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A. Introduction / Indicationsnavigator

  1. Therapy of choice for nearly all patients with end-stage renal disease (ESRD)
    1. Patients with chronic renal failure (CRF) who progress to ESRD
    2. ESRD is that level of renal function in compatible with life
    3. These patients are placed on peritoneal or hemodialysis
    4. Nearly all patients on any dialysis are candidates for transplantation
    5. Dialysis prior to transplantation increases risk of long term allograft failure [2]
    6. In patients with single kidney, severe acute damage to that kidney is also an indication
  2. Most common type of transplant in USA
    1. Nearly 10,000 transplants per year in USA
    2. Majority are cadavaric (75%); remainder are living related donor
    3. There are over 70,000 patients in the USA with functioning kidney transplants
    4. Blacks are more likely than whites to progress to ESRD and need kidney transplant [7]
  3. CRF Progressing to ESRD is most commonly due to:
    1. Diabetic nephropathy
    2. Hypertension (HTN)
    3. Polycystic Kidney Disease
    4. Autoimmune disease (SLE, MCTD, Scleroderma)
  4. National sharing of HLA-matched cadaveric kidneys is advocated [33]
  5. For organ donation sites, see reference [8]

B. Types of Transplantsnavigator

  1. Living: ~15%
    1. Parent with 1 haplotype match~30%
    2. Sibling with 1 haplotype match: ~25%
    3. Identical Twin: ~20%
    4. Living Unrelated Donor
    5. Paired kidney donation (may be "incompatible" but still good initial results [52])
    6. After 5-10, ~5mm Hg blood pressure increase above age-matched controls in living donors [16]
  2. Cadavaric (including donor without a heartbeat): ~85%
  3. Transplant is usually placed in the pelvis and vascular anastamoses made
  4. Mean waiting time for transplant ~420 days
  5. Role of Major Histocompatibility Complex (MHC) in Transplantation Success [14]
    1. MHC believed to have major role in transplantation success
    2. Pre-existing anti-MHC panel reactive antibodies (PRA) associated with rejection
    3. 10-year graft survival rates in >4000 kidney transplants from HLA-indentical siblings:
    4. Graft survival with no PRA 72%
    5. Graft survival with 1-50% PRA 63%
    6. Graft survival with >50% PRA 55%
    7. Therefore, non-HLA mechanisms are involved in long term graft function
  6. MHC class I-related chain A (MICA) A
    1. Polymorphic MHC-related antigens
    2. Mismatches can elicit antibodies (Abs) against MICA
    3. Presence of anti-MICA Abs associated with ~5% reduced 1 year graft survival no Abs [18]
  7. Minor Histocompatibility Antigen
    1. H-Y is a male specific minor histocompatibility antigen
    2. Donor male kidneys into female recipients has slightly increased (1.06-1.08X) risk of graft loss than all other combinations of donor-recipients [58]

