KidneyTransplantation¶
Chapter 325 | Part 9: Disorders of the Kidney and Urinary Tract · Part 9 – Renal & Urinary Tract Disorders · Chapter 325
Key Clinical Points¶
- 1-year allograft survival rates in the US: Living donor 98%, Deceased donor 93%.
- Kidney Donor Profile Index (KDPI) <20% allocated to recipients with highest expected posttransplant survival.
- Absolute contraindications: Active malignancy, active infection, psychosocial issues affecting adherence, chronic illness limiting survival <2 years.
- Induction therapy: Antithymocyte globulin (ATG) for high-risk/sensitized; Basiliximab for low-risk.
- Maintenance regimen: Calcineurin inhibitor (Tacrolimus/Cyclosporine) + Antimetabolite (Mycophenolate/Azathioprine) + Steroids.
- Antibody-mediated rejection (ABM) hallmark: C4d deposition in peritubular capillaries and glomerular basement membrane + circulating donor-specific antibody.
- C4d deposition serves as a footprint of complement activation and diagnostic criterion of antibody-mediated rejection.
- CMV prophylaxis: Valganciclovir for seronegative recipients of seropositive donors.
- Malignancy incidence in transplant recipients: 5–6% (approximately 100x higher than the general population).
- DCD kidneys (Non-Heart-Beating Donors) from categories III and IV are not shown to be inferior to other deceased-donor kidneys.
- KDPI 85% kidneys (previously expanded criteria donor [ECD]) are directed toward patients expected to fare less well on dialysis.
DEFINITION & OVERVIEW¶
• Definition: Kidney transplantation is the treatment of choice for patients with end-stage kidney disease (ESKD). • Procedure: Surgical placement of a donor kidney into the recipient to restore renal function. • Historical Context: ◦ 1954: First successful transplant between identical twins. ◦ 1960s: Introduction of azathioprine and prednisone allowed for non-identical allografts. ◦ 1970s–1980s: Significant improvement in survival following the introduction of calcineurin inhibitors (CNI). • Current Status: ◦ 1-year survival rates: Living-donor 98%, Deceased-donor 93%. ◦ Average allograft survival: 19 years for living-donor; 12 years for deceased-donor. ◦ Age-related mortality (first year): 2% (18–34 years), 3% (35–49 years), 6.8% (≥50–60 years). ◦ Survival benefit over chronic dialysis is typically evident within days to months post-transplant.
EPIDEMIOLOGY¶
• Survival Rates (Table 325-2): ◦ Deceased donor grafts: → 1-year: 94% (Graft), 95% (Patient) → 5-year: 76% (Graft), 77% (Patient) → 10-year: 54% (Graft), 67% (Patient) ◦ Living donor grafts: → 1-year: 98% (Graft), 99% (Patient) → 5-year: 87% (Graft), 87% (Patient) → 10-year: 70% (Graft), 83% (Patient) • Risk Factors: ◦ Non-modifiable: Age, race (e.g., African-American ESKD population with higher prevalence of blood type B), genetic factors (APOL1 risk alleles). ◦ Modifiable: Diabetes, cardiovascular status, hypertension, obesity, active substance abuse, psychosocial issues affecting adherence. • Malignancy: ◦ Incidence: 5–6% in transplant recipients (approx. 100x higher than general population). ◦ Major causes of death: Cardiovascular events (29%), infection (18%), malignancy (17%).
ETIOLOGY & PATHOPHYSIOLOGY¶
• Chronic Allograft Loss: Result of interstitial fibrosis, tubular atrophy, vasculopathy, and glomerulopathy. ◦ Mechanisms: Combination of alloimmune response, drug toxicity, and other insults. • Immunology of Rejection: ◦ T-cell mediated rejection: → CD4+ lymphocytes respond to MHC II (HLA-DR) → release pro-inflammatory cytokines. → CD8+ cytotoxic lymphocytes respond to MHC I (HLA-A, -B) → cause direct tissue damage. → Requirement: T-cell receptor binding + costimulatory molecules (CD28 on T cells; CD80/CD86 on APCs). ◦ Antibody-mediated rejection: → Triggered by circulating antibodies against donor antigens. → Mechanism: Follicular helper T cells (Tfh) → B cell differentiation into plasma cells → production of donor-targeting antibodies. → Marker: C4d deposition in peritubular capillaries and glomerular basement membrane (indicator of complement activation). ◦ Eplet matching: Short sequences of polymorphic amino acids on surface of HLA antigens; eplet mismatches in class II HLA DQ loci are risk factors for acute rejection. • Chronic Lesions: ◦ Causes: Chronic active ABM, recurrent glomerular disease, hypertension, CNI nephrotoxicity, secondary focal glomerulosclerosis. ◦ Vascular changes: Intimal proliferation and medial hypertrophy.
