Kidney Transplantation 

Updated: Oct 17, 2019
Author: Bradley H Collins, MD; Chief Editor: Ron Shapiro, MD 

Overview

Background

Kidney transplantation is the treatment of choice for a minority of patients with end-stage renal disease (ESRD). Most adult patients with ESRD are never referred for evaluation for transplantation, and have a 70% 5-year mortality on dialysis. Marked improvements in early graft survival and long-term graft function have made kidney transplantation a more cost-effective alternative to dialysis.

Since 1988, over 455,000 kidney transplants have been performed in the United States.[1]  During 2018, a record number of kidney transplants were performed in the US, including 21,167 kidney-alone and 836 kidney plus at least one additional organ. Of those transplants, 6442 were identified as originating from living-donors (29.3%) and 15,561 (70.7%) from deceased-donors.[2] In 2017, more than 220,000 patients were alive and with a functioning transplanted kidney; currently, more than 90,000 adult patients are waiting for kidney transplants.[3]

Before the advent of immunosuppression, kidney transplantation was limited to identical twins and was not applicable to the vast majority of patients with ESRD. The introduction of combined azathioprine-steroid therapy in 1963 produced encouraging results and became the mainstay of immunosuppression. Although this therapy improved the results of transplantation, acute rejection and complications associated with steroid therapy persisted.

The introduction of cyclosporine in 1983 significantly improved the outcomes of all solid-organ transplants by reducing the risk of rejection. Further innovations, including anti–T cell antibodies (both monoclonal and polyclonal preparations), as well as other maintenance immunosuppressants (eg, tacrolimus, mycophenolate, sirolimus), have made a significant impact on both patient and graft survival. Currently, 1-year patient and graft survival rates exceed 90% in most transplant centers.

For patient education information, see Kidney Transplant and the Mayo Clinic's kidney transplant information Web page.

Indications

Indications for kidney transplantation include chronic kidney disease (CKD) and renal tumors. Studies show that kidney transplantation prolongs patient lifespan compared with dialysis. Although perhaps only 25% of adult patients on dialysis are being referred for transplant evaluation (probably 95% of pediatric patients with ESRD will be referred), the number of potential candidates has resulted in burgeoning waitlists and longer waiting times for patients in need of kidney transplants.  See Tables 1 through 4, below.

Table 1. Demographics of adult patients on the waiting list for kidney transplants, United States, 2016 [3] (Open Table in a new window)

Patient Characteristic

Number of Patients

Percentage

Age 18-34 y

8018

8.4

Age 35-49 y

23,691

24.8

Age 50-64 y

42,254

44.3

Age ≥ 65-74 y

21,493

22.5

Male

58,072

60.8

Female

37,384

39.2

White

34,745

36.4

Black

31,692

33.2

Hispanic

18,990

19.9

Asian

8505

8.9

Table 2. Primary causes of ESRD in adult patients on the kidney transplant waiting list: United States, 2016 [3] (Open Table in a new window)

Cause of ESRD

Number of Patients

Percentage

Diabetes

34,811

36.5

Hypertension

22,301

23.4

Glomerulonephritis

13,320

14.0

Cystic kidney

8106

8.5

Other or unknown cause

16918

17.7

ESRD = End-stage renal disease

 

 

Table 3. Demographics of pediatric patients awaiting kidney transplant: United States, 2016 [3] (Open Table in a new window)

Patient Characteristic

Percentage

Age < 1 y

0.2

Age 1-5 y

21.9

Age 6-10 y

18.8

Age 11-17 y

59.0

White

50.0

Black

18.7

Hispanic

23.9

Asian

4,8

Other or unknown

2.6

Table 4. Primary causes of end-stage renal disease (ESRD) in pediatric patients on the kidney transplant waiting list: United States, 2016 [3] (Open Table in a new window)

Cause of Renal Failure

Percentage

Focal segmental glomerulosclerosis

9.9

Glomerulonephritis

7.1

Congenital anomalies

37.3

Other or unknown

45.7

A resurgence of interest in living donation, possibly stimulated by the introduction of laparoscopic donor nephrectomy in 1994, has led to a substantial growth in the number of living-donor transplants, which is also associated with improved outcomes and significantly shorter waiting times.[4]   However, the rate of living-donor transplants began to decline in 2004 and has reached a plateau representing approximately 30% of all kidney transplantations.[2]

Some conditions may recur in the transplanted kidney, including immunoglobulin A (IgA) nephropathy, certain glomerulonephritides, oxalosis, and diabetes. Generally, the rate of recurrence is low enough to justify transplantation.

In some patients, kidney transplantation alone is not optimal treatment. Combined kidney-pancreas transplantation is the treatment of choice for patients who have type 1 diabetes and ESRD. Candidates for this combined procedure are typically younger than 50 years and do not have significant coronary artery disease (CAD).  At present, pancreas graft survival is worse in recipients of pancreas-after-kidney transplants than in recipients of simultaneous kidney-pancreas transplants; however, this is more than offset by the reduced waiting time, better overall patient survival, and better renal allograft survival that living-donor kidney transplantation affords; thus, for diabetic patients with living donors, living-donor kidney transplantation followed by pancreas-after-kidney transplantation is a reasonable option. Combined kidney-pancreas transplantation is covered in greater detail elsewhere (see Kidney-Pancreas Transplantation).

