Kidney Transplantation



Kidney Transplantation


Phuong-Thu T. Pham

Phuong-Chi T. Pham

Michelle J. Hickey

Jonathan E. Zuckerman



EVALUATION OF THE POTENTIAL KIDNEY TRANSPLANT CANDIDATE



  • Kidney transplantation is the treatment of choice for suitable candidates with end-stage kidney disease (ESKD).



    • It confers survival advantage over remaining on dialysis across all ages and in both diabetic and nondiabetic transplant recipients.


    • It offers long-term economic benefits compared to dialysis.


    • Although there has been no consensus on the upper age limit at which patients are accepted for kidney transplantation, 80 years of age has been suggested to be a sensible biologic limit. Suitability for transplantation should be assessed on a case-by-case basis.


  • The routine assessment of a kidney transplant candidate includes thorough history and physical examination, psychosocial evaluation, and psychiatric evaluation as needed. In addition, patients should attend a patient education session and undergo a number of routine laboratory testing and imaging studies as outlined in Table 9.1.


  • The absolute and relative contraindications to transplantation are outlined in Table 9.2.


  • The United Network for Organ Sharing (UNOS) listing criteria for deceased donor kidney: chronic kidney disease (CKD) with glomerular filtration rate (GFR) ≤ 20 mL/min or ESKD


  • Transplant candidates with a history of malignancies: Table 9.3 provides general guidelines for minimum tumor-free waiting periods for common malignancies.


  • Disease recurrence after transplantation: Patients should be informed of the risk of disease recurrence after transplantation and the risk of graft loss associated with disease recurrence (discussed in a later section).









Table 9.1 Pretransplant routine laboratory testing and imaging studies















Laboratory evaluation


Comprehensive metabolic panel


Complete blood count with platelets


Prothrombin time panel (INR and PTT)


Urinalysis and urine culture


Hepatitis B (surface Ag, IgM and IgG core Ab, and surface Ab)


HCV Ab screening (if positive, check PCR confirmatory test)


HIV-1/HIV-2 Ag/Ab screening, fourth generation with reflex confirmation


CMV-specific IgG


EBV-VCA IgM/EBNA1 IgG panel


RPR or VDRL (FTA-ABS confirmatory test if positive RPR or VDRL)


Iron and iron-binding capacity, ferritin


Type and screen


Coccidioides IgG/IgM EIA (recommended for patients with history of valley fever or those who live in endemic areas)


Optional: serum immunofixation electrophoresis if age > 60 y old (Currently, routine testing transplant candidates for MGUS is not recommended. However, practice may differ among centers.)


Special laboratory evaluation


Hypercoagulability panel in patients with history of recurrent thrombosis or spontaneous fetal losses


PSA screening for men with family history, obstructive voiding symptoms, or hematuriaa


Serologic testing based on risk factors (endemic mycoses or travel history): Coccidioides IgM and IgG antibody, histoplasma immunodiffusion antibody antigen, Strongyloides stercoralis antibody, Leishmania spp., Trypanosoma cruzi antibody, human T-cell lymphotropic virus (HTLV-1/2) antibody


Other evaluation


Electrocardiogram


Chest X-ray


PPD skin test or preferably the interferon-γ release assays (QuantiFERON-TB Gold Test)


Renal ultrasound to assess for acquired cystic disease or mass


Abdominal ultrasound in diabetics to evaluate for gallstones


Cardiac evaluation (myocardial perfusion study or stress test with imaging—choice of cardiac studies differs among centers); echocardiogram to assess ejection fraction


Colonoscopy screeningb


Pap smear and mammogram screening (appropriate for age similar to the general population)


Urologic evaluation if history of bladder/voiding dysfunction, recurrent urinary tract infections, or history of urologic abnormalities


Immunologic studies


Blood group and HLA typing


Bead-based single-antigen antibody, class I and II (see Chapter 8 Transplant Immunobiology)


Sera for crossmatch


a Routine screening may be more harmful than protective because it does not appear to confer a survival benefit and may delay listing and decrease transplantation rates (single-center study, =3,782 men > 18 years of age undergoing primary kidney transplant evaluation).

b Appropriate for age or at the discretion of the clinician (for a detailed discussion, see Pham and Pham [2020]).


Abbreviations: Ab, antibody; Ag, antigen; CMV, cytomegalovirus; EBNA1, Epstein-Barr nuclear antigen 1; EBV, Epstein-Barr virus; EIA, enzyme immunoassay; FTA-ABS, fluorescent treponemal antibody absorption; HCV, hepatitis C virus; HLA, human leukocyte antigen; IgG, immunoglobulin G; IgM, immunoglobulin M; INR, international normalized ratio; MGUS, monoclonal gammopathy of undetermined significance; PCR, polymerase chain reaction; PPD, purified protein derivative; PSA, prostate-specific antigen; PTT, partial thromboplastin time; RPR, rapid plasma reagin; VCA, viral capsid antigen; VDRL, venereal Disease Research Laboratory.










Table 9.2 Contraindications to kidney transplantation













Absolute contraindications


Recenta or active malignancy, metastatic malignancy


Untreated current infection or ongoing nonhealing ulcers


Severe irreversible extrarenal disease (e.g., severe cardiovascular disease not amenable to intervention or severe pulmonary disease)


Life expectancy < 2 y


Recalcitrant treatment nonadherence


Poorly controlled psychiatric illnesses


Active substance abuse


Aggressive native kidney diseaseb


Limited, irreversible rehabilitation potential


Decompensated liver cirrhosis (unless simultaneous liver-kidney transplantation)


Primary oxalosis (consider simultaneous liver-kidney transplantation)


Chronic severe and uncorrectable hypotension (may compromise posttransplant graft perfusion potentially leading to graft primary nonfunction)


Relative contraindications


Morbid obesity (center dependent)


Advanced age (center dependent—consensus on the upper age limit is lacking)


History of multiple myeloma or plasma cell dyscrasia (Assess on a case-by-case basis. Hematology/Oncology consultation strongly recommended)


Other evaluation


ABO incompatibilityc


Positive T- and/or B-cell flow cytometry crossmatchc


Post-percutaneous coronary intervention patientsd


Transplant surgery not recommended:




  • Within 4 wk of coronary revascularization with balloon angioplasty



  • Within 1 mo of bare metal stent placement



  • Within 6 mo of drug-eluting stent (DES) placement (with the newer generation DES)


a See Table 9.3.

b See Table 9.28—Glomerular disease recurrence after transplant.

c Pretransplant preconditioning regimen or desensitization may allow successful transplantation across these barriers (discussion is beyond the scope of this chapter). See Chapter 8 Transplant Immunobiology for different crossmatch methods. Other options: paired donor exchange or kidney-paired donation (KPD) at the internal (involving one single-transplant center), regional (involving multiple transplant centers within close geographical or system networks), or national level (via the National Kidney Registry). Interested readers are referred to Pham, McGuire et al. (2020).

d The following recommendations are for patients who had undergone elective percutaneous coronary intervention (PCI) procedure. Patients with acute coronary syndrome must wait for one year regardless of stent type. Cardiology consult is recommended.



Candidates With Preexisting Infectious Diseases


Hepatitis B



  • Diagnostic tests for hepatitis B virus (HBV) are listed in Table 9.4. Patients with hepatitis B surface antigen (HBsAg) positive with or without evidence of active viral replication should be referred to hepatology (the latter as assessed by the detection of HBV DNA by reverse transcriptase polymerase chain reaction [PCR]).


  • Assessment of severity of liver disease



    • Liver biopsy is often indicated to assess the severity of liver disease (grade and stage) because liver enzymes may be spuriously normal in patients with CKD despite advanced liver disease.


    • Transient elastography (FibroScan) is increasingly being used to assess the severity of fibrosis, but liver biopsy remains gold standard.









