A nurse is assessing a client who is 1 week postoperative following a living donor kidney transplant

In addition to the surgical transplantation procedure itself (see Kidney Transplantation), management includes organ procurement, the provision of immunosuppressive therapy to the recipient, and short- and long-term follow-up to look for indications of renal allograft dysfunction and other complications.

For pregnant women, there are special obstetric considerations associated with renal disease necessitating transplantation. There are also special considerations for newborns, who are more often born premature and have lower birth weights for expected ages. Severely ill transplanted patients who are on long-term steroid therapy are at risk for adrenal insufficiency and should be treated with stress doses of hydrocortisone (100 mg IV every 8 hours).

In a population-based retrospective cohort study of 264 pregnant women with a functional kidney transplant and 267 pregnant women with ESRD on dialysis, kidney transplant recipients were less likely to have placental abruption, less likely to receive blood transfusions, and were less likely to have growth-restricted and small-for-gestational-age infants. Kidney transplant recipients were more likely to undergo an instrumental delivery and there was a trend toward an increase in delivery by cesarean section. Fetal death was less likely among women with a kidney transplant. Four maternal deaths occurred among the women with ESRD on dialysis and no maternal deaths occurred among kidney transplant patients. [15]

In the United States, 90,029 patients were waiting for a kidney transplant as of March 2022. [4] Many of those patients will die before receiving a kidney. It is hoped that heightened attention to the task of identifying potential donors in emergency settings can help meet the escalating need for solid organ transplantation.

Identification of potential donors

The warm ischemia time (ie, the time from cessation of circulation to removal of the organ and its placement in cold storage) should be no longer than 30 minutes. This reality and other practical and logistical factors prevent “code victims” in the emergency department (ED) from becoming solid-organ donors, though these patients may still be considered for donation of other tissues (eg, bone, skin, veins, heart valves, and ocular components).

The role of ED physicians and other providers is to identify moribund patients who are appropriate candidates for transplantation and to set into motion the process of acquisition by contacting the local organ procurement organization (OPO). A list of OPOs in the United States can be found on the AOPO website.

The task of discussing organ donation with a patient’s family is best left to the OPO representative, who is highly trained for such discussion, is not involved in the acute care of the patient, and therefore does not have to weigh competing obligations. The ED physician and other healthcare providers should focus on providing the family with a realistic prognosis for the patient.

Assessment of donor suitability

Increasing demand for donor organs and improvements in transplant immunology have greatly expanded the pool of patients eligible to donate organs. Absolute contraindications for organ donation include COVID-19 infection, sepsis, and non–central nervous system (CNS) malignancy. Advanced age is a relative contraindication; most OPOs do not harvest solid organs from individuals older than 75 years. However, rejection of questionable transplant donations should be deferred to an OPO representative.

The pretransplantation workup of a potential donor should include screening for transmissible infectious agents such as herpesvirus (CMV, herpes simplex virus [HSV], EBV); HIV; hepatitis viruses A, B, C, D and E; and COVID-19. [16]

An investigation by Peters et al of the influence of age, sex, obesity, and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects who were potential kidney donors found the following [17] :

• GFR declined with age, significantly faster in women than men.

• Young women (< 30 years) had higher GFR than young men but the reverse was true in the elderly (> 65 years).

• Obesity did not affect GFR in men, but obese women had lower GFR than non-obese women.

• Obesity did not affect the age-related decline in GFR.

Determination of donor brain death

The Uniform Determination of Death Act provides guidelines outlining neurologic criteria for brain death, which is defined as complete and irreversible loss of brain and brainstem function. Criteria include the following:

• Cerebral unresponsiveness

• Brainstem areflexia

• Apnea in the absence of hypothermia and drug intoxication

Because of the lengthy process required for actual organ procurement, the ED physician or team looking after the patient should not wait for the formal declaration of brain death before involving the transplant team. If a potential donor may meet brain death criteria in the near future, a transplant coordinator should be called early on.

Patients with brain death and preserved cardiovascular function who are identified as potential donors should be quickly admitted to an intensive care unit (ICU); only in this setting can their cardiorespiratory status be maintained against the onslaught of physiologic insults that ensue once neurologic function has ceased. Once stabilized, the organ donor may officially be designated as brain-dead and transferred to the operating room for organ procurement. [18]

In certain situations, patients may be considered donors after circulatory death (DCD). This practice has increased the availability of life-saving organs.

Medical management of donor

After brain death, a number of physiologic changes ensue that necessitate medical intervention if donor organ perfusion is to be preserved. Increasing cerebral edema after a trauma or stroke initially results in elevated catecholamine release and hypertension. With brainstem necrosis, catecholamine levels rapidly drop to a fraction of normal values, causing hypotension. Such hypotension should be corrected with fluids and vasopressors.

Approximately three fourths of organ donors develop diabetes insipidus as a consequence of pituitary necrosis. If this condition goes untreated, significant hypovolemia may result. Systemic thermal control is often lost because of hypothalamic ischemia. This occurs in most donors and results in detrimental effects on potential donor organs, including coagulopathy, hypoxia, hepatic dysfunction, and cardiac dysfunction.

Patients who are brain-dead require invasive hemodynamic monitoring and aggressive fluid and pressor management to keep mean arterial pressure (MAP) above 60 mm Hg and urine output above 0.5 mL/kg/h. [19]

All kidney transplant recipients require life-long immunosuppression to prevent an alloimmune rejection response. The goals are to prevent acute and chronic rejection, to minimize drug toxicity and rates of infection and malignancy, and to achieve the highest possible rates of patient and graft survival. There is no consensus as to which immunosuppressive protocol can best meet those goals, and each transplantation program uses various combinations of agents slightly differently.

