Dr. Emerich Ullmann (1861-1937) performed the first experimental transplant in a dog. He was able to autotransplant a kidney from its normal position to the vessels of the neck in March 1902.
Ullmann worked in Vienna and transplanted a kidney from one dog into the neck veins of another dog, with the establishment of urine flow. Voronoy was a Russian surgeon in the Ukraine, who transplanted a human kidney of blood group B to a recipient of group O suffering from acute renal failure as a result of mercuric chloride poisoning. The donor kidney was obtained from a patient dying of a head injury and was placed in the thigh vessels under local anesthesia. The major blood group mismatch which resulted in a graft that never worked. The patient died 2 days later. Kuss, Servelle and Dubost in France, and Hume at Peter Bent Brigham Hospital--he used ACTH and cortisone in small doses but thought that endogenous immunosuppression due to uremia was responsible for the good results rather than the drug regimen. He died at the age of 55 in a plane crash Prednisone and azathioprine used in combination became the standard for over 15 years.
To summarize: HLA matching may improve both short and long term outcome Contraindications for standard therapy transplant include ABO incompatibility Or positive crossmatch High PRA levels make a positive crossmatch more likely, and therefore increase time awaiting transplant.
CD8 and CD4 cells are the basic effector molecules of acute rejection. (point at CD8CD4 antigen) CD4 cells all express a surface recognition complex known as the T cell receptor, or TCR. point The TCR recognizes antigens presented in the groove of MHC molecules. point Noncovalent interactions between the CD3 initiates intracellular signals. point CD8 cells also express TCR that bind with MHC molecules and initiate intracellular signals via CD3 receptor. Co-stimulatory pathways do not involve interactions between the MHC complex and TCR. Rather, these pathways contribute to the formation of a tight “immunological synapse” between APCs and t lymphocytes that guarantess that the TCR/MHC/CD3 signals are sustained enough to induce T cell proliferation. Most well studied pathways include T cell CD28/B7-1 or B7-2 on APC (point) And CD40L on Tcell/CD40 on APC
A specific costimulatory pathway that has been well studied is the CD40L (ligand) and CD40 pathway. CD40L/CD40 binding may stimulate multiple pathways of immune cell activation: On CD4 and CD8 cells (point) CD40 can also stimulate humoral immunity via Tcell activated B cell activity CD40L/CD40 interactions can also stimulate monocyte and endothelial cell proliferation. Importantly, if costimulatory pathways are blocked, T cell activation does NOT occur with antigen binding leading to a state of anergy Anergy is a state where T cells recognize specific antigens but their proliferative responses and ability to secret cytokines are severely diminished
Stimulation of CD3 on TCR initiates intracellular events activation of phospholipase C leads to the generation of IP 3 and DAG IP 3 stimulates mobilization of calcium from intracellular stores DAG actives PKC NF-AT (nuclear factor of activated T cells) is dephosphorylated by calcineurin/calmodulin complex and leads to translocation of NF-AT to the nucleas where it binds to the promoter region of the IL-2 gene and leads to production of IL-2 IL-2 production leads to gene expression required for clonal proliferation of T cells IL-2 triggers activation of tyrosine kinases leading to expression of DNA-binding proteins (e.g. c-jun, c-fos) Stimulation of TCR alone is insufficient to fully commit the T cell to activation Co-stimulatory signals to CD2, CD28, CTLA-4 on T cell are also required
G0: resting state APC and TCR/co-stimulatory signals G1: new protein and RNA are synthesized IL-2 production S: DNA is doubled DNA is synthesized from purines and pyrimidines G2+M: duplicated chromosomes line up in metaphase and cell division occurs
Azathioprine action Polyclonal antibodies against human lymphocyte Equine: ATGAM Rabbit: Thymoglobulin Mouse monoclonal against CD3 receptor: OKT3 IL-2R antibodies: Daclizumab, Basiliximab Calcineurin inhibitors: cyclosporine, tacrolimus, sirolimus
Total 4546 from inception in 1992 through 2000. 65.4% initiated on PD 34.6% initiated on HD
Importantly, roughly 50% of all ESRD in childhood is secondary to top 4 diagonses. Unlike in adults where diabetic nephropathy accounts for about 40% of all ESRD, diabetic nephropathy accounts for less than 0.1 % of ESRD in children.
