] Treatment of HCV-related glomerulonepritis after renal transplant should involve supportive measures; antiviral therapy has the same problems described earlier. A small series of rituximab-treated patients was reported; severe complications were common.[70]

Drug and Radiocontrast Nephrotoxicity

A variety of drugs can cause acute dysfunction of the renal allograft. In many cases, the offending agent (e.g., an aminoglycoside or amphotericin) is a well-recognized cause of AKI in native kidneys. However, a number of drug-related nephrotoxic effects are more common in the setting of transplantation (see Table 65-10 ). Many of these effects are due to interaction with the CNIs. Diltiazem, verapamil, ketoconazole, and the macrolide antibiotics, particularly erythromycin, impair CNI metabolism and may lead to acute CNI nephrotoxicity unless there is concomitant dose reduction of the CNI. There are reports implicating the newer antidepressants and some of the antiretroviral drugs in this regard.[71] High-dose SMX-TMP may cause an acute increase in plasma creatinine by inhibiting tubule secretion of creatinine (in this case GFR per se is not compromised and plasma creatinine decreases within 5 days of stopping SMX-TMP). Rarely, SMX-TMP can provoke allergic interstitial nephritis; this is treated by cessation of the drug and administering high-dose steroids.

Not surprisingly, ACE-Is or ARBs have been implicated in precipitating ARF in the presence of transplant renal artery stenosis. Overall, if carefully prescribed, these agents are well tolerated. The use of ACE-Is or angiotensin II antagonists in the immediate post-transplant period, when volume status and CNI dosages are fluctuating, is not recommended.

Drugs with known nephrotoxic effects such as aminoglycosides, amphotericin, and NSAIDs, probably have enhanced toxicity when used concomitantly with a CNI. Nevertheless, they are sometimes required in transplant recipients. Use of the lysosomal preparation of amphotericin is prefer-able because it is less nephrotoxic than the standard preparation.

Statins are commonly prescribed to renal transplant recipients. These drugs are generally well tolerated; however, there is an increased risk of rhabdomyolysis and AKI when they are used with cyclosporine. This is due mainly to cyclosporine-mediated impairment of statin metabolism. Coadministration of diltiazem or other drugs that also inhibit the cytochrome P450 system further increases plasma concentrations of statins.[72] These interactions have rarely been reported with tacrolimus, which could reflect less interaction with this particular CNI or less overall patient exposure to the tacrolimus plus statin combination. To minimize the risk of statin toxicity in renal transplant recipients, the following measures are advised: (1) consider pravastatin or fluvastatin, which have less potential for interaction with cyclosporine; (2) start with low doses of statins; (3) avoid other inhibitors of cytochrome P450 system; (4) avoid fibrates; (5) monitor plasma creatine kinase (CK); and (6) advise patients to seek medical attention if muscle symptoms occur.

The risk of developing AKI after administration of radiocontrast to renal transplant recipients has not been well defined. One study found an increase in the plasma creatinine level greater than 25% in 21% of cases.[73] Presumably, risk factors for contrast nephrotoxicity are similar to those in patients who have not undergone transplant surgery (see Chapter 27 ). Thus, the same preventive measures should be used (see also Chapter 27 ).

Late Allograft Dysfunction and Late Allograft Loss (>3 to 6 Months)

By far, the most important cause of allograft dysfunction after the first 6 to 12 months is chronic allograft nephropathy (CAN). The causes of late dysfunction are summarized in Table 65-11 and further discussed in the following sections. Certain causes such as transplant renal artery stenosis and urinary tract obstruction have been discussed earlier. The main causes of allograft loss (in order of importance) are patient death, CAN, late acute rejection/non-compliance, and recurrent disease.

TABLE 65-11   -- Causes of Late Chronic Allograft Dysfunction


Transplant renal artery stenosis


Chronic allograft nephropathy

CNI toxicity

Chronic rejection (cellular or antibody mediated or both)

Polyoma virus nephropathy

Recurrence of primary disease

New disease


Urinary tract obstruction


CNI, calcineurin inhibitor.




Chronic Allograft Nephropathy.

After censoring for death, CAN is the most frequent and important cause of long-term allograft loss. Halloran and colleagues[74] have defined CAN as a “state of impaired renal allograft function at least 3 months post-transplant, independent of acute rejection, overt drug toxicity, and recurrent or de novo specific disease entities, with typical features on biopsy.”

Histopathologic changes are seen in the tubulointerstitium, vessels, and glomeruli. These changes are not unique to CAN but include (1) atrophy and fibrosis of the tubulointerstitium, (2) fibrointimal thickening of arterial walls, (3) transplant glomerulopathy (thickening and double contouring of capillary walls and increased mesangial matrix).[75] The degree of damage of the tubulointerstitium determines the stage of CAN (see Table 65-9 ). There are proposals to improve the histopathologic classification of causes of chronic allograft damage. [76] [77]

The pathogenesis of CAN remains incompletely understood. Alloantigen-dependent and alloantigen-independent factors are considered to be important. Several of these factors probably interact in all patients with CAN. Figure 65-5illustrates some of the postulated mechanisms through which these factors interact and lead to CAN. There is accumulating evidence that the humoral immune system contributes to the development of CAN and that chronic AMR is particularly associated with transplant glomerulopathy. [51] [78] [79] For example, antibodies against HLA antigens (although not necessarily those of the donor) are associated with much higher rates of subsequent allograft failure.[80]

FIGURE 65-5  Alloantigen dependent (oval shaded) and independent factors (rectangular shaded) thought to be involved in the pathogenesis of chronic allograft nephropathy.


Typical clinical features are hypertension, proteinuria, and falling GFR. Onset is rarely less than 6 months after transplant. Earlier onset or other atypical features should prompt a search for another diagnosis such as recurrent disease or primary donor renal disease. Often there is a history of overt acute rejection episodes that may have responded poorly to antirejection treatment. The rate of decrease in the GFR varies widely between patients but is usually progressive and irreversible. Proteinuria is usually subnephrotic range but may be severe enough to cause nephrotic syndrome. Severe proteinuria and inadequately controlled hypertension are associated with more rapid deterioration in renal function.

The differential diagnosis of chronic allograft dysfunction is shown in Table 65-11 . Renal ultrasound should be performed to rule out an obstructive cause. If there is suspicion of renal artery stenosis, further testing is indicated. Allograft biopsy helps characterize the predominant form of damage. [76] [77]

Treatment options are very limited. If there is histologic evidence of a component of acute rejection, pulse steroids are often used. If the clinical and histologic picture suggests a significant component of chronic CNI nephrotoxicity, the CNI dosage can be reduced. Alternative agents such as MMF or sirolimus can be substituted,[81] but patients should be watch closely for late acute rejection. Sirolimus should probably be avoided in those with proteinuria or GFR of less than 40 mL/min.[23]

Hypertension and hyperlipidemia should be rigorously controlled. There are no randomized controlled trials in CAN but ACE-I or angiotensin receptor blockers are often used. See also management of the failing allograft below.

Prevention of CAN is obviously a major focus of current research. Strategies under investigation include CNI minimization, adequate “dosing” of functioning nephrons (including dual kidney transplantation), minimizing ischemia-reperfusion injury, further reduction in the incidence of acute rejection, aggressive treatment of hyperlipidemia and hypertension, and interruption of pathways leading to fibrosis.[82]

Late Recurrence of Primary Disease

Table 64-3 in Chapter 64 summarizes the conditions that recur at any time after transplantation. Diseases that recur early have been discussed earlier. The incidence of late recurrence is difficult to estimate: the original cause of ESRD is often unknown, transplant kidney biopsies are not always performed; and most relevant studies are small and retrospective with variable follow-up periods. In one large study of patients who underwent transplantation after developing ESRD from glomerulonephritis, recurrence was the third most frequent cause of graft loss at 10 years (after chronic rejection and death).[83]

IgA Glomerulonephritis

Studies with longer follow-up times have shown that histologic recurrence of this condition is common. In one recent series, it was at least 35%.[84] On multivariable analysis, recurrence was not associated with greater risk of graft failure. It seems reasonable to treat clinically significant recurrence as for native kidney IgA glomerulonephritis.

Lupus Nephritis

Allograft and patient survival overall are similar in patients with ESRD due to lupus nephritis compared with those with ESRD from other causes.[85] Recurrence of severe systemic lupus erythematosus, either systemically or within in the graft, is uncommon. This probably reflects patient selection, disease activity “burning out” on chronic dialysis, and the effects of powerful post-transplant immunosuppression. As with other glomerular diseases that can recur, transplant should not be performed until the systemic lupus erythematosus is clinically quiescent. Many centers prefer a 6 to 12 month period of clinical quiescence before proceeding with transplantation to reduce the risk of recurrence. If the patient is receiving anticoagulation for anti-phospholipid syndrome (APS) before transplantation, anticoagulation should be resumed as soon as safely possible (initially with intravenous heparin) after the transplant surgery. This procedure is used to reduce the risk of thrombosis of the allograft or other sites.

