Kidney transplantation

Kidney transplantation represents a complex overlapping of immunology, nephrology, and surgery. We will initially describe the important role of tissue typing, tissue compatibility and histocompatibility testing in donor-recipient selection.

13.1 Tissue typing and compatibility

Histocompatibility Testing

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Tissue typing
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  Serological (identifying Ag on cell membranes: reaction between cells of the subjects and antibodies to specific HLA antigens): microlymphocytotoxicity test
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  Molecular techniques (DNA typing): polymerase chain reaction (PCR) (DNA nomenclature: name has four digits, first two correlate with serologic name: A1, B3, etc.; last two indicate allelic name)
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HLA antibody (Ab) identification (panel reactive antibodies—PRA): cytotoxic test, ELISA, flow cytometry
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Crossmatching with T- and B-lymphocytes (to predict hyperacute rejection):
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  T cells do not constitutively express HLA class II so the result of a T-cell crossmatch generally reflects antibodies to HLA class I only
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  B cells on the other hand express both HLA class I and II so a positive B-cell crossmatch may be due to antibodies directed against HLA class I or II or both
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  Microlymphocytotoxicity test with patient’s serum and donor’s lymphocytes (T & B)—screen for preformed Ab
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  Flow cytometry (flow cytometric crossmatch [FCXM] method): more sensitive, allows the detection of antibodies against T-lymphocytes (anti-HLA class I antibodies) and B-lymphocytes (anti-HLA class I and/or HLA class II antibodies)
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  Antiglobulin crossmatch
Lymphocytotoxicity test used in almost all of the above tests—complement-dependent cytotoxicity (CDC) assay:
Ag + Ab + complement → lysis of lymphocytes (may be used to look for a specific Ag or Ab)

13.2 Donor selection and the role of tissue matching

1.

Blood type: while there are some transplant centers that transplant across ABO groups, typically it is required that donor and recipient would have the same blood type (though blood type O can be a universal donor). Also, multiple studies have demonstrated the safe and effective transplantation of blood group B kidney transplant recipients with kidneys from donors having the less immunogenic non-A1 subtype.
2.

HLA match: higher degree of HLA match is associated with proportionally increased long-term graft survival. Matching by the 6 alleles of HLA-A, -B, and –DR is considered matching compatibility for practical purposes.
3.

Preformed donor antibodies: presence of preformed antibodies against donor-specific HLA antigens is a barrier to transplantation and an important cause of allograft loss, increasing the risk for early antibody mediated rejection. Desensitization protocols can be used: plasmapheresis, IVIg, immunoabsorption (not presently in use in the USA), and rituximab.

13.3 Factors affecting transplant graft outcome ^,^,

Donor Characteristics:

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Live or deceased donor
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Age, BMI, race (worse outcome in Black or Hispanic donors), comorbidities, gender (better with kidneys from males), creatinine level

Recipient Characteristics:

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Age, race (worse outcome in Black recipients), BMI, gender (better in males)
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First transplant (outcome of each consecutive transplant is generally worse) ^,
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RRT modality (PD or prior transplant are both better than HD)
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Timing of transplant—see charts below
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Duration of ESKD
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Cause of ESKD (e.g., SLE is associated with inferior outcome ^,)
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Presence of CVD
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Individual socioeconomic factors (education level, type of insurance, alcohol use) and composite social adaptability index (higher index is associated with better outcome)

Other Factors:

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HLA match of donor and recipient
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Cold ischemia time of kidney
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Procedure (worse outcome with kidney-pancreas, en-bloc transplant)
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Higher transplant volume of transplant center
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State of the economy
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Delayed graft function

BMI , Body mass index; CVD , cardiovascular disease; ESKD , end-stage kidney disease; HLA , human leukocyte antigen; PD , peritoneal dialysis; RRT , renal replacement therapy; SLE , systemic lupus erythematosus.

