p. 726

p. 727

Rejection

CASE 34-1, QUESTION 7: G.P. was started on rabbit antithymocyte globulin 1.5 mg/kg as a 6-hour IV

infusion on days 0, 1, 2, and 3 for induction, but because of his delayed graft function, he received an additional

dose on day 5. He received this along with his prednisone taper and MMF. Tacrolimus PO 3 mg BID was

initiated on day 5 after transplant. G.P.’s urine output has increased gradually to 1,600 mL/day after stopping

rabbit antithymocyte globulin. His weight has decreased to 73 kg, and the following is recorded:

BP, 142/84 mm Hg

Heart rate, 82 beats/minute

Temperature, 36.7°C

BUN, 23 mg/dL

SCr, 3.2 mg/dL

K, 4.6 mEq/L

Sixty days after stopping rabbit antithymocyte globulin, he is on a regular diet and taking all oral medications.

His current medications include MMF 750 mg BID, prednisone 5 mg daily, tacrolimus 5 mg BID, ranitidine 150

mg at bedtime, dioctyl sodium sulfosuccinate 100 mg BID, amlodipine 10 mg daily, metoprolol 50 mg PO BID,

glargine insulin 40 IU daily Novolog 10 IU with meals, valganciclovir 450 mg daily, and trimethoprim–

sulfamethoxazole (TMP–SMX) double-strength, one tablet on Mondays, Wednesdays, and Fridays. His weight

increased to 75.6 kg, and note the following:

BP, 160/94 mm Hg

Heart rate, 98 beats/minute

Temperature, 37.6°C

BUN, 30 mg/dL

SCr, 3.4 mg/dL

K, 4.8 mEq/L

Trough whole blood tacrolimus concentration, 5 ng/mL (target range 8–10 ng/mL)

Urine output decreased during the last 24 hours to 750 mL

He feels tired and has a decreased appetite, but his fluid intake has been adequate during the past day. What

evidence is consistent with rejection in G.P.?

Although significant improvements in reduction in acute rejection and improved

graft survival have occurred over the past decade, certain types of acute rejection

and chronic rejection continue to be a major reason for graft loss in kidney

transplants. Rejection episodes can be categorized as cellular and/or antibody

mediated, hyperacute, accelerated, acute, or chronic. Kidney biopsy is considered the

gold standard for making the diagnosis of rejection after kidney transplant. Approved

criteria are used to classify and grade the type and severity of rejection.

HYPERACUTE REJECTION

Hyperacute rejection, which occurs within minutes to hours after transplantation of

the allograft, is the result of preformed cytotoxic antibodies against donor-specific

class I antigens. This type of rejection is rare because of ABO matching and

improved HLA typing before transplant, but it remains associated with a poor

prognosis. Clinically, the patient presents with anuria, hyperkalemia, hypertension,

metabolic acidosis, pulmonary edema, and, in some cases, disseminated

intravascular coagulopathy. A perfusion scan of the kidney would indicate no uptake.

If other causes of anuria are excluded and this diagnosis is made, then the

transplanted kidney must be removed.

ACCELERATED REJECTION

Accelerated rejection usually occurs within a few days after organ transplantation.

This is a result of prior sensitization to antigens that are similar to those of the donor

and newly developed donor-specific antibodies to the donor graft. Accelerated

rejections of transplanted kidneys occur primarily in recipients who have had prior

transplantation, multiple pregnancies, or blood transfusions. These patients usually

maintain good renal function for a few days before developing acute renal failure.

Accelerated organ rejections generally are more resistant to pharmacologic therapy.

