Transplant Evaluation and Selection
Overview
Kidney transplantation offers superior outcomes to dialysis for appropriate candidates: improved quality of life, longer survival, and lower cost per patient-year compared to dialysis [1]. Comprehensive pretransplant evaluation identifies absolute contraindications, assesses medical/surgical risk, and screens for malignancy, infection, and cardiovascular disease. Immunologic workup (HLA typing, PRA assessment, crossmatching) guides donor selection and immunosuppression strategy. This guide synthesizes transplant evaluation, donor-recipient matching, immunosuppression regimens, and post-transplant complication management.
Key Clinical Pearl
“The best renal transplant is a preemptive living-donor transplant from a biologically related donor with minimal immunologic mismatch. However, even an older, EBV+ donor kidney in a well-screened recipient with excellent adherence is superior to a lifetime on dialysis.”
Part 1: Transplant Evaluation Framework
Timing of Referral
KDIGO Recommendation: - G3b CKD (eGFR 30–44): Offer education on all RRT options (dialysis, transplant, conservative care) - G4 CKD (eGFR 15–29): Refer for transplant evaluation if appropriate - G5 CKD (eGFR <15): Complete evaluation and list if transplant-eligible - Pre-emptive transplant: Ideal; can occur before dialysis initiation (especially living-donor)
Goals of Transplant Evaluation
- Determine transplant eligibility: Identify absolute/relative contraindications
- Optimize health status: Treat cardiovascular disease, diabetes, infections
- Assess immunologic risk: HLA sensitization, crossmatch compatibility
- Educate on RRT options: Living vs deceased donor, risks/benefits
- Assess psychosocial readiness: Adherence capacity, social support, mental health
Part 2: Contraindications to Transplantation
Absolute Contraindications (Transplant Not Offered)
| Contraindication | Rationale | Duration |
|---|---|---|
| Active malignancy | Immunosuppression accelerates tumor growth | Until treatment complete |
| Active infection (systemic) | Uncontrolled sepsis; immunosuppression worsens outcome | Until resolved |
| Active tuberculosis (untreated) | Immunosuppression causes dissemination | Until fully treated (6 months) |
| Uncontrolled psychiatric disease | Risk of non-adherence; transplant failure | Until stabilized |
| Inability to comply with immunosuppression | Ensures graft survival; non-adherence = rejection | Lifelong |
| Life expectancy <5 years (from non-renal disease) | Risk/benefit unfavorable | N/A |
| Uncorrected cardiac disease with high operative risk | Cannot tolerate transplant surgery | Until correctable |
| Severe hepatic cirrhosis (Child-Pugh C) | Poor synthetic function; cannot metabolize drugs | Permanent |
Relative Contraindications (Assessed Case-by-Case)
| Contraindication | Assessment | Decision Pathway |
|---|---|---|
| History of malignancy | Type, stage, time since treatment | >2–5 years cancer-free may be acceptable |
| Age >70 years | Functional status, comorbidities, life expectancy | Chronologic age alone not contraindication |
| Severe obesity (BMI >40) | Surgical risk, graft function, compliance | May accept if motivated; weight loss recommended |
| Significant proteinuria (>2 g/day) | Etiology; assess for GN | May transplant if stable; treat underlying disease |
| History of nonadherence | Assess reasons; psychosocial support | Intensive counseling may improve outcomes |
| Active substance abuse | Addiction active vs in remission | Usually requires 6 months sobriety |
| Severe coronary artery disease | Assess with stress testing; revascularize if possible | May accept high-risk CAD if revascularized |
| Hepatitis C antibody positive | HCV RNA+ state; assess liver fibrosis; transplant HCV- donor if possible | Direct-acting antivirals cure HCV; may improve candidacy |
| Hepatitis B surface antigen+ | Assess HBeAg, HBV DNA; vaccination status | Lamivudine/TDF prophylaxis minimizes progression |
Part 3: Immunologic Workup
HLA Typing
HLA (Human Leukocyte Antigen): Polymorphic proteins on cell surface that trigger immune recognition.
HLA Classes: - Class I (HLA-A, -B, -C): On all nucleated cells; target of acute/chronic rejection - Class II (HLA-DR, -DQ, -DP): On antigen-presenting cells; elicit T-helper response
Clinical importance: - Identical twins: 0 HLA mismatch; no rejection risk (theoretically) - Haplo-identical (one parent/sibling): 3 HLA mismatch (one haplotype shared); acceptable - Unrelated: Often 6 HLA mismatch (highest rejection risk without sensitization history)
Effect on graft survival: Each additional HLA mismatch ~5% reduction in 5-year graft survival.