Wegener Granulomatosis and Microscopic Polyangiitis

Renal and extrarenal recurrence of these diseases has been described. In one of the largest reported series, with a mean follow-up time of 44 months, antineutrophil cytoplasmic antibody (ANCA)–associated small vessel vasculitis recurred in 17% of cases; renal involvement recurred in 10% of cases; the recurrence rate was not lower with cyclosporine therapy.[86] This and other studies have found that positive ANCA serology at the time of transplant does not predict later relapse. Of course, patients with ESRD secondary to ANCA vasculitis should not undergo transplant surgery until the disease is clinically quiescent. Recurrences usually respond to cyclophosphamide.

Membranoproliferative Glomerulonephritis

The primary forms of types I and II MPGN can recur after transplant. The risk of recurrence is unclear because these are rare conditions and some cases of “primary” MPGN may, in fact, have been related to HCV infection (see later). Furthermore, type I MPGN is difficult to distinguish histologically from primary transplant glomerulopathy. One series found recurrence of type I MPGN in 33% of cases; graft survival was significantly poorer when this recurred.[87] Case reports have suggested a benefit of steroids, cyclophosphamide, and plasmapheresis. Type II MPGN recurs, at least by histologic criteria, in most allografts.[88] Early reports suggested that associated graft failure was unusual. However, more recent series have documented allograft loss from recurrent type II MPGN in more than 20% of cases.[88]

Membranous Nephropathy

Membranous nephropathy may recur after transplant or arise de novo. The associated clinical features vary from minimal to nephrotic syndrome. In one series of 30 patients, the actuarial risk of recurrence at 3 years was 29% and recurrence was associated with poor graft survival.[89] De novo membranous nephropathy is often associated with CAN. As with native kidney disease, HCV infection and other causes of this glomerulopathy should be excluded. Management includes treatment of the underlying cause and supportive measures such as ACE-I. Intensification of immunosuppression solely to treat this lesion should probably be avoided.

Diabetic Nephropathy

Recurrence of diabetic nephropathy in the allograft has not been well studied. This reflects the poor long-term survival of diabetic transplant recipients; the duration of exposure to the diabetic milieu is often insufficient to allow development of severe diabetic nephropathy. Kim performed a case control study of 78 patients with ESRD due to type I diabetes mellitus who had undergone transplant surgery.[90] Overall graft survival was poorer in the diabetic group. If death was excluded as a cause of allograft failure, however, graft survival was little different. Six of 16 patients who were biopsied had histologic evidence of recurrence, but this resulted in graft loss in only one case. The onset of diabetes mellitus after transplant is a common problem.[91] This can also lead to diabetic nephropathy; histologic evidence of this may occur quite rapidly after transplant.[92]


The most convenient and widely used method for assessing outcomes is measurement of allograft survival. Other important measures include allograft function (typically measured by plasma creatinine), patient survival, number of rejection episodes, days of hospitalization, and quality-of-life indices. Registry data from the USRDS, the Collaborative Transplant Study (CTS), and ANZDATA are very useful for assessing these outcomes.

Actual and Actuarial Allograft and Patient Survival

Allograft survival is calculated from the day of transplantation to the day of reaching a defined end point (either return to dialysis or retransplantation or death). One year, 5-year, and 10-year actuarial survival rates are frequently presented, but projected survival may ultimately not be as impressive as actual survival.[93] Another actuarial measure commonly used is allograft half-life (median allograft survival).

Traditionally, allograft survival is assessed under two distinct time phases: early and late. Early allograft loss refers to loss in the first 12 months; late loss to any time thereafter. This distinction is empiric but makes clinical sense. In the first 12 months, allograft loss is relatively common, because of technical complications such as graft thrombosis and because of severe rejection. After 12 months, the incidence is lower but remains stable over time. Usually, analysis of long-term survival is restricted to those allografts that have survived to 12 months after transplant. The causes of late allograft loss are also different and are discussed later. Note that using the earlier definition, patient death is equivalent to allograft loss. Allograft survival can also be calculated after censoring for patient death.

Survival Benefits of Renal Transplantation

Comparison of survival between the general dialysis population and transplanted patients is greatly affected by selection bias; only relatively healthy patients are referred for transplantation. Thus, comparisons between patients on the waiting list who do or do not receive a transplant are usually performed instead. Of course, such analyses assume that the two groups (those who have undergone transplant sugery or those still on the list) can otherwise be matched; this is not necessarily true.

One study of USRDS found that during the first 106 days after transplantation, the relative risk of death was greater than remaining on the waiting list (on dialysis). This mainly reflected the risks associated with the transplant procedure itself. Thereafter, however, transplantation conferred a survival benefit. On the basis of 3 to 4 years of follow-up, transplantation reduced the risk of death overall by 68%.[94] Transplantation was particularly life saving in diabetic patients.

Current Short-Term Outcomes in Renal Transplantation

Current adjusted 1-year survival probabilities for deceased donor allografts (first or subsequent transplant) are 89% and for living donor allografts (first or subsequent transplant) are 95%.[29] First transplants have slightly better survival than subsequent ones. One-year allograft survival has improved steadily over the last 25 years ( Fig. 65-6 ). The principal causes of allograft loss in the first post-transplant year are acute rejection, thrombosis, primary nonfunction, and patient death.

FIGURE 65-6  One-year renal allograft survival probabilities (all transplants), adjusted by age, gender, race, primary diagnosis, transplant number. Reference cohort is 1996 incident patients.  (From USRDS. USRDS 2005 Annual Data Report: NIH and NIDDK, Bethesda, MD, 2005.)



The current adjusted 1-year survival probability for recipients of deceased donor allografts (first or subsequent transplant) is 91%, this rate has slowly but steadily improved over the past 25 years. The current adjusted 1-year survival probability for recipients of living donor allografts (first or subsequent transplant) is 95%.[29] These outcomes have also improved over the past 25 years ( Fig. 65-7 ). The principal causes of patient death in the first year are cardiovascular disease and infection (malignancy is a much less common cause).

FIGURE 65-7  One year renal transplant recipient survival probabilities (first transplants), adjusted by age, gender, race, primary survival diagnosis. Reference cohort is 1996 incident patients.  (From USRDS. USRDS 2005 Annual Data Report: NIH and NIDDK, Bethesda, MD, 2005.)



Current Long-Term Outcomes in Renal Transplantation

There has also been an improvement in long-term allograft survival ( Fig. 65-8 ). Recently, this increase has occurred mainly in higher risk patients such as those receiving retransplants ( Figure 65-8 includes a large percentage of such patients). When first deceased donor transplants alone are assessed, recent improvements are less impressive.[45] These findings indicate that improving long-term allograft survival is not just a matter of preventing early acute rejection.

FIGURE 65-8  Five-year renal allograft survival probabilities (all transplants; conditional on surviving 1 year post transplant), adjusted by age, gender, race, and primary diagnosis. Reference cohort is 1996 incident patients.  (From USRDS. USRDS 2005 Annual Data Report: NIH and NIDDK, Bethesda, MD, 2005.)



Beyond the first post-transplant year, the principal causes of renal allograft loss are patient death and CAN; less common causes are late acute rejection and recurrent disease.[82] The primary cause of death remains cardiovascular disease, followed by infection and malignancy ( Fig. 65-9 ). In children, however, death is a much less common cause of allograft loss; conversely in the elderly, it is more common.

FIGURE 65-9  Mortality rates by cause, as a function of time after transplant.  (From USRDS. USRDS 2005 Annual Data Report: NIH and NIDDK, Bethesda, MD, 2005.)



Factors Affecting Renal Allograft Survival

Prospective studies and analyses of registry data have shown that many variables influence renal allograft survival. These can be considered as donor, recipient, or donor-recipient factors. Many of them contribute to the development of CAN and have been discussed earlier.

Donor-Recipient Factors

Delayed Graft Function

DGF and probably SGF (see both earlier) are associated with poorer allograft and patient survival and poorer allograft function.[28] Registry data show that DGF reduces allograft half-lives by 30%, a larger effect than early acute rejection.[30]

Human Leukocyte Antigen Matching

Registry data demonstrate that, even with current immunosuppression regimens, better HLA-matched allografts have better survival. This benefit applies both to living and deceased donor kidneys. The better outcomes are presumably related to fewer immunologic failures. Recent evidence suggests that the benefits of HLA matching are diminishing and are much less pronounced in living donor recipients[95] (although a large survival advantage is still seen in those with two haplotype matches). The limited effect of HLA mismatching on living donor transplant survival is important because this means that there is no contraindication to a living unrelated transplant from a general immunologic perspective.