The treatment of oxalosis is controversial. In some cases, kidney transplantation in conjunction with pyridoxine therapy can produce good results, but combined liver-kidney transplantation is generally preferred; in some patients, staged liver-kidney transplantation may be preferable. Hemolytic-uremic syndrome (HUS), a not uncommon cause of renal failure in children, may recur after transplantation in response to cyclosporine-based or tacrolimus-based immunosuppression. Renal tumors (eg, Wilms tumor in children or renal cell carcinoma in adults) can be treated with transplantation. A 2-year disease-free interval before transplantation is strongly advised, except in adults with small asymptomatic renal cell cancers, where a waiting period after radical nephrectomy may not be needed.

Contraindications

A number of contraindications exist for kidney transplantation. Some are contraindications for surgery, others are contraindications for immunosuppression, and still others derive from various concomitant disorders and conditions.

Contraindications for surgery

Contraindications for surgery include the following:

  • Metastatic cancer
  • Ongoing or recurring infections that are not effectively treated
  • Serious cardiac or peripheral vascular disease
  • Hepatic insufficiency (patients may be candidates for simultaneous liver-kidney transplantation)
  • Serious conditions that are unlikely to improve after kidney transplantation (ie, the patient’s life expectancy can be finitely measured)
  • Demonstrated and repeated episodes of medical noncomplianceInability to perform rehabilitation adequately after transplantation

HIV seropositivity is NOT a contraindication for kidney transplantation, provided that the patient meets the following criteria[5] :

  • The CD4 count has been higher than 200/µL for at least 6 months
  • HIV-I RNA is undetectable
  • The patient has been stable on antiretroviral therapy for at least 3 months
  • The patient has no major infectious or neoplastic complications

Adverse effects of immunosuppressive drugs may exacerbate atherosclerosis, hypertension, diabetes, and lipid disorders and thus may increase cardiac risk after transplantation. Currently, patient death from cardiac disease (ie, death with a functioning kidney) is the most common cause of renal allograft failure, not direct failure of the graft.

Contraindications for immunosuppression

Infection and malignancy are the primary medical conditions to be considered. Acute infections should be fully resolved at the time of transplantation. As noted (see above), HIV infection is no longer an absolute contraindication for kidney transplantation if certain conditions are met[5] ; with these conditions satisfied, outcomes are equivalent to those of patients without HIV infection.[6]

In general, one should wait about 5 years after successful treatment of breast cancer, colorectal cancer, melanoma, diffuse bladder carcinoma, and non–in situ ovarian cancer. The risk of recurrence is about 50% if the transplant is performed within 2 years of such treatment, about 35% if it is performed between 2 and 5 years, and only about 10% if it is performed after 5 years.

Some tumors may permit shorter waiting times. For isolated nodules of prostatic carcinoma and focal bladder carcinoma, 1 year (or even less) is reasonable; for in situ uterine carcinoma, some kidney tumors (eg, clear cell, Wilms, urothelioma), and basal cell carcinoma or squamous cell skin carcinoma, no waiting time at all may be reasonable.

Poor social support, substance abuse, and intractable financial problems can compromise postoperative management and immunosuppression, contraindicating transplantation.

Other contraindications

The risk of recurrent disease is not a contraindication for kidney transplantation. In about 3% of transplants, evidence of recurrence is observed by 2 years, and it is observed in about 20% of transplants by 8 years.

Glomerulonephritides (eg, mesangiocapillary glomerulonephritis type 1 and IgA nephropathy) are most likely to recur. However, loss of the kidney generally occurs late; thus, these diseases are not contraindications for transplantation. Focal segmental glomerulosclerosis is associated with a highly variable rate of recurrence in the first allograft, which approaches 30% in some series; however, if the first allograft is lost to recurrent disease, the risk of recurrence in the second allograft is approximately 85%.

Similarly, patients with diabetes mellitus have poorer outcomes after transplantation than patients without diabetes; nearly all of them demonstrate histologic evidence of diabetic nephropathy within 4 years. However, the improved quality of life for patients with diabetes after transplantation justifies its use as the treatment of choice for these patients if they have ESRD.

Increasingly, the treatment of choice for patients with type 1 diabetes and renal failure is combined kidney-pancreas transplantation or pancreas-after-kidney transplantation. The latter option is particularly attractive when the patient can receive the initial kidney transplant from a living donor.

Hereditary oxalosis is associated with a high rate of recurrence after kidney transplantation and graft failure. Optimal management remains controversial, but it may involve (1) intensive preoperative dialysis to reduce the oxalate burden and (2) combined or staged liver-kidney transplantation.

Outcomes

The prognosis after kidney transplantation is generally excellent, with 1-year graft survival rates ranging from 93% to 98% and 5-year survival rates from 83% to 92%.[1] Many factors influence the anticipated outcome. HLA-identical (HLA-ID) transplants from living related donors have the best overall graft survival rate, whereas transplants from complete-mismatch cadaveric donors have the worst. Complete-mismatch living-donor transplants have outcomes equivalent to those of zero-mismatch deceased-donor transplants.

Other factors affect outcomes after kidney transplantation. One such factor is kidney preservation time. Prolonged cold ischemia can result in delayed graft function immediately after transplantation and may result in a somewhat shorter lifespan for the transplant. Another factor is donor age: older age in the donor can adversely affect both immediate graft function and long-term outcomes. In general, both delayed graft function after transplantation and early rejection episodes adversely affect the long-term outcome of the transplant.