Panel Reactive Antibody (PRA) and Sensitization Assessment
PRA (% panel reactive antibody): - Definition: Percentage of donors in a panel to whom recipient has preformed anti-HLA antibodies - Measured by: Flow cytometry, Luminex (most sensitive) - Interpretation: - PRA 0%: Non-sensitized; low rejection risk; easiest to match - PRA 1–49%: Moderately sensitized; acceptable transplant candidates with good matching - PRA >50%: Highly sensitized; need compatible donor or desensitization; longer wait times
Causes of sensitization: - Prior transplant rejection (most common) - Multiple blood transfusions - Pregnancy (female recipients) - Prior exposure to alloantigen (repeat transfusions, failed prior grafts)
Donor-Specific Antibodies (DSA)
Definition: Antibodies against specific donor HLA antigens (determined after donor identified).
Test: Single-antigen Luminex bead assay (identifies exact HLA antibodies).
Clinical significance: - Donor-specific IgG antibodies: HIGH risk of antibody-mediated rejection (AMR); may necessitate desensitization or declining donor - Donor-specific IgM antibodies: Variable risk; typically lower than IgG - Complement-fixing antibodies: Higher rejection risk than non-complement-fixing
Crossmatch Test
Definition: In vitro test of recipient serum against donor lymphocytes to detect anti-donor antibodies.
Test methods (from least to most sensitive): 1. Complement-dependent cytotoxicity (CDC): Gold standard historically; detects IgG/IgM 2. Flow cytometry crossmatch: More sensitive; detects low-level IgG; better predictor of rejection 3. Luminex: Single-antigen beads; identifies exact HLA antibodies vs donor antigens
Interpretation: - Negative crossmatch: Safe to proceed (IgG antibody unlikely to cause hyperacute rejection) - Positive IgG crossmatch: CONTRAINDICATION to transplant (hyperacute rejection risk; graft loss within hours) - Positive IgM only: Acceptable; IgM typically clears quickly
ABO Incompatibility
Traditional rule: ABO-incompatible transplants were contraindicated (hyperacute rejection from IgM ABO antibodies).
Modern approach (ABO-incompatible transplant): - Desensitization: Plasmapheresis, low-dose IVIG, rituximab (anti-CD20) - Result: Successful ABO-incompatible transplants now possible (5-year graft survival ~80% vs 85% for ABO-compatible) - Advantage: Expands living-donor pool; reduces wait times for O recipients
Part 4: Living vs Deceased Donor Selection
| Characteristic | Living Donor | Deceased Donor | Impact on Graft |
|---|---|---|---|
| Donor evaluation | Comprehensive; healthy baseline | Variable; often limited pre-mortem history | Living = better outcomes |
| HLA matching | Often related (0–3 mismatch) | Usually unrelated (3–6 mismatch) | Each mismatch ~5% 5-yr graft loss |
| Cold ischemia time | 0 (immediate transplant possible) | 12–24+ hours | Longer ischemia time = more dysfunction |
| Delayed graft function (DGF) | 5–10% | 20–40% | DGF increases acute rejection risk |
| Acute rejection rate | 20–30% | 40–45% | Living > deceased in intermediate-term |
| Graft survival at 5 years | 80–85% (living-related); 75–80% (living-unrelated) | 70–75% | Living-related superior |
| Recipient survival | Better (better health; pre-emptive options) | Variable | Living donor recipients have better outcomes |
| Cost analysis | Higher upfront surgical cost (evaluating donor + surgery) | Lower upfront but more dialysis time before Tx | Long-term cost similar; transplant always cheaper |
Kidney Paired Donation (KPD)
Definition: Cross-matching incompatible recipient-donor pairs to find compatible matches.
Example: - Patient A incompatible with Donor A - Patient B incompatible with Donor B - BUT: Patient A compatible with Donor B; Patient B compatible with Donor A - Solution: Swap donors → two successful transplants
Impact: Increases transplant options for highly sensitized recipients and ABO-incompatible pairs.
