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Transplant Rejection, Emergency Medicine

Basics

Description

- 3 phases of rejection: - Hyperacute: - Immediate postoperative period - Antibody reaction to red cells or HLA antigens - Endothelial damage - Platelets accumulate, thrombi develop, and tissue necrosis occurs. - Rare with careful donor " “recipient matching

- Chronic: - Occurs over years - Results in gradual organ failure

- Renal transplant rejection: - Progressive systemic HTN - Decreased urine output - Swelling, fever, and tenderness: - Uncommon with IS therapy

- Peritransplant hematoma - Urinary leak - Obstructive uropathy - Bleeding after renal graft biopsy

- Kidney, heart, lung, and liver rejection: - Administer high-dose steroids - Stress-dose corticosteroid coverage is also indicated in any ill-appearing transplant patient. Consult with transplant service early - Avoid blood transfusions because these need special screening to prevent transmission of disease.

Immune response to a grafts genetically dissimilar antigens resulting in rejection of the transplanted organ: ‚

  • HLA incompatibility:Most common cause of rejectionRejection of solid organ transplants
  • Blood group incompatibility:Much less of a risk to graft survival than HLA incompatibilityMay result in hyperacute rejection of primarily vascularized grafts (kidney and heart)
  • 3 phases of rejection:Hyperacute:Immediate postoperative periodAntibody reaction to red cells or HLA antigensEndothelial damagePlatelets accumulate, thrombi develop, and tissue necrosis occurs.Rare with careful donor " “recipient matching
  • Acute:Within the 1st 3 mo postopAt any time if immunosuppressant (IS) medication is stoppedT-cell " “dependent process. Inflammatory cells infiltrate allograft, release cellular and humoral factors, destroys graftPresents with constitutional symptoms and signs of transplant organ insufficiency
  • Chronic:Occurs over yearsResults in gradual organ failure

Epidemiology

Incidence and Prevalence Estimates ‚

  • Solid organ transplants:End of 2007: 183,222 living transplant patients27,281 organs transplanted in 2008Most transplanted organs: Kidney (59%), liver (21%), heart (8%), lung (5%), pancreas (4%)Most common diagnosis from visit to ED: Infection (36%), GI/GU pathology (20%), dehydration (15%), electrolyte (10%), CV and pulmonary pathology (10%), injury (8%), rejection (6%). 60% required hospitalization
  • Hematopoietic stem cell transplants:4,300 transplants in 2008Acute graft-versus-host disease incidence: 20 " “80%.

Etiology

  • Reduction or noncompliance with medication:Medication interactions with cyclosporine, tacrolimus, or sirolimus:Phenobarbital, phenytoin, carbamazepine, rifampin, isoniazid
  • Kidney transplant rejection:Early rejection caused by T and B lymphocytes, which attack microvasculature and impair graft perfusion; volume depletion, hypotension, infectionChronic rejection caused by progressive nephrosclerosis of renal vessels, infection
  • Liver transplant rejection:Acute: 48% by 6 wk, 65% by 1 yrCommonly follows reduction in the IS regimenChronic: <5%1 wk to 6 mo MC range to experience
  • Cardiac transplant rejection:Acute rejection:75 " “85% of patients within the 1st 3 " “6 mo due to T-cell " “mediated responseChronic rejection:Accelerated atherosclerosis is the hallmarkAssociated with change in IS therapy
  • Lung transplant rejection:Acute rejection develops early:Can occur up to 6 times in the 1st yearChronic rejection:25 " “40% of patients postopMCC of death in 2nd postop yearRejection caused by endothelial, vascular, and lymphocyte inflammation, recurrent acute rejection
  • Bone marrow transplant rejection:Acute graft-versus-host disease:Immune attack of donor marrow on lung tissueChronic graft-versus-host disease:Marrow rejection:MC in patients with plastic anemia who do not receive total body radiotherapy or in patients receiving mismatched or unrelated transplants

