Blog from the 2011 Transplantation Symposium at East Carolina University – Brody School of Medicine


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3:30 PM — Agenda is provided for the Kim Thomas Annual Update on Renal Transplantation

Welcome and Overview — Robert Harland, MD

Improving Long-Term Graft Survivial — Jason Rolls, MD

Patient Panel Discussion — led by Barbara Lee, MSW and Clif Hill, MSW

Breakout Session I: Management of Cardiovascular disease pre- and post-transplant — Peter Wagner, DO

Breakout Session II: Screening and treatment of skin cancer in the immunosuppressed patient — Jennifer DeFazio, MD

Breakout Session III: When to refer a patient for access surgery or transplant — Carl Haisch, MD

Breakout Session IV: Maintaining optimal dialysis access while awaiting transplantation — Robert Harland, MD

Dinner

Key Note Speaker: Recent Developments in Pancreas Transplant — A. Osama Gaber, MD, FACS, FRCS (Methodist Hospital, Houston, TX)

Discussion and Q & A

Adjourn

Going to be a long and interesting meeting!


4:00 PM — Welcome and Overview

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Dr. Harland begins with his opening remarks — w/o his powerpoint presentation because of a technical problem.

Dr. Harland encourages all of us to complete the evaluations of the symposium. He thanks the sponsors who provided financial support — Astellas, Genzyme, Hemosphere, Novartis, Genentech. No disclosures to report except Dr. Wagner (Pfizer and Forrest Pharmaceuticals).

The breakout sessions are new to the symposium, offering a more detailed learning environment with small class sizes.

The key emphasis today is on the length of time that we are caring for transplant patients. Today, graft survival is easily over 90% at one year. Dr. Rolls will be speaking about this topic next.


4:10 PM — Improving long term renal allograft survival

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Historically, there was a time when transplantation was an insane procedure. Now, we know transplantation clearly saves lives than being on dialysis. And end-stage renal disease is increasingly common. ESRD prevalenece (2010 USRDS data) is growting almost exponentially, with hemodialysis being 354K in 2008. Internationally, the US has the third greatest prevalence (behind Taiwan and Japan). In terms of incidence, we are second (behind only Japan).

The etiology of ESRD is DM and HTN (38% and 24%, respectively). Geographically, most ESRD patients were in the Southeast (1998) — 10 years later, we see ESRD spreading to all over the country. USRDS data from 1998-2008 regarding 10-year adjusted survival for all comers (regardless of age, race, or etiology of kidney failure) is < 20%. For a deceased donor transplant recipient, 10-year adjusted survival is 43.3%, and living donor 51.1%. However, these survival rates are extremely impressive for diabetic patients, with a 3x increase in survival between ESRD patients and deceased donor recipients.

2008 USRDS data regarding costs: 1st year post-transplant costs about $110k/year, but each subsequent functioning year is $19K. Yearly dialysis costs per patient is about $76K. Doing the math, transplantation begins offering savings after 3 years.

Dr. Rolls begins to detail the history of transplantation. In brief:
1906 — first transplant of a pig kidney into a sheep.
1912 — Alexis Carrel wins the Nobel prize for realizing the concept of histocompatibility
1936 — Yu Yu Voronoy in Russia performs the first human-to-human transplant, which lasted for 2 days
1940 — Illinois — first deceased donor transplant in the US on Ruth Tucker, a 44-year old with PKD. 10 months later, kidney rejected because there was no immunosuppression at that time
1954 — Bostons — first successful kidney transplant by Joseph Murray of identical twins (he won the Nobel Prize in 1990).
1957 — AZA is synthesized by Gertrude Elion and George Hitchings (who won the Nobel prize in 1998)
1966 — Terasaki develops the crossmatch, lowering hyperacute rejection rates
1968 — the Southeast Organ Procurement Foundation is formed — which is the forerunner of UNOS
1972 — Medicare covers dialysis treatments
1972 — cyclosporine developed
early 1980′s — cyclosporine drives allograft survival to up to 80% at one year
1990′s — graft survival now 90% at one year

What’s happening now? Living donor allograft survival is about 95% at one year, but linearly decrease up to 10 years. SCD have a median survival of 9 years, living donor grafts of 11-13 years. Asian recipients receiving a living donor have the longest graft survival. African-Americans receiving a deceased donor have the shortest graft survival.

Graft survival has to do with HLA expression. These are highly polymorphic. For more information about HLA expression and crossmatching, click here.