13.4 Timing of transplantation

First Transplant	Retransplantation
• Preemptive transplantation seems to be beneficial • However, being on dialysis for up to 6 months is associated with the same outcome as preemptive transplantation	• Unlike the first transplant, preemptive retransplantation might be associated with a higher risk of graft loss by 36%. • However, among those on dialysis in between transplants, longer time on dialysis is associated with higher risk.

13.5 Preemptive transplantation versus transplantation after initial period of dialysis

13.6 Immunosuppression

The following diagram is a schematic representation of the mechanism of action of the most commonly used immunosuppressive medications (see immunological pathways described at the end of this chapter).

13.7 Action of immunosuppressive medications

The goal of immunosuppression therapy is to suppress the immune system to the point of avoiding rejection, but at the same time to minimize the potential side effects of excessive immune suppression.

This table represents a summary of the mechanisms of action, doses, and side effects of the most commonly used immunosuppressive medications.

Immunosuppressive medications commonly utilized

	Mechanism	Initial Dose	Complications
Cyclosporine (Neoral, Sandimmune)	1. Binds with cyclophilin; this complex inhibits calcineurin ⇒ ↓ expression of T-cell activation genes 2. Inhibits IL-2 driven proliferation of activated T-cells (inhibits IL-2 message); affects G0-G1 cell cycle 3. Enhances the expression of TGF-β	• PO: 8–15 mg/kg/day, change in 2-mg/kg increments according to level • IV daily dose = 1/3 PO daily dose • Levels may be influenced by drugs affecting p-450	• Nephrotoxicity (acute: reduction of renal blood flow b/o increased sympathetic tone and RA system; chronic: interstitial fibrosis after 6–12 months of treatment b/o chronic ischemia and toxicity and enhanced apoptosis) • HTN • Hyperlipidemia • Diabetes (less than tacrolimus) • Infections (CMV, BK virus, bacterial, etc.) • ↓ T-cell proliferation • Tremors • Hirsutism • Hepatotoxicity • CNS toxicity • Gingival hypertrophy • Renal vascular damage • Malignancies • Drug–drug interaction reduces mycophenolate level16
Tacrolimus (FK506, Prograf)	1. Similar to cyclosporine; binds with FKBP12; blocks calcineurin 2. Inhibits IL-2 (inhibits IL-2 message), -3, -4, and TNF production 3. Affects G0–G1 cell cycle	• 0.15–0.3 mg/kg/day	Similar to cyclosporine: • Nephrotoxicity (same as for cyclosporine) • Neurotoxicity (tremor, low seizure threshold, headaches, nightmares) • HTN (less than cyclosporine) • Hyperlipidemia (less than cyclosporine and sirolimus) • GI: diarrhea, anorexia • Glucose intolerance/DM • Infections (CMV, BK virus, bacterial, etc.) • Hyperkalemia • Malignancies
Sirolimus (Rapamycin)	1. Binds with FKBP12, interferes with TOR (target of rapamycin) and blocks T-cell activation; blocks IL-2 response 2. Affects G1-S cell cycle	• Start at 2 mg/day and follow levels	• Hypercholesterolemia, hypertriglyceridemia (treat with statins) • Stomatitis (dose reduction or transient discontinuation [DC]) • Myelosuppression: pancytopenia including thrombocytopenia (more common in combination with MMF, responds to dose reduction or transient DC) • HTN (treatment of choice: ACEI/ARB, but may worsen anemia) • Wound/incision complications, lymphocele (more common with high levels, in DM and obesity, responds to dose reduction or transient DC) • Pneumonitis (interstitial lung disease/BOOP/pulmonary fibrosis: increased risk with higher level, may respond to dose reduction or DC) • May potentiate nephrotoxic effect of cyclosporine, increases MMF level (but not tacrolimus level) • Infections (CMV, BK virus, bacterial, etc.) • Asthenia, headaches, epistaxis, diarrhea, arthralgia • Proteinuria