CLINICAL FEATURES¶
• Signs of Rejection: ◦ Primary indicators: Rise in serum creatinine, reduction in urine volume (may occur without reduction in volume). ◦ Rare signs: Fever, swelling, tenderness over the allograft. • Postoperative Dynamics: ◦ Postoperative diuresis: Loss of sodium, potassium, and water due to acute tubular injury from ischemia. ◦ Slow recovery or oliguria: Indicates need for biopsy to rule out superimposed rejection on acute tubular injury (AT1). • Infection Symptoms: ◦ Often atypical due to immunosuppression. ◦ CMV: Asymptomatic viremia, systemic syndrome (fever, leukopenia), or tissue-specific manifestation (hepatitis, gastroenteritis, retinopathy). ◦ Pneumocystis jirovecii: Rare but critical; may require transbronchial or open-lung biopsy. ◦ Fungal infections: Aspergillus, Nocardia, Candida.
DIFFERENTIAL DIAGNOSIS¶
• Primary Goal: Rule out other causes of functional deterioration (AT1, CNI toxicity, BK nephropathy, recurrent glomerular disease). • Rejection vs. Toxicity vs. Recurrence: ◦ Acute T-cell mediated: Identified by immune cell infiltration in interstitial, tubular, or vascular compartments (Banff classification). ◦ Antibody-mediated: Identified by endothelial injury + C4d deposition in peritubular capillaries + circulating donor-specific antibody. ◦ Calcineurin toxicity: Identified via monitoring of drug levels. ◦ BK nephropathy: Identified by renal biopsy showing interstitial nephritis and tubular cytopathic changes. • Infection Differential: ◦ Pneumocystis jirovecii, CMV, Fungal (Aspergillus, Nocardia, Candida), Bacterial (Nocardia, Candida, Aspergillus).
INVESTIGATIONS & DIAGNOSIS¶
- Initial Evaluation: ◦ Multidisciplinary assessment (medical, surgical, social, psychosocial). ◦ Cardiovascular risk assessment (coronary artery disease, valvular disease, heart failure).
- Imaging: ◦ Ultrasound: Identify urinary obstruction or perirenal collections (urinoma, hematoma, lymphocele). ◦ Doppler ultrasound: Assess allograft vasculature and blood flow.
- Laboratory Monitoring: ◦ Serum creatinine and urine volume to detect early changes. ◦ Viral loads (e.g., CMV) and cultures (blood, urine, drain fluids) for infection workup.
- Biopsy (Gold Standard): → Indicated if kidney function remains inadequate or low → used to distinguish subacute cellular rejection from recurrent disease or secondary focal sclerosis.
Donor Evaluation¶
• Living Donor: → Principle: "First, do no harm" → exclude hypertension, diabetes, and/or proteinuria. → Risk of ESKD after donation: 0.3–0.4% (not greater than general population). • Deceased Donor: → Must be free of malignancy, hepatitis, and HIV. → Ischemic time: <24 h preferred. • Tissue Typing & Cross-match: → Molecular typing: HLA via genomic sequencing. → Cytotoxic crossmatch: Positive result → indicates preformed donor-specific anti-HLA class I antibodies (predicts hyperacute rejection). → Flow cytometric crossmatch: Detects anti-HLA IgG not detected on cytotoxic crossmatch.
MANAGEMENT & TREATMENT¶
- Induction Therapy: → High-risk (High %PRA, prior transplant, autoimmune GN, donor age >60, ischemia >24h, high KDPI) → Antithymocyte globulin (ATG). → Low-risk (Low %PRA <10%, no prior tx, etc.) → Basiliximab.
- Maintenance Therapy: → Glucocorticoids (Prednisone/prednisolone). → Calcineurin Inhibitors (CNI: Tacrolimus or Cyclosporine). → Antimetabolites (Mycophenolate mofetil/sodium or Azathioprine).
- Treatment of Rejection: → T-cell mediated → High-dose steroids (Methylprednisolone 0.5–1 g/d imes 3 days) → If failed, use ATG. → Antibody-mediated → Plasmapheresis, IVIG, Rituximab, or Bortezomib.
- Management of Infection: → Pneumocystis jirovecii: Prophylaxis (e.g., TMP-SMX). → CMV: Valganciclovir (prophylaxis and treatment). → BK virus: Monitor viral load → reduce maintenance immunosuppression.