Cytomegalovirus Status of Donor and Recipient

Registry data show a small but definite effect of donor and recipient CMV serologic status on renal allograft and recipient survival.[29] Donor-negative-recipient-negative pairings have the best outcomes, whereas donor-positive-recipient-negative pairings have the worst. CMV probably affects graft outcomes through overt infection, but subclinical effects on immune function may also be important.

Timing of Transplantation

In the case of living donor transplantation, there is evidence that preemptive (before initiation of dialysis) transplantation is associated with a lower risk of acute rejection and allograft failure.[96] Other retrospective studies have shown that longer time on dialysis is independently associated with poorer graft and patient survival.[97] Minimizing time on dialysis has many potential benefits; this strategy should thus be pursued whenever possible. Whether this benefit applies to pre-emptive retransplantation needs further investigation.[98]

Center Effect

Not surprisingly, reported outcomes have varied from transplant center to center. This reflects normal statistical variance as well as center expertise. Outcomes are confounded by many donor and recipient factors that differ across centers. Thus, between-center comparisons are difficult. USRDS data suggest minimal difference in outcomes between small and large transplant centers in the United States.[99]

Genetic Polymorphism

It has been hypothesized that genetic variation (with regard to the organ donor or recipient) may influence post-transplant outcomes such as susceptibility to infections, acute rejection or allograft survival. Candidate polymorphic genes are those encoding cytokines, chemokines, components of the angiotensin II system, adhesion molecules, and their relevant receptors. The relevant literature has many caveats: studies, usually single center, have been retrospective, have often not incorporated multivariable analysis, and in some cases, have yielded contradictory results. Thus, it is premature to alter immunosuppression or other aspects of post-transplant care based on the data available.

Donor Factors

The quality of the kidney immediately before transplantation has a major impact on long-term graft function and the risk of developing CAN.

Donor Source: Deceased Versus Living Donor

The donor source is one of the most important predictors of short- and long-term allograft outcomes. In general, living donor are superior to deceased donor allografts (see Figs. 65-7 and 65-8 [7] [8]). This benefit applies across all degrees of HLA mismatching. The better outcomes reflect several factors: very healthy living donors, the absence of brain death, the general benefits of elective as opposed to semi-emergency surgery, avoidance of ischemia-reperfusion injury, high nephron mass and probably the effects of a shorter waiting time (see earlier). Excellent results are now being demonstrated with living unrelated kidney transplantation in which HLA matching is not optimum.[100] This further emphasizes the importance of the “healthy transplant kidney” effect. Allograft outcomes are superior from deceased donors with trauma as opposed to non-trauma being the cause of death.[29]

Donor Age

Kidneys from donors older than 50, and particularly 65, years of age have poorer outcomes. This effect is especially pronounced in deceased donor allgrafts. These results are thought to reflect a higher incidence of DGF and of nephron “underdosing.” Allografts from older donors have fewer functioning nephrons because of the aging process and donor-related conditions such as hypertension and atherosclerosis. However, because of the organ donor shortage, elderly deceased donor kidneys are being increasingly used. Donor age younger than 5 years is also associated with poorer outcomes, reflecting higher rates of technical complications and probably nephron underdosing (see later). En bloc transplantation from donors aged 0 to 5 years significantly improves survival, however.[101]

Donor Sex

There is evidence that allografts from female donors have slightly poorer survival. [29] [102] Again, this probably reflects a nephron underdosing effect (see later), because women have a smaller renal mass than men. However, differences in the antigenicity of female grafts may also be a factor.[102]

Donor Nephron Mass

An imbalance between the metabolic/excretory demands of the recipient and the functional transplant mass has been postulated to play a role in the development and progression of CAN. Nephron underdosing, exacerbated by perioperative ischemic damage and postoperative nephrotoxic drugs, might lead to nephron overwork and eventual failure, similar to the mechanisms occurring in native kidney disease. Thus, kidneys from small donors transplanted into recipients of large body surface area or large body mass index would be at highest risk of this problem. There is support for this hypothesis from animal[103] and retrospective human studies.[104]

Cold Ischemia Time

Prolonged cold ischemia time is associated with higher risk of DGF and poorer allograft survival.[105] Registry data suggest that more than 24 hours is particularly deleterious to the graft. DGF has been discussed earlier.

Expanded Criteria Donors

As the discrepancy between the number of patients awaiting kidney transplant and the number of available organs increases, many countries are now using ECD allografts (see Chapter 64 ). By definition, ECD allografts have poorer survival than standard criteria donor ones. The definition of an ECD allograft involves an estimated relative risk of failure greater than 1.7 compared with an ideal reference group.[106] Survival of ECD kidneys is, on average, shorter for two general reasons: first, the baseline GFR of these kidneys is likely lower, and second, ECD kidneys tend to be transplanted into older recipients, who have higher rates of post-transplant death. It should be emphasized that transplantation with an ECD kidney confers a survival advantage to certain patients as opposed to remaining on the transplant waiting list (on dialysis).[107] Different allocation algorithms are being developed for ECD allografts to minimize cold ischemia times.[108] Transplantation of both kidneys (if suboptimal) into one recipient would obviously double the functioning nephron number; limited data suggest that outcomes of this procedure are good.[109]However, the number of recipients is obviously halved.

Donors with Cardiac Death

The use of kidneys from such donors has been controversial because short-term outcomes (such as rates of DGF) are inferior to those seen with brain dead donors. This reflects the longer period of warm ischemia. There is accumulating evidence, however, that long-term allograft survival is similar to standard criteria donors, although renal function may be inferior.[110]

Recipient Factors

Recipient Age

In general, allograft survival rates are poorer in those at the extremes of age, that is, younger than 17 or older than 65 years of age.[29] In the young, technical causes of graft loss such as vessel thrombosis are relatively more common. Acute rejection is also a more common cause of allograft loss; conversely, death with a functioning graft is relatively rare. Death with a functioning allograft is a more common cause of graft loss in the elderly (responsible for more than 50% of graft failures). Conversely, acute rejection may be less common. Thus, although randomized controlled trials are not available, it seems reasonable, in general, to use less aggressive immunosuppression in the elderly.

Recipient Race

In the United States, black recipients have poorer deceased donor allograft survival compared with that of whites.[29] There is also a trend toward poorer survival of living donor allografts in black as opposed to nonblack recipients. This probably reflects multiple factors including higher incidence of DGF, higher incidence of acute and late acute rejection, stronger immune responsiveness, a predominantly white donor pool (with resultant poorer matching of HLA and non-HLA antigens), altered pharmacokinetics of immunosuppressive drugs, and a higher prevalence of hypertension. Socioeconomic factors associated with inability to pay for transplant medications (an issue in the United States, where universal health coverage does not exist), poorer access to high-quality medical care and noncompliance probably also play a role.[111] There is some evidence that blacks have equivalent outcomes to whites in Europe.[112] Asian and Latino recipients have superior outcomes to whites; the reasons for this are unknown.

Strategies that should improve outcomes in black recipients include increasing living and deceased donation by blacks and use of higher doses of immunosuppression (such as MMF 3 g/day). [15] [113]

Recipient Gender

Registry studies of the association of recipient gender with transplant outcomes have yielded differing results. In the CTS database, female recipients had slightly better allograft survival than male recipients of deceased donor kidneys or HLA-identical kidneys.[102] Data from US transplant centers has shown better allograft survival in male as opposed to female recipients of living donor kidneys.[114] An important difference between female and male transplant candidates is the higher degree of sensitization of the former to HLA antigens, probably non-HLA antigens also. Women tend to be more sensitized because of pregnancy and possibly because of more blood transfusions related to menstruation.

Recipient Sensitization

Patients who are highly sensitized (PRA greater than 50%) generally have poorer early and late graft survival compared with nonsensitized recipients. This is mainly related to an increased incidence of complications in the early post-transplant period such as DGF and acute rejection. The principal reasons for sensitization are previous transplants, pregnancy, and blood transfusion. Thus, allograft survival is poorer in recipients of second or third transplants compared with recipients of a first transplant.[29] Highly sensitized patients are usually given more intensive immunosuppression.

