Renal Transplantation

What are the contra-indications for receiving renal transplant

        Unfit for anaesthesia

        Limited life expectancy because of cardiac or respiratory disease or intractable neurological condition

        Not free of malignancy – for most malignancy a 5 year disease-free interval is required since last treatment (exceptions are non-melanoma skin cancers and low grade TCC).

            T1N0M0 CRC, a 2 year disease free interval is sufficient

            T1N0M0 breast ca, a 5 years is required.

        Non-compliant with medications

        HIV is no longer a contra-indication as with HAART and prophylaxis against opportunistic infection results are similar.

        Active sepsis, TB, Patients with HepC (consider interferon treatment before Tx or liver/Kidney Tx if ESLD)

        There is no upper age limit as physiological age is more important than chronological

What is the pre-op assessment

        History and physical examination. – find cause of renal failure, associated diseases (IHD, DM), previous treatment (dialysis). Examine lower abdomen for scars which may make access difficult.

        Review the cause for ESRD (DM, HT and glomerulonephritis most common). FSGS is likely to recur. HUS is also likely to recur. Oxalosis will recur unless the patient receives a liver/kidney Tx.

        Investigations:

o   ECG, Echo, Stress test. PTCA or CABG is undertaken before Tx if required.

o   Screening for malignancy as required – colonoscopy, pap smear, mammography

o   Urological evaluation – MSU and US is minimum. Voiding cystourethrogram, cystoscopy, urodynamics are used in patients with history of urological problems. Pre-op bladder augmentation or TURP may be required.

o   Consider if nephrectomy will be required (chronic pyelonephritis, uncontrolled HT, severe bleeding or proteinuria, gross enlargement leaving insufficient space, staghorn calculus, PCKD with infection, acquired cystic kidney disease with increased risk of malignancy

o   Investigations for pro-coagulant state – PC/PS, ATIII, anti-cardiolipin Ab, APCR, PT gene 20210A.

How do you select a patient for living donor nephrectomy

        May be related (parent, sibling), unrelated (spouse) or altruistic donor.

        Must have normal renal function.

        Must have normal health – no DM, HTN, IHD. ECG, CXR, UA and bloods are taken.

        Donation must be altruistic and free of coercion. Donor should be interviewed separately.

        Exclude malignany or transmissible diseases – HIV, HBV/HCV, CMV (prophylaxis is required)

        ABO incompatibility is not an absolute contra-indication (can perform ABO incompatible Tx or consider paired exchange).

        A cross match is performed between donor and recipient.

        Once all these conditions are satisfied then more invasive tests

o   CT angiogram to define arterial anatomy and detect anatomic abnormalities.

o   Isotope renography is used to determine which kidney is provides most function.

o   Generally the left kidney is preferred, but the donor will keep the better kidney if there is a discrepancy in renal function.

        Donor must be counselled about the complications (including death 0.03%, general complications, and specific). Donors do have increased risk of HTN in long term. There may be a small increased risk of ESRD.

        Laparoscopic donation is as safe as open and allows quicker recovery.

What are the complications of kidney transplantation

Immediate

        Bleeding – requires re-exploration.

        Thrombosis of renal vessels – due to kinking or poor technique. Requires immediate re-exploration.

        Hypercaute rejection – due to pre-formed complement-fixing Ab. Usually failure of cross-match. Presents with intra-renal thrombosis. Requires nephrectomy.

Early

        Infection – wound, pneumonia, UTI or more common because of immunosuppression.

        Bleeding – haematoma in wound

        Lymphocele (may present with vascular or ureteric complications from compression). Confirm by aspiration – if same Cr concentration as serum then lymphocele. Small observe, large drain via a peritoneal window. Avoid by ligation of all vessels individually.

        Urine leak – either from the bladder, ureteric anastomosis or calyx which has been damaged. Small leaks managed with nephrostomy. Large leaks with exploration

        Early obstruction of ureter at site of anastomosis can be treated by stenting

        General risk: MI, pneumonia, DVT/PE, death

        Delayed graft function – dialysis is required in first week – must exclude rejection, vascular and ureteric complications. Fluid should be restricted and dialysis is required when electrolyte imbalance or fluid overload are encountered.