3-month graft survival in the last 20 years increased from 92% to 97%, with almost all the improvement occurring in the 1st year of transplantation. After the 1st year, since 1991 the rate of graft failure has not changed.

Dr. Rolls diverges a bit to discuss the types of deceased donors.
ECD — donor between age 50-60 with at least 2 of the following:
creatinine > 1.5, or death by stroke, or h/o HTN
or a donor > 60 (regardless of comorbid conditions)

ECD criteria are oversimplifications and can cause surgeons to pass up good kidneys because of comorbidities that may have no effect on the kidney. Dr. Rolls insists that there is a better, more mathematical way of determining the quality of a donor kidney — donor profile index. The index is a number — lower scores indicate a longer median graft survival.

Dr. Rolls then discusses the immunologic factors of the recipient, specifically the panel reactive antibody. This is a measure of one’s level of sensitization. The result is reported as a percentage — the higher the percentage, the more likely you are to react to most allografts offered. These patients can still be transplanted, but require proper pre-transplant immunosuppressive preparation (desensitization). For these patients, Jordan from Cedars Sinai (in LA) has been giving pooled donor Ab’s and rituxan –> successful desensitization of high PRA patients. At ECU, the largest number of patients have 0% PRA; the second largest group has 90% or greater PRA’s.

Dr. Rolls now turns his attention to rejection episodes after transplantation. We are much better at dealing with acute rejections, but the key to increasing long-term survival is to adequately treat or mitigate chronic allograft rejection. In one study by Terasaki, the presence of donor specific antibodies can increase the rate of rejection to 89% (from 43% of those patients without DSA’s). Drs. Haisch and Reballato (at ECU) are working on this issue.

BK virus also impacts graft survival, and it appears to be endemic to eastern North Carolina. The best treatment thus far is a reduction in immunosuppression, but that leaves the kidney open to acute rejection. Some new studies suggest that ciprofloxacin can be used prophylactically, and is being studied at ECU currently.

Calcineurin inhibitors are nephrotoxic, and provide a paradox in that these drugs, used to prevent acute rejection, increase the risk of chronic toxicity. Sirolimus, a newer drug originally used as an antifungal agent, can be used w/o nephrotoxicity. Everolimus is a derivative of sirolimus, and approved last year. Belatacept is an interesting drug — it blocks costimulation. It is not nephrotoxic and is currently being studied by the ECU Nephrology group.


5:00 PM — Patient Panel Discussion

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As patients enter the auditorium (volunteers), theme song from Rocky plays in the background to smiles and hearty laughs.

Barbara Lee uses multiple, clever and interesting Rocky analogies to describe what a patient thinks and feels after receiving the news that he/she has kidney failure.

Clif Hill introduces our 4 patients — to keep with HIPAA, I will not indicate their names.

5:10 PM
First patient: thanks her doctors and nurses first. Recalls how her husband had to push her through the dialysis center doors to start her first treatment. She converted to home dialysis after 3 months, which was much better for her. Except that she had great difficulties fulfilling the needs of her 6-year-old son. She never saw her time on dialysis as good or bad days, but rather good days and better days. Her mother was also on dialysis at the same time as she was. Unfortunately, her mother developed cancer while on dialysis. Her support structure helped her get through dialysis (physicians and nurses), especially because she couldn’t be as available to her mother as she wanted to. She was so happy to finally receive the kidney call, only to learn that she still needed dialysis post-transplant. She then takes out her “intimidation cup”, which is a standard 1 liter jug offered to all inpatients — she simply could not drink that much water, but kept trying. Through all of these good days, she had family, friends, and physicians/nurses to get her through into the better days. Finally, she insists that you have to encourage yourself because no one else will, having faith in a higher power and doing what the doctor tells you (including drinking plenty of water!) (audience laughs heartily).

5:20 PM
Patient 2: Talks about his primary nephrologist who began talking about transplant long before he started dialysis. One of the biggest mistakes he had was thinking that he was fine because he was still making urine. He started with hemodialysis for 2 months until he was first introduced to peritoneal dialysis. He chose peritoneal dialysis, which was a little better to tolerate than hemo. Surprisingly, he tested O+ and no one in his family was a match. He was shocked about this because he had always believed that O was the most common blood type. Some in his family thought he was adopted (audience laughs). Amazingly, a friend of a friend of a friend began discussing his case and ran into someone who was O+. Both are from different parts of the country, but living in the same town and willing to donate his kidney to him (a stranger). He is very thankful for living donors. They are truly altruistic and are genuine lifesavers (strong applause by the audience).