C. Preparation navigator

  1. Harvesting Kidney [28]
    1. Kidney surgeons responsible for renal retrieval
    2. Goal is to minimize time and damage to organ prior to retrieval
    3. Nearly ~25% of kidneys are damaged at retrieval
    4. However, this damage is not associated with poor long term outcomes
    5. Kidneys from donors without a heartbeat have delayed graft function but similar long term outcomes to living donors [43]
  2. Anti-T Cell Therapy [9]
    1. For patients receiving cadavaric (or live) transplants
    2. Anti-OKT3 (Orthoclone®, Muromonab)
    3. Anti-lymphocyte globulin
    4. Rabbit antithymocyte globulin, 1.5-5mg/kg IV over several hours, prior to transplant
    5. Permits early engraftment without use of cyclosporine A (CsA) in early graft period
    6. Appears most effective in recipients who are presensitized to graft antigens [21]
    7. Basilizimab (see below), may substitute for rabbit anti-thymocyte globulin, though associated with slightly higher acute (but not chronic) graft rejection rates [55]
    8. Overall, effects wain after 2 years
    9. Unclear benefits in classical "high risk" transplant groups
    10. After induction with antithymocyte globulin, maintenance tacrolimus monotherapy could often be weaned slowly to alternating days or 1-2 doses per week [49]
    11. Slow but steady weaning of tacrolimus should be considered during maintenance phase
    12. Anti-T cell therapies are not used by all centers
  3. Daclizumab (Zenapax®) [19,23]
    1. This is a humanized (IgG1 Fc) anti-IL2R alpha chain (CD25) Ab
    2. Reduces acute rejection episodes in moderate and high risk patients
    3. Reduced biopsy proven acute rejection from 35% to 22% in combination with other drugs
    4. Used in combination with CsA, glucocorticoids, and azathioprine
    5. Excellent side effect profile with no increase in infections versus control
    6. Approved by FDA for prevention of acute renal allograft rejection
    7. Half life of the drug is ~20 days
    8. Dose is 1mg/kg over 15 minutes, given 24 hours before transplant and biweekly x 4
    9. Daclizumab induction with myophenolate, glucocorticoids, and tacrolimus may improve outcomes versus regimens with or without daclizumab induction and CsA or sirolimus [57]
  4. Basiliximab (Simulect®) [23]
    1. Chimeric IgG1 mouse Fab / human Fc monoclonal Ab
    2. Binds to anti-IL2R alpha chain (CD25) similar to daclizumab
    3. Used in combination with CsA, glucocorticoids and mycophenolate or azathioprine
    4. Reduced acute rejection rate at 6 months from 44% to 30%
    5. Excellent side effect profile
    6. Approved by FDA for prevention of acute renal allograft rejection
    7. Associated with similar graft loss and chronic graft function as rabbit antithymocyte globulin, though has higher acute (25% versus 15%) rejection episodes [55]
    8. Half-life of the drug is ~7 days
    9. Dose is 20mg IV on day of transplantation and 20mg IV four days later
  5. Anti-HLA Ab Sensitized Patients [59]
    1. Have circulating anti-HLA Ab which prevent (limit) transplantation
    2. Patients treated with rituximab (Rituxan®, anti-B cell antibody) + intravenous immunoglobulin
    3. Of 20 patients receiving this combination, 16 were transplanted
    4. One year after treatment and transplant, 15 of 16 grafts survived with 0% mortality
    5. Rituximab + IVIg treatment may permit transplantation in HLA-Ab bearing patients
  6. Glucocorticoids (see below)
  7. Azathioprine or Mycophenolate or Sirolimus (Rapamycin)
  8. CsA (see below)
  9. Oral valacyclovir reduced incidence of CMV disease and acute rejection episodes [26]