      Table 9.3 Tumor-free waiting period for common pretransplant malignanciesa,b



































      No waiting time


      Long-standing history of MGUS. Hematology/Oncology consult is advisable in patients with newly diagnosed monoclonal gammopathy


      No waiting time if cure at the time of transplantation


      Incidental renal cell carcinoma, in situ carcinoma of bladder, in situ carcinoma of cervix, basal cell carcinoma


      Waiting time varies with staging, tumor size


      Breast cancer


      2-5 y


      2 y waiting time for ductal carcinoma in situ


      Patients with stage III or IV breast cancer should be advised against transplantation


      Prostate cancer


      Old paradigm: 2 y tumor-free waiting time


      Current trendb: Shorter waiting time is acceptable for patients with grade group 1 or 2 prostate cancer (Gleason score ≤ 6 or Gleason 3 + 4, respectively)


      Renal cell carcinoma


      2 y if <5 cm


      5 y if >5 cm or <5 cm with invasion


      Skin squamous cell carcinomab,c (SCC)


      Old paradigm: 0-2 y waiting time


      New paradigmd: Low-risk SCC: surgical excision with clear margins or Mohs surgery and no waiting time


      High-risk SCC: no perineural invasion: surgical excision with clear margins or Mohs surgery and 2 y waiting time


      High-risk SCC with perineural invasion: surgical excision with clear margins or Mohs surgery and/or adjuvant radiation therapy and waiting time of 5 y


      High-risk SCC with local nodal disease: surgical excision, lymph node dissection, adjuvant radiation therapy, and 5 y waiting time


      Melanomab,c


      Old paradigm: 5 y waiting time


      New paradigmd: In situ: wide excision and no waiting time


      Stage Ia: wide local excision and 2 y waiting time


      Stage Ib/IIa: wide local excision and/or sentinel lymph node biopsy and 2-5 y waiting time


      Stage IIb/IIc: wide local excision and/or sentinel lymph node biopsy and 5 y waiting time


      Stage III or IV: not a transplant candidate


      PTLD (retransplantation)


      At least 1-2 yb


      Waiting time 2-5 yb


      2 y waiting time: invasive bladder, uterine body, Wilms tumor


      2-5 y waiting time: lymphoma, invasive cervical carcinoma, colorectal carcinoma (at least 5 y for Dukes B1 or higher)


      aCertain cancers may recur despite a tumor-free waiting period.


      bOncology evaluation or consultation with the Israel Penn International Transplant Tumor Registry at ipittr.uc.edu may be invaluable.

      c Dermatology consultation is recommended.

      d Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant. 2017;17(10):2509-2530.


      Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; PTLD, posttransplantation lymphoproliferative disorder.



  • Hepatocellular carcinoma screening with the following studies is recommended every 6 months (particularly in high-risk patients such as those with high HBV viral load, hepatitis B e-antigen [HBeAg] positive, HBsAg positive, HBV genotype C, Asian or African ethnicity):



    • Abdominal ultrasound


    • α-Fetoprotein before and after transplant









      Table 9.4 Diagnostic tests for hepatitis B and hepatitis C














      Hepatitis Type


      Diagnostic Tests and Interpretation


      Hepatitis B




      • Hepatitis B surface antigen (HBsAg): HBV infection



      • IgM antibody to hepatitis core antigen (IgM anti-HBc): acute or recent HBV infection



      • IgG antibody to hepatitis B core antigen (IgG anti-HBc): chronic or remote HBV infection



      • Antibody to hepatitis B surface antigen (HBsAb): immunity to HBV (prior infection or through vaccination)



      • Hepatitis B e-antigen (HBeAg): can persist in carriers and is usually associated with detectable HBV DNA (HBV viremia): active viral replication


      Hepatitis C




      • Anti-HCV: used for initial screening. The third-generation ELISA 3.0 has excellent sensitivity and specificity



      • Nucleic acid testing for detection of HCV RNA



      • HCV qualitative




        • More sensitive than quantitative test



        • Used to confirm HCV infection in anti-HCV-positive patients



        • Useful in immunocompromised patients (dialysis patients, transplant recipients)



      • HCV quantitative




        • More reproducible than qualitative tests



        • Used to assess viral load



        • Useful in monitoring response to therapy



      • HCV genotyping: may predict response to treatment (helpful in treatment decision)


      Abbreviations: ELISA, enzyme-linked immunosorbent assay; HBV, hepatitis B virus; HCV, hepatitis C virus; IgG, immunoglobulin G; IgM, immunoglobulin M.



  • Transplant considerations



    • Kidney-alone transplantation is acceptable after sustained viral response in patients with precirrhosis or compensated liver cirrhosis (defined as absence or mild portal hypertension with hepatic portal venous gradient < 10 mm Hg). Hepatology consult is recommended.


    • Patients with decompensated liver disease should be referred for simultaneous liver-kidney transplant (SLKT).


  • Antiviral therapy considerations



    • Transplant candidates with active HBV replication (i.e., detectable HBV DNA)



      • Initiate antiviral therapy pretransplant.


    • Transplant recipients with HBV infection (i.e., positive HBeAg or HBsAg)



      • All patients should be placed on antiviral therapy after transplantation to avoid HBV reactivation and progression of liver disease associated with the use of immunosuppressive therapy.


      • Risk factors for posttransplant progression of HBV-related liver disease: duration of infection, genotype C, higher HBV DNA titer, hepatitis C or hepatitis D coinfection, immunosuppressive therapy


    • The authors advocate antiviral prophylactic therapy in all HBsAg-positive candidates at the time of transplantation.


Hepatitis C



  • Diagnostic tests for hepatitis C virus (HCV) are presented in Table 9.4. Serologic testing is the initial screening tool for HCV infection. The third-generation
    enzyme-linked immunosorbent assay (ELISA 3.0) has excellent sensitivity and specificity even for patients with CKD. Confirmation of chronic HCV infection requires detection of HCV RNA by reverse transcriptase PCR.


  • All patients should be referred to hepatology.


  • Assessment of severity of liver disease: Liver biopsy is often indicated to assess the severity of liver disease (grade and stage) because liver enzymes may be spuriously normal in patients with CKD despite advanced liver disease.


  • Transplant considerations



    • Kidney-alone transplantation is acceptable with HCV treatment in patients with precirrhosis or compensated liver cirrhosis (absence or mild portal hypertension with hepatic portal venous gradient < 10 mm Hg). Hepatology consult is recommended.


    • Patients with decompensated liver disease should be referred for SLKT.


    • Kidney transplantation from hepatitis C-positive donors may be offered to hepatitis C-positive candidates (who are viremic) and who have consented to receive such kidney (informed consent should preferably be obtained at the time of pretransplant evaluation).


    • Hepatitis C-positive donors to hepatitis C-negative candidate and preemptive therapy with direct-acting antiviral agents (DAAs) after transplantation is a potential therapeutic option for waitlisted transplant candidates who consent to receive such kidney. Further studies are needed. Discussion is beyond the scope of this chapter.


  • Antiviral therapy considerations



    • Active viral replication at the time of transplant has been shown to be associated with a higher incidence of long-term clinical liver disease and worse allograft function and graft survival compared with HCV-positive recipients with persistently negative viremia. The advent of DAA in ribavirin- and interferon (INF)-free regimen should improve outcomes in hepatitis C-positive kidney transplant recipients.


    • In HCV-positive transplant candidate without a living donor, consider delaying DAA therapy until after transplant due to a considerably shorter waiting time for a deceased HCV-positive transplant candidate. Nonetheless, among those with advanced fibrosis, treatment before transplant is recommended by experts in the field. In those with mild-to-moderate fibrosis, treatment can be deferred until after transplant.


Human immunodeficiency virus



  • Highly active antiretroviral therapy (HAART) regimen has allowed successful transplantation of stable human immunodeficiency virus (HIV) patients, defined as:



    • Undetectable HIV viral load


    • CD4 lymphocyte count > 200/mm2


    • Absence of opportunistic infections in the previous year


  • Specific recommendations may vary from center to center.