- Management of Chronic Complications: → Hypertension: Use Calcium channel blockers to slow progression of allograft dysfunction. → Malignancy: Monitor for tumors (100x higher risk than general population).
Maintenance Drug Profiles (Table 325-3)¶
• Glucocorticoids: → Mechanism: Binds cytosolic receptors/heat shock proteins; blocks IL-1, -2, -3, -6, TNF-α, and IFN-γ. → Side effects: Hypertension, glucose intolerance, dyslipidemia, osteoporosis. • Cyclosporine (CsA): → Mechanism: Trimolecular complex with cyclophilin and calcineurin → block IL-2; stimulates TGF-β. → Side effects: Nephrotoxicity, hypertension, dyslipidemia, glucose intolerance, hirsutism/hyperplasia of gums. • Tacrolimus: → Mechanism: Trimolecular complex with FKBP-12 and calcineurin → block IL-2; may stimulate TGF-β. → Side effects: Similar to CsA, but hirsutism/hyperplasia of gums is unusual; diabetes more likely. • Mycophenolate mofetil/sodium: → Mechanism: Inhibits purine synthesis via inosine monophosphate dehydrogenase. → Side effects: Diarrhea/cramps; liver/marrow suppression uncommon. • Sirolimus/everolimus: → Mechanism: Complexes with FKBP-12 → blocks p70 S6 kinase in IL-2 receptor pathway. → Side effects: Hyperlipidemia, thrombocytopenia. • Belatacept: → Mechanism: Binds CD80 and CD86, prevents CD28 binding. → Side effects: Posttransplant lymphoproliferative disease (PTLD).
PROGNOSIS & COMPLICATIONS¶
• Causes of Death: → Cardiovascular events (29%). → Infection (18%). → Malignancy (17%). • Chronic Allograft Dysfunction: → Most allografts eventually succumb to interstitial fibrosis, tubular atrophy, vasculopathy, and glomerulopathy. → Causes: Chronic active ABM, recurrent glomerular disease, hypertension, CNI nephrotoxicity, secondary focal glomerulosclerosis.
SPECIAL CONSIDERATIONS¶
• Absolute Contraindications: → Active malignancy. → Active infection. → Psychosocial issues affecting adherence. → Chronic illness limiting survival <2 years. • DCD (Non-Heart-Beating Donor) Categories (Table 325-1): → I: Brought in dead. → II: Unsuccessful resuscitation. → III: Awaiting cardiac arrest. → IV: Cardiac arrest after brainstem death. → V: Cardiac arrest in a hospital patient. → Note: Only categories III and IV are commonly used; survival not shown to be inferior to other deceased-donor kidneys. • Additional Considerations: → KDPI 85% (formerly ECD) → directed toward patients expected to fare less well on dialysis. → HCV-positive donors → accepted for HCV-positive or -negative recipients since 2017 (9% of cases). → HOPE Act: Allows organ donation from HIV-positive candidates. → Blood group B candidates: Eligible for allograft from A blood type donors if low anti-A titer.
KEY PEARLS & CLINICAL TRAPS¶
• C4d Marker: C4d deposition in peritubular capillaries and glomerular basement membrane is a hallmark of antibody-mediated rejection. • KDPI Logic: KDPI ≥ 85% kidneys are directed toward patients expected to fare less well on dialysis. • Immune Pathways (Figure 325-1): → Direct Pathway: CD8+ T cells recognize MHC I → Cytotoxic response. → Indirect Pathway: CD4+ T cells recognize MHC II on self-APCs → B-cell activation → Plasma cells → Antibody production. • Infection Timing (Table 325-4): → Peritransplant (<1 month): Wound infections, Herpesvirus, Oral candidiasis, UTI. → Early (1–6 months): Pneumocystis carinii, CMV, Legionella, Listeria, Hepatitis B/C. → Late (>6 months): Aspergillus, Nocardia, BK virus (polyoma), Herpes zoster.
FLOWCHARTS & ALGORITHMS¶
- Immune Recognition Pathways (Figure 325-1): → Direct Pathway: Allogeneic APCs → CD8+ T cells recognize MHC I → Activation of cytotoxic CD8 T cells (GrzB, Perforin) → Cellular Rejection and Organ Damage. → Indirect Pathway: Allogeneic peptides processed by self-APCs → CD4+ T cells recognize MHC II → Differentiation into T_H1, T_H2, or T_H17 → Interaction with Naive B Cells → Plasma Cells → Antibody production → Antibody Mediated Rejection.