Most recent published data on pediatric renal transplantation from the NAPRTCS registry was in 2001 in Pediatric Transplantation and reviewed data from 1987-1999. 24 % of transplants were performed pre-emptively, without undergoing dialysis. Percentage of caucasians receiving tx is also decreased from 68% in the first 5 years to 62.9%
This slide demonstrates some trends in pediatric transplantation demgraphics over the first 12 years of NAPRTCS data collection. Decreased number of tx over the last 3 report years may be due to reporting lag, but certainly may be related to decreasing availability of cadaver donor organs throughout the US
Number of patients < 1 year of age has decreased when compared to 1987-1991 cohort which comprised 6%. What has prompted a decline in the number transplants in the very youngest children?
Patient survival not different overall between cadaveric and lr donor recipients Overall surivival: CD: 1year 96.5% 3year 95.4 % 5 year 92% (primary tx) LD: 1 year 97.6% 3 year 96% 5 year 94.7% However, major difference when analyzed by age. Increased death rate in infants is unclear and may be due to an increase in the number of bacterial infections and cardiopulmonary events in this age group as the cause of death.
CD 1 year 83% LD: 1year 91% 3 year 75% 3 year 85% 5 year 65% 5 year 80% Compare 1987-1991 cohort CD 1 year 74% and 3 year 63% LD 1 year 88% and 3 year 81%
These data demonstrate that graft survival is much lower in both groups in the youngest infants (0-1) Number of children < 1 year of age has decreased from 5.1% 1987-1991 to 6% from 1991-1999. Reasons are not clear, and may be due to “relative increased immunoreactivity” and technical complications. Many centers do not routine transplant an infant if renal replacement therapy is effective.
A very important point I would like to make this morning that despite recent improvements in overall graft survival, renal transplantation in 2003 is NOT a cure for kidney failure.
Study using NAPRTCS data base and published by Tejani in American Journal of Transplantation 2002 assessed the risk factors for the development of chronic rejection in children. Reviewed a cohort of 1551 LD and 1226 CD transplants between 1995-2000 and compared differences between patients with graft failure due to chronic rejection vs. graft failure due to other causes. Late rejection (> 365 days post tx) Chronic rejection (progressive loss of renal func leading to graft failure > 90 days post tx. No difference in chronic rejection based on primary disease Conclusions: Improvement in prevention of acute rejection has lead to a decrease in chronic rejection. Unclear why african american race increases risk. One theory is that A.A. are more likely to receive a cadaver kidney and therefore is more likely to be mismatched. However, rr of chronic rejection occurs even in AA who receive LRD. Also, unclear how acute rejection increases chronic rejection
Decline in acute rejection: CD 71% to 45% LD 55% to 38%
In a study that compared acute rejection episodes in 2 different cohorts from NAPRTCS 1987-1989 and 1997-1999, Demonstrated decrease in rejection rate in the first year 60% rejection free after 1 year in 1997-1999 group compared to 29% in 1987-1989 cohort. Importantly these identified risk factors for acute rejection in the first year post transplant were only seen in the cohort from 1987-1989. No signficant factors were identified as risk factors for acute rejection in the 1997-1999 cohort perhaps related to the reduced number of rejection episodes in this group
3 controlled studies demonstrate acceleration of growth posttransplant with useof rhGH
Treatment for CMV includes gancyclovir or valacyclovir 90 days post transplant in CMV + donor to CMV - recipient Prophylaxis includes anti-CMV antibody (cytogam)
Other malignancies assoc with EBV include smooth muscle tumors (sarcomas), and T-cell lymphomas. This compares with a risk in liver of 2.2%, cardiac 7.9% , heart-lung 9.4% and small bowel 28.5% Since more children have not been exposed to EBV than adults, the risk of PTLD is higher in children Incidence was reviewed in NAPRTCS data in 2001.