  • Clinicians should remain vigilant to significant drug-drug interactions between HAART and immunosuppressive drugs metabolized by CYP450, such as the calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors (see also Immunosuppressive Agents section). Raltegravir is the first integrase inhibitor approved by the Food and Drug Administration (FDA) for use in
    the treatment of HIV-1 infection in combination with other antiretroviral agents. It is not a cytochrome P450 substrate and, therefore, lacks drug-drug interactions with the CNIs (see also Chapter 10 Pharmacology).


Latent tuberculosis



  • All potential kidney transplant candidates should undergo a purified protein derivative (PPD) skin test or preferably the INF-γ release assays (QuantiFERON-TB Gold test) because the latter has lower false-positive rates associated with prior BCG vaccine.


  • A positive skin test or INF-γ released assay result or a prior history of tuberculosis (TB) mandates further evaluation to rule out active disease.


  • Obtain chest X-ray (part of routine pretransplant workup).


  • Isoniazid (INH) prophylaxis for a total of 9 months is recommended for those with evidence of latent TB.


  • Clinical, radiologic, or culture evidence of active TB infection is a contraindication to transplantation.


Pregnancy After Transplantation



  • Patient must be at least 1-year posttransplant and on stable immunosuppression.


  • Allograft function:



    • No acute rejection episodes in the previous year


    • Serum creatinine < 2.0 mg/dL, preferably < 1.5 mg/dL (higher creatinine level increases the risk of allograft loss and maternal and fetal complications)


    • Minimal or no proteinuria/albuminuria (minimal proteinuria defined as < 500 mg/24 hours)


    • Normal kidney allograft ultrasound


  • Well-controlled hypertension (HTN) on minimal antihypertensive regimen


  • No acute infections that may impact fetal growth and well-being (e.g., congenital cytomegalovirus [CMV] infection can cause birth defect and/or developmental delays)


  • Drug safety in pregnancy:



    • Drugs that may be used during pregnancy:



      • Cyclosporine, tacrolimus, and azathioprine (AZA)


    • Drugs that should not be used during pregnancy:



      • Mycophenolic acid (MPA) derivatives (mycophenolate mofetil [MMF] or mycophenolate sodium) due to increased risk of first-trimester pregnancy loss and congenital malformation


      • mTOR inhibitor sirolimus or everolimus has been shown to be associated with increased fetal mortality, decreased fetal weights, and delayed ossification of skeletal structures.


      • Use reliable contraception while on MPA derivatives or mTOR inhibitors and for 3 months after discontinuation.


    • Belatacept: Clinical studies on belatacept use in pregnancy are currently limited. To date, only two cases of successful pregnancy and delivery have been reported to the Transplant Registry International (US FDA pregnancy category: not assigned).


    • Breastfeeding (see Appendix A)



Male Fertility



  • Fertility, as assessed by sperm counts, improves in half of patients.


  • There is no increased incidence of neonatal malformations in pregnancies fathered by kidney transplant recipients.


LIVING DONOR EVALUATION


Options



  • Living related, living unrelated, kidney-paired donation (KPD), paired kidney chain donation, altruistic, voucher donation



    • KPD, paired kidney chain donation:



      • Approximately 30% of potential living donors are incompatible to their recipients due to blood group incompatibility or the presence of preformed donor-specific human leukocyte antigen (HLA) antibody or both.


      • KPD is a program in which an incompatible donor-recipient pair is swapped with another incompatible donor-recipient pair. A number of transplant centers in the United States offer KPD and/or desensitization protocols to such willing but incompatible healthy donor-recipient pairs. Sometimes, these “swaps” may include multiple pairs.


      • Paired kidney chain donation (formerly known as domino-paired kidney donation or never-ending altruistic donation [NEAD]). The nondirected donor donates a kidney to a compatible recipient who has an intended but incompatible living donor. The recipient’s incompatible living donor will, in turn, donate his or her kidney to the next incompatible pair, generating a domino effect. The chain can terminate when the final donor donates to a recipient on the deceased donor waiting list. Alternatively, the final donor can wait until a suitable match is found with a new incompatible pair. As such, the final donor becomes a bridge donor to continue the chain until no match can be identified through paired kidney donation, and the final donor’s kidney is directed to a recipient on the deceased donor waitlist.


    • Voucher donation:



      • Novel concept whereby the donor donates a kidney at a time that is optimal for the donor, whereas the intended recipient is not yet in need of a transplant or may never need a transplant.



        • Example: A 66-year-old grandmother can donate a kidney to a nondirected recipient now to allow her 7-year-old grandson with CKD to receive priority for a future living donor kidney transplant if needed later in life.


        • Advantages: Vouchers for future kidney transplantation overcome “chronologic incompatibility” between living donors and recipients.


  • The Declaration of Istanbul on organ trafficking and transplant tourism and the World Health Organization (WHO) prohibit and condemn the exploitation of vulnerable living donors (defined as illiterate or impoverished individuals, undocumented immigrants, and political or economic refugees).


General Assessment



  • Complete history and physical examination, and psychosocial assessment



  • Psychosocial assessment by the transplant center psychiatrist or social worker is recommended to evaluate for any significant psychiatric problem and any possibility of coercion. The presence of either of these would preclude donation.


  • Suggested routine evaluation and optional testing are listed in Table 9.5.

Absolute and relative contraindications to living kidney donation are listed in Table 9.6.


Evaluation for Specific Conditions


Diabetes mellitus



  • 2015 American Society of Transplantation (AST) Living Donor Community of Practice



    • Prediabetes increase future risk for diabetes-associated kidney disease in the donor.


    • Potential donors with diabetes mellitus are excluded from donation per UNOS.


    • Potential donors with prediabetes need to make lifestyle changes including diet change and increased exercise and weight loss to normalize glucose metabolism and reduce future diabetes risk.


  • 2017 Kidney Disease: Improving Global Outcomes (KDIGO) inclusion and exclusion criteria for donation



    • Donor candidates with type 1 diabetes should not donate.


    • Donor candidates with prediabetes or type 2 diabetes



      • Decision for kidney donation should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.


      • Donor candidates should be counseled that their condition may progress over time and may lead to end-organ complications.


Hypertension



  • 2015 AST Living Donor Community of Practice



    • Medical evaluation of potential donors suspected to have HTN should include:



      • Ambulatory blood pressure monitoring


      • Evaluation of end-organ damage (e.g., retinal evaluation, echocardiogram)


    • Caucasian donors with HTN should not be precluded from donation if the following criteria are met:



      • HTN is well controlled (per Amsterdam guidelines).


      • Candidates are reliable and agree to long-term follow-up.


    • Living donation among young African Americans with HTN is generally discouraged due to their possible genetic predisposition to ESKD and higher rates of ESKD.


  • 2017 KDIGO Clinical Practice Guidelines



    • Donor candidates with HTN that can be controlled to systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg using one or two antihypertensive agents, who do not have evidence of end-organ damage, may be acceptable for donation.


    • Donors candidates should be informed that:



      • Blood pressure may rise with aging.


      • Donation may accelerate the rise in blood pressure and the need for antihypertensive treatment over that expected with normal aging and among those

        with high-normal blood pressure before donation (particularly in African Americans).








