Renal Transplant

Background

• Most common causes of ESRD (in descending order):
  1. Diabetes
  2. Hypertension
  3. Glomerulonephritis
  4. Cystic renal disease
• ESRD in children may result in:
  • Growth failure
  • Poor nutrition
  • Psychiatric problems
• A hypercoagulable state can occur in nephrotic syndrome with urinary loss of the natural anticoagulants: antithrombin III, protein C, and protein S.
• Patients age > 50  have a 20% mortality in the first year of dialysis
  • The most common causes of death in patients with renal failure are heart disease, sepsis, and stroke
  • Survival after renal transplantation is significantly better than that of patients treated with dialysis
• Hyperphosphatemia due to renal failure leads to severe itching, conjunctival irritation, and alterations in bone metabolism
  • Phospho-soda enemas are contraindicated in patients with poor renal function as they cannot easily eliminate a large phosphate load.
    • If the serum calcium × phosphorus product > 60 mg2/dL2, vascular calcium deposits can lead to arterial thrombosis and calciphylaxis
• Peritoneal dialysis solution containing icodextrin may lead to false point-of-care glucose readings

Selection of kidney transplant recipients

• Diseases associated with increased risk of recurrence and secondary failure of the transplanted kidney (7): MO-SHAFF
  1. Membranoproliferative glomerulonephritis
  2. Primary Oxalosis
  3. Sickle cell disease
  4. Hemolytic-uremic syndrome
  5. Amyloidosis
  6. Primary Focal segmental glomerulosclerosis
  7. Fabry disease
• Diseases associated with increased risk of recurrence that generally do not result in secondary failure of the transplanted kidney
  • IgA nephropathy (Berger disease)
    • Commonly recurs in the transplant kidney yet rarely leads to graft failure
    • Most common cause of glomerular hematuria
  • Hypertension and diabetes
    • Generally take many years to show evidence of disease in the transplant
• Diseases that do not recur in the transplanted kidney DACA
  1. Renal Dysplasia
  2. Autosomal dominant polycystic kidney disease (ADPKD)
  3. Cystinosis
  4. Alport syndrome without anti–glomerular basement membrane antibodies
• Patients with primary oxalosis and other metabolic diseases may benefit from combined kidney and liver transplant
• Absolute contraindications to transplantation (5): TICCC
  1. Unsuitable conditions for Technical success
  2. Active Infection
  3. Comorbid (high probability of perioperative mortality)
  4. Non-Compliance
  5. Active Cancer
     • 5-year disease free waiting period is generally recommended
     • Prostate cancer
       • Low-risk
         • Should not be considered a contraindication to transplantation
           • In most cases, the morbidity and mortality of having ESRD is greater.
           • Patients who have low-risk disease felt to be amenable to active surveillance should be considered candidates for transplantation as long as they adhere to their surveillance regimen.
       • Immediate or high-risk
         • Need to undergo definitive treatment to be considered a kidney transplant candidate.
       • Patients that have undergone radical prostatectomy or radiation for prostate cancer can be evaluated for transplantation as soon as they have recovered from their treatment.
         • Waiting time after prostate cancer treatment should be dictated by the expected survival and probability of prostate cancer recurrence after treatment.
     • Skin cancer
       • Melanoma
         • Should also have a 5-year disease free period
       • Most other skin cancers
         • Not a contraindication
     • Ontario Listing Criteria§
       • Most renal transplant candidates with a history of malignancy should wait a period of time between successful treatment and transplantation. Patients who do not meet the following waiting period criteria are not eligible for kidney transplantation.
         • Bladder Cancer: ≥2 years
           • Superficial low-grade lesions may not require any waiting time.
         • Renal Cell Carcinoma: ≥2 years
           • Small, incidental tumours may not require any waiting period.
           • Large or invasive or symptomatic tumours may require a waiting period of 5 years.
         • Testicular Cancer: ≥2 years
         • Wilms’ Tumour: ≥ 1 year
         • [Prostate Cancer not mentioned]
           • EAU guidelines: patients with a history of appropriately treated low stage/grade renal cell carcinoma or prostate cancer can be listed for renal transplant without additional delay; no description of wait time after intermediate/high-risk disease
         • Skin Cancer
           • Melanoma: ≥ 5 years
             • In situ melanoma may be considered for transplantation after waiting ≥ 2 years
           • Basal Cell: no waiting time required after successful removal
           • Squamous Cell: no firm recommendation on wait time
         • Breast Cancer: ≥ 5 years
           • Early in situ (e.g., ductal carcinoma in situ) lesions may only require a 2-year wait.
         • Cervical Cancer: ≥ 2 years
           • In situ cervical lesions may proceed with transplantation before the 2 year wait period
         • Colorectal Cancer: ≥ 5 years
           • Shorter waiting time of 2–5 years may be sufficient in patients with localized disease
         • Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, Post-Transplant Lymphoproliferative Disorder, or Leukemia: ≥ 2 years
         • Lung Cancer, Thyroid Cancer: ≥ 2 years
• See CW11 Table 47-1 for Recommendations for Additional Urologic Studies in Renal Transplant Candidates
• Surgical evaluation
  • Preparation of a patient for kidney transplantation requires a careful assessment of the peripheral vascular system
• Indications for pre-transplant nephrectomy (7):
  1. Symptomatic renal stones not cleared by minimally invasive techniques or lithotripsy
  2. High-grade solid renal tumors
  3. Polycystic kidneys that are symptomatic, extend below the iliac crest, have been infected, or have solid tumors
  4. Persistent anti–glomerular basement membrane antibody levels
  5. Significant proteinuria not controlled with medications or angioablation
  6. Recurrent pyelonephritis
  7. Grade 4 or 5 vesicoureteral reflux with urinary tract infections
  • Of these indications for pretransplant nephrectomy, only severe proteinuria can safely and reliably be managed by pretransplant transcatheter embolization and infarction.
• Even small defunctionalized bladders will frequently regain normal volume within weeks of transplantation
• A point system that has evolved in the United States for the selection of cadaver kidney transplant recipients includes the following variables: waiting time; human leukocyte antigen panel reactive antibody > 80%; age < 18; donor of kidney, liver segment, lung segment, partial pancreas, or small bowel segment; and histocompatibility. For most kidney transplant candidates, the most important factor in receiving an organ is time spent on the waiting list
• The best outcomes are achieved with renal transplantation immediately prior to the need for dialysis. In the United States, a patient must have documentation of a GFR < 20 mg/dL to be placed on the national waiting list for deceased donors.
• Potential recipients with a history of urolithiasis should undergo a complete metabolic stone workup.