Although advances in immunosuppression have led to significant decreases in the incidence and severity of posttransplant acute rejection, these decreases have not led to corresponding increases in long-term graft and patient survival. The most likely explanation for this discrepancy is that at present, the most common cause of kidney graft loss is death of the recipient with a functioning graft, and the nephrotoxicity of immunosuppression.

To achieve significant improvements in graft and patient survival, patients’ comorbid conditions must be addressed more effectively. Chief among these is cardiac disease, which can be exacerbated by complications of immunosuppression. The risk of cardiovascular events in kidney transplant recipients is 3.5–5% per year, which is 50-fold higher than that of the general population, and the prevalence of hypertension is greater than 80%.[7] Thus, special attention should be paid to cardiac risk factors after transplantation, including hypertension, hyperlipidemia, and diabetes.

Clinical practice guidelines on the management of blood pressure (BP) in kidney transplant recipients recommend maintaining BP at 130/80 mmHg or less. However, office BP measurements may be unreliable: a longitudinal study in kidney transplant recipients that compared routinely measured office BPs with 24-h ambulatory BPs (ABPs) found white coat hypertension in 25% of kidney transplant recipients and masked hypertension in 12%.[7]

 

 

Periprocedural Care

Preprocedural Evaluation

The pretransplant evaluation must address potential contraindications, should include baseline immunologic studies, and should assess the patient’s likelihood of success with transplantation.

Basic pretransplant studies

Either a need for dialysis or a creatinine clearance below 20 mL/min is generally an accepted definition of end-stage renal disease (ESRD). In the United States, a documented creatinine clearance of 20 mL/min or less is necessary to qualify for listing for transplantation. Typically, basic pretransplant studies are required, including the following:

  • Echocardiography and a stress study
  • Chest radiography
  • Pulmonary studies
  • Colonoscopy or barium enema (dependent on patient age)
  • Mammography, Papanicolaou (Pap) smear, and prostate-specific antigen (PSA) test, as indicated (depending on patient age)
  • Noninvasive vascular studies
  • Abdominal and renal ultrasonography
  • Serologic tests for HIV infection, hepatitis B and hepatitis C, cytomegalovirus (CMV) infection, and other viral infections
  • Studies of bladder capacity and function (if indicated)

Immunologic studies

Immunologic studies should include human leukocyte antigen (HLA) typing and measurement of the panel-reactive antibody (PRA) titer. The panel-reactive antibody titer approximates the likelihood that a randomly chosen kidney donor has a positive cytotoxic lymphocyte crossmatch with the potential recipient, thereby ruling out that particular donor-recipient combination. Screening for donor-specific antibodies in the potential recipient by using HLA-coated beads is currently becoming routine at many transplant centers.

Evaluation of potential living donors

Evaluation of potential living donors may involve some of the studies detailed above. The choice of studies in this setting is subject to great variation among programs; however, assessment of renal function, evaluation of general health, imaging of the renal vasculature, HLA typing, and crossmatching are essential in all cases. Most centers require a donor to have a glomerular filtration rate (GFR) of at least 80 mL/min. The authors find that spiral computed tomography (CT) allows evaluation of the renal vasculature and parenchymal abnormalities.

All donors should be in good health and should not have conditions that may compromise their renal function in the future, such as hypertension or diabetes. Some centers require potential donors to undergo 24-hour ambulatory blood pressure monitoring.

Monitoring and Follow-up

Postoperative management involves two key tasks. The first task is to manage the dynamic fluid balance of a new kidney that is capable of responding to the high urea nitrogen load with an osmotic diuresis but is less capable of concentrating urine or reabsorbing sodium. With improving renal function, fluid balance must be maintained, hypertension management may need modification, and electrolyte abnormalities may require correction.

As with other surgical procedures, standard postoperative care for kidney transplant patients includes application of graduated compression stockings. However, Sener and colleagues reported reduced hospitalization times and improved short-term outcomes with postoperative use of muscle-pump activators (MPAs). In their randomized trial, which included 221 patients who had undergone kidney or simultaneous pancreas and kidney transplantation, mid-calf leg circumference and patient weight (both markers of fluid retention), were significantly lower in the MPA group than in the patients who received traditional compression stockings with intermittent pneumatic compression devices for 1 week.[8]

At 30 days' followup, patients in the MPA group had greater urine output, improved blood flow to the transplanted kidney, and a 60% reduction in wound infection rates. They also recorded significantly more steps on a pedometer. The MPA did not appear to significantly affect measures of renal function, however, including the rate of delayed graft function, need for dialysis, and serum creatinine concentrations.[8]

The second task is the administration of immunosuppression. Current immunosuppressive therapy can be divided into two phases: induction and maintenance. For some patients, a state of immunosuppression is induced just before the operation. This induction phase is continued during and after transplantation and is carried out by using either antibody- or nonantibody-based regimens.

Typical antibody-based induction immunosuppression uses either monoclonal or polyclonal antibody preparations directed at T cells in combination with calcineurin inhibitors (eg, cyclosporine and tacrolimus), antiproliferative agents (eg, azathioprine and mycophenolate), and corticosteroids. Maintenance therapy includes various combinations of a calcineurin inhibitor, an antiproliferative agent, and prednisone.