D. Maintenance Therapy navigator

  1. CsA (Sandimmune®, Neoral®) [20]
    1. 10mg/kg/d when creatinine <3.0mg/dL
    2. Maintain at trough levels 200-300 ng/mL for first year
    3. Maintenance trough levels 75-125 ng/mL (low dose) as effective as normal 150-250
    4. By using low dose CsA, numbers of cancers were reduced by ~30%
    5. However, low dose group had more rejection episodes (similar long term outcomes)
    6. Grapefruit juice increases peak drug levels [10]
    7. Major toxicity is renal due primarily to vasoconstriction of renal arterioles
    8. Calcium channel blockers such as diltiazem may reduce this toxicity
  2. Tacrolimus (FK506; Prograf®)
    1. Inhibits T cell receptor-mediated, calcium dependent signalling
    2. Binds to FK506-binding protein and inhibits calineurin phosphatase activity
    3. Dose is 0.30mg/kg in kidney transplant
    4. Appears to be effective for refractory acute kidney rejection
    5. More effective than CsA microemulsion in preventing acute kidney rejection [41]
    6. Acute rejection rate with tacrolimus ~20% versus ~37% with CsA microemulsion [41]
    7. Hypertension and hypercholesterolemia more common with CsA than tacrolimus
    8. May be useful as initial maintenance therapy in patients with CsA toxicity
    9. Following induction with antithymocyte globulin, may be used as maintenance montherapy and tapered to alternating day or 1-2 doses per week [49]
    10. Low dse tacrolimus containing regimen after daclizumab induction may provide better outcomes in renal allograft transplants compared with other calcineurin inhibitors [57]
  3. Rapamycin (sirolimus, Rapamune®) [26,31]
    1. Approved for prevention of acute renal graft rejection with CsA
    2. Structurally related to tacrolimus, but blocks a T cell coactivation
    3. Substantially reduced nephrotoxicity compared with CsA and Tacrolimus
    4. Used in combination with CsA, permits CsA dose reduction
    5. Combined with rabbit antithymocyte globulin induction, can be chronic as monotherapy [46]
    6. Superior to azathioprine as add on therapy with CsA
    7. Can replace CsA in patients with Kaposi's sarcoma (KS) and renal transplant leading to regression of KS and maintenance of graft function [50]
    8. Dose in combination with CsA is 6mg loading and 2mg/d 4 hours after CsA is taken
    9. Dose as monotherapy in renal transplant is 15mg initially, then 5mg qd with modulated trough levels of 10-15µg/L [46]
    10. Main side effects are thrombocytopenia, leukopenia, and hyperlipidemia
    11. Arthralgias and rash commonly occur
    12. Pneumonitis (lymphocytic alveolitis) with radiologic appearing bronchiolitis obliterans organizing pneumonia (BOOP) can occur and discontinuation of drug is required []
  4. Glucocorticoids
    1. Prednisone po or methylprednisolone iv initially at high doses (1mg/kg/d) then tapered
    2. Oral prednisone10-15mg per day is the goal dosage
    3. Steroid withdrawal after 1-6 yrs is reasonable in many patients with stable renal function provided frequent monitoring is carried out
  5. Mycophenolate (CellCept®) [11]
    1. Approved for oral use in preventing graft rejection, replacement for azathioprine
    2. Hydrolyzed in vivo to mycophenolic acid which inhibits inosine monophosphate
    3. This enzyme is found in T and B cells
    4. Dose is 1gm po bid; cost is ~$450 per month
    5. As effective as and more costly than azathioprine for preventing acute rejection [4]
    6. May be renal protective for chronic graft nephropathy
    7. Diarrhea, leukopenia may occur
  6. Azathioprine (Imuran®)
    1. Glucocorticoid "sparing" agent
    2. Direct T cell suppression
    3. 2-3mg/kg/day
    4. Not as effective in short or long term as CsA
    5. As effective as mycophenolate for prevention of acute rejection [4]
  7. Belatacept (LEA29Y) [51]
    1. Fusion protein of CTLA-4 and IgFc region
    2. Blocks T cell costimulation by binding CD80 and CD86, preventing interaction with CD28
    3. Assessed in maintenance therapy versus CsA for renal transplantation
    4. Induction with basilizimab, mycophenolate, glucocorticoids then maintenance therapy
    5. Similar acute rejection rate (7%) at 7 months for belatacept versus CsA
    6. Chronic allograft nephropathy, renal function better with belatacept versus CsA at 1 year
  8. Most of these agents appear to be safe in pregnancy