Azathioprine (Imuran)	1. Inhibits purine nucleotide synthesis ⇒ inhibits gene replication and T-cell activation, suppresses myelocytes 2. Effectiveness is not blood-level–dependent	• Start at 3–4 mg/kg/day, adjust the dose to WBC count • IV daily dose = 1/2 PO daily dose	• Bone marrow suppression/leukopenia • Hepatitis, cholestasis—occasionally • Avoid concomitant allopurinol- bone marrow toxicity; check for thiopurine methyltransferase (TPMT) mutation before initiation to avoid bone marrow toxicity
Mycophenolate mofetil (MMF) (CellCept)	1. Binds to protein MPA, affects IMPDH, inhibits IL-2 production (inhibits IL-2 message) and response 2. Inhibits de novo pathway of purine biosynthesis by blocking inosine monophosphate dehydrogenase activity 3. Blocks proliferation of T- and B-cells, Ab formation, generation of cytotoxic T-cells	• 1000 mg PO twice daily (1500 mg twice daily when greater immune suppression is desired with cyclosporine)	• GI: dyspepsia, diarrhea, hepatic injury, inflammatory colitis • Hematological: leukopenia, anemia • CMV (as all other immunosuppressives) • Infections (CMV, BK virus, bacterial, etc.) • Malignancies • Congenital malformations (avoid in pregnancy)
Corticosteroids	1. Inhibit the expression of cytokine genes: IL-1, -2, -3, -6, TNF-alpha, gamma-interferon 2. Nonspecific immunosuppressive effect	• Taper to 5 mg/day, or stop early if on early steroid withdrawal protocol (center specific)	• Osteoporosis • Hyperlipidemia, glucose intolerance • Neuropsychological (anxiety) • Infections (opportunistic) • Impaired wound healing • Growth impairment in children
Nonlymphocyte-depleting antibodies; IL-2 inhibitors; daclizumab (Zenapax), basiliximab (Simulect)	1. Monoclonal Ab’s against IL-2 receptors; used for induction therapy	• Zenapax 1 mg/kg on day of surgery, postop at 2-wk intervals up to 4 doses • Simulect: 20 mg on day of surgery, again on POD#4	• Zenapax: hyperlipidemia, diabetes, CMV • Simulect: anaphylaxis, infections
Lymphocyte-depleting antibodies (ATG, TMG, OKT3)	1. Ab’s against CD3. For patients with high risk: retransplant, Blacks, sensitized (PRA >30%), as induction in pancreas transplant	• Dose may vary; e.g., for induction with ATG, 1.25 mg/kg IV every other day for 3 doses	• Malignancies, e.g., PTLD: greatest risk EBV donor positive to recipient negative • Anaphylaxis, serum sickness • Bone marrow suppression (leukopenia, thrombocytopenia) • Infections (CMV)
CTLA 4-Ig(Belatacept)	1. Costimulatory blocker, selectively blocks T-cell activation	• 5–10 mg/kg (monthly maintenance dosing)	• PTLD (black box warning EBV D+/R-) • PML • Infections

ACEi , Angiotensin-converting-enzyme inhibitor; ARB , angiotensin II receptor blocker; b/o , because of; BOOP , bronchiolitis obliterans organizing pneumonia; CMV , cytomegalovirus; CNS , central nervous system; DC , discontinuation; DM , diabetes mellitus; GI , gastrointestinal; HTN , hypertension; IMPDH , inosine-5´-monophosphate dehydrogenase; IV , intravenous; MMF , mycophenolate mofetil; MPA , mycophenolic acid; OKT3 , muromonab-CD3; PML , progressive multifocal leukoencephalopathy; PO , by mouth; POD , post-operative day; PTLD , posttransplant lymphoproliferative disease; RA , renin angiotensin; TMG , thymoglobulin; TNF , tumor necrosis factor; TPMT , thiopurine methyltransferase; WBC , white blood cell.