ACUTE REJECTION

Acute rejection is the most common type of kidney rejection in transplant recipients

and most episodes respond to therapy. Most episodes of acute rejection are T-cellmediated (cellular), although some can be B-cell (antibody or humoral)-mediated,

and others are a combination of both types. Acute rejection of a transplanted kidney

is associated with reduced the half-life and survival of both living-donor and

deceased-donor transplants. Acute rejection often occurs in the first week to months

after kidney transplantation. The prophylactic use of antibody induction may,

however, delay the onset for several weeks, as illustrated by G.P.’s case. If acute

rejection occurs, its onset is generally within the first year, with most episodes

occurring within the first 60 days after transplantation. Acute rejection can, however,

also occur at any time after transplant and can be a result of patient nonadherence

(also called noncompliance) to medications and monitoring. The clinical presentation

of patients with acute rejection of a kidney ranges from an asymptomatic patient with

mild renal dysfunction as indicated by an elevated serum creatinine, which is

common, to patients presenting with a flulike illness, hypertension, and acute oliguric

renal failure. G.P. presents with subjective complaints of malaise or tiredness and

lack of appetite. Such nonspecific complaints occur often in patients with rejection

and can be accompanied by myalgias. Objectively, G.P.’s increased weight,

hypertension, decreased urine output, and increase in serum creatinine are consistent

with acute kidney rejection. In addition, the tacrolimus trough concentration is low,

suggesting inadequate immunosuppression. Acute rejection of a transplanted kidney

must be distinguished from CNI nephrotoxicity, and infections (e.g., pyelonephritis,

CMV, polyomavirus BK) also must be ruled out. Although the clinical evidence in

G.P. probably represents an acute cellular rejection, a kidney biopsy is the gold

standard for establishing the diagnosis. Biopsy results usually are available within 6

to 8 hours. If there is acute rejection, the biopsy will show an interstitial infiltration

of mononuclear cells with tubulitis or intimal arteritis in more severe cases. The

severity of acute rejection will be classified and graded according to standardized

pathologic criteria and is important in determining treatment. Less severe grades will

receive high-dose steroids, whereas more severe grades will often receive raATG.

6

ANTIBODY-MEDIATED REJECTION

Antibody-mediated (previously called humoral) rejection can be either acute or

chronic rejection mediated by antibodies. Over the past several years, there has been

an increased recognition of the importance and detrimental impact of this type of

rejection on graft outcomes. Antibody-mediated rejection (AMR) is ≤10% of acute

rejection episodes but graft loss is near 30%. Histologically, criteria for AMR differ

from ACR. Presence of positive staining for the complement component C4d

indicates antibody-mediated rejection, although this type of rejection can also occur

with negative C4d. Many patients either prior to transplant or after have donorspecific antibodies (DSAs) that can occur hours to years after transplantation.

Antibody-mediated rejection often is associated with hemodynamic compromise and

is more resistant to drug therapy.

30

CHRONIC REJECTION

Chronic rejection is a major cause of long-term kidney graft loss after the first year. It

can be either cellular- or antibody-mediated.

p. 727

p. 728

It occurs slowly in most cases over several years. The characteristic signs of chronic

rejection are hypertension, proteinuria, and a progressive decline in renal function

leading to renal failure. Because no specific treatment exists, therapy is supportive

(e.g., dialysis in the case of kidney transplantation). Ultimately, retransplantation is

needed. Some data suggest that some patients may benefit from some of the newer

agents, such as mycophenolate and sirolimus, that are considered non-nephrotoxic,

but this requires further study. The diagnosis of chronic rejection is determined by

clinical signs and biopsy findings indicative of fibrosis of hollow structures and

vessels within the graft. The chronic rejection of a kidney must be distinguished from

chronic CNI nephrotoxicity, chronic infection, recurrence of the original kidney

disease, and other causes of chronic allograft injury and other causes.

CHRONIC ALLOGRAFT INJURY

Chronic allograft injury (CAI) is a term that has been used, generally, as a diagnosis

of exclusion that indicates a slow deterioration of renal function over months to years

after kidney transplant, where the exact cause is unknown and results in graft loss.

Immunologic and nonimmunologic mechanisms play a role in CAI. Immunologic

factors that increase the likelihood of CAI include a history of acute rejection,

inadequate immunosuppression, nonadherence with immunosuppressive therapy, and

previous infection, such as CMV. Nonimmunologic factors are donor-related (age,

hypertension, diabetes), increased ischemic times, recipient hypertension,

hyperlipidemia, CNI nephrotoxicity, and elevated body mass index. Another term,

interstitial fibrosis/tubular atrophy (IF/TA) is another term used to describe this

deterioration. It is often considered irreversible and unaffected by increased

immunosuppressive therapy.