Part 5: UNOS Allocation System for Deceased Donors
Kidney Allocation System (KAS) Principles
Goals: 1. Maximize graft longevity (longer-surviving grafts to younger recipients) 2. Eliminate transplant list waiting time based solely on time accumulated 3. Achieve better HLA matching when possible 4. Improve equity across geographic regions
Key Metrics
Kidney Donor Profile Index (KDPI): - Composite score (0–100) predicting donor kidney function - Low KDPI (<35%): Better quality; longer expected survival - High KDPI (>85%): Lower quality; shorter expected survival
Estimated post-transplant survival (EPTS): - Score predicting recipient’s expected lifespan post-transplant - Low EPTS (<20%): Longer life expectancy; allocated best kidneys - High EPTS (>80%): Shorter life expectancy; lower-quality kidneys may be appropriate
Allocation priority: - High-KDPI kidneys → low-EPTS recipients (best match) - Low-KDPI kidneys → can be allocated based on compatibility/geography
Part 6: Induction and Maintenance Immunosuppression
Induction Therapy (At Time of Transplant)
Goal: Prevent acute cellular rejection in immediate post-transplant period.
Options:
| Agent | Type | Dosing | Use | Mechanism |
|---|---|---|---|---|
| Basiliximab | Anti-IL-2R mAb | 20 mg IV day 0, 4 | Standard induction | IL-2 receptor blockade |
| Daclizumab | Anti-IL-2R mAb | 1 mg/kg day 0, 4 | Alternative (rarely used) | IL-2 receptor blockade |
| Alemtuzumab | Anti-CD52 mAb | 0.3 mg/kg IV day 0 | Highly sensitized; ANCA+ | T-cell and B-cell depletion |
| Rituximab | Anti-CD20 mAb | 375 mg/m² day 0 | B-cell targeting; ABO-incompatible Tx | B-cell depletion |
| Antithymocyte globulin (ATG) | Polyclonal antibody | 1.5 mg/kg daily × 3–5 days | Induction; steroid-sparing | T-cell depletion |
Preferred approach: Basiliximab induction + calcineurin inhibitor + MMF + corticosteroids (standard triple therapy).
Maintenance Therapy (Long-Term)
Standard triple therapy:
| Agent | Class | Dosing | Mechanism | Monitoring |
|---|---|---|---|---|
| Tacrolimus | Calcineurin inhibitor | 1–2 mg 2×/day (level 5–12 ng/mL initially) | Inhibits IL-2 T-cell signal | Trough level; renal function; K; Mg |
| Mycophenolate mofetil (MMF) | Antimetabolite | 500–1000 mg 2×/day | Inhibits IMPDH; depletes GTP in T/B cells | CBC (monitor for leukopenia) |
| Prednisone | Corticosteroid | 5–10 mg daily (taper from 20 mg day 0) | Anti-inflammatory; blocks cytokine production | Weight; glucose; BP; osteoporosis risk |
Alternative combinations:
| Scenario | Preferred Regimen | Rationale |
|---|---|---|
| EBV-negative recipient | Basiliximab + tac + MMF + pred | Standard |
| CNI-intolerant (diabetes, nephrotoxicity) | Basiliximab + sirolimus + MMF + pred | Avoid CNI nephrotoxicity |
| High immunologic risk (sensitized) | Alemtuzumab + tac + MMF + pred | More intensive T/B-cell depletion |
| Older recipient, excellent match | Lower-intensity (belatacept + pred alone) | Belatacept (T-cell co-stimulation blocker) |
Calcineurin Inhibitor (CNI) Toxicity
Tacrolimus and cyclosporine both cause: - Nephrotoxicity: Chronic CNI nephropathy → GFR decline 5–10 mL/min/yr over 5 years - Hypertension: 50–80% of recipients (vasoconstriction) - Hyperkalemia: Impairs K secretion; requires careful monitoring - Hypomagnesemia: Increases cardiac arrhythmia risk - Diabetes (new-onset): 15–20% of recipients; glucose intolerance
Management: - Monitor trough CNI levels (narrow therapeutic window) - Monitor renal function; decline >20% warrants assessment - Antihypertensive therapy (aim SBP <130 mmHg) - Potassium monitoring; restrict K if elevated - Screen for NODAT (new-onset diabetes after transplant)
Part 7: Post-Transplant Complications
Acute Cellular Rejection (ACR)
Timing: Usually 1–12 months post-transplant (can occur anytime).
Pathophysiology: T-cell mediated infiltration of graft; interstitial inflammation, tubulitis.
Clinical presentation: - Rising serum creatinine (30–50% above baseline) - Decreased urine output - Possible fever, graft tenderness, proteinuria
Diagnosis: Renal biopsy (gold standard); shows mononuclear infiltrate, tubulitis.
Treatment: - Mild-moderate ACR: Increase corticosteroid dose (pulse methylprednisolone 500 mg IV daily × 3 days) - Severe/steroid-resistant: Antithymocyte globulin (ATG 1.5 mg/kg daily × 3–5 days) OR rituximab
Outcomes: 80–90% respond to treatment; steroid resistance associated with worse long-term outcomes.