5:30 PM
Patient 3: Her journey with transplant started in 1995 when she took a quinine pill for leg cramps during a cross-country car ride. She developed flu-like symptoms so she took another quinine pill, and her symptoms worsened. The next morning she awoke with blotchy red skin spots. Her husband took her to the local ER and had pulmonary edema w/o any urine output. She was helicoptered to the closest large hospital. Subsequently, she developed acute respiratory distress requiring intubation and emergent dialysis. She was given the diagnosis of TTP-HUS. Ultimately, she continued with dialysis (hemo first, then PD). But she was thankful that she had a good friend who offered her a kidney transplant. Interestingly, she was the least scared about undergoing the transplant surgery than at any other point during her time on dialysis.

5:40 PM
Patient 4: A pastor, mother of 4, grandmother of 13, diagnosed with lupus. She felt that the disease was more of a mental and emotional challenge than a physical one. More people die from the fear of a disease than the disease itself.

Standing ovation for all the patients by the audience.


5:45 PM
Break


6:00 PM — Management of Cardiovascular disease pre- and post-transplant

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Will focus on the pre-, peri-, and post-op management of cardiovascular diseases. Coronary heart disease is a relative contraindication to transplantation. Coronary heart disease is the major cause of death after transplantation, and therefore, pre-op evaluation and risk modification is quite important. Non-invasive testing has limitations in CKD patients, especially those with diabetes. In fact, the optimal non-invasive test in this population is still unclear, and perhaps heavily dependent on the expertise of the cardiologist. Angiography may be required, and should be done judiciously because it can accelerate renal disease and the onset of dialysis. SPECT CT, coronary CT angiography and calcium scoring are some newer non-invasive tests. SPECT CT is coming to ECU in the near future. Coronary CT isn’t very helpful in patients who have extensive calcifications, like advanced CKD patients. Calcium scoring may be a good test, but more data is required in the ESRD/CKD 5 population.

ECU Cardiology algorithm (in brief): Calcium scores > 1000 lead to an automatic cath. If the score is > 400 in any one particular vessel, the patient will go to the cath lab. If the score is not at or above those limits, a stress test is performed and cath subsequently if ischemia is evident.

Overall, no one knows the best pre-op evaluative approach to the pre-transplant patient. No matter what algorithm you choose, eligible patients for transplantation are asymptomatic patients (w/ or w/o non-invasive testing, so long as it is negative), patients on appropriate medical therapy, or patients who have had successful interventions.

Dr. Wagner did not want to go into details about perioperative care.

Cyclosporine is one of the worst drugs — it interacts with many cardioprotective medications, like statins. Lipids should be managed with statins, especially in patients using mycophenolate mofetil (which does not have an adverse drug-drug interaction). Statin therapy should be used aggressively in post-transplant patients. Fibrates are excellent adjunct therapies with statins. Nicotinic acid is useful in raising HDL; it is the most effective drug to do this, and should be used in conjunction with statins to achieve the optimal LDL:HDL ratio. Post-transplant patients should be considered as high risk patients, requiring the most aggressive lipid lowering therapy that can be prescribed.

Dr. Wagner goes into the different types of anti-hypertensive medications, focusing on drug-drug interactions with calcineurin inhibitors (but only a cursory discussion).


6:30 PM — Maintaining optimal dialysis access while awaiting transplantation

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38% of the Medicare costs of ESRD are related to accesses. It is about $13K to replace a catheter and is the #2 cause of admission at US hospitals. Peritoneal dialysis is less expensive and allows more freedom and most patients who can perform PD will likely be compliant with transplantation.

70-80% of patients start with a catheter first and strategies are underway to minimize catheter accesses as the first access. All patient survival data show a direct relationship to the type of access they have. Catheter patients have more infections but also more cardiovascular complications. The catheter is called “the white snake of death”. Infected catheters cause $23-45K per infection, with about 17 days length-of-stay. Patients who receive an AVF need to be followed by the surgeons until the access is used successfully.

PTFE (e.g., Goretex) is the most prevalent material for AVG’s. AVG’s have greater infection rates than AVF, but certainly much less than the tunneled catheters.

Dr. Harland believes the HeRO vascular access device might be better than a leg graft. This is in part, because the HeRO can provide outflow to an established, but non-functional, AVF or AVG. Femoral accesses can make future transplantation difficult.