The choice of induction strategy depends on several factors. Some centers routinely use antibody induction. Of the centers that do not, most agree that antibody induction should still be used in immunologically higher-risk transplant cases, such as the following:

  • Repeat transplants, especially when the first kidney was lost to acute or chronic rejection
  • African-American patients
  • Patients with evidence of significant prior sensitization to HLAs, as evidenced by a high panel-reactive antibody titer

Calcineurin inhibitors have been the mainstay of clinical immunosuppression since the introduction of cyclosporine in the early 1980s. Calcineurin inhibitors were the first agents to target proliferating T cells by blocking the elaboration of cytokines (eg, interleukin [IL]–2) essential for proliferation. Both cyclosporine and tacrolimus are naturally occurring products and have significant toxicities. In particular, they have a significant dose-related nephrotoxicity.

This nephrotoxicity, combined with erratic absorption and complex pharmacokinetics, necessitates ongoing monitoring to maintain therapeutic drug levels while avoiding toxicities. Although most centers follow drug trough levels, some have used pharmacokinetic modeling to good effect.[9] Both cyclosporine and tacrolimus are metabolized in the liver by the cytochrome P-450 (CYP-450) system. Drugs that alter CYP-450 metabolism can result in higher blood levels (eg, fluconazole or verapamil) or lower drug levels (eg, rifampin or phenytoin).

The adverse consequences of long-term cyclosporine use for solid-organ transplant rejection (eg, hypertension and renal impairment) have prompted exploration of various treatment regimens. Gallagher et al studied long-term graft survival by comparing the following three immunosuppressive regimens in 489 patients with a median follow-up of 20.6 years[10] :

  • Azathioprine and prednisolone (AP)
  • Long-term cyclosporine alone (Cy)
  • Cyclosporine initiation followed by withdrawal at 3 months and azathioprine and prednisolone replacement (WDL)

Mean graft survival (with deaths censored) was longer in the WDL group (14.8 y) than in the AP group (12.4 y) or the Cy group (12.5 y). Without deaths censored, graft survival was again longer in the WDL group (9.5 y) than in the AP group (6.7 y) or the Cy group (8.5 y). Patient survival was comparable in the 3 groups. Renal function was superior in the AP group at 1, 10, and 15 years after transplantation and in the WDL group at 1, 5, 10, 15, and 20 years in comparison with the Cy group.[10]

Another strategy involves the use of sirolimus, an immunosuppressant that targets T cells at a different site in the activation pathway.[11] Sirolimus can be used in conjunction with reduced doses of calcineurin inhibitors or as a replacement for these agents in immunologically low-risk recipients. Although it lacks the nephrotoxicity of calcineurin inhibitors, it reduces wound healing and may cause myelosuppression.[12] Patients at high immunologic risk (see above) may be maintained on a combination of mycophenolate or sirolimus, tacrolimus or cyclosporine, and steroids for the first year after transplantation.

Mycophenolate reversibly inhibits de novo synthesis of purines during the S phase. Because the salvage pathway of purine synthesis is less active in lymphocytes than in other tissues, lymphocytes depend more on this pathway. Mycophenolate is far more selective than its predecessor, azathioprine, and it inhibits proliferation of both B and T cells. When used in conjunction with other agents (usually calcineurin inhibitors), mycophenolate significantly reduces the incidence of acute cellular rejection.

Mycophenolate can be administered either as a mofetil ester or as a sodium salt in enteric-coated form. It also reportedly reduces interstitial fibrosis associated with chronic rejection in animal models. Mycophenolate’s principal toxicities involve the gastrointestinal (GI) tract and principally manifest as nausea and diarrhea. These toxicities may limit its use, but patients who can tolerate them may experience significant reductions in allograft rejection.

Although steroids play a key role in induction and maintenance of immunosuppression and in treatment of rejection, they are associated with many complications of immunosuppression (eg, bone disease, hypertension, peptic ulcer disease, glucose intolerance, growth retardation, infection, obesity, and lipid abnormalities). Efforts to reduce steroid exposure have involved minimizing or completely avoiding their use. Steroids have been completely avoided in a few carefully selected cases, albeit with some increase in the rejection rate (but no long-term deterioration in graft survival).

Steroid doses have been reduced and rapidly tapered without significant increasing the risk of rejection.[13] Steroid reduction has been associated with decreases in hypertension, diabetes, and other adverse events associated with steroid therapy. Patients with stable graft function and no significant rejection episodes can often be weaned off steroids within the first 3-12 months and maintained on either combination therapy with a calcineurin inhibitor and an antiproliferative agent or, occasionally, monotherapy with a calcineurin inhibitor.[14]

 

Technique

Donor Procedure

Kidneys are recovered from either living donors or deceased (brain-dead or donation after cardiac death) donors. Living-donor donation typically occurs between individuals who share an emotional bond but are not necessarily related. Good Samaritan living donors are altruistic (often anonymous) donors who wish to donate their kidney to individuals whom they do not know.

The incidence of living unrelated transplants (those performed between individuals who are not related by blood) is increasing.[4] These living unrelated transplants generally have excellent outcomes that are superior to those of the best-matched deceased-donor transplants, though the results are still slightly inferior to those of human leukocyte antigen (HLA)-identical (HLA-ID) and haploidentical living-donor transplants.