Antibody-Mediated Rejection (AMR)
Pathophysiology: Donor-specific antibodies (anti-HLA, anti-MICA, anti-endothelial) activate complement; endothelial inflammation.
Presentation: - Rising Cr - Proteinuria - May be accompanied by acute cellular rejection (“mixed rejection”)
Diagnosis: Renal biopsy with IF shows C4d deposition (along peritubular capillaries); DSA+ serum.
Treatment: - Acute AMR: Plasmapheresis (remove DSA) + IVIG (inhibit complement) + rituximab (deplete B cells producing antibodies) - Chronic AMR: Long-term plasmapheresis, IVIG, rituximab; prognosis poor (median graft survival ~5 years)
Chronic Antibody-Mediated Rejection (cAMR)
Definition: Slower decline in graft function associated with persistent DSA + C4d+ and/or chronic pathologic lesions (transplant glomerulosclerosis, transplant vasculopathy).
Pathologic features: - Transplant glomerulosclerosis (TGS): Duplication of GBM, capillary collapse - Transplant vasculopathy: Intimal hyperplasia in arteries - Interstitial fibrosis/tubular atrophy (IF/TA): Secondary to chronic rejection
Outcomes: Progressive graft loss; median 5–10 year graft survival with cAMR.
Infections Post-Transplant
Timeline and pathogens:
| Timing | Common Pathogens | Pathophysiology |
|---|---|---|
| 0–1 month | Bacterial UTI, wound infection, HSV (reactivation) | Post-surgical; high-dose initial immunosuppression |
| 1–6 months | CMV (primary/reactivation), PCP, Toxoplasma, Cryptococcus, Aspergillus | Peak immunosuppression period; opportunistic |
| >6 months | Community organisms (S. pneumoniae), mycobacteria, late CMV | Immunosuppression lower; community exposure |
CMV Prophylaxis: - High-risk (seropositive donor, seronegative recipient): Valganciclovir 900 mg daily × 3–6 months - Lower-risk: IVIG or valganciclovir based on risk stratification
PCP Prophylaxis: - CD4 <200 or heavy immunosuppression: TMP-SMX double-strength daily or 3×/week
Fungal prophylaxis: - Nystatin oral rinse for first 3 months (Candida) - Fluconazole if high-risk or previous fungal infection
Malignancy Post-Transplant
Increased risk: 4–5× higher than general population due to chronic immunosuppression.
Most common: 1. Skin cancer (basal cell, squamous cell, melanoma): 40% of cancers 2. Post-transplant lymphoproliferative disorder (PTLD): EBV-driven B-cell lymphoma; 1–2% of recipients 3. Renal cell carcinoma: Native kidney cancer (not graft); slightly elevated risk 4. Cervical cancer (women); anal cancer; lung cancer
Risk factors: - Duration of immunosuppression - Type of immunosuppression (higher risk with mTOR inhibitors, azathioprine) - EBV serostatus (EBV-negative recipients: higher PTLD risk) - Sun exposure, HPV infection, age
Screening: - Annual skin exam (dermatology) - Cervical cancer screening (pap smear annually) - Cancer awareness; report symptoms promptly
PTLD management: - Early lesion: Reduce immunosuppression + observation - Advanced/symptomatic: Rituximab ± chemotherapy (CHOP)
BK Virus Nephropathy
Etiology: BK polyomavirus reactivation in immunosuppressed recipients; direct viral cytopathic effect on tubular epithelium.
Presentation: - Rising Cr months 3–12 post-transplant - Often asymptomatic; discovered on lab monitoring - Decoy cells on urine cytology (pathognomonic)
Diagnosis: Biopsy shows viral inclusions in tubular epithelium; PCR in urine/serum >10,000 copies indicates active viremia.
Treatment: - Reduce immunosuppression (lower CNI target level; reduce MMF dose) - Antivirals: Cidofovir (nephrotoxic; use with caution) or fluoroquinolones (limited evidence) - Monitor viral load with serum/urine PCR
Prognosis: ~50% progress to graft loss despite treatment; early detection improves outcomes.
CMV Infection/Disease
CMV viremia vs disease: - Viremia: Positive blood culture/PCR without symptoms; may progress to disease - Disease: Viremia + end-organ involvement (colitis, esophagitis, retinitis, pneumonitis)
Diagnosis: PCR quantitative (viral load in blood); tissue biopsy with viral culture/histology.
