Eric Langewisch, MD
Jason C. Hedges, MD, PhD
BASICS
DESCRIPTION
• The hallmark of renal transplant rejection is immunologic damage to the transplanted kidney due to donor-specific response by recipient immune system
• Classification of rejection:
– Hyperacute (immediately after revascularization of the kidney graft)
Kidney becomes mottled and cyanotic usually in the OR
– Accelerated (days to weeks after transplantation)
– Acute (weeks to months after transplantation)
– Chronic (months to years after transplantation)
EPIDEMIOLOGY
Incidence
15% rejection rate in 1st yr for those rejection-free at hospital discharge after transplantation
Prevalence
N/A
RISK FACTORS
• Presence of preformed human leukocyte antigen (HLA) antibodies
• Positive crossmatch between donor and recipient
• Previous transplant, pregnancy, blood transfusion
• Prior rejection episodes
• Delayed graft function
• African American race
• Noncompliance with immunosuppressant medications
Genetics
Greater degree of HLA mismatch between donor and recipient increases risk of rejection
PATHOPHYSIOLOGY (1)
• Hyperacute rejection: Mediated by preformed cytotoxic antibodies against kidney graft (develop after prior transfusion, transplantation, and child birth)
• Acute rejection: Most cases are acute cellular rejection (ACR) mediated by T-cell recognition of donor major histocompatibility (MHC) proteins that are presented by antigen-presenting cells (APCs) and T-cell activation. This results in mononuclear cell infiltration of interstitium, tubules (tubulitis), and endothelium (vasculitis)
• Acute antibody-mediated rejection (AMR) is mediated by circulating donor-specific antibodies (DSAs) to foreign donor HLA. Recipient antibodies bind to donor HLA, activate complement, and recruit inflammatory mediators.
• Chronic rejection: Fibrosis and atrophy from chronic allograft damage. Limited viable allograft with active inflammation.
ASSOCIATED CONDITIONS
Common causes of end-stage renal disease: Diabetes, hypertension, glomerulonephritis, cystic renal disease
GENERAL PREVENTION
• Avoid incompatible donors for kidney transplant recipient. Avoid transplants across a positive crossmatch or with preformed DSAs.
• Induction immunosuppression with lymphocyte-depleting agents, especially for high immunologic risk recipients
• Compliance with immunosuppressant medications
• Monitor renal function and maintain therapeutic immunosuppressant drug levels
• Minimize sensitizing events (eg, blood transfusions and pregnancies)
DIAGNOSIS
HISTORY
• Medication noncompliance or tapering off immunosuppression for a failed allograft
• Often asymptomatic with plasma creatinine elevation as sole abnormality.
• Severe rejection may result in decreased urine output and pain over kidney transplant.
• Fluid retention/weight gain
PHYSICAL EXAM
• May be normal
• Increased blood pressure
• Volume overload
• May have tenderness over kidney transplant
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Rising BUN/plasma creatinine
– Otherwise unexplained plasma creatinine rise >20% over baseline is suggestive of rejection.
• Urinalysis and urine culture
– Rule out pyelonephritis.
• Determine drug levels (tacrolimus or cyclosporine)
– 12-hr trough level (usually before morning dose)
– Suspect calcineurin inhibitor (CNI: Tacrolimus or cyclosporine) toxicity if abnormally high levels
– Target levels vary by patient and assay
• If antibody-mediated rejection (AMR) is suspected, test for donor-specific antibodies (DSAs)
Imaging
• Renal ultrasound
– Rule out obstructive uropathy or stone.
– Assess for diminished renal blood flow.
Color flow Doppler evaluates vascular status
– Detect graft swelling (with acute rejection; graft may be small with chronic rejection).
• Nuclear medicine renal scan:
– Rejection: Decreased renal blood flow/glomerular filtration rate
– Arterial or venous thrombosis: Decreased or absent perfusion. With complete obstruction, a reniform photopenic area can be seen
– Acute rejection/acute tubular necrosis: Marked parenchymal retention with normal or mildly reduced perfusion. Rejection will show progressive decrease in function over time.
Diagnostic Procedures/Surgery
• Needle biopsy of transplant kidney (confirmation of rejection)
– Usually under ultrasound guidance
– Automated biopsy gun device, needle sizes 14–18 gauge
– Adequate sample
≥2 cores of cortex, ≥7 glomeruli, and ≥2 arteries required
Pathologic Findings
• Acute cellular rejection
– Interstitial mononuclear cell infiltrate
– Tubulitis
– Vasculitis (in more severe cases)
• Acute antibody-mediated rejection
– Pathology variable
– Acute tubular necrosis (ATN)
– Glomerulitis
– Peritubular capillaritis
– Fibrin thrombi
– C4d staining (C4d is a complement split product that covalently binds to tissue indicating antibody-mediated complement activation)
• Chronic rejection
– Interstitial fibrosis
– Tubular atrophy
DIFFERENTIAL DIAGNOSIS
• Prerenal: volume depletion or hypotension
• CNI (calcineurin inhibitor) toxicity (tacrolimus or cyclosporine)
• Pyelonephritis
• ATN
• Technical complications
– Arterial or venous thrombus,
– Arterial stenosis
– Ureteral obstruction or urine leak (early posttransplant)
• Obstructive uropathy
• Recurrence of original renal disease
TREATMENT
GENERAL MEASURES
• Attempt to reverse rejection with medical therapy
• Graft removal may be necessary in severe rejection eg, hyperacute rejection.