Again, using the NAPRTCS database from 1992-1997, 1365 transplants were reviewed and 36 children developed PTDM Published in transplantation in 2001. Increase incidence of acute rejection, but rate of hospitalization and graft survival not apparently different.
Uncontrolled steroid withdrawal protocols published by several authors and a multicentered controlled, prospective, randomized study is underway. An important open label study published in Transplantation by Stanford group employed a completely steroid free protocol in 10 unsensitized pediatric patients. --prolonged induction with IL-2R blocker --protocol biopsies --tacrolimus and cellcept were oral agents Results: No increased incidence of acute rejection, increase in bacterial infections, or rehospitalizations No hypertension, hyperlipidemia, or body disfigurement At least 20 maintenance immunosuppression combinations are available—a far cry from the prednisone, azathioprine combination of just 15 years ago.
Current immunosuppressive therapy is somewhat analogous to the Baathist regime of Sadam Hussein. Our current strategy generally employs repression or suppression of the immune system. Rejections are squelched with more powerful doses of these same immunosuppressive medications. A novel strategy under investigation utilizes the concept of tolerance. That is, inducing a state in which the immune system does not respond to a specific antigen. In the case of renal transplant patients, inducing the recipient’s immune system to “tolerate” the foreign antigens of the donor kidney. Obviously, this is an exciting concept since this would potentially obviate the need for lifelong medication. Nonhuman primate studies that blockade of CD28 and CD40L appear promising, but the long term effects are not clear Other paths of interest include the CTLA4 and FasL costimulatory paths that I have not mentioned yet. CTLA4 is a homolog of CD28 and binds to B71 and 2. However, the effect of CTLA4 binding turns off clonal proliferation of t cells. FasL is in the family of TNF proteins and activation of FasL leads to apoptosis of the T cell.
The mechanisms through which xenoantigens activate immune responses in humans is beyond the scope of this talk. However, this is an area of intense activity in the biology of transplantation currently. We are all familiar with the term zoonosis, or infections in humans transmitted through contact with animals Xenoses, is a term coined for the potential infections arising from organ xenografts. As early as the 1960’s invetigators betan experimental xenotransplantation using nonhuman primates, including chimpanzees, baboons, and rhesus monkeys. Chimpanzees were thought to be most suitable donor, but chimpanzees are not widely or easily available, and have been listed as an endangered species. Baboons are about 30 times more plentiful as chimpanzees, but their breeding is difficult (long gestation and few offspring). Additionally, transmission of infectious agents such as HIV and Ebola to transplant recipients may endanger the entire community, and primate donors are thought to pose the greatest risk for transmission of latent organisms including retroviruses. So, investigators have turned to pigs. 90 million pigs are raised and slaughtered in US each year. Pigs breed well in captivity, have large litters and have raised less regulatory issues regarding introduction of new pathogens to humans given the history of contact with this species. Of course, the risk is present (think bovine spongioform encephalopathy) mad cow disease. Studies underway between pig/baboon
maintenance doseage from 2-10 mg/kg/day initially 1-2 months: 0.3 mg/kg/d 3-4 months: 0.25 mg/kg/d 4-6 months: 0.18-0.2 mg/kg/d 6-12 months: alternate day dosing rejection dosage IV: 5-30 mg/kg/d PO: 500mg/m2 for 1 week, taper to 2 mg/kg/d 1-2 weeks, then taper
2 fungi: cylindorcarpon lucidum, and Trichoderma polysporum drug has a MW of 1200 kD and comprises 11 amino acids, most of which are hydrophobic, thus cyclosporine is only soluble in lipids or organic solvents vasoconstriction is afferent arteriolar and leads to chronic ischemia TIN is secondary to chronic ischemia as well de-novo thrombotic microangiopathy is to be differentiated from recurrent HUS of the transplant kidney, may be due to reduced prostacycline synthesis. hypomagnesemia is due to CSA induced renal magnesium wasting Type IV RTA due to impaired aldosterone synthesis and metabolism