- Early Posttransplant Care (Figure 325-2): → Step 1: Risk Stratification. → High Risk: High %PRA, prior transplant, autoimmune GN, donor age >60, ischemia >24h, high KDPI. → Low Risk: Low %PRA (<10%), no prior tx, donor age 15–35, ischemia <12h, low KDPI. → Step 2: Induction & Initial Therapy. → High Risk → Antithymocyte globulin (ATG) + Steroids; MMF + CNI (few days later). → Low Risk → Basiliximab + Steroids; MMF + CNI (1–2 days later). → Step 3: Clinical Assessment. → If Good urine output / Improvement in Cr → Outpatient follow-up. → If Persistent allograft dysfunction / Delayed graft function → Adjust CNI dose → If still inadequate → Allograft biopsy. → Step 4: Post-Biopsy Management. → If No rejection → Adjust CNI dose + Supportive care (BP, fluid) → Outpatient follow-up. → If Acute rejection → IV methylprednisolone (0.5–1 g/d imes 3 days) or ATG.
Reference Tables¶
TABLE 325-1 Definition of a Non-Heart-Beating Donor (Donation After Cardiac Death a [DCD]) I: Brought in dead II…¶
Harrison's 22e, p.2405
- I: Brought in dead
- II: Unsuccessful resuscitation
- III: Awaiting cardiac arrest
- IV: Cardiac arrest after brainstem death
- V: Cardiac arrest in a hospital patient
TABLE 325-2 Mean Rates of Graft and Patient Survival for Kidneys Transplanted in the United States from 1999 to 2018 a…¶
Harrison's 22e, p.2406
| 1-YEAR FOLLOW-UP | 5-YEAR FOLLOW-UP | 10-YEAR FOLLOW-UP | ||||
|---|---|---|---|---|---|---|
| GRAFTS, % | PATIENTS, % | GRAFTS, % | PATIENTS, % | GRAFTS, % | PATIENTS, % | |
| Deceased donor | 94 | 95 | 76 | 77 | 54 | 67 |
| 98 | 99 | 87 | 87 | 70 |
TABLE 325-3 Maintenance Immunosuppressive Drugs AGENT Glucocorticoids¶
Harrison's 22e, p.2408
| AGENT | PHARMACOLOGY | MECHANISMS | SIDE EFFECTS |
|---|---|---|---|
| Glucocorticoids | Increased bioavailability with hypoalbuminemia and liver disease; prednisone/prednisolone generally used |
Binds cytosolic receptors and heat shock proteins. Blocks transcription of IL-1, -2, -3, -6, TNF-α, and IFN-γ |
Hypertension, glucose intolerance, dyslipidemia, osteoporosis |
| Lipid-soluble polypeptide, variable absorption, microemulsion more predictable |
Trimolecular complex with cyclophilin and calcineurin → block in cytokine (e.g., IL-2) production; however, stimulates TGF-β production |
||
| Tacrolimus | Macrolide, well absorbed | Trimolecular complex with FKBP-12 and calcineurin → block in cytokine (e.g., IL-2) production; may stimulate TGF-β production |
Similar to CsA, but hirsutism/hyperplasia of gums unusual, and diabetes more likely |
| Mercaptopurine prodrug | Hepatic metabolites inhibit purine synthesis | ||
| Mycophenolate mofetil/sodium |
Metabolized to mycophenolic acid | Inhibits purine synthesis via inosine monophosphate dehydrogenase |
Diarrhea/cramps; dose-related liver and marrow suppression is uncommon |
| Macrolide, poor oral bioavailability | Complexes with FKBP-12 and then blocks p70 S6 kinase in the IL-2 receptor pathway for proliferation |
||
| Belatacept | Fusion protein, intravenous injections | Binds CD80 and CD86, prevents CD28 binding and T-cell activation |
Posttransplant lymphoproliferative disease (PTLD) |
TABLE 325-4 The Most Common Opportunistic Infections in Renal Transplant Recipients Peritransplant (<1 month)¶
Harrison's 22e, p.2410
| Peritransplant (<1 month) | Late (>6 months) |
|---|---|
| Wound infections | Aspergillus |
| Herpesvirus | Nocardia |
| Oral candidiasis | BK virus (polyoma) |
| Urinary tract infection | Herpes zoster |
| Early (1–6 months) | Hepatitis B |
| Pneumocystis carinii | Hepatitis C |
| Cytomegalovirus | |
| Legionella | |
| Listeria | |
| Hepatitis B | |
| Hepatitis C |