Living-donor transplantation

Living donation is a scheduled event that offers the advantage of optimal preparation of both recipient and donor. Such scheduling allows better logistical control, which helps minimize organ preservation time. The total ischemia time from removal of the donor kidney to restoration of blood flow in the recipient can be less than 1 hour (although, in paired donation, may be considerably longer, without any compromise in the likelihood of immediate function). As a result, rates of initial poor graft function tend to be very low, with most grafts producing high volumes of urine within a few hours and a concomitant clearance of creatinine within the first day.

Previously, living donation required a flank incision, often accompanied by rib resection. However, the introduction of laparoscopic and laparoscopy-assisted techniques has proved to be a major improvement in surgery for living donation.[15] Laparoscopic donor nephrectomy (see the video below) has many of the benefits associated with other laparoscopic procedures: It reduces donor postoperative hospital stays by several days and recovery time in motivated patients by several weeks.

Laparoscopic donor nephrectomy.

In the authors’ experience, patients undergoing laparoscopic donor nephrectomy share the advantages noted in other programs,[16] with less need for pain medication, earlier discharge (typically on the morning of postoperative day 1), and more rapid functional recovery than patients undergoing open donor nephrectomy.

Early experience has shown that laparoscopic donor nephrectomy is associated with a considerable increase in the willingness to donate. Transplant programs have noted increases in their overall kidney transplant volumes because potential donors face less postoperative morbidity and fewer economic disincentives when this technique is used.[4]

Laparoscopic donor nephrectomy poses a number of surgical challenges. For instance, the pneumoperitoneum required for laparoscopic surgery may decrease venous return and compromise graft perfusion; however, with skillful anesthesia (and increased volume administration), this problem can be overcome.

Careful laparoscopic technique is required to recover grafts with adequate vessel length and with a well-preserved blood supply to the ureter. Given careful technique, the authors do not consider multiple renal arteries to be a contraindication to recovery, except in the rare case where four or more approximately equal-sized arteries are present. The left kidney is preferred because of implantation advantages associated with a longer renal vein; however, in some donors, the right kidney is preferable because of anatomic issues.

Deceased-donor transplantation

Whereas living donation typically occurs among persons who know each other, deceased donation is generally anonymous. Allocation of organs from deceased donors is based on a waiting list system, with special priorities given to the following:

  • HLA zero-mismatch pairings (because of their documented improved graft survival rate)
  • Pediatric recipients (to minimize the impact of chronic renal failure on growth)
  • Patients with a high panel-reactive antibody titer (to increase their probability of transplantation)

The list is managed by the United Network for Organ Sharing, based in Richmond, VA. A newly implemented kidney allocation system characterizes donors on a percent scale, using the kidney donor profile index, and allocates the 20% of deceased donor kidneys with the greatest expected posttransplant longevity to the 20% of candidates with the best expected posttransplant survival; kidneys that are not accepted are then offered to the remaining 80% of candidates.[17]

Currently, most deceased-donor kidneys come from cadavers whose brains are dead but whose hearts are beating. The families of severely brain-injured patients may desire to withdraw support in conjunction with organ donation. Increasingly, donation after cardiac death (DCD), particularly in the controlled setting of withdrawal of support in the operating room, is becoming a source of kidney allografts. Outcomes for DCD allografts approach those obtained after brain death, especially if the DCD kidneys are preserved by pulsatile perfusion.

Contraindications to deceased-organ donation include most active infections, HIV infection (although this may change before too long), and extracranial malignancy. Relative contraindications include poor renal function in the donor, advanced donor age (especially if paired with hypertension or diabetes), and other factors likely to compromise long-term graft function.

Donors positive for hepatitis B core antibodies are routinely paired with recipients who have documented hepatitis B immunity as a result of immunization or prior infection. Kidneys from donors with chronic hepatitis C virus infection are frequently transplanted into recipients with hepatitis C and minimal hepatic damage (stage 2 fibrosis or less).

The donor operation is now typically part of a complex multiorgan recovery process that includes the kidneys, liver, pancreas, heart, and lungs (see Organ Procurement). Organ recovery essentially involves perfusion of the involved organs with cold (ie, 4°C) preservation solution. These solutions typically contain high levels of potassium to depolarize cell membranes, thereby reducing the metabolic demands associated with maintaining sodium and potassium gradients.

Organ preservation solutions may also contain impermeant sugars to prevent cell swelling, albumin or dextrans to maintain osmolality and to prevent swelling of the extravascular extracellular fluid compartment, and free radical scavengers and other agents (eg, allopurinol) to reduce reperfusion injury. The most commonly used preservation solution was first formulated by Folkert Belzer at the University of Wisconsin (UW).

After intravascular perfusion with a cold preservative solution, the kidneys are removed, with care taken to preserve the renal vasculature and the ureter with the blood supply contained in its investing tissue. The kidneys are packed sterilely in UW solution and kept at 4° C during transport to the appropriate transplant center. To provide target cells for the crossmatch, lymphoid tissue (eg, lymph nodes or spleen) is obtained at the time of organ recovery (see Organ Preservation).

The steadily increasing demand for kidney transplantation has prompted consideration of ways to expand the pool of potential donors. Expanded living donation has had the greatest quantitative effect. Increased use of DCD donor kidneys and the efficient use of expanded-criteria donors (ECDs) can, to a lesser degree, increase organ availability. ECD kidneys come either from donors who are older than 60 years or from donors who are older than 50 years and have two of the following three characteristics:

  • History of hypertension
  • Cerebrovascular injury as the cause of death
  • Creatinine level higher than 1.5 mg/dL at any time

In routine use, ECD kidneys are associated with a significantly higher risk of nonfunction and delayed graft function. These kidneys are currently allocated in an expedited manner to patients who have agreed to accept these risks. They are often placed on pulsatile perfusion pumps to assess their flow and resistance to flow characteristics.