 

Late

        Vascular:

o   Renal artery stenosis or stenosis at anastomosis (can present with HTN). Treat with PTA or surgery. In anastomtic stricture, PTA is less successful than surgery.

o   False aneurysm at anastomosis or mycotic aneurysm. A rapidly expanding tender aneurysm requires Abx and removal of Tx.

o   Late renal vein thrombosis – suspect if sudden onset haematuria

        Ureteric :

o   Stricture at anastomosis – stent, endoscopic strictureplasty, re-implantation (Boari flap)

o   Stricture due to ischaemia – usually require re-operation (re-implantation, uretoureterostomy or Boari flap). Assocated with Polyoma virus infection

o   VUR –

        Immunosupression complications:

o   Infection – increased risk of Viral (CMV, EBV, HSV, shingles, BK virus), bacterial (TB, Listeria, nocardia), Fungal (Candida, aspergillus, cryptococcus), protozoal (PCP). Prophylaxis for CMV using ganciclovir, PCP using co-trimoxazole, fluconazole for candia, TB prophylaxis for patients with history or PPD conversion. BK virus infection (causes tubulitis) requires reduction in immunosuppression.

o   Malignancy –

             risk of SCC skin (SCC:BCC ratio on immunoRx is 2:1 – usually 1:5)

             Kaposi Sarcoma

            Anal carcinoma due to HPV 16,18,31,33

            Post-transplant lympoproliferative disorder ranging from polyclonal      proliferations (reduced immunosuppression) to monoclonal NHL B cell             lymphoma (Rituximab if CD20 positive).

o   Metabolic – diabetes, HTN, vascular disease all more common with immunosuppression

        Graft failure –

o   May be due to acute rejection (treat by increasing immunosuppression)

o   May be due to chronic allograft nephropathy – combination of chronic rejection, damage due to immunosuppression,

o   Return of renal disease (esp FSGS)

How do you evaluate reduced urine output in the post-op period

        Ensure foley is not blocked  - flush catheter

        Check volume status using CVP, PCWP. Restore volume status

        Perform duplex and renal US to ensure normal flow in vessels and no ureteric obstruction (eg lymphocele)

        DTPA scan – kidney uptake within 6 seconds, peak within 2 minutes and then gradual decline over next 30 mins.

        If none of these abnormal then delayed function is diagnosed – reduce calcinurin and use Ab therapy to protect graft from rejection.

        Early biopsy to diagnose rejection is helpful

What are the determinants of graft outcome

Graft factors:

        The age of donor – extremes of age of donor are associated with worse outcome

        Live donor have a better outcome than cadaveric irrespective of HLA matching

        Hyptertension or diabetes in donor is associated with worse outcome

        Cadaveric donors: Heart beating donors have a lower rate of primary graft non-function and delayed function than non-heart beating donors – although long-term outcomes appear similar.

        HLA match: the greater the number of HLA matched loci, the better the outcome with identical twins or HLA matched siblings achieving the best outcomes.

        ABO-incompatible donation is possible but is associated with greater morbidity and worse long-term outcome

        Ischaemic times: Warm ischaemic times exceeding 45 minutes (organ in the body temperature after its blood supply has been cut off or reduced) and cold ischaemic times greater than 22 hours are associated with poorer outcomes (organ stored in UW solution before reaching body temperature during implantation procedure).

            Prolonged ischaemic times are associated with increased risk of ATN and poorer long      term and short term outcomes

Recipient factors:

        The age of donor – extremes of age of donor are associated with worse outcome

        Cause of renal failure – certain disease recur more commonly in transplanted kidney – FSGS (focal segmental glomerulosclerosis)

        Length of time on dialysis – transplantation before dialysis is associated with best outcome, the longer the length of dialysis the worse the outcome

        First transplant or second transplant – outcomes are worse in patient’s whose first kidney failed early

        Medical co-morbidity in donor – graft survival is determined by recipient survival. Donors with medical conditions – HTN, IHD, DM, Stroke, Cancer, HIV, HCV or HBV have worse outcomes.

        Patient compliance and support has been shown to improve outcome.

 

Treatment factors:

        Surgical: Meticulous surgical technique in vascular anastomosis, ureteric implantation and peri-opertaive Mx including minimizing warm ischaemia have lead to improved outcomes. Larger volume centers and surgeons may achieve better outcomes

        Medical: The use of cyclosporin produce substantially improved outcomes compared to sterioid and MCP.

        Newer agents may improve long term outcomes by reducing rates of chronic graft nephropathy related to CNI (eg MMF, Rapa).