Diagnosis

Signs and Symptoms

  • Renal transplant rejection:Progressive systemic HTNDecreased urine outputSwelling, fever, and tenderness:Uncommon with IS therapy
  • Liver transplant rejection:Fever, RUQ pain, jaundice
  • Heart transplant rejection:Fever, dyspnea, chest pain, hypo- or hypertension, palpitations, nausea, vomiting, syncope, sudden deathCan be asymptomatic
  • Lung transplant rejection:Cough, dyspnea, fever, rales, and rhonchi
  • Bone marrow transplant rejection:Fever, wasting, mucositis, keratoconjunctivitis, dysphagia, cough, dyspnea, hypoxia, chest pain, abdominal pain, diarrhea, jaundice, rash, encephalopathy, seizures

Diagnosis Tests & Interpretation

Lab

  • CBC
  • IS medication levels:Levels may not represent through if patient took medication prior to ED visit.
  • Blood cultures
  • Renal transplant rejection:Electrolytes, BUN, creatinine, CRPUrinalysis with micro:Proteinuria may signal early rejection. Presence of leukocytes may be seen during rejection as well as with infection.FENa helps differentiate rejection from iatrogenic causes
  • Liver transplant rejection:Coagulation panel, lipase, cultures (blood, urine, ascites), liver function testsLate acute rejection presents with elevated bilirubin and transaminases.
  • Heart transplant rejection:
  • Lung transplant rejection:ABG, electrolytes, kidney function, CRP, liver function, bilirubin, LDH, CPK, EBV, CMV, cyclosporine levels
  • Bone marrow transplant rejection:ABG, liver function tests

Imaging

  • CXR:Acute lung rejection:Diffuse infiltrates are seen earlyNormal or unchanged >1 mo after transplantationBone marrow transplant rejection:Interstitial infiltrates, pleural effusion, pulmonary edema
  • Renal US:Indicated for suspicion of renal transplant rejection:Hydronephrosis implies obstructive uropathy and may need urgent percutaneous nephrostomy.
  • Liver transplant:
  • Echocardiography:Heart transplantAssess for changes in cardiac output.
  • MRI:Renal transplant:May be done with or without contrastConsult transplant team before giving contrast

Diagnostic Procedures/Surgery

  • Liver transplant rejection:
  • Heart transplant rejection:EKG:Commonly demonstrates 2 P waves because the native sinus node is spared
  • Lung transplant rejection:Peak flow reduced FEV1Early bronchoscopy and biopsy to differentiate infection from rejection

Essential Workup

  • Consider drug toxicity and infection as well as rejection.
  • Ask about medication dose or compliance changes
  • Low threshold for screening labs and imaging even with minimal signs and symptoms

Differential Diagnosis

  • Infections:Wide variety of bacterial, mycobacterial, fungal, viral, and parasitic pathogens can cause opportunistic infections in transplant patients.
  • IS toxicity
  • Drug interactions with IS medication
  • Renal transplant rejection:Any disorder that can affect the native kidneys can also occur in the transplantIatrogenic nephrotoxicity: Cyclosporine, tacrolimus, other medicationsUTI/pyelonephritis:Classic organisms as with native kidney infectionsTubulointerstitial nephritis caused by the BK-polyomavirus (incidence 3 " “5%)Acute occlusion of the transplant renal artery or vein:Acute occlusion usually occurs within the 1st post-transplant week (incidence 0.5 " “8%) and causes oliguria and acute renal failure.Peritransplant hematomaUrinary leakObstructive uropathyBleeding after renal graft biopsy
  • Liver transplant rejectionAscending cholangitis:Possible from colonized postop biliary stent.Cholestatic hepatitis from azathioprineMethotrexate-induced hepatotoxicity
  • Lung transplant rejectionMC bacterial infection in lung transplant is cytomegalovirus pneumonia.MC fungal infection is Aspergillus.Upper respiratory infection or bronchitis:Mimic chronic lung rejectionMedication-induced pneumonitis

Treatment

Pre-Hospital

Avoid aggressive fluid resuscitation. ‚

Initial Stabilization/Therapy

  • ABCs
  • Shock state treated with IV fluids, and pressor agents.
  • Treat hypertensive crisis like other hypertensive emergencies.