E. Infectionnavigator

  1. Bacterial
    1. Urinary tract infections quite common
    2. Trimethoprim/Sulfamethoxazole (Bactrim®, Septra®) perioperatively reduces risk
  2. Pneumocystis carinii
    1. High risk in T cell deficient patients - that is, early in graft course
    2. TMP/SMX (Bactrim®, Septra®) is extremely effective prophylaxis
  3. Cytomegalovirus (CMV)
    1. CMV especially problematic in CMV- recipients of CMV+ grafts
    2. Valacyclovir reduced risk of CMV by >90% and acute rejection episodes by 50% [26]
    3. CMV specific immunoglobulin reduces severity, not incidence, of primary CMV infection
    4. Ganciclovir is useful in treatment of symptomatic CMV disease
    5. Ganciclovir is effective in preventing disease in CMV Ab+ patients during transplant
    6. Strongly consider prophylactic valacyclovir 2gm qid po (adjust for renal function) in both seropositive and seronegative patients
  4. Hepatitis C Virus
    1. Contributes to graft failure in chronic setting
    2. Immunosuppression promotes hepatitis C toxicity
    3. Hepatitis C+ donor grafts should generally not be tranplanted to HCV- recipients
  5. Human Herpesvirus 8 (HHV-8) [24]
    1. HHV-8 causes Kaposi Sarcoma (KS) in immunocompromised persons
    2. Risk of KS is increased in solid-organ transplanted patients
    3. Renal transplant donors can transmit HHV-8
  6. Other Herpesviruses
    1. Herpes simplex (HSV) and herpes zoster (shingles) viral infections are increased
    2. Valacyclovir reduced incidence of HSV infections
  7. Polyomavirus Type BK [32,44]
    1. Nonenveloped, polyomavirus (double stranded DNA)
    2. Genome 5300 base pairs
    3. Related to JC virus, the cause of progressive multifocal leukoencephalopathy (PML)
    4. Causes nephropathy and renal graft failure in transplant patients
    5. Fatal vasculopathy due to systemic endothelial cell infection reported [40]
    6. BK virus levels can be detected in plasma with polymerase chain reaction
    7. Reduction of immunosuppressive agents usually fascilitates clearance of BK virus
    8. Plasma viral load levels can be used to monitor levels and therapy
  8. Lymphocytic Chroiomeningitis Virus (LCMV) [54]
    1. Rodent-borne arenavirus with minimal symptoms in healthy persons
    2. Transmission documented with kidney transplantation
    3. Associated with fatal outcome in kidney transplants
    4. One survivor of 8 LCMV infections received ribavirin and reduced immunosuppression
  9. Chronic immunosuppression also associated with lymphoma, particularly with Epstein-Barr virus (EBV)

F. Delayed Graft Function (DGF) [13]navigator

  1. Most cadavaric and some live-donor kidney transplants exhibit DGF
  2. DGF is a form of acute renal failure (ARF) leading to post-transplant oliguria
    1. Increases allograft immunogenicity
    2. Increases risk of acute rejection episodes
    3. Reduces long term survival
  3. DGF Recovery Times
    1. ~50% of patients with DGF recover renal function by day 10 post-transplant
    2. ~33% regain function within 10-20 days
    3. ~15% regain function >20 days
    4. Primary non-function occurs in ~2% of cases
  4. Risks for DGF Occurring
    1. Cadavaric > Live Donor
    2. Inotropic support of donor
    3. Cold storage preservation and cold ischemia time
    4. Prerenal factors
    5. Inherited thrombophilias
    6. Cyclosporin toxicity
    7. Acute tubular necrosis
    8. Ureteral leakage, obstruction
    9. Donor age >55 years previously a risk, but recently disputed) [12]
  5. Both ischemic and reperfusion injury play a role
  6. Dialysis is used to manage DGF
  7. Reduction or elimination of calcineurin inhibitors should be considered