Several immunosuppressive agents have been approved by the US Food and Drug Administration (FDA), and several others are in clinical trials. Immunosuppressive agents may be divided into 2 broad categories: antirejection induction agents and maintenance immunotherapy agents.

Antirejection induction agents

Induction immunotherapy consists of a short course of intensive treatment with intravenous (IV) agents. Such agents include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera (eg, antilymphocyte globulin [ALG], antilymphocyte serum [ALS], and antithymocyte globulin [ATG]) are equine, goat, or rabbit antisera directed against human lymphoid cells. They significantly lower, and sometimes almost abolish, the circulating lymphoid cells that are critical to the rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period in which the calcineurin inhibitors are either delayed or given in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, as in recipients of kidneys from living donors, especially human leukocyte antigen–identical (HLA-ID) grafts.

The most commonly used induction agents are basilixumab, rabbit antithymocyte globulin, and alemtuzumab. A 2011 prospective, randomized, multicenter evaluation of induction demonstrated that in low-risk patients, alemtuzumab yielded significantly lower rejection rates than basilixumab, without any significant differences in safety outcomes. [20]

Maintenance immunotherapy agents

Several immunosuppressive agents are currently in use for maintenance immunotherapy in kidney transplant recipients, including prednisone, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, and belatacept. An optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for the patient’s entire life.

A single-center, randomized trial of 3 distinct maintenance immunosuppression protocols found the combination of tacrolimus plus mycophenolate mofetil to be superior with respect to graft function and rejection rates, compared with tacrolimus plus sirolimus and with cyclosporine plus sirolimus. [21]

Dose requirements and trough levels are essentially the same for generic tacrolimus as for brand-name tacrolimus; cost savings can be realized with the use of generic tacrolimus. However, post-conversion monitoring is important because patients may require dose titration. [22]

Primary use of mechanistic target of rapamycin inhibitors (mTORI: sirolimus and everolimus) without calcineurin inhibitors (CNI; tacrolimus or cyclosporin) is associated with greater risks of allograft failure and death compared with a CNI-based regimen. [23]

Belatacept has shown promise for enhancement of kidney graft function. If this promise is borne out in further studies, this drug may help reduce the current dependence on calcineurin inhibitors (eg, tacrolimus and cyclosporine) for immunosuppression. [24] Belatacept gained full FDA approval in June 2011.

In the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT) and the extended BENEFIT trial (BENEFIT-EXT), belatacept-based regimens maintained better renal function and improved cardiovascular and metabolic risk profiles when compared with cyclosporine regimens. Patient and graft survival rates were comparable with the two regimen types. [25]

A study in six kidney transplant recipients with presumed acute calcineurin inhibitor toxicity and/or interstitial fibrosis/tubular atrophy found that conversion from tacrolimus to belatacept resulted in improved kidney function with no concurrent increase in risk of rejection. After the switch, which took place a median of 4 months after transplantation, the peak mean estimated glomerular filtration rate (eGFR) improved from 23.8 ± 12.9 to 42 ± 12.5 mL/min/1.73 m2 (P = 0.03) at a mean follow-up of 16.5 months postconversion. [26]

No new rejection episodes were diagnosed despite a prior history of rejection in two of the six patients. Surveillance biopsies performed in five of the six patients did not show subclinical rejection. No patient developed donor-specific antibodies. [26]

The primary goal of short-term and long-term medical follow-up is to enable surveillance for signs and symptoms of renal allograft dysfunction. [27] Renal parenchymal dysfunction has many causes, and the differential diagnosis must be approached systematically. The clinical manifestation is typically an increase in serum creatinine level. The critical considerations are as follows (see Complications of Transplantation):

• Rejection

• Nephrotoxicity of calcineurin inhibitors

• Recurrence of native kidney disease

The time interval between transplantation and the rise in serum creatinine level is often helpful in determining the etiology of graft dysfunction. For example, delayed graft function immediately after transplantation is usually due to acute tubular necrosis (ATN), related to warm and cold ischemic time. The frequency is variable among the different transplant centers and is approximated at roughly 20-30% of deceased donor transplants.

The nephrotoxicity of the calcineurin inhibitors cyclosporine and tacrolimus is dose-related. Occasionally, performing a renal allograft biopsy is necessary if the serum creatinine level does not respond to a reduction in dose.

Hemolytic uremic syndrome (HUS) and thrombotic microangiopathy (TMA) may occur in the setting of endothelial injury associated with calcineurin inhibitors and the development of CMV infection. [28] A systemic process reveals anemia, reduced haptoglobin levels, rising lactic dehydrogenase (LDH) levels, and a peripheral blood smear with schistocytes, all of which are consistent with the diagnosis.

At times, HUS and TMA are confined to the kidney and do not give rise to any systemic findings. The definitive diagnosis, whether local or systemic, is made with the aid of renal allograft biopsy that shows glomerular microthrombi.

Recurrent renal disease in renal kidney transplant recipients accounts for fewer than 2% of all graft losses, though it affects as many as 10% of recipients. A few diseases are associated with a high risk of renal allograft loss, including focal segmental glomerulosclerosis, HUS oxalosis, and membranoproliferative glomerulonephritis. Diabetic nephropathy can recur in renal allografts, but the time to onset is similar to that seen in native kidneys, and in general, this condition is an uncommon cause of graft loss.