        Table 9.5 Suggested routine evaluation and optional testinga













        Laboratory tests


        ABO blood group, HLA tissue typing, crossmatch testing


        Urinalysis and urine culture


        24-h urine for albumin, protein,b and creatinine clearance (or GFR determination by nuclear medicine test)


        CBC with platelets, INR, and PTT


        Comprehensive metabolic panel (electrolytes, transaminase levels, albumin, bilirubin, calcium, phosphorous, alkaline phosphatase, fasting blood glucose)


        Fasting lipid profile


        Serologies: Hepatitis B (surface Ag, IgM and IgG core Ab, and surface Ab). HCV Ab screening (if positive, check PCR confirmatory test), HIV-1/HIV-2 Ag/Ab screening, fourth generation with reflex confirmation,c CMV, EBV, HSV, West Nile antibodies (IgG and IgM), RPR or VDRL (FTA-ABS confirmatory test if positive RPR or VDRL), Strongyloides stercoralis antibodies


        Geographic residence or environmental exposure that may require additional testing: coccidioidomycosis, schistosomiasis, malaria, HHV-8, HHV-6. Trypanosoma cruzi


        Women < 55 y: Human chorionic gonadotropin quantitative pregnancy test


        Prospective donors > 60 y: Serum protein electrophoresis and serum immunofixation electrophoresis


        African Americans: Hemoglobin electrophoresis (to rule out sickle cell trait)


        Other tests


        Electrocardiogram


        Chest X-ray


        Pap smear appropriate for age similar to the general population


        Mammogram appropriate for age similar to the general population


        Renal imaging: spiral computed tomography (CT), CT angiogram, or magnetic resonance angiogram


        Further testing depending on age, history, abnormal laboratory findings, family history


        Cardiac screening: exercise treadmill or nuclear medicine stress test, echocardiogram


        Colonoscopy for prospective donors ≥ 50 y


        24-hour ambulatory blood pressure monitoring


        Renal biopsy


        Cystoscopy


        PPD skin test or preferably QuantiFERON-TB Gold test


        Screening for hypercoagulability


        Oral glucose tolerance test in patients with family history of diabetes or in those with risk factors for diabetes


        Prostate-specific antigen screening for men with family history at the discretion of the clinician (routine screening may be more harmful than protective)


        African Americans: screening for APOL1 G1/G2 mutation (see text)


        aMay vary among centers.

        b KDIGO guidelines recommend that donor proteinuria should be measured as albuminuria, not total urine protein. In the authors’ opinion, both urine albumin and total protein should be measured because the former does not detect light-chain immunoglobulins.

        c HIV-1/HIV-2 screening as close as possible but within 28 days prior to organ recovery and HCV RNA by nucleic acid testing (NAT) as close as possible but within 28 days prior to organ recovery.


        Abbreviations: Ab, antibody; Ag, antigen; CMV, cytomegalovirus; EBV, Epstein-Barr virus; FTA-ABS, fluorescent treponemal antibody absorption; GFR, glomerular filtration rate; HCV, hepatitis C virus; HHV, human herpes virus; HLA, human leukocyte antigen; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; INR, international normalized ratio; PCR, polymerase chain reaction; PPD, purified protein derivative; PTT, partial thromboplastin time; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.









        Table 9.6 Absolute and relative contraindications to living kidney donation (criteria may vary among centers)













        Absolute Contraindications (At Most Transplant Centers)


        Relative Contraindications




        • Evidence of kidney disease (GFR < 80 mL/min/1.73 m2 and/or microalbuminuria ≥ 30 mg/24 hr [or equivalent]) (see relative contraindication regarding KDIGO guidelines)



        • Significant renal or urologic abnormalities



        • Transmissible infectious disease (HIV,a hepatitis B infection, hepatitis C infection,b Trypanosoma cruzi infection [Chagas disease])c



        • Active malignancy



        • Chronic illness that places patient at significant risk of undergoing surgery



        • Poorly controlled psychiatric illness or active substance abuse



        • Cognitive deficit



        • Current pregnancy



        • Hypertension (clinically significant)



        • Diabetes mellitus



        • Recurrent nephrolithiasis or bilateral stones



        • History of thrombotic disorders with risk factors for future events or inherited hypercoagulable states (e.g., the presence of lupus anticoagulant or anticardiolipin antibody, factor V Leiden, or prothrombin gene mutation FII-20210)



        • High suspicion for covert coercion



        • BMI > 30-35 kg/m2 (center dependent)



        • Urologic abnormalities of donor kidney




        • Age < 18 y (seldom performed) or >70 y (need to evaluate on a case-by-case basis)



        • Borderline or mild hypertension



        • Borderline urinary abnormalities in the absence of renal function impairment



        • Single prior episode of kidney stone without evidence of secondary risk (see Table 9.7)



        • Obesity (center dependent, generally defined as BMI > 30 kg/m2)



        • Metabolic syndrome and fatty liver (must resolve or demonstrate significant improvement through lifestyle changes before donation)



        • Young donor with risk factors for future development of diabetes mellitus



        • Jehovah Witness



        • African Americans with two mutated alleles of APOL1 G1/G2



        • Sickle cell trait (sickle cell trait is considered as an absolute contraindication to living donation at some centers)



        • Cigarette smokers (must stop at least 4 wk prior to surgery to decrease pulmonary complications). At some centers, current cigarette smoking is considered a contraindication to donation.



        • KDIGO guidelines for GFR between 60 and 80 mL/min/1.73 m2 and/or albumin excretion rate between 30 and 100 mg/d: Decision should be individualized based on demographic and health profile in relation to the transplant center’s acceptance risk threshold.


        a The first living donor HIV-to-HIV kidney transplant was performed in the United States in March 2019 (HIV Organ Policy Equity [HOPE] in Action is an ongoing prospective multicenter, clinical trial of HIV-to-HIV deceased donor kidney transplantation).

        b Kidneys from hepatitis C-positive donors may be offered to hepatitis C-positive transplant candidates (who are viremic) who have consented to receive such kidneys.

        c UNOS policy: If transplantation from an infected donor is planned, recipients should receive specific information regarding risk of transmission and limited data regarding the risk, especially pertaining to live donors, posttransplantation monitoring, potential toxicities associated with treatment for Chagas disease. Detailed discussion is beyond the scope of this chapter.


        Abbreviations: BMI, body mass index; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes.



      • Antihypertensive medication is more likely to be prescribed after donation.


Donor with history of nephrolithiasis



Hereditary Renal Disease


Autosomal dominant polycystic kidney disease



  • Most commonly encountered hereditary renal disease









    Table 9.7 Prospective donors with history of kidney stones











    Kidney Donation Acceptable


    Contraindications to Donation if One or More of the Following Risk Factors Are Present




    • Distant history of stone (>10 y) without metabolic abnormalities associated with stone formation (e.g., hypercalcemia, hyperuricemia, hyperoxaluria, hypocitraturia, or metabolic acidosis)



    • Current asymptomatic single stone if:




      • Stone is <1.5 cm or potentially ureteroscopically removable from explanted donor kidney (before transplantation), and



      • Further evaluation must reveal no evidence of metabolic abnormalities, urinary tract infection, or nephrocalcinosis.



    • Single stone episode associated with treated primary hyperparathyroidism and normocalcemia does not necessarily preclude donation (must evaluate on a case-by-case basis).


    AST Living Donor Community of Practice Guideline




    • The following are considered acceptable for donation:




      • Small incidental stones (<2-3 mm) and negative metabolic stone evaluation



      • Candidates with a distant history of a single passed stone without recurrent stone on imaging and negative metabolic evaluation




    • Cystinuria



    • Sarcoidosis



    • History of struvite stones



    • Inflammatory bowel disease



    • Evidence of nephrocalcinosis



    • Primary or enteric hyperoxaluria



    • History of bilateral stones, multiple stones, recurrent stones despite preventive therapy


    Abbreviation: AST, American Society of Transplantation.


    Online calculator that may be used to predict stone recurrence: www.qxmd.com/calculate-online/nephrology/recurrence-of-kidney-stone-roks.



  • Diagnostic criteria are age and genotype dependent (i.e., polycystic kidney disease 1 or 2 [PKD1 or PKD2]).



    • PKD1



      • Younger than 30 years of age: ≥ one cysts in each kidney or ≥ two cysts in one kidney


      • 30 to 59 years of age: ≥ two cysts in each kidney


      • 60 years of age: ≥ four cysts in each kidney


    • PKD2



      • May present later in life. The use of PKD1 diagnostic criteria may lead to false-negative results. Asymptomatic patients from families with known and well-characterized pathogenic mutations in the PKD2 locus, genetic testing is more definitive than ultrasound.


    • At risk but unknown familial genotype



      • Between the ages of 15 and 39 years: at least three unilateral or bilateral kidney cysts


      • 40 to 59 years of age: ≥ two cysts in each kidney


      • 60 years or older: ≥ four cysts in each kidney


  • Ultrasound screening is acceptable for prospective donors older than 30 years of age.