As the number of patients listed for kidney transplantation continues to increase, transplant professionals continue to search for methods of increasing the donor pool.[18]

Transplanting across a positive crossmatch

A significant number of patients have preformed antibodies to potential living donors. The antibodies develop as the result of exposure to foreign antigens by prior transplantation, blood transfusions, or pregnancy. Consequently, these recipients have positive crossmatches against identified living donors.

Many transplant centers have protocols that enable these sensitized patients to receive kidneys from living donors against whom they have a positive crossmatch. This usually involves several pretransplant pheresis sessions to remove the offending antibodies and administration of intravenous immunoglobulin (IVIg) to inhibit the return of antibodies. The living-donor transplant is then performed when the crossmatch converts to negative. Postoperatively, the recipient usually receives additional pheresis treatments and IVIg infusions.[18]

Donor exchange

Another option for patients with a positive crossmatch with a potential donor is to enroll in a donor exchange program. Incompatible donor-recipient pairs are screened against other incompatible pairs to determine whether the donors could donate to another recipient. The most equitable method involves two recipients exchanging or swapping their donors, with both recipients receiving kidneys of equal quality. More complicated metrics have been proposed and used.[19]

Implantation of Renal Allograft

Various approaches to kidney transplantation have been developed. The Gibson incision is the most common approach: it involves a curvilinear incision in a lower quadrant of the abdomen, with division of the muscles of the abdominal wall and dissection of the retroperitoneal space to expose the iliac vessels and the bladder. Occasionally, a midline incision is used; this approach is useful when a recipient has prior transplants in both lower quadrants or when a large kidney is to be placed in a small recipient.

The authors’ preferred approach involves direct end-to-side anastomosis of the renal artery to the external iliac artery (see the image below), though the common iliac may also be used. The inferior vena cava and aorta are accessible via the right-side approach. Anastomoses are typically performed with permanent vascular sutures (5-0, 6-0, or 7-0, as mandated by operating conditions). Numerous surgical options are available, including patch techniques, use of vascular autograft and allograft, and use of recipient hypogastric or epigastric arteries.

End-to-side anastomosis between donor main renal a End-to-side anastomosis between donor main renal artery just above its bifurcation and recipient external iliac artery.

Ureteroneocystostomy

The ureter is anastomosed to the bladder through the formation of a ureteroneocystostomy. This procedure may involve bringing the ureter through a tunnel in the bladder submucosa (Leadbetter-Politano approach), or it may involve creating an anastomosis between the tip of the ureter and the bladder mucosa, then partially covering this with bladder muscularis (Lich approach). The standard of care for ureteral anastomosis in kidney transplant is via the extravesical approach.[20]

The decision to use a ureteral stent to facilitate the ureteroneocystostomy and reduce the risk of obstruction in the early postoperative period is highly individualized. Some surgeons routinely place stents; others avoid them. The authors typically perform Lich ureteroneocystostomies and insert stents when ureter or bladder tissue appears marginal. Arranging for cystoscopic stent removal within a few weeks of transplantation is important: A forgotten stent can cause hematuria and become a nidus for stone formation and infection.

Ureteroureterostomy

In rare clinical situations, anastomosis of the ureter to the bladder is not possible. If the donor ureter is devascularized during recovery and must be cut to a length that is too short to reach the bladder, then other options must be considered. In rare cases, it is impossible to mobilize the bladder sufficiently to allow creation of the standard anastomosis. Anastomosis of the donor ureter to the native ureter is a viable option.

Complications

Numerous complications are associated with kidney transplantation. These include the following:

  • Delayed graft function
  • Vascular thrombosis and stenosis
  • Ureteral obstruction
  • Urinary leakage

Delayed graft function

The incidence of delayed graft function (as defined by the need for dialysis in the first week after transplantation) varies according to donor, recipient, and transplant characteristics. Delayed graft function is rare with living donor grafts, probably because of the short cold ischemia time and the recovery of the kidney from a healthy live donor. For deceased donor kidneys, cold ischemia time remains the best predictor of delayed graft function.

While most delayed-graft-function kidneys eventually function, they do have a somewhat diminished lifespan compared with kidneys that function immediately.[21] Delayed allograft function is associated with increased hospital stays and increased perioperative expense.

Vascular thrombosis and stenosis

Renal artery thrombosis occurs in about 1% of transplants, usually from small-caliber arteries. Nephrectomy is generally required if thrombectomy is unsuccessful. Arterial stenosis occurs in 2-10% of cases, may occur within months or years following transplantation, and is associated with hypertension. It is often suspected on the basis of findings from Doppler ultrasonography.

D efinitive diagnosis generally requires angiography to confirm the presence of the stenosis and exclude proximal vascular disease. One author has found carbon dioxide angiography to be useful, especially in the setting of renal insufficiency, because it eliminates the need to use nephrotoxic contrast material.[22] Management of arterial stenoses has increasingly turned to percutaneous techniques, including angioplasty and stent placement.

Doppler ultrasonography can also be used to monitor for fluid formation, a potential sign of hematoma.