Ed Treatment/Procedures

Always discuss with transplant service early unless unstable, especially when adding or changing medications. ‚

Caution with use of NSAIDs; there are many associated complications in these patients. ‚

  • Kidney, heart, lung, and liver rejection:Administer high-dose steroidsStress-dose corticosteroid coverage is also indicated in any ill-appearing transplant patient. Consult with transplant service earlyAvoid blood transfusions because these need special screening to prevent transmission of disease.
  • Heart transplant rejection:Pressors and inotropics work as usual in the transplanted heart.Atropine will have no effect on bradycardia because there is no vagal innervation.Use dopamine, epinephrine drips, or external pacing to increase heart rate if bradycardia is symptomatic.IV methylprednisolone: 1 gm/d for 3 days
  • Lung transplant:Treat for infection and rejectionIV methylprednisolone: 15 mg/kg daily ƒ — 3 days
  • Graft-versus-host disease:1 " “2 mg/kg daily PO or IV steroidsFor chronic, may need adjustments of IS therapy.
  • Common IS regimens are cyclosporine, prednisone, and azathioprine or tacrolimus and prednisone.

Medication

As directed by transplant team ‚

Follow-Up

Disposition

Admission Criteria

  • Admit transplant recipients with fever, shortness of breath, signs or symptoms of rejection, abdominal pain, or other signs of organ infection, pneumothorax, and respiratory failure.
  • Admit to the ICU patients who are septic, in acute renal failure, or have cardiopulmonary compromise.

Discharge Criteria

Nontoxic patients in whom rejection or serious infection has been excluded may be discharged with close follow-up and in consultation with their transplant service. ‚

Issues for Referral

Treatment decisions should be made in consultation with the patients oncologist, transplant surgeon, or organ specialist. ‚

Follow-Up Recommendations

  • The patients transplant team should actively participate in the follow-up plan:
  • All attempts at verbal communication with the covering transplant physician should be made while the patient is in the ED with any symptoms suggestive of rejection.

Pearls and Pitfalls

  • Transplant patients presenting with minor complaints are at high risk for rejection and require an in-depth assessment in the ED, in conjunction with their transplant team.
  • Patients with signs of possible transplant rejection should also be considered for infection and drug toxicity.
  • A high percentage require admission

Additional Reading

  • Ferrara ‚ JL, Levine ‚ JE, Reddy ‚ P, et al. Graft-versus-host disease. Lancet. 2009;373(9674):1550 " “1561.
  • Patel ‚ JK, Kittleson ‚ M, Kobashigawa ‚ JA. Cardiac allograft rejection. Surgeon. 2011;9(3):160 " “167.
  • Razonable ‚ RR, Findlay ‚ JY, O 'Riordan ‚ A, et al. Critical care issues in patients after liver transplantation. Liver Transpl. 2011;17(5):511 " “527.
  • Schuurmans ‚ MM, Tini ‚ GM, Zuercher ‚ A, et al. Practical approach to emergencies in lung transplant recipients: How we do it. Respiration. 2012;84(2):163 " “175. doi:10.1159/000339345. Epub 2012.
  • Venkat ‚ KK, Venkat ‚ A. Care of the renal transplant recipient in the emergency department. Ann Emerg Med. 2004;44(4):330 " “341.

Codes

ICD9

  • 996.80 Complications of transplanted organ, unspecified
  • 996.81 Complications of transplanted kidney
  • 996.82 Complications of transplanted liver
  • 996.83 Complications of transplanted heart
  • 996.84 Complications of transplanted lung
  • 996.85 Complications of transplanted bone marrow
  • 996.86 Complications of transplanted pancreas

ICD10

  • T86.11 Kidney transplant rejection
  • T86.41 Liver transplant rejection
  • T86.91 Unspecified transplanted organ and tissue rejection
  • T86.21 Heart transplant rejection
  • T86.01 Bone marrow transplant rejection
  • T86.810 Lung transplant rejection

SNOMED

  • 213148006 transplanted organ rejection (disorder)
  • 236570004 Renal transplant rejection (disorder)
  • 235911006 Liver transplant rejection (disorder)
  • 233933006 Cardiac transplant rejection (disorder)
  • 234519006 Bone marrow transplant rejection (disorder)
  • 312603000 Lung transplant rejection (disorder)
  • 431506006 Rejection of pancreas transplant