  • Magnetic resonance imaging (MRI)-based criteria for disease exclusion in at-risk individuals younger than 40 years of age. The finding of < five cysts is sufficient for disease exclusion.



  • For prospective donors with positive family history and age < 30 years, direct mutation analysis for PKD1 and PKD2 is required at some centers.


Apolipoprotein L1 gene mutations



  • Two risk allele mutations (homozygous G1/G1, homozygous G2/G2, or compound heterozygous G1/G2) are found in 13% of African Americans and are associated with increased risk of nondiabetic glomerulosclerosis and focal segmental glomerulosclerosis (FSGS) and more rapid CKD progression compared with their non-black counterparts. African American kidney donors are at higher risk of developing ESKD than their European American counterparts. The UNOS data demonstrated that the risk of ESKD 15 years postdonation was 74.4 per 10,000 African American donors compared with 22.7 per 10,000 European American donors.


  • Prospective younger African American donors and those with significant family history of ESKD should be tested for the presence of two risk alleles for apolipoprotein L1 (APOL1) variants (G1 and G2).


  • Final kidney phenotypes may not yet manifest in young adults and must be considered when potential young African American donors are being evaluated.


  • Donor candidates with two APOL1 risk alleles should be informed of the increased lifetime risk of kidney failure, but the precise kidney failure risk after donation cannot currently be quantified.


  • Renal allograft from living and deceased donors with two risk alleles for APOL1 variants has an increased risk for rejection and transplant failure.


Pregnancy



  • Desire to become pregnant is not a contraindication to donation. However, prospective female donor of childbearing age should be informed to avoid becoming pregnant from the time of approval for donation (or preferably from the time of donor evaluation to the time of recovery after nephrectomy).


  • Female donor candidate should not donate while pregnant.


  • Evaluating for donation 6 months postpartum is reasonable.


  • Prospective female donor candidates of childbearing age should be informed that kidney donation may increase the risk of gestational HTN and preeclampsia (11% vs. 5% among healthy nondonors counterparts).


  • 2017 KDIGO Clinical Practice Guidelines:



    • Women with prior history of hypertensive disorders of pregnancy (e.g., gestational HTN, preeclampsia, or eclampsia) may be acceptable for donation if their long-term postdonation risks are acceptable.


    • Women with childbearing potential who proceed with donation should be counseled on how to reduce the risk of complications in future pregnancies (close follow-up with a nephrologist during pregnancy is advisable).


Donor Safety and Long-Term Renal Function



  • Surgical mortality within 90 days of live kidney donation: 3.1 in 10,000 donors (UNOS database consisting of 80,347 live kidney donors)


  • Despite the loss of 50% renal mass, unilateral nephrectomy only reduces renal function by approximately 20% to 30% at long-term follow-up because of
    compensatory hyperfiltration. The degree of compensation is determined by age-related reserve.


  • One-third of healthy donors will have estimated GFR (eGFR) < 60 mL/min/1.73 m2. However, the fall in eGFR usually does not decrease with time beyond the rate associated with natural aging.


  • Systematic review and meta-analysis of 52 studies involving more than 110,000 living kidney donors (average follow-up of 1 to 24 years):



    • The relative risk (RR) for ESKD was nearly ninefold higher among living donors compared with their nondonor counterparts. However, the absolute risk was low, with an estimated incidence rate of less than 1 case per 1,000 person-years (RR, 8.83 [95% confidence interval or CI, 1.02 to 20.93]. Incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1,000 person-years).


    • The RR for preeclampsia in female donors was twofold higher among living donors compared with their nondonor counterparts, with an estimated incidence rate of nearly 6 cases per 100 pregnancies (RR, 2.12 [CI, 1.06 to 4.27]. Incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies).


  • Risk for ESKD: male sex, greater body mass index (BMI), donors with first-degree biologic relationship to the recipient, lived in lower socioeconomic status neighborhoods, younger ages at donation for Blacks, and older ages at donation for Whites. (data source: Organ Procurement Transplantation Network [OPTN] database with ESKD ascertained via Centers for Medicare & Medicaid Services linkage; n > 120,000 living kidney donors)


  • African Americans have higher rates of developing postdonation CKD due to HTN and use of antihypertensive medication compared to white donors.


  • Systematic review, meta-analysis, and meta-regression study (n > 5,000 donors from 27 countries): Kidney donation resulted in small increases in urinary albumin, which increased with time after donation. An initial decrement in GFR was not followed by accelerated losses over the subsequent 15 years.


  • The OPTN policy requires informing donor candidates that the risk of ESKD after donation may exceed that of healthy nondonors with medical characteristics similar to living kidney donors.


  • For interested readers, a calculator to assess the risk of developing kidney disease in the absence of donation can be found at www.transplantmodels.com/esrdrisk/. This risk model is intended for low-risk adults considering living donation in the United States. This risk calculator should not replace clinical judgment.


  • May increase risk of HTN, hyperuricemia, gout, and hyperthyroidism


  • Association between living kidney donation, race, HTN, and eGFR:



    • Study design: Longitudinal multicenter study of 1,295 living kidney donors. Controls: n = 8,233 healthy nondonors drawn from the ARIC (Atherosclerosis Risks in Communities) and CARDIA (Coronary Artery Risk Development in Young Adults) studies


    • Results:



      • Median follow-up: 6 years


      • Black race was associated with a 27% higher risk of HTN, regardless of whether the individual donated a kidney. Although the baseline risk of HTN was higher for blacks, donation was associated with a 19% higher risk of HTN compared with healthy nondonor controls, regardless of race (white or black).



      • Although kidney donors experienced an increase in eGFR over time after donation (attributed to adaptive hyperfiltration), their eGFR plateaued after they developed HTN.


      • The study finding suggests that incident HTN adversely affects GFR after kidney donation.


    • Study limitations: Factors that might impact the effect of HTN on eGFR such as blood pressure control, quality of care for subjects with HTN, and use of antihypertensive medications were not assessed.


  • Impact of age on long-term safety:



    • Study design: Single-center study: N = 539 consecutive live kidney donors (422 donors were <60 years and 117 were 60 years or older). Older donors had lower mean predonation GFR (80 vs. 96 mL/min/1.73 m2), higher BMI, and higher American Society of Anesthesiologists (ASA) classification compared with younger donors.


    • Results:



      • There was no difference in the mean maximum decline in eGFR between the two groups at a median follow-up of 5.5 years (maximum decline in eGFR was 38% ± 9%).


      • The percentage maximal decline was comparable between the two groups.


      • At 5 years follow-up, significantly more elderly had an eGFR < 60 mL/min/1.73 m2 compared with younger donors (94% vs. 80%, p < 0.001). However, renal function stabilized during follow-up, and no donor had an eGFR of < 30 mL/min/1.73 m2.


    • Conclusion: After kidney donation, decline in eGFR is similar in younger and older donors. As kidney function does not progressively decline, live kidney donation by elderly is considered safe.


  • No apparent adverse effect on life expectancy. However, obese living kidney donors might be at increased risk of long-term mortality.



    • In a study using the Scientific Registry of Transplant Recipients database (n = 119,769 living kidney donors with a maximum follow-up of 20 years), obese living kidney donors (BMI ≥ 30) were found to have a 30% increase risk of long-term mortality compared with their nonobese counterparts (adjusted hazard ratio: 1.32, p = 0.006).



      • Study limitations:



        • Of the 119,769 living kidney donors, BMI data at donation were only available in approximately two-thirds of the study cohort (n = 78,592). Multiple imputation was used for one-third of the cohort with missing BMI data at donation.