7:15 PM — Recent Developments in Pancreas Transplantation

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Dr. Gaber starts off highlighting the costs of diabetes, since it is the most common etiology of end-stage renal disease. From 1998 to 2008, the costs have increased from $98 billion to $180 billion. Obesity, closely linked to diabetes, is now the a common problem in almost every country. Diabetes is not about managing blood sugar only. The true problem with diabetes are the numerous complications, specifically retinopathy, nephropathy, neuropathy, and vascular disease.

Diabetes is a very slow disease, taking years to manifest its complications. Dr. Gaber then provides a simple explanation of the pathologic changes in the glomerulus in uncontrolled diabetes. He makes a key emphasis on the fact that glomerular changes are reversible (up to a certain point in time) if diabetes is controlled aggressively.

The first pancreas transplants occurred in 1968, but the results were poor. Dr. David Sutherland continued the process of pancreas transplantation and has contributed to the body of knowledge in this area. These early cases had the pancreas anastomosed to the bladder. The problem with this method was the loss of electrolytes and occasional necrosis of the bladder and/or urethral valves. A modified technique has the pancreas anastomosed to the duodenum. Dr. Gaber anastomoses the pancreas to the portal venous system and has proven this technique as equally safe as anastomoses to the systemic circulation.

Does pancreas transplantation improve life expectancy? If you co-transplant a pancreas with a cadaveric kidney, you can add 20-24 years of additional life! Regardless of the type of kidney transplant, the addition of the pancreas (e.g., pancreas after kidney, simultaneous pancreas/cadaveric or living kidney) will increase life span. The problem in the US is that pancreas transplantation has become a competitor of kidney transplantation. Those patients that require a heart or liver obtain the kidney and, as a result, the number of pancreas/kidney transplantation has decreased.

DCCT trial: a 20-year old study that showed that if blood sugars were controlled, patients did better. There were 2 groups: standard group with an A1c of 8%, and a controlled group with an A1c of 7.5%. If you give someone a pancreas transplant, their A1c remains below 6% without any need for insulin. Diabetes patients have a mortality rate of 43% within the first 3 years, primarily because of the development of diabetic cardiomyopathy. Pancreas transplantation can actually reverse diabetic cardiomyopathy (shown by Dr. Gaber in a paper in 1994).

Pancreas transplantation also improves microangiopathy and improves the arterial thickness/plaque thickness. Therefore, regardless of the measurement you use to assess the progression of diabetes, pancreas transplantation can cure diabetes. In particular, patients who receive a kidney-pancreas transplant do better than a kidney transplant alone.

7:35 PM

Can a pancreas transplant prevent diabetic nephropathy? The short answer: yes. 42 patients with diabetic nephropathy were given a pancreas transplant and followed with protocol kidney biopsies. Their nephropathy improved histologically.

Does pancreas transplantation improve neuropathy? Again, the short answer: yes. In a study looking at pancreas transplant patients who lost their transplant versus those who continued with their transplant, the former group had a higher rate of developing neuropathy than the latter. Dr. Gaber’s group looked at gastric emptying (diabetic gastroparesis). They developed an electrogastropathy measurement (similar to the ECG). Patients with pancreas-kidney transplants had a higher rate of normal gastro-mobility than those without at 24 months.

Does pancreas transplantation improve retinopathy? An initial early study did not show any improvement in retinopathy. This study, however, did not follow the patients for a long period of time. Future studies have shown more stabilization of the retinopathy in patients with a pancreas transplantation if followed at least 2 years post-transplantation.

7:50 PM

The 1/2 life of a pancreas transplant is the lowest of all transplantable organs. A pancreas alone has a 1/2 life of 2.3 years, but 9.6 years with a pancreas-kidney dual transplant. Dr. Gaber thinks this has to do with the rate of early pancreas rejection, but he will go into this in further detail at tomorrow’s surgery grand rounds (no blog for this).

EDIC study: A relook at the DCCT trial. Once the study finished, they followed the patients for an additional 10 years. The A1c’s in both groups converged to the same mean. When we look at the cardiac complications, the incidence of such outcomes was less in the patients who were originally in the intense group. At 15 years, the patients who initially had a lower A1c during the DCCT had a lower rate of cardiac complications, despite having 10 subsequent years of the same A1c level as the standard A1c group.
Thus, any amount of good control will pay dividends in the future. Even if the 1/2 life of a pancreas transplant is only 2.3 years, those years of good A1c control will pay dividends in the future.


End of conference and blog

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