Acute Rejection

Acute rejection has been consistently associated with an increased risk of allograft loss. This is due to irreversible graft injury at the time of the acute rejection and probably ongoing subclinical immune-mediated injury. Such damage accentuates the effects of poor-quality donor tissue, perioperative ischemic injury and nephron underdosing. Acute rejection refractory to steroids, acute rejection with a humoral component, and late acute rejection have particularly negative impacts on allograft and patient outcomes.[93] Although current immunosuppressive regimens have steadily decreased rates of acute rejection, this has not necessarily translated into a major improvement in long-term graft survival.[45]

Recipient Immunosuppression

Undoubtedly, the improvements in short- and long-term allograft survival reflect, in part, the effectiveness of the newer antirejection drugs such as the CNIs and MMF. The contribution of long-term CNI therapy, particularly with currently used maintenance doses, to chronic renal allograft dysfunction remains controversial. Traditionally, the CNIs have been thought to have greater beneficial effects on short-term compared with long-term renal allograft survival. Certainly, in some nonrenal transplant patients (e.g., those with cardiac allografts or autoimmune disease), prolonged intake of CNIs can cause severe kidney injury. CNIs could contribute to chronic allograft dysfunction by induction of chronic renal ischemia, by stimulation of intragraft production of the fibrogenic cytokine transforming growth factor-β (TGF-β), and by promotion of systemic hypertension. Balancing these effects, of course, is the high efficacy of CNIs in preventing acute rejection, one of the most important determinants of graft outcomes. The increases in short- and long-term graft survival in the CNI era (cyclosporine became widely used in the early 1980s) suggest that these antirejection effects override the nephrotoxic effects. Furthermore, lower dosages of cyclosporine (<5 mg/kg/day) have been associated with the development of CAN.[115]

Registry data analysis suggests that MMF improves long-term graft survival both by preventing overt acute rejection and by other mechanisms.[13] Although antilymphocyte antibody preparations are widely used, particularly in the setting of DGF, their beneficial effect on long-term allograft survival has not been well documented.

Recipient Compliance

Poor compliance with the immunosuppressive regimen greatly increases the risk of acute rejection (particularly late acute rejection) and allograft loss. In one recent meta-analysis, a third of the allograft losses were linked to patient noncompliance.[116]

High Recipient Body Mass Index

Morbid obesity is associated with more transplant surgery-related complications, more DGF, and poorer allograft survival.[117] Poorer long-term graft survival probably reflects the effects of DGF, nephron overwork, and more difficult dosing of immunosuppressive drugs. Nevertheless, most studies of patients with body mass index (BMI) greater than 30 kg/m2 suggest that transplant provides a survival benefit over remaining on the waiting list (on dialysis), at least up to a BMI of 41 kg/m2.

Recipient Hypertension

Retrospective studies have shown that the greater the severity of post-transplant hypertension, the higher the risk of allograft loss and recipient death.[118] Of course, hypertension could also be secondary to graft damage and not just a cause. However, control of hypertension is associated with improved allograft survival.[119] Common sense dictates that treatment of hypertension should be the goal, to prevent both its renal and nonrenal complications.

Recipient Hyperlipidemia

The prominence of the vascular lesions in CAN and the similarity of these lesions to atherosclerosis suggest that hyperlipidemia plays a role in the pathogenesis of CAN and allograft failure. Some studies have suggested that hypercholesterolemia or hypertriglyceridemia, or both, are associated with poorer graft outcomes. Again, common sense dictates that hyperlipidemia should be treated aggressively to prevent both its renal and nonrenal complications.

Recurrence of Primary Disease

As discussed earlier, determining the incidence and prevalence of recurrent or de novo renal disease is difficult. A recent Australian study of patients with biopsy-proven glomerulonephritis found a 10-year incidence of graft loss from recurrence of 8.4%.[83] Overall allograft survival was not inferior, however, in patients whose primary renal disease had been biopsy-proven glomerulonephritis. It is likely that if renal allograft survival improves, recurrent or de novo disease will be increasingly diagnosed (both clinically and histologically) and will become a more important cause of late graft loss.


Proteinuria, even when modest, is associated with poorer allograft survival.[120]

Improving Renal Allograft Outcomes

Measures that would likely further improve allograft survival are summarized in Table 65-12 . Probably the most important (in terms of achievable impact) is increased use of living kidney donors. Ideally, most living donor kidneys would be transplanted before the recipient begins dialysis. It is critical, however, that donation should be allowed only when the risk of medical and psychological complications to the donor are minimal.

TABLE 65-12   -- Measures that Should Improve Renal Allograft Survival



Increased living donor donation: both related and nonrelated

Underused in many countries

Pre-emptive transplantation

Underused in many countries

Increased donation from younger, previously healthy deceased donors

Difficult to achieve; Spain best example of succesful high donation rates

Zero mismatching of HLA antigens

Already practiced in many countries

Better donor preparation, improved organ preservation; faster matching and transplantation; reduced cold ischemia time

Somewhat neglected area of transplantation. Controversial if machine perfusion improves long-term graft function

ACE inhibitors, angiotensin receptor blockers

No data in transplant patients per se showing that renal function is better preserved; reasonable to extrapolate from native kidney disease

Nephron dosing (matching of donor-recipient sex, BMI, and so on)

No large randomized controlled trials; complex to administer in practice

High quality general medical care (aggressive control of hyperlipidemia, hypertension etc.)

No randomized controlled trials showing benefits in transplant patients but benefits likely


ACE, angioten-converting enzyme; BMI, body mass index; HLA, human leukocyte antigens.




The criteria used for allocation of deceased donor allografts can have an important impact on overall allograft survival. A purely utilitarian approach (to maximize allograft survival) would direct organs only to the youngest and healthiest. In practice, a balance must be struck between utility and equity (ensuring that anyone medically fit for a transplant has a reasonable chance of obtaining one). In many countries, this balance is achieved by means of a points system, points being awarded for characteristics such as fewer HLA mismatches and time on the waiting list. There is evidence that preferential allocation of organs of younger donors to younger recipients (as opposed to the current system where some organs of younger donors are transplanted into elderly patients) would significantly improve overall allograft survival.[121] Results from the Eurotransplant Senior Program of transplanting older kidneys to older patients are encouraging.[122] Considerable debate is required before such a strategy can be implemented in the United States.


More emphasis is being placed on the general medical management of transplant patients. Although transplantation is generally preferable to dialysis, there is an increased appreciation that the post-transplant state is often one of chronic kidney disease. The management of common electrolyte, endocrine, and cardiovascular complications after transplant is discussed in the following sections.

Electrolyte Disorders

Hypercalcemia and Hypophosphatemia

Hypercalcemia is common and is due mainly to persistent hyperparathyroidism or administration of calcium and vitamin D. The management of post-transplant hyperparathyroidism is discussed later. Hypophosphatemia is also common in the early post-transplant period, particularly when allograft function is excellent. This is mainly due to excess urinary excretion of phosphate. This hyperphosphaturia has several causes: residual hyperparathyroidism, glucocorticoids, low vitamin D state (relative to the degree of hypophosphatemia), and a putative humoral factor, phosphatonin.[123] Rarely, phosphate depletion is severe enough to cause profound muscle weakness, including respiratory muscle weakness. Because a persistent negative phosphate balance probably contributes to post-transplant bone disease, attempts should be made to increase the plasma phosphate level to 2.5 to 4.0 mg/dL.[123] Treatment involves high-phosphate diet (e.g., low-fat dairy products), oral phosphate supplements, and vitamin D analogs.


Mild hyperkalemia is common, even with good allograft function. The principal cause is CNI-induced impairment of tubule potassium secretion. Hyperkalemia may be exacerbated by poor allograft function and ingestion of excess potassium (e.g., in phosphate compounds) and other medicines such as ACE-I and β-blockers. Because the hyperkalemia is usually not severe and improves with reduction in CNI dosage, treatment is often not required; exacerbating factors should be minimized.

Metabolic Acidosis

Mild metabolic acidosis is also common and often associated with hyperkalemia. In most cases, it has the features of a distal (hyperchloremic) renal tubular acidosis. This reflects tubule dysfunction caused by CNIs, rejection, or residual hyperparathyroidism. Oral bicarbonate is given in severe cases.

Other Electrolyte Abnormalities

Hypomagnesemia is common and due to a magnesuric effect of the CNIs. It is usually asymptomatic. Magnesium supplements are sometimes prescribed when the plasma magnesium level is less than 1.5 mg/dL. However, their effectiveness is limited, they can cause diarrhea, and they add more complexity to the multidrug regimen of the transplant recipient.

Bone Disorders after Renal Transplantation

Bone disease in the ESRD patient is multifactorial and involves varying degrees of hyperparathyroidism, vitamin D deficiency, slow turnover, aluminum intoxication, and amyloidosis (see Chapter 52 ). Successful renal transplantation offers the potential to reverse or at least prevent further progression of these conditions. Unfortunately, bone disease can remain a problem after transplantation owing to persistence of the conditions discussed earlier and to the superimposed effects of immunosuppressants on bone.


Hyperparathyroidism is very common in the first post-transplant year. Less obvious hyperparathyroidism may persist for years; one study found elevated serum PTH in 23 (54%) of 42 normocalcemic patients more than 2 years after transplant who had plasma creatinine levels less than 2 mg/dL.[124] Not surprisingly, the main risk factors for post-transplant hyperparathyroidism are the degree of pretransplant hyperparathyroidism and the duration of dialysis.[125]Inadequate vitamin D stores and poor allograft function probably contribute to persistence of the condition.