Selection of kidney transplant donors

• Donors may be declared dead by neurologic (NDD) or cardiorespiratory criteria (donation after circulatory death, DCD)
  • DCD typically occurs when a potential donor does not meet brain death criteria despite being comatose and ventilator dependent
• DCD kidneys
  • Subject to varying lengths of warm ischemia time and are thus susceptible to delayed graft function.
  • Long-term graft survival is comparable to that of an NDD kidney
• Extended criteria donors (ECD)
  • Age ≥ 60 or
  • Age 50 - 59 with ≥ 2 risk factors:
    1. Death from a stroke
    2. Hypertension
    3. Elevated creatinine just before organ recovery
• Standard criteria donors (SCD)
  • Age < 60 and do not meet any of the criteria for being an ECD
• ECD organs have a 2-year graft survival of 80% vs. 88% for an SCD organ
• ABO incompatibility
  • ABO incompatible renal transplants have been achieved
    • If a kidney is transplanted between ABO-incompatible individuals, antibodies will bind to the non-inherited antigens expressed on endothelial cells, leading to activation of the complement cascade, coagulation, thrombosis, and rapid graft loss. However, if these antibodies have a low titer at the time of transplantation and production of antibody can be limited with immunosuppressive medications, then ABO incompatible renal transplants have been achieved
      • In ABO incompatablity, plasmapheresis and immunoadsorption are used to remove antibodies, while immunoglobulin administration and anti CD-20 antibody are used to prevent antibody reformation
  • Paired exchange is another option
• Histocompatibility
  • HLA class I genes are expressed by all nucleated cells. HLA class II genes are expressed by antigen-presenting cells (dendritic cells, monocytes, macrophages, and B-lymphocytes) and inflamed tissues, including endothelial cells.
    • Class I antigens are HLA-A, HLA-B, and HLA-C.
    • Class II antigens are HLA-DR, HLA-DQ, and HLA-DP
  • A recipient with mismatched (unshared) HLA antigens in the donor is at risk for development of antibody and cellular rejection.
  • HLA antibodies may be formed by the recipient before transplantation as a result of:
    1. Pregnancies
    2. Previous transplants
    3. Blood transfusions
    4. Possibly some infections
  • Individuals with antibodies directed at 20% of the population are said to be sensitized; those with antibodies to 80% of the population are considered highly sensitized.
    • Sensitized transplant candidates, particularly those who are highly sensitized, may face extreme difficulty in finding a donor to whom they will have a negative crossmatch.
  • The most sensitive test for finding donor-specific HLA antibodies is solid-phase single-antigen bead testing
• Crossmatch techniques
  • The percentage of donors that cause a positive crossmatch is known as the panel-reactive antibody (PRA); a potential recipient with a PRA of 80% is likely to have a positive crossmatch with 80% of the donor population