Venous thrombosis occurs in 0.5-4% of cases. In a few cases, thrombosis of the main renal vein has been successfully treated with thrombolytic agents, though the graft typically has undergone infarction by the time the thrombosis is detected. Graft infarction may occur with patent main arteries and veins, and nephrectomy is generally required. Graft thrombosis associated with sepsis carries a significant recipient mortality. Prompt nephrectomy is indicated.

Ureteral obstruction

With exception of infection, ureteral obstruction is the most common urinary tract problem associated with transplantation. It may occur early or late.

Early obstruction may result from clot, edema, or technical problems associated with the ureteroneocystostomy. If Foley catheter placement and expectant management do not resolve the problem, surgical revision of the ureteroneocystostomy over a stent may be required. Late obstruction, when not caused by external compression (eg, from lymphocele or pregnancy), is most commonly associated with fibrosis or nephrolithiasis. Management typically involves radiologic or cystoscopic stent placement and stricture dilatation.

Urinary leakage

Urine can leak at any level of the urinary tract, from the renal pelvis to the urethra. Suspect urinary leakage when a patient with good or improving graft function develops a fluid leak from the wound or abdominal pain or perineal swelling, typically within a month of transplantation. Fluid leaking from the wound can be collected and assayed for creatinine. Nuclear renal scanning is probably the most sensitive test for urinary leakage.

Small bladder leaks often can be managed by means of bladder decompression with a Foley catheter. Larger and more proximal leaks typically call for exploration and repair.

Lymphocele

Leakage from perivascular lymphatic vessels can lead to significant collections of lymph between the lower pole of the transplanted kidney and the bladder. A lymphocele can manifest as swelling, pain, and impaired renal function within the first year after transplantation. Ultrasonography or computed tomography (CT) demonstrates the collection well and is used to facilitate treatment planning.

Aspiration occasionally resolves the problem, but prolonged catheter drainage is associated with a significant risk of infection. Sclerotherapy with 10% povidone-iodine solution may be successful in treating small nonloculated collections, but the lymphocele is highly likely to recur. Some early success has been obtained by instilling fibrin glue that contains gentamicin and iodine solution. However, the current standard of care is internal drainage of the lymphocele into the abdominal cavity. Increasingly, this procedure is performed laparoscopically.

Infection

The risk of opportunistic infections is increased after transplantation.[23] These infections are typically caused by commonly encountered pathogens such as cytomegalovirus, BK virus, fungi, Pneumocystis jiroveci, and Legionella species.[24] Early after transplantation, urinary tract infections are most common, and are often caused by Escherichia coli.[25] For more information, see Infections After Solid Organ Transplantation.

Rejection

With improved immunosuppression, acute rejection after transplantation has become less of a problem. In the first year after transplantation, acute rejection is observed in about 10-25% of patients. Rejection is usually asymptomatic, though it is sometimes associated with fever and pain at the graft site. It usually presents as an unexplained rise in serum creatinine levels and can be confirmed with biopsy. Typical biopsy findings include lymphoplasmacytic infiltration of the renal interstitial areas with occasional penetration of the tubular epithelium by these cells.

Most rejection episodes can be treated successfully with a short course of increased steroid doses. Failure to respond to steroid therapy for a particularly aggressive appearance determined by biopsy may prompt a change of treatment strategy (eg, use of antilymphocyte antibody agents).

"Chronic rejection" (termed interstitial fibrosis/tubular atrophy in the current literature) appears to have both immunologic and nonimmunologic components. Risk factors include initial poor function of the graft and a history of acute rejection episodes. Chronic rejection is not treatable.

Other complications

Posttransplant diabetes, hypertension, and hyperlipidemia are all complications of immunosuppressive agents.

 

Medication

Medication Summary

The goals of pharmacotherapy are to prevent graft rejection, reduce morbidity, and prevent complications. Immunosuppression is often started prior to or during surgery. Transplant recipients are maintained on an immunosuppression regimen that includes 1-3 drugs. Immunosuppressant drug classes include calcineurin inhibitors, corticosteroids, antimetabolites, mTor inhibitors, and other immunosuppressants. Several regimens can be used, including pretransplantation induction therapy and simple postoperative maintenance therapy; the choice of regimen depends on the training and experience of the transplantation center. For additional information, see Immunosuppression.

Calcineurin Inhibitors

Class Summary

These agents induce immunosuppression by inhibiting the first phase of T-cell activation by binding to immunophilins (eg, cyclophilin, FK binding proteins) to form complexes that then bind to and inhibit the activated calcineurin phosphatase . Calcineurin is essential for the dephosphorylation of the nuclear factor of activation of T cells (NFAT) that activates T-cells. The first phase of T-cell activation causes transcriptional activation of interleukin (IL)-2, IL-3, IL-4, tumor necrosis factor (TNF) alpha, and interferon gamma that allow T-cells to progress from the G0- to G1-phase.

Tacrolimus (Prograf, Astagraf XL, Hecoria, Envarsus XR)

Tacrolimus is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine, but its adverse effects include renal dysfunction, neurotoxicity (tremor, insomnia, and paresthesias of the extremities), and new-onset diabetes. Levels are adjusted according to renal function, hepatic function, and adverse effects. Tacrolimus has essentially replaced cyclosporine as the calcineurin inhibitor of choice, because of less rejection, less steroid-resistant rejection, more salvage after conversion from cyclosporine because of rejection, and in some studies, superior graft survival. Currently, 80-90% of patients receive tacrolimus after kidney transplantation instead of cyclosporine, and this change has persisted over the past 10-15 years. Astagraf and Envarsus are once-daily formulations of tacrolimus. A number of generic formulations of the original tacrolimus are available.