        • Lack of data on predonation metabolic syndrome


        • Lack of data on postdonation development of other comorbidities such as HTN, diabetes, or cardiovascular disease (CVD)


KIDNEY ALLOCATION SYSTEM



  • Kidney donor profile index (KDPI)




    • Deceased donor kidneys are given a KDPI value ranging from 0% to 100% based on longevity-matching concepts. Ten donor characteristics used to calculate KDPI:



      • Donor age


      • Height


      • Weight


      • Ethnicity


      • History of HTN


      • History of diabetes


      • Serum creatinine


      • Cause of death


      • Hepatitis C status


      • Donation after circulatory death status


    • Lower KDPI values are associated with longer estimated function, whereas higher KDPI values are associated with shorter estimated function (e.g., a kidney with KDPI of 20% is expected to have longer longevity than 80% of recovered kidneys).


  • UNOS listing criteria:



    • CKD with eGFR ≤ 20 mL/min or


    • On dialysis


  • Factors determining kidney allocation:



    • Waiting time



      • Preregistration dialysis time allows transplant candidates to gain waiting time upon listing (e.g., patient who has been on dialysis for 5 years prior to UNOS registration will have 5 years of waiting time upon listing).


      • Candidates not yet on dialysis at the time of registration will still begin to accrue waiting time once they are registered on the waiting list.


    • Geographic area: allocation prioritized to candidates in areas closest to donor


    • Degree of allosensitization (calculated panel reactive antibody [cPRA] ≥ 20%)



      • Higher cPRA scores indicate increasing difficulty in getting a kidney with a negative or acceptable crossmatch (discussion is beyond the scope of this chapter).


      • Prioritization points will be assigned based on a sliding scale, beginning with a cPRA score of 20%. Examples:



        • Candidates with a cPRA of 20% will receive 0.08 points, which is equivalent to about 1 month of waiting time.


        • Candidates with cPRA of 75% to 79% will receive 1.58 points (equivalent to 1.5 years of waiting time).


        • Candidates with cPRA of 80% to 84% will receive 2.46 points (equivalent to 2.5 years of waiting time).


        • Candidates with cPRA of 98%, 99%, or 100% will receive 24.4, 50.09, and 202.10 points, respectively. Such candidates will also receive local, regional, and national priority.


        • The cPRA-based allocating points improve access for highly sensitized candidates.


    • Pediatric candidate


    • Prior living donor



    • Patient/donor HLA-A, HLA-B, and HLA-DR mismatch at the time of allocation



      • Prioritization of zero HLA-A, HLA-B, HLA-DR mismatch (also known as 0MM)


      • Zero-DR mismatch: 2 points


      • One-DR mismatch: 1 point


    • Estimated posttransplant survival (EPTS) score



      • The EPTS score is designed to ensure that those kidneys expected to function the longest are transplanted into those candidates expected to live the longest. It is based on four factors: candidate’s age, length of time on dialysis, prior transplant of any solid organ, and current diabetes status. A lower EPTS score is associated with longer posttransplant longevity.


      • Candidates with EPTS scores of ≤20% will receive increased priority for offers of kidneys with KDPI scores of ≤20% before other candidates at the local, regional, and national levels of distribution.


      • The EPTS score will only be used in kidney allocation when the donor has a KDPI of ≤20%.


      • EPTS scores will not be calculated for pediatric candidate until the candidate turns 18 years.


  • The kidney allocation system also provides greater access to deceased donor kidneys for blood type B candidates who can safely accept a kidney from an A2 or A2B blood type donor.


  • Anticipated kidney allocation policy change (not yet implemented at the time of this writing):



    • Under the new allocation system, kidneys will be offered first to candidates listed at transplant hospitals within 250 nautical miles of the donor hospital. Offers not accepted for any of these candidates will then be made for candidates beyond the 250 nautical mile distance.


    • Candidates will also receive proximity points based on the distance between their transplant program and the donor hospital. The point assignment will be highest for those closest to the donor hospital and will decrease as the distance increases.


IMMUNOSUPPRESSIVE AGENTS


The Three-Signal Model of the Alloimmune Response



  • T-cell activation requires three signals (Fig. 9.1).



    • Signal 1 is initiated by the binding of the alloantigen on the surface of antigen-presenting cell (APC) to the T-cell receptor (TCR)-CD3 complex.


    • Signal 2 is a nonantigen-specific costimulatory signal provided by the engagement of B7 on the surface of APC with CD28 on T cell. These dual signals activate the intracellular pathways that trigger T cells to activate the transcription of interleukin-12 (IL-2) and other growth-promoting cytokines.


    • Signal 3: Engagement of IL-2 to its receptor activates the mTOR pathway to provide signal 3, which leads to cell proliferation. If a TCR is triggered without the accompanying costimulatory signal 2, the T cell is driven into an anergic state.







      FIGURE 9.1 The three-signal model of the alloimmune response and targets of different immunosuppressive agents. Signal 1: binding of alloantigen (red oval) on the surface of the APC to TCR/CD3 complex on T cell. Signal 2: binding of B7 on the surface of APC to CD28 on T cell. These dual signals (i.e., signals 1 and 2) activate the intracellular pathways that trigger T cells to activate the transcription of IL-2 and other growth-promoting cytokines. Signal 3: binding of IL-2 to its receptor leads to activation of mTOR, which leads to T-cell proliferation.

      aCalcineurin is a phosphatase that dephosphorylates and facilitates the translocation of NFAT (and other nuclear factors) to the nucleus. Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines), thereby reducing the proliferation of T cells.

      Abbreviations: Anti-IL-2R, anti-IL-2 receptor; APC, antigen-presenting cell; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells.


  • Lymphocyte proliferation, which requires the synthesis of purine and pyrimidine nucleotides, is inhibited by the antimetabolites MMF, enteric-coated mycophenolate sodium, and AZA.


  • T cells also express cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a cell surface molecule that is homologous to CD28. However, unlike CD28, the binding of B7 to CTLA-4 produces an inhibitory signal that inhibits T-cell proliferation and helps terminate the immune response.


Targets of Various Immunosuppressive Agents



  • The targets of various immunosuppressive agents are shown in Figure 9.1.



    • Agents targeting both signals 1 and 2:



      • Cyclosporine and tacrolimus are termed calcineurin inhibitors (CNIs) due to their common mechanism of action.


      • Calcineurin is a phosphatase that dephosphorylates and facilitates the translocation of the nuclear factor of activated T cells (NFAT) and other nuclear factors to the nucleus. Once translocated into the nucleus, NFAT promotes the translation of specific genes, including that of the growth-promoting cytokine IL-2. Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines), thereby reducing the proliferation of T cells.


    • Agents targeting signal 2:



      • Belatacept (Nulojix) is a humanized fusion protein, composed of CTLA-4 fused with the Fc domain of human immunoglobulin G1 (CTLA-4Ig). Belatacept binds to B7 with high affinity and inhibits the costimulatory pathway.



    • Agents targeting signal 3:



      • Basiliximab is a humanized monoclonal antibody that targets against the α chain of the IL-2 receptor (also known as anti-IL-2 receptor or anti-CD25 antibody), blocking IL-2-mediated responses.


      • mTOR inhibitors: sirolimus and everolimus



        • The mTOR is a key regulatory kinase in the cell division process. Its inhibition reduces cytokine-dependent cellular proliferation at the G1 to S phase of the cell division cycle.


  • Lymphocyte-depleting agents:



    • Thymoglobulin is a polyclonal antibody preparation made by immunization of rabbits with human lymphoid tissue. The purified immunosuppressive product contains cytotoxic antibodies directed against a variety of T-cell markers.


    • Alemtuzumab is a humanized monoclonal antibody targeting against CD52 on the surface of both B and T lymphocytes, leading to a rapid and profound depletion of peripheral and central lymphoid cells.


  • Antimetabolites:



    • Mycophenolic acid (MPA) derivatives (MMF, mycophenolate sodium)



      • MMF (Cellcept) is a prodrug that must be hydrolyzed to the active agent—MPA—in the gastric acidic milieu. MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (a rate-limiting enzyme in the de novo synthesis of purines). Depletion of guanosine nucleotides by MPA has a relatively selective antiproliferative effect on lymphocytes due to their reliance on the de novo pathway of nucleotide synthesis.