Living kidney donors

• Absolute contraindications for living donors (6): A Real Gift Is Starting Peepee
  1. Age < 18
  2. Diseases that would increase the Risk of kidney failure
  3. GFR < 60 mL/min§
  4. Active Infection
  5. Ongoing Substance abuse
  6. Psychiatric disorders such as schizophrenia
• Relative contraindications:
  • Obesity
    • Ideally, BMI should be < 30
  • Hypertension
    • In recent years, some transplant centers have accepted donors who have hypertension that is well controlled with a single anti-hypertensive medication
• Urinary stones are not necessarily an absolute contraindication to donation
  • Multiple stone episodes, or the presence of multiple stones at the time of the donor evaluation, are generally considered a contraindication to donation.
  • Patients with a single, small stone can be considered for donation if their metabolic evaluation is normal; in general, the kidney with the stone is used for donation
• After living donor nephrectomy, the renal donor is expected to have ≈75% of total renal function
  • Hyperfiltration injury has not been a problem for living renal donors

Kidney transplant operation

• Donation
  • Most laparoscopic donor nephrectomies are left sided (because of the longer left renal vein)
  • The ureter is mobilized to the point at which it crosses the iliac vessels. It is unnecessary to include the gonadal vein with the ureter, and the gonadal artery should also be left intact for the donor when possible
  • Hem-o-lock clips are contraindicated in laparoscopic donor nephrectomies because they have been associated with living-donor deaths when used to seal the aortic side of the donor renal artery.
• Allograft preparation
  • Branches that drain into the renal vein, such as the left adrenal vein, should be ligated
  • Fatty tissue close to the renal hilum should be ligated, because this tissue often contains lymphatic channels that may otherwise contribute to a postoperative lymphocele.
  • The best solution for preservation of all abdominal organs is University of Wisconsin (UW) solution
  • The quality of early graft function is directly correlated with cold ischemia time
• Recipient operation
  • Ideally, the kidney is transplanted extraperitoneally with the vascular anastomosis to the right external iliac artery and veiniliac.
    • The extraperitoneal approach minimizes potential bowel complications and postoperative ileus
    • The transplant is usually to the right iliac fossa so that the ureter is medial
  • The central venous pressure should be maintained between 10-15 cm H2O with IV crystalloid and colloid solutions to achieve a mean arterial pressure ideally > 80 mm Hg
  • A bladder irrigant, preferably a broad-spectrum antimicrobial solution such as bacitracin or neomycin–polymyxin B, is used
  • The inferior epigastric vessels (deep to tranversalis fascia) can usually be gently retracted, but they may be divided if surgical exposure is compromised. Similarly, the round ligament may be preserved in females. The spermatic cord is identified in men as it travels inferiorly exiting the peritoneum and is carefully preserved.
  • Lymphatic tissue overlying the vessels should be ligated or sealed with electrocautery. Care is taken to avoid injury of the genitofemoral nerve that lies anterior to the psoas muscle just lateral to the external iliac artery.
  • The venous anastomosis is generally performed first to limit ischemia to the leg
  • Before reperfusion, an IV bolus of furosemide and mannitol may be administered to facilitate diuresis and act as a free-radical scavenger.
  • Urinary tract reconstruction is usually by antireflux ureteroneocystostomy
  • The routine use of a ureteral stent for all cases of renal transplantation has been shown to reduce the incidence of ureteral complications