Cyclosporine (Neoral, Sandimmune, Gengraf)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.

For children and adults, base dosing on ideal body weight. Maintaining appropriate levels of the drug in the bloodstream is crucial to the maintenance of the allograft. Foods and time of administration can alter the level of the drug. Medication must be taken at the same time every day.

Neoral is the capsular form of the newer formulation of cyclosporine, available in 25- and 100-mg capsules. Sandimmune is the liquid form of the original formulation. Genraf is the branded generic form of the newer formulation, available in 25- and 100-mg capsules. There are many generic formulations of both the original and modified formulations.

Corticosteroids

Class Summary

At pharmacologic doses, glucocorticoids suppress immune responses.

Prednisone (Deltasone)

Prednisone is an immunosuppressant used for the prevention or treatment of rejection. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is an oral steroid with approximately 4 times the potency of endogenous steroids. All patients receive steroids around the time of the transplant; perhaps one third have steroids withdrawn within a few days of the transplant (steroid near-avoidance), and perhaps 10% have steroids withdrawn at a subsequent date. In spite of the numerous side effects, most transplant patients are maintained on long-term low-dose steroids.

Prednisolone (Orapred, Pediapred, Millipred)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.  Prednisolone is very similar to prednisone.

Methylprednisolone (Medrol, Solu-Medrol)

Methylprednisolone is an immunosuppressant used to prevent or treat rejection. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It is the intravenous (IV) form of prednisone.

Antimetabolites

Class Summary

Used for maintenance therapy in conjunction with a calcineurin inhibitor and prednisone.

Mycophenolate mofetil (CellCept, Myfortic)

Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thus inhibiting their proliferation. It inhibits antibody production. It is the most prescribed immunosuppressive agent in transplantation. Two forms exist, mycophenolate mofetil (MMF, CellCept) a prodrug for mycophenolic acid (MPA, Myfortic). These agents are used in regimens containing a calcineurin inhibitor and corticosteroids for prevention of renal allograft rejection. There are many generic formulations.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity. Antimetabolites are used to block the uptake of vital nutrients needed by the cells. As implied, these drugs affect not only the cells of the immune system but also other cells of the body. The potency of therapy is dose-dependent. Azathioprine is not effective treatment for acute rejection episodes but remains an economical choice for long-term immunosuppression.  It was supplanted very quickly by mycophenolate mofetil when the latter became available.

mTor Inhibitors

Class Summary

Inhibit T-cell activation and proliferation. Unlike calcineurin inhibitors, sirolimus and everolimus inhibit the second phase of T-cell activation. The second phase involves signal transduction and clonal proliferation of T-cells. These agents inhibit interleukin-induced proliferation of T-cells resulting in cell cycle arrest in hte late G1-phase and prevents progression to the S-phase. Sirolimus inhibits interleukin (IL)-2, IL-4, IL-7, IL-15, and IL-17. Everolimus inhibits IL-2 and IL-15.

Sirolimus (Rapamune)

Sirolimus, known in the past as rapamycin, is a macrocyclic lactone produced by Streptomyces hygroscopicus. It is a fairly potent immunosuppressant that inhibits T-cell activation and proliferation by a mechanism that is unknown but distinct from that used by all other immunosuppressants. This inhibition suppresses cytokine-driven T-cell proliferation by inhibiting progression from the G1 phase to the S phase in the cell cycle.  It is used in a minority of transplant recipients.

Everolimus (Zortress)

Everolimus is indicated for prophylaxis of organ rejection in patients with low to moderate immunologic risk following kidney transplantation. It is used in combination with reduced-dose cyclosporine, as well as basiliximab and corticosteroids. It inhibits the second phase of T-cell activation.

Other Immunosuppressants

Class Summary

These agents may be used in various immunosuppressant regimens.

Belatacept (Nulojix)

Belatacept is a monoclonal antibody that inhibits T-cell CD28 activation and proliferation by binding costimulatory ligands (CD80, CD86) of antigen presenting cells. It is indicated for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent kidney transplant rejection.

Basiliximab (Simulect)

Interleukin-2 receptor antagonist indicated for prophylaxis of kidney transplant rejection. It is used as part of a regimen that includes a calcineurin inhibitor and corticosteroids. More recently, it has been used as part of induction regimens.

Antithymocyte globulin rabbit (ATG rabbit, Thymoglobulin)

Acts against human T-cell surface antigens and depletes CD4 lymphocytes. It is indicated for treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression. It is also widely used off-label for induction. 

Alemtuzumab

Alemtuzumab is a humanized recombinant monoclonal antibody against CD52 that is approved by the FDA for chronic lymphocytic leukemia and multiple sclerosis. It is used off-label as part of various induction regimens in patients undergoing kidney transplantation. In numerous phase 3 clinical trials, alemtuzumab has demonstrated steroid-sparing effects, including improved glycemic stability. Leukopenia and neutropenia were reported. Careful patient selection is required. Long-term follow-up results from the 3C trial (NCT01120028) is pending regarding alemtuzumab’s role in reducing calcineurin inhibitor exposure by using a more potent induction regimen.