G. Acute Rejection [1] navigator

  1. Biopsy of the transplant is usually performed to prove etiology
    1. Noninvasive methods of assessing rejection are being developed
    2. Urinary cell mRNA levels of granzyme B and perforin increase during rejection [38]
    3. Recipient mesenchymal cells can migrate into donor kidney allograft in kidneys undergoing rejection [39]
    4. These host cells contribute to neointimal enlargement and tubulointerstitial disease [39]
    5. Activating antibodies to angiotensin II receptors (AT1) may play a role in refractory rejection by enhancing vascular constriction, wall hypertrophy [17]
    6. Measurement of FOXP3 mRNA in urine corresponds well to presence of acute rejection on kidney biopsy [53]
  2. Immunology [27]
    1. Key is to determine major effectors: humoral (antibodies) versus cellular immunity
    2. Antibody mediated rejection is treated distinctly from T cell mediated rejection [48]
    3. Anti-allogeneic T lymphocytes play major role
    4. Antigen-presenting cells also critical - including activated (graft) endothelial cells
    5. T cell costimulation is required - CD28, CD40L, CD2, LFA-1, and CD5 all play some role
    6. Activation of T cells requires calcineurin, a phosphatase
    7. CsA and tacrolimus block T cell activation by inhibition of calcineurin
    8. Activated T cells release cytokines which induce leukocyte adhesion molecules on leukocytes and co-receptors on endothelial cells
    9. Activated leukocytes traverse post-capillary venules and enter graft
    10. Cytolytic T cells (CTL), macrophages, B cells, endothelium and other cells are involved
    11. Dense clusters of B cells in biopsy is associated with severe graft rejection [5]
    12. Microarray gene expression profiling shows that histologically similar graft rejection is quite heterogeneous at the gene expression level [5]
  3. Vascular Damage [36]
    1. Acute rejection is associated with damage to graft endothelium
    2. Recipient endothelial cells are found in the grafts of patients who had had rejection
    3. High levels of recipient endothelial cells were found amongs patients with vascular rejection
    4. Endothelium that is damaged by vascular rejection is likely replaced by host endothelium
    5. Thus, host endothelium may be a marker for vascular rejection
  4. Initial Treatment of Rejection [9]
    1. High dose glucocorticoids are the mainstay of therapy
    2. Activity mediated through glucocorticoid response elements in cytokine gene promoters
    3. Inhibit cytokine gene expression - including IL1, IL2, IL6, IFNg and TNFa
    4. Antibody mediated rejection treated with plasmapheresis ± intravenous immunoglobulin [48]
  5. Anti-CD3 Monoclonal Antibody (OKT3)
    1. Used in acute rejection epidosed to block T lymphocytes
    2. Binds CD3 on all mature T cells, eventually leading to death of T cells
    3. Initial reaction is cytokine release by T cells
    4. This causes a cytokine release syndrome: myalgias, nausea, vomiting, edema, hypoxemia
    5. Increased risk of CMV disease and post-transplant lymphoproliferative disorder
  6. Tacrolimus appears to treat refractory acute renal allograft rejection
  7. Other Agents (Experimental)
    1. Platelet Activating Factor (PAF) Antagonist - blocks acute rejection in early studies
    2. IL2-toxin conjugates and Anti-IL2-R (anti-CD25) Abs have shown minimal activity
    3. CTLA4-Ig - binds to accessory cell CD80/86 (B7-1/2); blocks T cell activation
    4. Anti-CD40L (CD154) antibodies - binds to activated T lymphocytes, blocks function
    5. Anti-CD4 antibodies - high levels of T lymphocyte depletion with minimal activity
    6. Anti-LFA-1 (CD11a) Abs - insufficient to prevent rejection
    7. Anti-ICAM-1 (CD54) Abs - insufficient to prevent rejection
  8. Maternal HLA presence in sibling donor graft and not recipient is a better long term prognostic feature than the presence of paternal HLA on donor and not recipient [25]
  9. BK virus infection is an important cause of graft failure (see above) [32]