Post-transplant care

• The best predictor of immediate graft function following living donor renal transplantation is donor kidney output just prior to nephrectomy.
• Low-molecular-weight heparin is eliminated by the kidney and must be used cautiously in the setting of unpredictable metabolism to minimize bleeding complications.
• In patients with reasonable bladder capacity, the urinary catheter may be removed on postoperative day 3 and the closed suction drain removed later in the day if drain output remains low.
• The most common early complications of renal transplantation include (6):
  1. Infection
  2. Bleeding
  3. Urinary leak
     • Leaks manifest in the early post-operative period with decreased urine output from the urinary catheter and increased output from the closed suction drain.
     • If the leak occurs after the urethral catheter has been removed, the catheter should be replaced immediately.
     • Many anastomotic leaks will heal with the ureteral stent in place and catheter drainage.
       • Leaks that do not heal with conservative measures may require placement of a percutaneous nephrostomy tube or open repair
  4. Lymphatic leak
     • Lymphoceles can originate from the transplant kidney or the lymphatic channels that surround the iliac vessels
     • Incidence of lymphoceles can be reduced by routine placement of a closed suction drain that is removed when the output is < 50 mL/day.
     • Many lymphoceles are small and inconsequential, but large lymphoceles may:
       • Cause pain
       • Become infected
       • Compress the allograft, leading to dysfunction
     • Lymphoceles are well visualized on ultrasound
     • Management
       1. If intervention required, initially treated with image-guided aspiration
       2. If this fails, a closed suction drain is inserted
       3. If this fails, sclerosing agents may be used
       4. If this fails, creating of a peritoneal window can aid in reabsorption
  5. Vascular thrombosis
     • Transplant renal artery thrombosis
       • Generally occurs within 3 days of the transplant
       • Associated with hypercoagulable state or delayed graft function
         • Patients at risk for thrombosis should be given anticoagulation therapy
       • Diagnosis and Evaluation
         • Sudden cessation of urine output
         • Doppler ultrasound reveals no blood flow to the graft
       • Management
         • Emergent thrombectomy and antithrombolytics should be attempted, but rarely successful
     • Transplant renal vein thrombosis
       • Associated with hypercoagulable state, kinking or stenosis of the vein, acute rejection, and hypotension
       • Diagnosis and Evaluation
         • Doppler ultrasound may reveal a clot in the vein and decreased blood flow to the graft
       • Management
         • Emergent thrombectomy and antithrombolytics should be attempted, but rarely successful
     • Reasons for elevated renal arterial resistive index in a transplant kidney (7): ARVOCAD
       1. Renal Artery stenosis (if measured upstream from the stenosis)
       2. Transplant Rejection (acute or chronic)
       3. Renal Vein thrombosis
       4. Ureteric Obstruction
       5. Perinephric fluid Collection
       6. Acute tubular necrosis (ATN)
       7. Drug toxicity
       • Resistive Index = (peak systolic velocity - end diastolic velocity) / peak systolic velocity; normal = 0.60-0.70
  6. Rejection
     • Classified by temporal occurrence of graft loss:
       • Hyperacute (humoral) rejection
         • Occurs shortly after the reperfusion of kidney transplants
         • MOA: Recipient cytotoxic antibodies and complement react with donor vascular endothelial antigens, leading to a rapid activation of the coagulation cascade and graft thrombosis
         • Rarely seen clinically today because of sensitive crossmatch tests to detect DSA.
       • Acute rejection
         • Classically occurs ≈5 days after an allogeneic organ transplant without immunosuppression.
         • Most common presentation is increasing serum creatinine and decreasing urine output
         • Needle biopsy of the kidney graft is the current standard diagnostic test
       • Chronic rejection
         • Characterized by a gradual deterioration of kidney function
         • The histologic features of interstitial fibrosis, arteriolar sclerosis, and tubular atrophy rarely improve with augmented immunosuppression, and are in some cases the result of drug toxicity.
     • Allograft nephrectomy
       • Can be a technically challenging procedure and is reserved for few clinical situations.
       • Removal of an allograft that has failed during the first year post-transplant can lower levels of anti-HLA antibodies that may make subsequent transplantation more difficult due to positive cross matches.
• Immunosuppression
  • Advances in immunosuppressive drugs have improved early graft survival rates, but these improvements have had little impact on late graft loss, largely because of chronic rejection.
  • Mechanisms of Action of Immunosuppressants
    • Glucocorticoids: Reduce transcription of cytokine genes
    • Azathioprine: Inhibits purine synthesis
    • Mycophenolate mofetil: Inhibits purine synthesis
    • Sirolimus: Inhibits cell cycle progression
    • Everolimus: Inhibits cell cycle progression
    • Tacrolimus: Inhibits calcineurin and IL-2 production
    • Cyclosporine: Inhibits calcineurin and IL-2 production
    • Rabbit antithymocyte globulin: Depletes T lymphocytes
    • Rituximab: Depletes B lymphocytes
    • Alemtuzumab: Depletes T and B lymphocytes
    • Bortezomib: Proteasome inhibitor
    • Basiliximab: Blocks IL-2 receptor
    • Belatacept: Costimulation blockade
    • Eculizumab: Complement inhibitor
  • See CW11 Table 47-3 for Common Organ Targets for Toxicities of Immunosuppressant Therapy

