Outline Basics of transplantation Benefits of transplantation Immunosuppressive medications Common post-transplant problems

Basics of Transplantation Kidney transplantation is the most effective therapy for end-stage renal disease. The transplanted organ can come from either a live donor or deceased donor. Most deceased donor organs come from brain dead donors. Non-standard criteria donors: –Expanded criteria donors (ECD). –Donation after cardiac death (DCD).

Anatomy of Renal Transplantation

Recipient Selection Very few contraindications. General medical condition. Cardiovascular screening. Age-appropriate routine cancer screening (pap smear, mammography, colonoscopy, PSA). Infection (HIV, Hepatitis, TB). Presence of preformed antibody (PRA). –Pregnancy, prior transplant, blood transfusion Psychosocial evaluation, including compliance.

Benefits of Transplantation Life expectancy Cardiovascular benefits Quality of life Socioeconomic benefits

Life Expectancy Ojo, J Am Soc Neph, 2001;12:589

Quality of Life Numerous studies have detailed improved quality of life. Life satisfaction, physical and emotional well-being and ability to return to work higher in transplant recipients. Uremic complications more fully reversed. Fertility returns.

Immunosuppressive Medications Slide courtesy of Dr. Meier-Kriesche

Immunosuppressive Medications Induction: –Corticosteroids –Anti-thymocyte globulin (ATG) –IL-2 receptor antagonists Maintenance: –Corticosteroids –Calcineurin inhibitors (CNIs) –mTOR inhibitors –Antimetabolites

Immunosuppressive Medications Treatment of Rejection: –Corticosteroids –Anti-thymocyte globulin –Intravenous Immunoglobulin (IVIG) –Rituximab –Plasmapheresis

Corticosteroids Used for induction, maintenance and treatment of rejection. Mechanism of action: –Inhibit function of dendritic cells. –Inhibit translocation to nucleus of NF-κB. –Suppress production of IL-1, IL-2, IL-3, IL-6, TNF-α, and γ-IFN. Adverse effects numerous and well-known.

Corticosteroids Component of >80% of transplant protocols. Given IV at high doses ( mg/day) for induction or treatment of rejection. Tapered to maintenance dose of 5-10 mg/day in early post-transplant phase. Should NOT be tapered off: increased risk of rejection and graft loss! Steroid free regimen: overall some benefits but graft survival likely worse.

Anti-thymocyte Globulin (Thymoglobulin®) Used for induction and treatment of rejection. Prepared by immunization of rabbits with human lymphoid tissue. Causes depletion of peripheral blood lymphocytes. Administered generally via central line for 3-10 days. Premedication required: acetaminophen, corticosteroids and antihistamine.

Anti-thymocyte Globulin: Adverse Effects Infusion-related reactions: chills, fevers, arthralgias. Lymphopenia. Thrombocytopenia. Prolonged immunosuppression: increased risk of opportunistic infections (PCP, CMV, fungal). Possibly increased risk of BK virus nephropathy.

IL-2 Receptor Blockers Basiliximab (Simulect ® ) and Daclizumab (Xenapax ® ). Block CD25 (IL-2 receptor) on activated T cells. Used for induction only. Almost no side effects, but also much less potent.

Calcineurin Inhibitors Used for maintenance immunosuppression. Two agents in clinical practice: –Cyclosporine (Sandimmune ®, Gengraf ®, Neoral ®, generic; CysA) –Tacrolimus (Prograf ®, generic; FK506). Generics NOT clinically therapeutically equivalent. At present are key to maintenance immunosuppression and a component of the majority of transplant protocols.

Calcineurin Inhibitors: Dosing and Monitoring  Both medications are generally dosed twice per day, 12 hrs apart.  Trough levels monitored: check approximately 12 hrs after last dose.  In some cases C2 levels might be checked 2 hrs after administration.  Cyclosporine is 35-40% bioavailable, tacrolimus approximately 25%.  Oral to IV conversion 3-4:1.  Both are metabolized by cytochrome P450 3A4 & 3A5.

Calcineurin Inhibitors: Interactions Drugs to use with caution: –NSAIDs—avoid. –Amphotericin B & Aminoglycosides– worsened nephrotoxicity. –ACEi & ARBs– use with caution. –Statins– avoid lovastatin, start others at lowest possible dose.

mTOR Inhibitors Target site is the mammalian target of rapamycin (mTOR), a key regulatory kinase in cell division. Sirolimus (Rapamune ® ) only available mTOR inhibitor in the US. Administered once daily, 24-hour trough levels monitored. Also metabolized by P450 3A system, with interactions similar to the CNIs.

Sirolimus: Adverse Effects Nephrotoxicity: –Delays recovery from ATN. –Potentiates cyclosporine Nephrotoxicity. –Induces proteinuria. –Tubulotoxic. Impairment of wound healing. Dyslipidemia (increased LDL and TGs). Pneumonitis. Cytopenias and anemia.

Antimetabolites Azathioprine (Imuran ®, generic) is a purine analogue that is incorporated into RNA and inhibits cell replication. A mainstay of transplantation for 30 years, it has largely been replaced by the below drugs. Mycophenolate mofetil (Cellcept ® ) and enteric- coated mycophenolate sodium (Myfortic ® ) are prodrugs of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH).

Antimetabolites: Adverse Effects Azathioprine: –Bone marrow suppression. –Hepatitis. –Azathioprine is inactivated by xanthine oxidase, therefore should not be used in combination with allopurinol. MPA prodrugs: –GI toxicity: diarrhea, nausea, esophagitis. –Leukopenia and anemia. –Not different between formulations.