H. Chronic Allograft Nephropathy [1,3]navigator

  1. Formerly called chronic rejection
  2. Clinical Presentation
    1. Gradual decrease in renal function
    2. HTN
    3. Low grade proteinuria
    4. Typically occurs months to years after transplantation
    5. By 10 years post-transplant, ~60% of kidneys have chronic allograft nephropathy
    6. Urine FOXP3 mRNA levels are not elevated in chronic allograph nephropathy versus normal kidney biopsy [53]
  3. Multiple Etiologic Contributions [3]
    1. Antigen-dependent and independent factors play a role
    2. Chronic lymphocytic infiltration - correlates with HLA matching
    3. Accelerated graft atherosclerosis
    4. Early rejection episodes
    5. Graft ischemia
    6. Infections
    7. HTN
    8. Diabetes mellitus - contributes to failure in 10-20% of grafts
    9. Improved diabetic control improved graft survival
    10. Recurrent glomerulonephritis (in patients with pre-transplant disease) [42]
    11. Hyperlipidemia
    12. Drug toxicity
  4. Chronic Graft Rejection
    1. Likely that chronic rejection is the major cause of long term graft failure
    2. Histology shows obliterative vasculopathy, interstitial fibrosis, mononuclear cells
    3. Result is leukocyte mediated glomerulosclerosis and eventual failure
    4. Focal segmental glomerular sclerosis is most common pathology
  5. Other Antigen-Independent Factors in Graft Rejection
    1. Donor age may not be a risk factor for rejection [12]
    2. Recipient body area (increasing rejection with increased area)
    3. Diabetes in recipient
    4. Asian Donor Race increases risk of graft failure
    5. Cyclosporin and other drug toxicity
    6. Hyperlipidemia in recipient
    7. Donor age >60 years associated with good outcomes if initial histology acceptable [12]
  6. CsA Toxicity
    1. Nephrotoxic agent with mild renal toxicity in long term
    2. Does not appear to cause progressive renal failure
    3. Affects tubular function, decrease urate excretion with increased serum uric acid
    4. Vasoconstrictive properties may be responsible for severe bone pain
    5. Bone pain (may include osteonecrosis) often responds to calcium blockers
    6. Causes hypertension and hyperlipidemia as well
    7. Tacrolimus has similar nephrotoxicity but less HTN and hyperlipidemia
  7. Accelerated Atherosclerosis
    1. Multiple contributing factors
    2. Chronic inflammation plays major role - direct graft endothelial injury
    3. Hypercholesterolemia and hypertriglyceridemia contribute
    4. Hyperhomocysteinemia - independent risk factor for early failure
    5. Treatment with Vitamin B6 (50mg/d) or B12 (0.4mg/d) + folate (5mg/d) reduces serum homocysteine levels by ~20%
    6. Diabetes mellitus
    7. Systemic HTN
  8. Cardiovascular Disease
    1. HTN is common in transplant recipients (~70%)
    2. Renal artery stenosis occurs infrequently in grafts (~2%)
    3. Renal artery stenosis is treated with angioplasty or surgery
    4. Calcium blockers, ACE inhibitors and diuretics are effective therapy for HTN
    5. ACE inhibitors or angiotensin II receptor blockers can be used with caution
    6. These agents are likely renal protective (in contrast to other agents)
    7. Calcium blocker nitrendipine improves blood pressure and is nephroprotective [29]
    8. Fluvastatin did not generally reduce rates of cardiac related mortality or interventions in renal transplant recipients [35]

I. Long Term Prognosis [37]navigator

  1. One Year Graft Survival [30]
    1. Living donors: 93.9% survival
    2. Cadavaric donors: 87.7% survival
    3. Half life for grafts from living donors is now >35 years
    4. Half life for grafts from cadavaric donors is now >19 years
    5. Acute rejection episodes correlate with shorter graft survival
    6. Primary graft: >90% for no HLA mismatches and ~80% for 4 HLA mismatches
    7. Secondary grafts 80%
    8. Subsequent grafts 79%
  2. 5 Year Graft Survival: Cadavaric 66%, Living Donor 79%
  3. 10 Year Graft Survival: Cadavaric 36%, Living Donor 55%
  4. Factors Affecting Transplant Outcome
    1. Early graft dysfunction and early graft ischemia
    2. Previous graft rejection (that is, >1 transplantation)
    3. Presence of preformed anti-HLA antibodies in serum of recipient
    4. Early rejection episodes - even if successfully treated
    5. Early rejection epidoses are strongly correlated with degree with HLA mismatching
    6. Increased cold-ischemia time of graft (particularly if >48 hours)
    7. Maternal HLA presence in sibling donor graft and not recipient is a better long term prognostic feature than the presence of paternal HLA on donor and not recipient [25]
    8. Blacks have poorer overall prognosis after transplant than whites [7]
    9. These differences likely include antigen dependent and independent factors
  5. Renal arterial resistance index (end diastolic versus systolic flow) >80 predicts very poor outcome for 88% of patients [6]
  6. Osteoporosis [22]
    1. Problematic in organ transplant patients
    2. Dialysis itself associated with increased hip fracture rates [47]
    3. Calcium and vitamin D may be helpful
    4. Bisphosphonate therapy is generally recommended
    5. Fracture rates are high in renal transplant recipients 1-3 years after transplant [47]
    6. Fracture rates overall are higher in liver transplants
  7. Nephrogenic Adenomas [45]
    1. Rare, benign tumors found within urothelial mucosa of urinary tract
    2. Particularly frequent in renal-transplant recipients
    3. In transplant recipients, clearly derived from donor renal tubular cells
  8. Donor age >60 years associated with good outcomes if initial histology acceptable [12]
  9. Kidney transplant associated with 3X or higher risks for 18 of 25 cancer types [56]

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