• • Corticosteroids most likely to impair wound healing
  • Prednisone, cyclosporine, and sirolimus all result in hyperlipidemia
  • Commonly used regimens to prevent infections and peptic ulcer disease include TMP/SMX for 3 months for prophylaxis against Pneumocystis pneumonia
  • Prophylaxis against cytomegalovirus disease is possible with ganciclovir, acyclovir, valacyclovir, or cytomegalovirus immune globulin
  • Cyclosporine and tacrolimus are metabolized by the cytochrome P450 system; doses may have to be adjusted with concomitant use medications that also involve the cytochrome P450 system (fluconazole, ketoconazole)
    • P450 Inducers  BullShit CRAP GPS INDUCES my rage!§
      • Barbituates
      • St. John’s wort
      • Carbamazepine
      • Rifampin
      • Alcohol (chronic)
      • Phenytoin
      • Griseofulvin
      • Phenobarbital
      • Sulfonylureas
    • P450 Inhibitors VICK’S FACE All Over GQ STOPS ladies in their tracks.§
      • Valproate
      • Isoniazid
      • Cimetidine
      • Ketoconazole
      • Sulfonamides
      • Fluconazole
      • Alcohol (acute)
      • Chloramphenicol
      • Erythromycin (macrolides EXCEPT azithromycin)
      • Amiodarone
      • Omeprazole
      • Grapefruit juice
      • Quinidine
  • Diltiazem and ketoconazole have been used to reduce calcineurin inhibitor dosing and cost while maintaining blood levels and immunosuppressive effect
  • Chronic immunosuppression increases the risk for malignancy
    • Skin cancer is the most common malignancy after solid-organ transplant
    • Malignancies associated with viral infection (4):
      1. Kaposi sarcoma (human herpesvirus 8)
      2. Non-Hodgkin lymphoma (EBV)
      3. Vulvar (human papillomavirus)
      4. Hepatocellular (Hepatitis C) carcinoma
    • The incidence of kidney, penile, and bladder cancers are also increased
      • Recall in HIV, increased risk of kidney, penile, and testis; metabolic syndrome has increased risk of kidney, bladder, and prostate
    • The incidence of prostate cancer is actually decreased in transplant recipients
    • Lymphoma may respond to a reduction in immunosuppression
• Fertility
  • After successful kidney transplantation, levels of FSH, LH, and testosterone usually become normal and spermatogenesis improves.
  • Among male recipients who have fathered children, there has been no increase in congenital abnormalities in the offspring. It is recommended, however, that impregnation be delayed for at least 1 year after transplantation.
  • Successful renal transplantation usually restores fertility in premenopausal women
• Hemorrhagic cystitis in an immunosuppressed patient has been most commonly associated with adenovirus

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 45