MEDICATION
First Line
• Acute cellular rejection: High-dose glucocorticoids
– Methyl prednisolone IV or high-dose oral prednisone (eg, 5 mg/kg) for 3–5 days followed by taper to maintenance dosing
• Antibody-mediated rejection: Plasmapheresis and intravenous immune globulin (IVIG) ± rituximab in attempt to remove, neutralize, or prevent the production of DSAs, respectively
• Chronic rejection: No effective therapy.
• Hyperacute rejection: Remove transplanted kidney (2)[A]
– Can result in DIC if not removed promptly
Second Line
• Acute cellular rejection: Lymphocyte-depleting agents such as antithymocyte globulin (ATG) or alemtuzumab may be given for severe rejection or rejection refractory to high-dose glucocorticoid therapy (3)[A].
– Significant reactions possible with 1st doses including anaphylaxis, pulmonary edema, fever, hemodynamic instability
– Must be inpatient for initiation of therapy
– Pretreat with glucocorticoids, diphenhydramine, and acetaminophen
– Monitor CBC for therapy-related leukopenia or thrombocytopenia (may be severe)
– Consider prophylaxis against cytomegalovirus (CMV) (eg valganciclovir)
– Continue maintenance immunosuppression
SURGERY/OTHER PROCEDURES
• Allograft nephrectomy
– Remove a symptomatic, irreversibly rejected kidney transplant.
– Remove an asymptomatic, chronically rejected kidney to withdraw immunosuppression and prevent further development of anti-HLA antibodies
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Severe rejection and graft failure may require acute dialysis
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Repeated episodes of acute rejection reduce allograft survival
• Relative risk of graft failure is 1.8 for patients who have had 1 episode of rejection compared to none (4)
COMPLICATIONS
• DIC can accompany hyperacute rejection
• Graft loss can result from untreated or unrecognized rejection episode
• Cyclosporin toxicity can resemble mild acute rejection.
• Need to resume dialysis
FOLLOW-UP
Patient Monitoring (5)
• Compliance with anti rejection critical
• Therapeutic drug levels: Including monitoring of CNI toxicity
• Plasma creatinine
• Monitor for recurrence of native kidney disease (ie, diabetes, hypertension, etc.)
• Protocol transplant biopsies (optional)
Patient Resources
National Kidney Foundation. http://www.kidney.org/atoz/content/kidneytransnewlease.cfm
REFERENCES
1. Sunthanthiran M. Acute rejection of renal allografts: Mechanistic insights and therapeutic options. Kidney Int. 1997;51:1289–1304.
2. Sunthanthiran M, Strom TB. Mechanisms and management of acute renal allograft rejection. Surg Clin North Am. 1998;78(1):77–94.
3. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant. 2008;8(4):753–760.
4. Pallardó Mateu LM, Sancho Calabuig A, Capdevila Plaza L, et al. Acute rejection and late renal transplant failure: risk factors and prognosis. Nephrol Dial Transplant. 2004;19:iii38–iii42.
5. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(suppl 3):S1–S155.
ADDITIONAL READING
• Brown ED, Chen MY, Wolfman NT, et al. Complications of renal transplantation: Evaluation with US and radionuclide imaging. Radiographics. 2000;20(3):607–622.
• Danovitch G. Handbook of Renal Transplantation. 5th ed. Lippincott Williams & Wilkins; 2009.
See Also (Topic, Algorithm, Media)
• Acute Kidney Injury, Adult (Renal Failure, Acute)
• Acute Kidney Injury, Pediatric (Renal Failure, Acute)
• Chronic Kidney Disease, Adult (Renal Failure, Chronic)
• Chronic Kidney Disease, Pediatric (Renal Failure, Chronic)
• Pyelonephritis, Adult
CODES
ICD9
996.81 Complications of transplanted kidney
ICD10
• T86.11 Kidney transplant rejection
• T86.12 Kidney transplant failure
CLINICAL/SURGICAL PEARLS
• Don’t confuse kidney transplant rejection with pyelonephritis.
• Cyclosporin toxicity can resemble mild acute rejection.