Treatment: - CMV viremia: Valganciclovir 900 mg 2×/day until PCR negative - CMV disease: IV ganciclovir (organ involvement requires higher doses) or valganciclovir
Part 8: Long-Term Graft Function and Outcomes
Determinants of Graft Longevity
| Factor | Impact | Modifiable |
|---|---|---|
| HLA matching | Each mismatch ~5% 5-yr loss | No (donor selection) |
| Donor age | Older donors → shorter graft lifespan | No |
| Cold ischemia time | >24 hrs associated with slower function recovery | No (deceased donor timing) |
| Recipient age | Younger = longer lifespan available for graft | No |
| Acute rejection | Any ACR episode associated with worse long-term outcomes | Yes (optimize induction/maintenance) |
| Serum creatinine trajectory | Early GFR decline (>10% first year) = poor prognosis | Yes (monitor CNI levels, BP, proteinuria) |
| Proteinuria | Proteinuria >1 g/day associated with worse outcomes | Yes (RAAS blockade) |
| Blood pressure control | SBP >130 associated with graft loss | Yes (antihypertensives) |
| CNI minimization | Long-term CNI toxicity; belatacept-based regimens may extend graft life | Yes (alternative induction/maintenance) |
| Adherence to immunosuppression | Non-adherence = #1 cause of late graft failure | Yes (education, monitoring, psychosocial support) |
Recurrent and De Novo Glomerulonephritis
Recurrent GN: Original disease recurring in transplanted kidney.
Frequency: 10–15% depending on primary disease.
High-risk diseases: - IgA nephropathy: 30–50% recurrence; 10% graft loss at 10 years - Lupus nephritis: 5–10% recurrence; often milder - FSGS: 20–40% recurrence (very high if primary form); can cause immediate graft dysfunction - Membranoproliferative GN: 20–30% recurrence
De novo GN: New glomerular disease in transplanted kidney (unrelated to original disease).
Management: - Monitor for proteinuria; repeat biopsy if rising Cr + proteinuria - Treat with RAAS blockade - Immunosuppression adjustment based on diagnosis
Part 9: Key Warnings
Warning 1: Non-Adherence is the Leading Cause of Late Graft Failure
50% of late graft failures due to non-adherence to immunosuppression. Risk factors: - Young age (forget medications) - Complex regimens (>3 medications) - Side effects (tremor, hirsutism, gum hyperplasia) - Psychiatric comorbidity, substance abuse
Prevention: Intensive patient education; psychosocial screening; simplified regimens when possible; consider directly-observed therapy if high-risk.
Warning 2: Acute Rejection in First 3 Years Predicts Poor Long-Term Outcomes
Any acute rejection episode (ACR or AMR) associated with 2–3× higher risk of chronic rejection and graft loss. Modern approach emphasizes preventing rejection through adequate induction + maintenance immunosuppression.
Warning 3: Calcineurin Inhibitor Nephrotoxicity Accelerates Chronic Graft Dysfunction
CNI-induced chronic nephropathy causes 30–50% GFR decline over 10 years. However, discontinuing CNI increases acute rejection risk. Balance: Monitor CNI levels; keep at lowest effective trough; consider switching to belatacept if CNI toxicity severe and HLA match good.
Warning 4: Sensitized Recipients Require Special Strategies
PRA >50%: Higher waiting time; longer time to compatible donor. Options: - Desensitization: For living-donor transplants (plasmapheresis + IVIG + rituximab) - Paired kidney exchange: Match with compatible donor pair - Accepting higher-risk donor: Older/lower-KDPI donor if waiting time prohibitive
References
[1] Hariharan S, McBride MA, Cherikh WS, et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62:311–318. PubMed
[2] Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant. 2009;9(suppl 3):S1–S155. KDIGO Guidelines
[3] Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made progress? Adv Chronic Kidney Dis. 2006;13:177–185. PubMed
[4] Loupy A, Haas M, Roufosse C, et al. The Banff 2019 Kidney Meeting Report (I): Acute and Chronic Glomerulonephritis, Pre-transplant Hypertensivity (Previously Called Humoral Rejection and Accommodation), Endothelial Injury, TMA and Atypical Deletion of C4d Staining. Am J Transplant. 2020;20:873–898. PubMed
[5] Orchanian-Cheff A, Cano AC, Lopez-Giacoman S, et al. Non-adherence to post-transplant immunosuppression: A systematic review and meta-analysis. Clin Transplant. 2018;32:e13419. PubMed
Last updated: 2026-02-28 Board-review quality curriculum for nephrology education.