 

What are the types of rejection

        Hyperacute (>24 hours)Pre-formed complement-fixing Ab. IgG class I (AB), IgM class I, IgM ABO Ab. Uncommon if cross matching is performed before Tx. Histology – PMNL infiltration, platelet thrombus, fibrin deposition

        Accelerated acute (<5 days): Means failure of crossmatch. Due to pre-formed non-complement-fixing Ab against HLA antigens. Results from activation of memory B cells. C4d staining on endothelium is characteristic. Usually not responsive to treatment – try plasmapharesis, Rituximab and ALG. May be detected by flow-cytometry x-match.

        Acute (<100 days): Presents with HTN, fever, poor urine output, tender graft and rising Cr.

o   Due to cellular immune response (Direct allorecognition where passenger/donor APC present Ag to recipient T cells) - Causes tubuitis, monocyte infiltration, oedema, vasculitis);

o   humoral immunity due to IgM ABO Ab and IgG HLA Ab (platelet thrombi, fibrinoid necrosis and endothelial damage).

o   Treat with pulse steroids and maximizing maintenance immunosuppression and OKT3 if recalcitrant.

        Chronic (>100 days): Results in vasculopathy (intimal proliferation and media necrosis of small and medium sized arteries), glomerulosclerosis. Presents with HTN, rising Cr, proteinuria. Most closely linked with DR mismatch. May be associated with nephrotoxic effects of drugs. Irreversible and not responsive to treatment. Immunsupression that reduces exposure to steroids and CNI’s may reduce long-term complications

What are the complications of immunosuppression

        Infectious

        Neoplastic

        Vascular

        metabolic

        Nephrotoxic

What are the types of immunosuppressive agent

        Steriods - inhibit IL-1 production by host APC(antigen presenting cell) required for activation of allo-reative APC

        CNI (CalciNeurin Inhibitor) Cyclosporine. bind to cellular binding proteins (cyclophilin for CSA and FKBP for Tacrolimus) and so bind to Calcinurin and inhibit its activity. Calcinurin is a calcium-calmodulin-dependant phosphatase which dephosphoraylates and actives NFAT allowing T cells to proliferate and produce cytokines (IL-2) and their receptors. Inhibit T cell proliferation and IL-2 production from helper T cells.

        Nucleoside synthesis inhibitorsAzothiaprine and MMF. Inhibit proliferation of activate T cell

o   MMF blocks synthesis of purine (Guanosine) by blocking inosine monophosphate dehydrogenase. Non-immune cells have active purine salvage pathway.

o   AZA – Purine analogue precursor of 6-Mecaptopurine. Inhibits cellular proliferation through blocking all RNA and DNA synthesis.

        MTOR inhibitors – Rapamycin. Prevents cells from progressing from G1 to S phase and so prevents cytokine-dependnat activation of T cells.

        Ab therapy

o   OKT3 – binds to CD3 causing profound deletion of T cells (precede by cytokine release  causing SIRS).

o   ATG – Polyclonal Ab against T cells.

o   Rituximab – Monoclonal Ab against CD-20 causing B cell depletion (Accelurated acute)

o   CTLA4-Ig – blocks Co-stimulation pathway

o   Anti-IL2 receptor

How is immunological assessment performed

o   HLA typing of donor and recipient – Traditionally performed with microlymphocytotoxicity assay. Lymphocytes under test are incubated with panel of allo-Ab covering all HLA specificity. Source of complement is added. Lysis indicates positive result. PCR and RFLP analysis can also be carried out as an alternative. The greater the degree of match the better the outcome. Most important are HLA-DR, HLA-B and HLA-A in decreasing importance. In organ allocation, the extent of HLA match is used as a factor in algorithm.

o   Direct X-matchperformed immediately before Tx. Recipient serum incubated with donor lymphocytes and complement. Lysis indicates likely HAR.

o   Flow cytometry X-match. Binding of non-complement fixing Ab in recipient serum to donor lymphocytes indicates increased risk of accelerated acute rejection.

o   Panel reactive Ab: Serum of recipients on the waiting list is periodically tested against  panel of cells of know HLA specificity. The percentage of cells with which the recipient serum reacts is the PRA. Most normal people it is 0-5%. Patients previously sensitized have high PRA (50-99%) suggests that the person is likely to have a positive X-match to many or most donors.

o   Mixed lymphocyte reaction used for living donation as takes some days: Donor cells are irradiated and proliferation of recipient cells is measured after a few days in co-culture. There is limited correlation between MLR and clinical transplant outcomes.