Typically, post-transplant hyperparathyroidism is manifest by a low plasma phosphate and a mild to moderate elevation in the plasma calcium. Serum PTH is inappropriately high for the level of plasma calcium. Post-transplant hyperparathyroidism is often asymptomatic and tends to improve with time. Therefore, in most cases, therapy involves cautious oral repletion of phosphate (see earlier) and administration of vitamin D analogs. Of course, vitamin D analogs must be used with caution and stopped if the plasma calcium exceeds 11.0 mg/dL or complications of hypercalcemia occur. Limited data on the use of cinacalcet in post-transplant hyperparathyroidism have been conflicting.[126] [127]

There are two main indications for post-transplant parathyroidectomy: (1) severe symptomatic hypercalcemia (usually in the early post-transplant period and now rare), and (2) persistent, moderately severe hypercalcemia for more than a year after transplantation). Subtotal parathyroidectomy is the procedure of choice.


The most important cause of hyperuricemia and gout after transplant is cyclosporine. Cyclosporine impairs renal uric acid clearance. Approximately 80% of cyclosporine-treated renal transplant recipients develop hyperuricemia, but only about 7% develop gout.[128]

Acute gout should be treated with colchicine or high-dose steroids; NSAIDs should generally be avoided. Colchicine-induced neuromyopathy is more common in cyclosporine-treated patients; therefore, lower doses should be used and patients should be monitored for muscle weakness and rising plasma CK. For prevention of further gouty attacks, either allopurinol or uricosuric drugs can be used (the latter only if GFR is greater than 30 mL/min). Note that the metabolism of azathioprine is greatly inhibited by allopurinol. If these drugs are coprescribed, the azathioprine dose should be reduced by 75% or more and the complete blood count closely monitored. A safer alternative is to change azathioprine to MMF; no adjustment of MMF is required. In cases of severe recurrent gout, it may be worthwhile switching cyclosporine to tacrolimus or stopping CNIs altogether. Readers are directed to a recent review for further information.[129]

Calcineurin Inhibitor-Associated Bone Pain

A syndrome of severe bone pain in the lower limbs has been associated with CNI use. This is uncommon and thought to represent a vasomotor effect of the CNIs. Osteonecrosis and other common bone lesions should be excluded before the diagnosis is made. Symptoms usually respond to reduction in CNI dosage and administration of calcium channel blockers. Magnetic resonance imaging (MRI) of the involved bones may show bone marrow edema.[130]


Osteonecrosis (avascular necrosis) is a serious bone complication of renal transplantation. The pathogenesis is not well understood, but high doses of steroids are one risk factor. Up to 8% of renal transplant patients develop osteonecrosis of the hips[131]; this figure may be falling with lower dose steroid protocols. The most commonly affected site is the femoral head; other sites are the humeral head, femoral condyles, proximal tibia, vertebrae, and small bones of the hand and foot. Many patients have bilateral involvement at the time of diagnosis. The principal symptom is pain; signs are nonspecific. Diagnosis is made by imaging studies; MRI is the most sensitive, plain radiography is the least sensitive, and scintigraphy is intermediate. However, MRI abnormalities do not always imply clinically significant osteonecrosis. Treatment remains controversial. Options include resting the joint, decompression, or joint replacement.


Osteoporosis is a common bone disorder (greatly trumpeted by the pharmaceutical industry) characterized by a parallel reduction in bone mineral and bone matrix so that bone mass is decreased but is of normal composition. The most commonly used definition is that based on the World Health Organization scoring system. Osteoporosis is defined as bone density greater than 2.5SD below the mean of sex-matched, young adults (T score); osteopenia, as 1.0 to 2.5SD below the T score. The greater the reduction in bone density in the nontransplant population, the greater is the risk of fracture.

Reduction in bone mineral density is now recognized as a very common complication of solid-organ transplantation. The pathophysiology and treatment of osteoporosis may differ from those seen in the nontransplant population. Most of the bone loss occurs in the first 6 months after transplant. The principal cause is steroids through direct inhibition of osteoblastogenesis, induction of apoptosis in bone cells, inhibition of sex hormone production (in both men and women), decreased gut calcium absorption, and increased urinary calcium excretion.[132] Other factors that may play a role include ongoing hyperparathyroidism, vitamin D deficiency or resistance, and phosphate depletion. Diabetes mellitus is associated with an increased risk of post-transplant fracture. The estimated total fracture rate in nondiabetic patients after renal transplantation is 2% per year, in pre-existing diabetics 5% per year, and in pancreas-kidney recipients up to 12% per year.[133]

Low bone mineral density is presumed to be a risk factor for fracture in renal transplant recipients; this has not yet been proven. In fact, limited evidence suggests that DEXA-identified low bone mineral density is not a risk factor for future fracture.[134] Furthermore, unlike nontransplant osteoporotic patients, fractures of the appendicular rather than vertebral skeleton are relatively more common.[133] Therefore, it is difficult to extrapolate from the general literature to renal transplant recipients. A recent meta-analysis reported no reduction of fracture risk with any therapy.[135] Generally accepted therapies to minimize bone loss in renal transplantation include weight-bearing exercise, steroid minimization, elemental calcium greater than 1000 mg/day and calcitriol. Any interventions to minimize post-transplant bone loss must occur in the first 3 to 6 months. The risks versus benefits of bisphosphonates in renal transplant recipients are still debated.

Post-transplant Diabetes Mellitus

Unfortunately, new-onset diabetes mellitus is common after renal transplantation. Risk factors include older age, obesity, positive hepatitis C antibody status, nonwhite ethnicity, family history, deceased donor allograft, steroids, CNIs (especially tacrolimus) and episodes of acute rejection. Strategies to prevent and treat new-onset diabetes mellitus include steroid minimization, avoidance of tacrolimus, and lifestyle modification.[91] Oral hypoglycemic drugs or insulin is frequently used. Metformin is probably the drug of choice in those with adequate GFR because it is the most effective in reducing complications of type 2 diabetes mellitus.[136]

Cardiovascular Disease

Death with a functioning allograft is the most common cause of early and late allograft loss. Data from both US and European registries show that the leading cause of death is cardiovascular disease (30% to 40% of cases).[29]Similar to chronic kidney disease (CKD) of the native kidneys, impaired kidney function is a strong and independent risk factor for cardiovascular disease and mortality.[137] The cumulative incidence of coronary heart disease, cerebrovascular disease and peripheral vascular disease at 15 years after transplant has been estimated at 23%, 15%, and 15%, respectively.[138] Congestive heart failure is also common. Risk factors for the high incidence of these conditions are probably multiple: first, traditional ones such as smoking, hypertension, diabetes mellitus, and second, uremic factors such as anemia, hyperphosphatemia, and chronic fluid overload. Addressing these mechanisms must now be an important component of standard management. Tobacco smoking should be strongly discouraged; there is growing evidence that it affects allograft function as well as recipient survival.[139] Conversion of cyclosporine to tacrolimus may improve risk factors for cardiovascular disease.[140] Aspirin should be considered for primary prevention.[141] Note that although the burden of cardiovascular disease is high after transplantation, transplantation may still reduce that burden compared to dialysis.


The prevalence of hypertension in the CNI era is at least 60% to 80%.[138] Causes include steroids, CNIs, weight gain, allograft dysfunction, native kidney disease, and transplant renal artery stenosis. The complications of post-transplant hypertension are presumed to be a heightened risk of cardiovascular disease and allograft failure. Hypertension should be aggressively managed in all patients. Joint National Commission (JNC) VII guidelines are a useful aid in this regard; the target blood pressure should be less than 130/80.[142] Nonpharmacologic measures such as weight loss, reduced sodium intake, reduced alcohol intake, and increased exercise should be encouraged. The dosage of steroids and CNIs should be minimized. Antihypertensive drug therapy is still required in most cases. Again, applying JNC VII guidelines, therapy should be started with one agent and the dose titrated up as needed; long-acting formulations are preferable; and diuretics should always be considered because they enhance the effects of other drugs. Table 65-13 shows the antihypertensive drugs commonly used in the post-transplant setting.

TABLE 65-13   -- Commonly Used Antihypertensive Drugs in Renal Transplant Recipients




β- blockers

Additional benefits in those with CAD or CHF; cheap

May exacerbate hyperkalemia; some studies suggest they should not be first-line therapy for hypertension

Loop diuretics

Treat hypervolemia; potentiate effects of other agents

Risk of hypovolemia, increased creatinine

Thiazide diuretics

Well proven to reduce complications of hypertension; cheap; potentiate effects of other agents

Risk of hypovolemia, increased creatinine; worsen hyperuricemia


Reduce proteinuria; many beneficial cardiovascular effects; possibly slow progression of allograft dysfunction

Risk of hyperkalemia, increased creatinine, anemia

Calcium channel blockers

Well tolerated; some studies suggest better allograft function in setting of cysclosporine/tacrolimus

Leg edema; diltiazem and verapamil impair metabolism of cysclosporine/tacrolimus


ACE-I, angiostensin-converting enzyme inhibitor; ARBs, angiotensin receptor blockers; CAD, coronary artery disease; CHF, congestive heart failure.