      • Mycophenolate sodium (Myfortic) is an enteric-coated formulation of MPA that dissolves at pH > 5.5. Therefore, unlike MMF, mycophenolate sodium bypasses the acidic milieu of the stomach and is absorbed in the intestines.


      • The use of antacids or proton-pump inhibitors (PPIs) can reduce the dissolution of MMF by increasing pH. In contrast, the bioavailability of mycophenolate sodium is not affected by antacids or PPIs.


    • Azathioprine (AZA)



      • AZA is a precursor of 6-mercaptopurine.


      • AZA inhibits DNA replication and subsequent T-cell proliferation. MMF/mycophenolate sodium has largely replaced AZA due to its greater efficacy in reducing acute rejection.


  • Corticosteroid:



    • Key component of all immunosuppressive regimens


    • Modulates inflammatory mediators


    • Blocks IL-1 and IL-2 production, thereby suppressing the early phase of the immune response


Basic Principles of an Immunosuppressive Protocol


Standard immunosuppressive protocol



  • A standard immunosuppressive protocol consists of induction and maintenance immunosuppression. All kidney transplant recipients also receive prophylactic therapy with an antibiotic, antiviral, and antifungal agents, and a nondihydropyridine calcium channel blocker to boost CNI or mTOR inhibitor levels (Table 9.8). The use of diltiazem or verapamil may permit CNI dose reductions up to 40% and 30% to 50%, respectively.









    Table 9.8 Components of a standard immunosuppressive protocol (immunosuppressive and nonimmunosuppressive agents)





















    Immunosuppressive Agents


    Options


    Induction


    Lymphocyte-depleting or nonlymphocyte-depleting agent


    Standard triple maintenance immunosuppression




    1. Calcineurin inhibitor



    2. Adjunctive agent



    3. Corticosteroid




    1. Cyclosporine or tacrolimus



    2. Mycophenolic acid derivatives, sirolimus (or everolimus), or azathioprine



    3. Maintenance dose: prednisone 5 mg daily


    Nonimmunosuppressive Agents


    Options


    Supplementary agents


    Nondihydropyridine calcium channel blockers


    Infection prophylaxis


    Pneumocystis jirovecii (trimethoprim and sulfamethoxazole, atovaquone, dapsone)


    Cytomegalovirus (acyclovir, valganciclovir)


    Antifungals (nystatin, fluconazole)



  • Induction therapy is used to rapidly create a therapeutic net state of immunosuppression in the first few days or week after transplantation in order to prevent rejection.



    • Induction therapy can be classified into lymphocyte-depleting and nonlymphocyte-depleting agents.



      • Lymphocyte-depleting agents: thymoglobulin (antithymocyte globulin [ATG]), alemtuzumab


      • Nonlymphocyte-depleting agent: basiliximab (anti-IL-2-receptor antibody)


    • The choice of one induction agent over the other is generally based on each individual immunologic risk factors or anticipated delayed graft function (DGF) or both (Table 9.9).


    • In the presence of anticipated DGF due to donor acute tubular injury (aka acute tubular necrosis), it is important to maintain adequate immunosuppression. It has
      been suggested that endothelial injury upregulates and exposes donor histocompatibility antigens, adhesion molecules, and costimulatory molecules, heightening the risk of acute rejection. Induction therapy with lymphocyte-depleting agent and delayed introduction of CNI may avoid the additive injury associated with CNI nephrotoxicity (due to afferent arteriolar vasoconstriction) while reducing the risk of allograft rejection at the time of heightened immunogenicity.








      Table 9.9 Induction therapy: lymphocyte-depleting versus nonlymphocyte-depleting agents



















      Lymphocyte-Depleting Agentsa


      Nonlymphocyte-Depleting Agents


      Comments


      Thymoglobulin (antithymocyte globulin [Rabbit])


      Basiliximab


      Thymoglobulin vs. basiliximab induction




      • Thymoglobulin: commonly used in high immunologic risk patients (e.g., highly sensitized or re-allograft transplant recipient, donor-specific antibody positive, high cPRAb) or anticipated delayed graft function to avoid early exposure to cyclosporine or tacrolimus (nephrotoxic)



      • Basiliximab: commonly used in low-to-moderate immunologic risk transplant recipients


      Alemtuzumab



      Alemtuzumab is used at a small number of transplant centers in the United States


      a Lymphocyte-depleting agents can cause first-dose reaction or cytokine-release syndrome, including chills, fever, arthralgia, and, rarely, serum sickness.

      b cPRA is discussed in Chapter 8 Transplant Immunobiology.


      Abbreviation: cPRA, calculated panel reactive antibody.









      Table 9.10 Side-effect profiles of cyclosporine and tacrolimus






















































      Cyclosporine


      Tacrolimus


      Comments


      Nephrotoxicity


      Nephrotoxicity


      CSA > Tac


      Hypertension and sodium retention


      Hypertension and sodium retention


      CSA > Tac


      Hyperlipidemia


      Hyperlipidemia


      CSA > Tac


      Diabetes mellitus


      Diabetes mellitus


      Tac > CSA


      Neurotoxicity (headache, tremors, confusion, paresthesia)


      Neurotoxicity (headache, tremors, confusion, paresthesia, insomnia)


      Tac > CSA


      Thrombotic microangiopathy


      Thrombotic microangiopathy


      Gastrointestinal side effects (hepatotoxicity approximately 4% first month, dose related)


      Gastrointestinal side effects (diarrhea, abdominal pain, nausea, vomiting, decreased appetite)


      Hyperkalemia


      Hyperkalemia


      Hypomagnesemia


      Hypomagnesemia


      Hyperchloremic metabolic acidosis


      Hyperchloremic metabolic acidosis


      Hyperuricemia, gout


      Hyperuricemia, gout


      CSA > Tac


      Others:


      Others:


      Hirsutism, gingival hyperplasia


      Alopecia, pancreatitis


      Abbreviations: CSA, cyclosporine A; Tac, tacrolimus.



  • Maintenance immunosuppression is used to sustain a therapeutic net state of immunosuppression in order to prevent rejection.



    • A standard immunosuppressive regimen consists of triple-drug therapy: CNI (cyclosporine or tacrolimus) + adjunctive agent + corticosteroid.



      • CNI: The choice of tacrolimus over cyclosporine A (CSA) or vice versa is generally based on the potential adverse effects of these agents. The side-effect profile of cyclosporine and tacrolimus are summarized in Table 9.10.


      • Adjunctive agents:



        • MMF, mycophenolate sodium, sirolimus, everolimus, AZA


        • MMF or mycophenolate sodium is the most commonly used adjunctive agent. The side-effect profiles of MMF and mycophenolate sodium are summarized in Table 9.11.


        • Note: MMF (or mycophenolate sodium) and sirolimus (or everolimus) must be discontinued in anticipation of pregnancy. MPA derivative use in pregnancy has been shown to be associated with first-trimester pregnancy loss and congenital malformation, whereas mTOR inhibitor use in pregnancy has been reported to be associated with fetal mortality, decreased fetal weight, and delayed ossification of skeletal structure.


        • AZA, sirolimus, or everolimus is generally used in place of MMF for special indications:









          Table 9.11 Side-effect profiles of mycophenolate mofetil and mycophenolate sodium















          Mycophenolate Mofetil (Cellcept)


          Mycophenolate Sodium (Myfortic) (enteric-coated mycophenolic acid derivative formulation)


          Diarrhea, nausea, vomiting, abdominal pain, flatulence, dyspepsia


          Potentially less gastrointestinal toxicity compared with Cellcept


          Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia


          Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia


          Comments: More than 2 g/d is usually not well tolerated


          Comments: Myfortic 180 mg = Cellcept 250 mg (similar efficacy)




          • Azathioprine (AZA):



            • AZA use is safe in pregnancy.


            • Avoid use with allopurinol (a xanthine oxidase inhibitor) because of the inhibition of AZA metabolism by xanthine oxidase inhibitors.


            • Febuxostat is a nonpurine selective inhibitor of xanthine oxidase. Hence, it should be avoided (or use with caution) in patients taking AZA.