Intravenous Immune Globulin Used primarily for treatment of antibody- mediated rejection. Mechanism of action: –Reduction of alloantibodies through suppression of antibody formation. –Increased catabolism of circulating antibodies. Adverse effects: –Infusion-related reactions (myalgias, headaches). –Severe headache & aseptic meningitis. –Autoimmine hemolytic anemia. –Sucrose-based IVIG can cause ARF.

Common Complications of Transplantation  Early complications  Surgical complications  Delayed or slow graft function  Lymphocele  Acute rejection  Acute cellular rejection  Antibody-mediated rejection  Infectious complications  Cytomegalovirus  BK virus  Others  Malignancy  Chronic allograft dysfunction

Surgical Complications  Graft thrombosis:  Caused by thrombosis of donor renal artery or vein.  Usually happens in first week.  Diagnosed by ultrasound with doppler studies.  Almost always requires explant of kidney.  Urine leak:  Elevated creatinine.  May or may not have abdominal pain.  Diagnose with nuclear medicine scans (DTPA or MAG3).  Surgical repair and/or relief of obstruction.

Delayed Graft Function Need for dialysis in the first week after transplantation. Causes: –ATN from prolonged cold ischemia. –Acute rejection. –Recurrent disease. Usually requires biopsy for diagnosis and management.

Acute Rejection May present with ARF or proteinuria. Diagnosis made by biopsy. Pathology is reported according to Banff classification. Acute cellular rejection: treat with steroids or ATG based on severity Antibody-mediated rejection: may require steroids, ATG, rituximab, IVIG or plasmapheresis based on severity and setting.

OUR KIMS

KIMS accrediteditations

Causes of ESRD

Hemodialysis Hemodialysis cleans and filters your blood using a machine to temporarily rid your body of harmful wastes, extra salt, and excess water. Hemodialysis helps control blood pressure and helps your body keep the proper balance of important chemicals such as potassium, sodium, calcium, and bicarbonate.

Dialysis Machine

At KIMS, Hemodialysis is carried out in a room with polite and well-trained dialysis technicians and nurses, round the clock, in three 'shifts'. B'Braun & Fresenius Hemodialysis machines. Disposable artificial kidneys and tubing ensure safe, predictable fluid removal and dialysis. Separate areas for HCV + and HBV + Pts

Continuous Ambulatory Peritoneal Dialysis (CAPD) Peritoneal Dialysis is another procedure that removes extra water, wastes and chemicals from your body. This type of dialysis uses the lining of your abdomen to filter your blood. This lining is called the peritoneal membrane and acts as the artificial kidney.

CAPD is the most common type of peritoneal dialysis. It requires no machine and can be done in any clean, well-lit place. With CAPD, your blood is continually being cleaned. The dialysis solution passes from a plastic bag through the catheter and into your abdomen, where it stays for several hours with the catheter sealed. The period that dialysis solution is in your abdomen is called the dwell time.

Next, you drain the dialysis solution back into the bag for disposal. You then use the same catheter to refill your abdomen with fresh dialysis solution so that the cleaning process can begin again.

Tenckhoff Catheter

KIMS also offers the option of CAPD. Skilled surgeons insert the catheter and dedicated staff train patients to dialyze themselves at home. CAPD fluids by leading companies like Baxter, Claris and J'Mitra are available for individual needs for home delivery.

Renal Transplantation Treatment of choice Improved quality of life Prolonged survival Free of dialysis & dietary constraints Improvements in anaemia & bone disease Cheaper

Present Indian Scenario: About 100,000 patients needs kidney transplant each year Approximately 5000 transplants performed each year 95 percent living & 5 percent cadaver donors % live donors are LRD 30-40% are LURD (Varies from time to time and place to place)

LRD Source:  Parents 53%  MOTHER - 76% FATHER - 24%  Siblings 25%  SISTER- 66% BROTHER - 34%  Spouse 22%  WIFE - 84% Husband 16%

Renal Transplant : 1985

Renal Transplant : 1984

Renal Transplant : 1987

Cadaver Transplantation in India Renal Transplantation KIMS Renal Transplant Programme started: 20th August 2004 First Cadaver transplant: 15th October 2006

Percent Graft Survival Graft Survival Rates at One, Three and Five Years Time After Transplant 94% 88% 78% 65%

Chief Transplant surgeon & Urologist Dr. S.Sahariah MS, MAMS, FICS, FACS

Dr. Sahariah, Chief of our kidney transplantation team, is arguably the most experienced transplant surgeon in the country with more than 3000 successful transplant surgeries to his credit. He has helped in starting Renal Transplant Programme in 24 centers across the country.

The Renal transplant programme was started in 2005, so far we have conducted more than 1,200(till Dec 2010) renal transplant surgeries with excellent results. Well trained medical, paramedical & nursing staff is associated with the programme who provide round the clock services to the patients. The institute strictly follows the ethical guidelines as per the Human Organ Transplantation Act, 1995 and performs only living related donor kidney transplantation.

KIMS attributes… We have also developed a vibrant cadaver donor transplantation programme since last three years and performed more than 60 cadaver renal transplantations during this short span which is one of the largest cadaver transplant series in the country. We also have the distinction of performing cadaver renal transplantation from the youngest (18 months old) and oldest (79 years old) cadaver donor in the country.

Cadaver Transplant at KIMS, Hyd 16 months79 years old

Cadaver Transplantation in India