The prevalence of hypercholesterolemia and hypertriglyceridemia after transplant is very high.[141] Steroids, CNIs (cyclosporine more than tacrolimus), and sirolimus are the principal causes. Some studies suggest that hyperlipidemia is associated with poorer allograft outcomes, although no cause-and-effect relationship has been established. Because cardiovascular disease is so common after transplant, it seems reasonable to use National Cholesterol Education Program guidelines for management. [141] [143] If one considers the renal transplant state as a coronary heart disease risk equivalent, then the target low-density lipoprotein cholesterol should be less than 100 mg/dL (or perhaps less than 70 mg/dL).[144]

Initial therapy includes weight loss, more physical activity, low cholesterol, and low saturated fat diet. Minimizing steroid dosage and switching cyclosporine to tacrolimus are also worthwhile. Many patients still require pharmacologic treatment to achieve target lipid values; usually statins are used. The main randomized controlled trial of statin therapy in renal transplant recipients showed no benefit in the primary outcome (composite of cardiac death, nonfatal myocardial infarction or coronary intervention procedure).[145] The issue of statin toxicity has been discussed earlier.


As in the general population, hyperhomocysteinemia has been proposed as a risk factor for cardiovascular disease in renal transplant recipients. Plasma homocysteine concentrations typically fall after transplant but do not normalize. Based on the results of recent, well-performed trials in the general population, interventions to lower homocysteine cannot be recommended at this time.[146]

Cancer after Renal Transplantation

Data on occurrence of cancer after transplant are derived mainly from the Israel Penn International Transplant Tumor Registry (IPITTR) and the Australia-New Zealand Dialysis and Transplantation (ANZDATA) Registry. [147] [148]These data clearly show that the overall incidence of cancer in renal transplant recipients is greater than in dialysis patients and the general population. This increase in incidence applies to many cancers but the effect is dramatic for certain ones ( Table 65-14 ).[149]

TABLE 65-14   -- Risk of Malignancies in Renal Transplant Recipients Compared with the General Population

Type of Cancer

Approximate Relative Risk

Common cancers including colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast


Testicular and bladder cancer


Melanoma, leukemia, hepatobiliary, cervical and vulvovaginal cancers


Renal cell cancer


Non-melanoma skin cancers, Kaposi sarcoma, and non-Hodgkin lymphomas


Adapted from Australia and New Zealand Dialysis and Transplant Registry.



There are several reasons why reported cancer incidence is increased. First, immunosuppression inhibits normal tumor surveillance mechanisms, allowing unchecked proliferation of “spontaneously occurring” neoplastic cells. There is also experimental evidence that cyclosporine has tumor-promoting effects mediated by its effects on TGF-β production.[150] Second, immunosuppression allows uncontrolled proliferation of oncogenic viruses ( Table 65-15 ). Third, factors related to the primary renal disease (analgesic abuse, certain herbal preparations, HBV or HCV infection) or the ESRD milieu (acquired renal cystic disease) may promote neoplasia.

TABLE 65-15   -- Viral Infections Associated with Development of Cancers in Renal Transplant Patients




Hepatocellular cancer


Hepatocellular cancer




Squamous cell cancers of anogenital area and of mouth


Kaposi's sarcoma


HBV, hepatitis B virus; HCV, hepatitis C virus; EBV, Ebstein-Barr virus; HPV, human papillomavirus; HHV-8, human herpes virus-8, PTLD, post-transplant lymphoproliferative disorder.




It is believed that the cumulative amount of immunosuppression rather than a specific drug is the most important factor increasing the cancer risk. However, there is evidence that the routine use of CNIs has increased the risk of skin cancers[151]; fortunately, these are usually not fatal. The long-term impact of currently employed powerful immunosuppression regimens on cancer incidence is unknown, but it is certainly of concern. The single most important measure to prevent cancers is to minimize excess immunosuppression. A general rule is that when cancer occurs, immunosuppression should be greatly decreased. In some cases, rejection of the allograft may result, but the risks and benefits of immunosuppression must be judged on a case-by-case basis.

There is now accumulating evidence that sirolimus has antineoplastic effects,[25] and it is commonly used in recipients who develop cancer.

Skin and Lip Cancers

Squamous cell carcinoma, basal cell carcinoma, and malignant melanoma are all more common in renal transplant patients. Thirty years after transplant, an estimated 70% of Australian patients will have developed skin cancer.[152]Risk factors include time after transplant, cumulative immunosuppressive dose, exposure to ultraviolet light, fair skin, and human papillomavirus infection. Primary and secondary prevention is important: Patients should be specifically counseled on minimizing exposure to ultraviolet light and to self-screen for skin lesions. Retinoids are sometimes used in high-risk patients.[153] Suspicious skin lesions should be surgically excised.

Anogenital Cancers

Cancers of the vulva, uterine cervix, penis, scrotum, anus, and perianal region are significantly more common. Furthermore, these cancers tend to be multifocal and more aggressive than in the general population. Infection with certain human papillomavirus strains is an important risk factor. Secondary prevention measures include yearly physical examination of the anogenital area and, in women, yearly pelvic examinations, and cervical histology. Suspicious lesions should be excised, and patients should be closely followed for recurrence.

Kaposi's Sarcoma

The incidence of Kaposi's sarcoma in both transplant and nontransplant patients depends greatly on ethnic background. Those of Jewish, Arab, and Mediterranean ancestry are at much greater risk. Other risk factors are cumulative immunosuppressive dose and human herpes virus-8 infection. Visceral (lymph nodes, lungs, gastrointestinal tract) and nonvisceral (skin, conjunctivae, oropharynx) involvement may occur. The prognosis for the former is poor, but for the latter it is good. Treatment involves various combinations of surgical excision, radiotherapy, chemotherapy and immunotherapy. Immunosuppression, of course, should be reduced or modified.[25]

Post-transplant Lymphoproliferative Disorder

Post-transplant lymphoproliferative disorder (PTLD) is one of the most feared complications of transplantation because it can occur early after transplant and it carries a high morbidity and mortality. The cumulative incidence in renal transplant patients overall is 1% to 2%.[154] More than 90% are non-Hodgkin's lymphomas, and most are of recipient B cell origin.[154] Most cases of PTLD occur in the first 24 months after transplant. Risk factors include (1) Epstein-Barr virus (EBV)–positive donor and EBV-negative recipient; (2) CMV-positive donor and CMV-negative recipient; (3) pediatric recipient (in part because children are more likely to be EBV negative); and (4) aggressive immunosuppression, especially with OKT3/polyclonals or tacrolimus.[155]

Important in the pathogenesis of PTLD is the infection and transformation of B cells by EBV; transformed B cells undergo proliferation that is initially polyclonal, but a malignant clone may evolve. Thus, the clinical and histologic spectrum of PTLD at presentation and its treatment can vary greatly ( Table 65-16 ). Extranodal, gastrointestinal tract, and central nervous system involvement is more common than in nontransplant lymphomas. The renal allograft may be involved. Treatment is summarized in Table 65-16 . Rituximab is being increasingly used because of its good therapeutic index.

TABLE 65-16   -- Clinical and Pathologic Spectrum of PTLD and Summary of its Management


Early Disease (50%)

Polymorphic PTLD (30%)

Monoclonal PTLD (20%)

Clinical features

Infectious mononucleosis-type illness

Infectious mononucleosis type illness +/- weight loss, localizing symptoms

Fever, weight loss, localizing symptoms


Preserved architecture; atypical cells infrequent


High-grade lymphoma with confluent transformed cells and marked atypia



Usually polyclonal



Reduce immunosuppression; acyclovir

Reduce immunosuppression; acyclovir; rituximab, if poor response then treat as here

Reduce immunosuppression to low-dose steroids only; combination surgery, chemotherapy, radiotherapy, immunotherapy, rituximab.






PTLD, post-transplant lymphoproliferative disorder.





Patients with cancer or those at high risk of cancer should be identified in the pretransplant evaluation (see Chapter 64 ). Excess immunosuppression should be avoided in all patients. Standard primary and secondary preventive strategies (e.g., smoking cessation, cervical smear, mammogram, colonoscopy) should be applied in all patients. If cancer occurs, immunosuppression should be greatly reduced.

Infectious Complications of Renal Transplantation

The transplant procedure itself and subsequent immunosuppression increase the risk of serious infection. The principal factors determining the type and severity of infection are the intensity of epidemiologic exposure (in the hospital and community) to potential pathogens and the overall state of immunosuppression.[156] Factors affecting the net state of immunosuppression are shown in Table 65-17 .