          • Sirolimus or everolimus (mTOR inhibitors)



            • Potential beneficial effect in patients with history of malignancy, particularly skin cancers, renal cell carcinoma (RCC), or Kaposi sarcoma. Its use in posttransplantation lymphoproliferative disorder (PTLD) has inconsistently been shown to be beneficial.


            • Not recommended in the early postoperative period (may impair wound healing and delayed recovery of acute tubular injury)


            • The side-effect profiles of sirolimus and everolimus are summarized in Table 9.12.


Steroid- or CNI-free maintenance immunosuppressive protocol



  • Must be individualized based on immunologic risk


  • Steroid withdrawal (CNI + MPA derivatives dual therapy)



    • Safe in low immunologic risk patients at short-term follow-up (long-term graft function and the risk of chronic rejection have not been thoroughly evaluated)


    • The 2016 Cochrane review suggests that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There is no difference in patient mortality or graft loss up to 5 years after transplantation. However, long-term consequences of steroid avoidance and withdrawal remain unclear due to the lack of prospective long-term studies.


  • Belatacept in CNI-free protocol



    • Clinicians must be familiar with its use.


    • May be considered in low immunologic risk patients with biopsy-documented CNI toxicity or CNI-induced thrombotic microangiopathy (TMA) and absence of acute rejection


    • Potential replacement for CNI in CNI-based immunosuppressive protocols


    • Typically used in combination with basiliximab induction, MPA derivatives, and corticosteroids: belatacept + MPA derivatives + corticosteroid









      Table 9.12 Side-effect profiles of mammalian target of rapamycin inhibitors (sirolimus or everolimus)































      Potential Side Effects


      Comments


      Delayed recovery of acute tubular injury (acute tubular necrosis)


      Not recommended in the early postoperative period


      Not recommended in patients with preexisting proteinuria ≥ 500 mg/d or at the discretion of the clinician (practice may differ among centers)


      Calcineurin inhibitor target level should be lowered when used in combination with mammalian target of rapamycin (mTOR) inhibitors


      mTOR inhibitor use is associated with the worst lipid profile compared to cyclosporine and tacrolimus


      Impaired wound healing


      Increased risk of lymphocele formation


      May potentiate calcineurin inhibitor nephrotoxicity


      Oral ulcers


      Diabetogenic


      Proteinuria


      Dyslipidemia (increased cholesterol; may significantly increase triglyceride levels)


      Peripheral edema


      Pulmonary toxicity


      Thrombotic microangiopathy


      Others: acne, rash, anemia, thrombocytopenia, decreased testosterone



    • US FDA black box warning: Belatacept is contraindicated in Epstein-Barr virus (EBV)-naïve kidney transplant recipients due to increased risk of PTLD predominantly involving the central nervous system (CNS).



Allograft Rejection: Types and Treatment Strategies



  • Allograft rejection can be classified into hyperacute, acute, and chronic rejection.


  • The 2017 Banff classification of renal allograft pathology is discussed in a later section. Hyperacute rejection is not classified under Banff categories.


Hyperacute rejection



  • Pathogenesis



    • Caused by preformed antidonor HLA antibodies


    • Preformed antidonor HLA antibodies bind to graft endothelial antigens and activate complement, leading to severe vascular injury, thrombosis, coagulative necrosis, and obliteration of the graft vasculature


  • With the current cytotoxic crossmatch and the advent of the single-antigen bead-based Luminex assays, hyperacute rejection has become virtually nonexistent.









    Table 9.13 Drug-drug and drug-food interactionsa





























































    Drugs That Increase CNI Level by Inhibition of CYP3A or by Competition for Its Pathways


    Calcium channel blockers: diltiazem, verapamil > nicardipine




    • Changing the dose of these drugs is equivalent to changing CNI dosage.



    • Brand vs. generic names and immediate vs. delayed-release formulations of diltiazem may have different effects on CNI levels.


    The “azole” antifungals: fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole, isavuconazole




    • The “azole” antifungals markedly increase CNI levels. Great care must be taken when starting and stopping these drugs.



    • The absorption of ketoconazole and itraconazole requires acidic gastric contents. The use of proton-pump inhibitors/H2 blockers may reduce CNI-absorption, hence blood levels.


    Antibiotics: erythromycin > other macrolide antibiotics (clarithromycin, josamycin, ponsinomycin)




    • Azithromycin (conflicting reports): A short course can generally be given without the need for CNI level monitoring.


    Antiretroviral agents: essentially all currently available protease inhibitors (e.g., ritonavir, ritonavir/lopinavir combination therapy, i.e., Kaletra, darunavir, indinavir/ritonavir, saquinavir, atazanavir, amprenavir)




    • Immunosuppressive management in HIV patients requires close collaboration with infectious disease specialist due to multiple drug-drug interactions.


    Hepatitis C protease inhibitors: telaprevir/boceprevir (no longer available in the United States)


    Others (less well established): amiodarone, carvedilol, allopurinol, bromocriptine, chloroquine


    Drugs that decrease CNI level by induction of CYP3A activity


    Antituberculous drugs: rifampin > rifabutin




    • Rifampin markedly reduces CNI levels, and its use should be avoided if possible.



    • Pyrazinamide and ethambutol may reduce drug levels. Their use requires drug monitoring.



    • Isoniazid (INH) can be used with careful drug level monitoring.


    Anticonvulsants: barbiturates > phenytoin > carbamazepine




    • Oxcarbazepine (Trileptal) may decrease cyclosporine level.



    • Gabapentin (Neurontin) and levetiracetam (Keppra) and other drugs in this category do not appear to have significant drug interactions.


    Corticosteroids




    • Discontinuation of steroid therapy may result in an increase in tacrolimus level by up to 25%


    Antidepressants herbal preparation: Hypericum perforatum (St. John wort)


    Others (less well-established/case reports): nafcillin, IV trimethoprim, IV sulfadimidine, imipenem, cephalosporins, terbinafine, ciprofloxacin


    Drugs or food that increase the absorption of CNIs


    Grapefruit, pomegranate, star fruit (also inhibits CYP3A)


    Metoclopramide




    • The effect of grapefruit juice may vary widely among brands and is concentration, dose, and preparation dependent.


    Drugs or food that decrease the absorption of CNIs


    GoLYTELY, sevelamer, olestra, cholestyramine


    Nephrotoxic drugs or drugs that may potentiate CNI toxicity


    mTOR inhibitors, NSAIDs, tenofovir, amphotericin, aminoglycosides, ACE inhibitors, ARBs




    • CNI target levels should be lowered when used in combination therapy with mTOR inhibitors.



    • Amphotericin and aminoglycoside-associated nephrotoxicity may occur earlier than anticipated when used with CNI therapy.


    Commonly used herbals that may have an immune-stimulating effect


    Ginseng, licorice, alfalfa sprouts, astragalus


    Cholesterol-lowering agents


    Cyclosporine has an inhibitory effect on CYP3A and P-glycoprotein. The concomitant use of cyclosporine and statins can result in a several-fold increase in statin blood level and an increased risk for myopathy and rhabdomyolysis and acute kidney injury.




    • All statins should be started at low dose. Any increase in dose requires close monitoring. Maximal dose should be avoided.



    • Rhabdomyolysis associated with tacrolimus and statin use is generally seen in patients on concomitant diltiazem therapy.



    • Concomitant lovastatin (or simvastatin) and gemfibrozil therapy increases the risk of rhabdomyolysis and should be avoided.


    Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CNI, calcineurin inhibitor; IV, intravenous; mTOR, mammalian target of rapamycin; NSAIDs, nonsteroidal anti-inflammatory drugs.




  • Hyperacute rejection can occur immediately following vascular anastomosis or within minutes to hours after graft revascularization.


  • Hyperacute rejection uniformly results in graft loss, requiring allograft nephrectomy.


Acute rejection

Jul 21, 2021 | Posted by in NEPHROLOGY | Comments Off on Kidney Transplantation
Premium Wordpress Themes by UFO Themes