TABLE 65-17   -- Factors Affecting the Net State of Immunosuppression

Immunosuppressive agents: dose, type, duration

Comorbidities (diabetes mellitus, urinary tract abnormalities)

Infection with viruses which affect immune system: CMV, HIV, HCV

Integrity of mucocutaneous barriers

Adapted from Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 338:1741–1751, 1998.

CMV, cytomegalovirus; HCV, heptatitis C virus; HIV, human immunodeficiency virus.





As outlined by Fishman and Rubin,[156] the patterns of infection after renal transplantation can be roughly divided into three time periods: 0 to 1 month, 1 to 6 months, and more than 6 months after transplant. These divisions of time serve as guidelines only. Maintenance immunosuppressive regimens are becoming more powerful, and more elderly patients are undergoing transplant surgery; on the other hand, antimicrobial prophylaxis is becoming more effective.

A general point is that at any time when life-threatening infection occurs, immunosuppression should be reduced to an absolute minimum or stopped altogether (so-called stress-dose steroids often are required). Early aggressive diagnosis (e.g., bronchoscopy in patients with pneumonitis) and therapy are essential.[156]

Infections in the First Month

The majority of infections in the first month are standard infections, as would be seen in nontransplant patients after surgery. Thus, infections of surgical wounds, the lungs, and the urinary tract, and infections related to vascular catheters predominate. Bacterial infections are much more common than fungal ones. Preventive measures include ensuring that donor and recipient are free of overt infection before transplant, good surgical technique, and SMX-TMP prophylaxis to prevent UTIs.

Infections from 1 to 6 Months after Transplant

Weeks of intensive immunosuppression now increase the risk of opportunistic infections. Infections with CMV, EBV, Listeria monocytogenes, Pneumocystis carinii, and Nocardia spp. are relatively common. Preventive measures include antiviral prophylaxis (for 3 to 6 months) and SMX-TMP prophylaxis (for 6 to 12 months).

Infections More than 6 Months after Transplant

With gradual reduction in immunosuppression, the risk of infection long-term usually diminishes. However, patients can be roughly divided into two groups based on risk. Group 1 patients (those with good ongoing allograft function and no need for late supplemental immunosuppression) rarely develop opportunistic infections unless exposure is intense (e.g., to Nocardia spp. from soil). Infection risk is similar to the background nontransplant population. Group 2 patients (those with poor allograft function) remain at risk for opportunistic infection. This probably reflects both poor allograft function and that many of these patients have received large cumulative doses of immunosuppression. Thus, the latter group should stay on long-term prophylaxis with SMX-TMP.[156]

Late amplification of immunosuppression may increase the risk of opportunistic infection in any patient. Therefore, any patient receiving a “late” steroid pulse or OKT3/polyclonal therapy should be restarted on SMX-TMP +/- anti-CMV prophylaxis (if donor or recipient were CMV positive). The role of EBV infection in causing PTLD has been discussed earlier; CMV and P. carinii pneumonia infection are discussed later.


Exposure to CMV (as evidenced by the presence in serum of anti-CMV IgG) increases with age; more than two thirds of adult donors and recipients are latently infected before renal transplantation. CMV infection after transplantation is taken to mean that there is only laboratory evidence of recent CMV exposure (e.g., a rise in IgG titers or demonstration of CMV in body fluids). Infection may arise from (1) reactivation of latent recipient virus, (2) primary infection with donor-derived virus (transmitted in the allograft or less commonly via blood products) or (3) reactivation of latent donor-derived virus. CMV disease means that there is infection with symptoms or with evidence of tissue invasion, or both. The risk of CMV infection or disease is highest in CMV-positive donor/CMV-negative recipient pairings, followed by CMV-positive donor/CMV-positive recipient pairings and then CMV-negative donor/CMV-positive recipient pairings. The risk is lowest with CMV-negative donor/CMV-negative recipient pairings. OKT3/polyclonal antibody therapy, particularly when prescribed for treatment of rejection, significantly increases the risk of subsequent CMV disease.

CMV disease usually arises 1 to 6 months after transplantation, although gastrointestinal and retinal involvement often occur later. Typical clinical features are fever, malaise, and leukopenia; there may be symptomatic or laboratory evidence of specific organ involvement ( Table 65-18 ). Urgent investigation and immediate empiric treatment are needed in severe cases. Confirmation of presumed CMV disease is by demonstration of the virus in body fluids or solid organs. Detection of CMV in blood or tissue fluids is best achieved by antigenemia or molecular assays. Low or negative CMV concentrations in peripheral blood do not exclude organ involvement (especially of the gastrointestinal tract); procedures such as bronchoscopy and endoscopy should be aggressively pursued according to symptoms and signs. The virus is best identified in involved tissue by immunohistochemistry techniques. A “tissue diagnosis” is also required to exclude coinfection with other microbes such as P. carinii. In addition to its direct effects, CMV may have indirect effects after transplant: increase risk of infection, rejection and PTLD.[157]

TABLE 65-18   -- Manifestations of CMV Disease in the Renal Transplant Recipient

Tissue Affected

Clinical Features



Fever, malaise, myalgia

Nonspecific but very important clue to CMV disease

Bone marrow


Usually not severe; reduce azathioprine or MMF. Valganciclovir can also cause leukopenia



May be life-threatening; exclude coinfection with other organisms

GI tract

Inflammation and ulceration of esophagus or colon

May be life-threatening; often occurs late



Rarely severe

Eyes (retina)

Blurred vision, flashes, floaters

Rare in renal transplants; if occurs, usually late


CMV, cytomegalovirus; GI, gastrointestinal; MMF, mycophenolate mofetil.




CMV disease should be treated with reduction in immunosuppression and intravenous antiviral therapy for 2 to 3 weeks (if infection is severe), followed by oral antiviral therapy for 3 to 6 months.[157] The agents of choice for IV and oral (PO) treatment are ganciclovir and valganciclovir, respectively. Dose adjustment of both are required in renal dysfunction. Intravenous antiviral therapy should not be stopped until there is clinical improvement and documented clearance of viral antigen from peripheral blood. Although supportive data are unavailable, it is reasonable to add CMV hyperimmune globulin in severe cases.[158] Because of its nephrotoxicity, foscarnet should only be used in the rare CMV-resistant cases.

The prevention of CMV disease is of great clinical importance. One strategy is to give prophylaxis to all patients at risk, that is, when the donor or recipient is CMV positive. Another strategy is to monitor recipients and begin prophylaxis only when there is evidence of active viral replication.[157] Disadvantages of universal prophylaxis include high expense and leukopenia (common with valganciclovir); advantages include simplicity and perhaps better prevention of other viral infections. If antiviral prophylaxis is being used, valganciclovir is often prescribed; it is very expensive, however. One randomized, controlled trial found valacyclovir to be effective in preventing CMV disease.[159]


Antimicrobial prophylaxis is very effective in preventing pneumonia due to P. carinii. The preventive agent of choice is SMX-TMP: It is cheap and generally well tolerated; furthermore, it prevents UTIs and opportunistic infections such as nocardiosis, toxoplasmosis, and listeriosis. Alternative preventive agents include dapsone and pyrimethamine, atovaquone, and aerosolized pentamadine.[160] Typical symptoms of pneumonia due to P. carinii are fever, shortness of breath, and cough. Chest radiography characteristically shows bilateral interstitial-alveolar infiltrates. Diagnosis requires detection of the organism in a clinical specimen by colorimetric or immunofluorescent stains. Because the organism burden is usually lower than in human immunodeficiency virus (HIV)–infected patients, the sensitivity of induced sputum or bronchoalveolar lavage specimens is lower in renal transplant recipients; tissue should be quickly obtained if these tests are negative and the clinical suspicion remains high.

The treatment of choice remains SMX-TMP.[160] High-dose SMX-TMP may increase the plasma creatinine without affecting GFR. There is no firm evidence to support the use of higher dose steroids during the early treatment phase of pneumocystosis in renal transplant recipients.

Immunization in Renal Transplant Recipients

Important general rules concerning immunization in renal transplant patients are the following: (1) Immunizations should be completed at least 4 weeks before transplantation; (2) immunization should be avoided in the first 6 months after transplant because of ongoing high doses of immunosuppression and a risk of provoking allograft dysfunction; and (3) live vaccines are generally contraindicated after transplantation. A comprehensive review of this issue has recently been published.[161] Household contacts of transplant recipients should receive yearly immunization against influenza.


Infections are a predictable complication of renal transplantation. Minimizing infections requires meticulous surgical technique, antiviral prophylaxis for the first 3 to 6 months, SMX-TMP prophylaxis for the first 6 to 12 months and, of course, avoidance of excess immunosuppression. A substantial increase in immunosuppression, no matter what the time period after transplant, should trigger resumption of SMX-TMP and probably antiviral prophylaxis.


Transplantation in Diabetics

The survival rate of diabetic patients after renal transplantation is lower than that of nondiabetic patients. Their survival, however, is still significantly improved by transplantation as compared with staying on dialysis.[94]Cardiovascular disease is highly prevalent in the diabetic ESRD population and should be aggressively treated. A subset of diabetic ESRD patients is also suitable for kidney-pancreas transplantation (see the following discussion).

Kidney-Pancreas Transplantation

The two main goals of transplanting whole pancreas allografts are to (1) allow freedom from insulin therapy and the metabolic derangements of type I diabetes mellitus and (2) potentially slow or reverse the progression of end-organ damage from this condition. Transplantation of solid pancreas allografts is somewhat technically difficult, and the recipient is exposed to relatively high levels of immunosuppression. Thus, patients must be carefully selected for this procedure. For diabetic ESRD patients deemed suitable candidates for kidney plus pancreas transplantation, two main options are currently available: simultaneous kidney and pancreas (SPK) transplantation or pancreas after kidney (PAK) transplantation (the latter allows living donor kidney transplantation). In contrast to SPK transplantation, there is some concern as to whether pancreas transplant alone/later improves patient survival. However, PAK transplantation offers the advantages of preemptive living donor kidney transplantation and better renal allograft outcomes.

Complications of pancreatic transplantation include thrombosis, infection, rejection. and problems related to drainage of the exocrine secretions. Safe drainage of the exocrine secretions is vital. Drainage of exocrine secretions into the bladder affords the advantages of sterility and of serial measurement of urinary amylase concentrations that can aid in early detection of pancreatic allograft dysfunction. Important disadvantages include severe cystitis, hypovolemia, and acidosis (the last two due to large losses of bicarbonate-rich fluid). Because rates of technical complications from enteric drainage have decreased, this technique is becoming more popular.[162]

Rates of DGF in kidney-pancreas transplantation have been relatively low, probably reflecting donor and recipient selection factors. In contrast, rates of acute renal allograft rejection have generally been higher. The latter finding may reflect the greater antigen “load” of two transplanted organs and a lower threshold for diagnosing acute rejection. In general, immunosuppression tends to be more intense than for kidney-alone transplantation.

There is evidence that, in selected patients, overall and cardiovascular mortality are reduced with combined kidney-pancreas transplantation compared with transplantation of the kidney alone. [163] [164] There are no randomized, controlled trials of the effects of also transplanting the pancreas allograft on reversing or halting the complications of diabetes mellitus. Overall, some benefit is likely.[165]

Injection of isolated pancreatic islet allograft tissue into the portal venous system can potentially avoid many of the technical problems associated with whole-organ transplantation. Shapiro and colleagues[166] reported excellent outcomes using a nonsteroid regimen of daclizumab, tacrolimus, and sirolimus, but duplicating these results has proven difficult, probably because of difficulty in transplanting sufficient numbers of viable islet cells and because of the vulnerability of islets to recurrent autoimmunity, rejection, and other damage. Recent guidelines recommend that islet transplantation only be performed in the context of a controlled trial.[167]

Renal Transplantation in Patients with Human Immunodeficiency Virus Infection

Until recently, HIV infection was considered an absolute contraindication to renal transplantation. This reflected fears that immunosuppression would promote severe infections and that the short survival of HIV-positive patients undergoing transplant surgery would waste valuable allografts. With dramatic improvements in the survival of HIV-positive patients, these premises are being re-examined.[168] Relatively good allograft and recipient survival has been reported.[169] These patients should be referred to centers specializing in the management of transplanted HIV-positive patients because their management is complex. One difficulty is the potential for interactions between the multiple antiviral medicines, some of which inhibit and some of which induce the cytochrome P450 system.[71]

Pregnancy in the Renal Transplant Recipient

Female and male fertility improves after successful renal transplantation. Pregnancy is generally considered safe for the mother, fetus, and renal allograft if the following criteria are met before conception: good general health for more than 18 months before conception, stable allograft function with a plasma creatinine level less than 2.0 mg/dL (preferably less than 1.5 mg/dL), minimal hypertension, minimal proteinuria, immunosuppression at maintenance doses, and no dilation of the pelvicalyceal system on recent imaging studies. Of course, some pregnancies occur in less optimal conditions where the risk of permanent allograft damage will be higher.

The National Transplantation Pregnancy Registry is a useful source of information regarding pregnancy outcomes in renal transplant recipients.[170] The latest data show that hypertension occurs in approximately 63% of cases and preeclampsia in 30%. UTIs and asymptomatic bacteruria are also common. At least 20% of pregnancies are lost in the first trimester due to spontaneous or therapeutic abortion, but most of the remainder result in live birth. Prematurity and low birth weight are common. Data on allograft function are overall reassuring. However, the average plasma creatinine does increase slightly (≈0.2 mg/dL) after pregnancy. It is possible that pregnancy may affect long-term allograft function by accentuating nephron hyperfiltration and overwork, but this has proved difficult to assess.

All pregnant renal allograft recipients should be managed as high-risk obstetric cases with nephrology involvement. Throughout the pregnancy, regular monitoring of blood pressure, proteinuria, renal function, and urine cultures is advised. Significant renal dysfunction occurs in a minority of cases; the principal causes are severe preeclampsia, acute rejection, acute pyelonephritis, and recurrent glomerulonephritis. Distinguishing these causes clinically may be difficult. Initial investigations should include plasma creatinine, creatinine clearance, 24-hour urinary protein excretion, urine microscopy, urine culture, and renal ultrasound. Acute rejection should be confirmed by allograft biopsy before instituting antirejection therapy. Pulse steroids are used to treat rejection.

There are no transplant-specific reasons to perform cesarean section; if it is performed (for obstetric reasons), care should be taken to avoid damaging the transplant ureter. Renal function should be monitored closely for 3 months post-partum because of the increased risk of HUS and possibly acute rejection.

Short-term and long-term data indicate that children born to transplant recipients using cyclosporine, steroids, or azathioprine do not have a significant increase in morbidity. Short-term data on tacrolimus are similarly reassuring. Dosages of cyclosporine and tacrolimus may need to be increased to maintain pre-pregnancy trough concentrations. Because MMF is teratogenic in animals, it should not be used in women contemplating pregnancy. Nevertheless, successful outcomes have been reported.[170] Sirolimus should also be avoided. Limited data regarding paternal use of cyclosporine, steroids, azathioprine, tacrolimus, and MMF are reassuring.

Surgery in the Renal Transplant Recipient

Allograft Nephrectomy

Allograft nephrectomy is not commonly required. Indications include (1) allograft failure with ongoing symptomatic rejection causing fever, malaise, and graft pain; (2) infarction due to thrombosis; (3) severe infection of the allograft such as emphysematous pyelonephritis; and (4) allograft rupture. The morbidity associated with allograft nephrectomy is relatively high. Ongoing rejection in a failed allograft can sometimes be controlled with steroids, but prolonged immunosuppression of a patient who is on dialysis is obviously not ideal. Rejection in this context is less likely to be controlled by small doses of steroids when it is acute and when the transplant is recent.

Nontransplant-Related Surgery or Hospitalization

Over time, many renal transplant recipients undergo nontransplant surgery or are hospitalized for nontransplant reasons. Common-sense measures such as maintenance of adequate volume status, avoidance of nephrotoxic medicines (including NSAIDs), and proper dosing of immunosuppressive drugs are usually all that are required to prevent dysf unction of the allograft. Whenever possible, immunosuppressive drugs should be given by the enteral route; if this is not possible, a regimen of intravenous steroids and intravenous CNIs usually suffices. A simple way to dose intravenous steroids is to prescribe the same milligram-for-milligram dose of intravenous methylprednisolone as the maintenance prednisone dose; supplemental stress-dose hydrocortisone is then prescribed separately. Intravenous cyclosporine should be prescribed in slow infusion form at one third of the total daily oral dose, and intravenous tacrolimus should be at one fifth of the total daily dose.

The Patient with the Failing Kidney

As for native CKD, management of anemia, hyperparathyroidism, hypertension, preparation for dialysis, and creation of appropriate dialysis access are important. If there are no contraindications (see Chapter 64 ), patients can be listed again for another transplant. The waiting time for may be prolonged, however, because of sensitization to HLA antigens.


Major areas of ongoing investigation include expansion of the donor pool, optimization of immunosuppression regimens (with particular focus on individualizing immunosuppression), and induction of tolerance and xenotransplantation. There is also growing interest in therapies that modulate B cell and plasma cell function, thus preventing or treating AMR. Some of these topics are discussed in greater detail in Chapters 63 , 66 , and 67 .


Improvements in short- and (to some extent) long-term renal allograft survival have been encouraging. This reflects multiple influences, including more effective immunosuppression, more use of living donors, and better medical and surgical care. The focus is likely to shift somewhat toward improving other post-transplant outcomes such as complications of immunosuppression, chronic allograft dysfunction, and morbidity from cardiovascular disease. Availability of adequate numbers of organs for transplantation remains an ongoing problem.


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