Improving Human Life by Advancing the Field of Transplantation
Ask the Expert
AST’s “Ask the Expert” service is a free online service designed to provide answers to frequently asked questions by physicians, nurses, pharmacists and other professionals interested in learning more about transplant immunobiology and clinical management of organ transplant recipients. Questions submitted to the Ask the Expert service should broadly apply to populations of transplant patients. Due to the large volume of questions received, only those questions deemed to be of broad interest will be answered. Answers will be posted below within four (4) weeks. Opinions rendered by experts are not necessarily those of AST.
In no event will patient-specific questions be answered.
All submissions to AST become the property of AST, including the copyright in such submissions. AST reserves the right to edit any question posed and to combine questions in any manner deemed advisable by AST.
Q: Is a history of gestational diabetes a contraindication to later living kidney donation?
It is difficult to predict who will develop diabetes.
Gestational diabetes along with...
It is difficult to predict who will develop diabetes.
Gestational diabetes along with obesity, ethnicity and family history are all risk factors for development of mature onset diabetes.
Better tests are needed but the most predictive available tests are the fasting blood glucose, insulin levels, and the 2 hour glucose tolerance test.In one study 35% of women who have gestational diabetes developed type 2 diabetes by 15 years after delivery.(ref 1)
A study of 241 diet treated women with GDM diagnosed between 1978 – 85 in Copenhagen found that 2-11 years later 34% had abnormal glucose (3.7% IDDM, 13.7% NIDDM, 17%IGT) in contrast to a control group where none had diabetes and 5.3% had IGT.(ref 2)
So clearly there is a risk. Importantly diet, excercise can modify this risk.
We therefore do not exclude patients simply on the basis of GDM but alo look at their current risk based on BMI at time of evaluation, and laboratories (fasting glucose and oral glucose tolerance).
The next question is what if the donor does develop diabetes. The existing data would suggest that the risk of micro and macro-albuminuria are increased. One of the most widely known studies is that of Silveiro (ref 3). Importantly microalbuminuria was noted an average of 23 years after nephrectomy, but was present as soon as five years after nephrectomy. The conclusions that can be drawn are that nephrectomy in an individual with diabetes, normal renal function and no dipstick identifiable proteinuria is likely not going to cause problems in the short term. However with time increasing proteinuria is common, and this may ultimately lead to loss of renal function and perhaps an increase in cardiovascular disease.
Putting all of this together – the key considerations are the age of your donor and an assessment of their current risk based on BMI and laboratory tests. If they are young, the risk may preclude donation, if they are older and their other risk factors are low – this may be acceptable with informed consent.
1)Linne Y et al. Br J obst and Gyne 58:193-200, 2002
2)Damm P. Dan Med Bull. 1998 Nov;45(5)495-509
3)Silviero Diabetes Care 21: 1521-24, 1998.
John Gill, MD, MS
University Of British Columbia
St. Paul’s Hospital
Member, AST Education Committee
Q: I'd like to know if the majority of transplant patients continue to take in antibiotics for most of their lives.
Most solid organ transplant programs encourage trimethoprim/sulfamethoxazole prophylaxis for approximately 3-12 months after transplantation. Although it is unknown whether prolonged prophylaxis is superior to temporary prophylaxis, extended prophylaxis beyond the specified period should be encouraged in the setting of ongoing rejection, increased immunosuppression, and/or graft dysfunction. In my opinion, lifelong trimethoprim/sulfamethoxazole prophylaxis should be considered in all transplant recipients who are able to tolerate the medication without side effects or toxicities. Potential benefits include prevention of the following infections that can occur at any point in the lifetime of a transplant recipient: Pneumocystis, Nocardia, Toxoplasma, bacterial pneumonia (e.g. Streptococcus pneumoniae), skin and soft tissue infections (e.g. MRSA), and bacterial urinary tract infections, among others.
Shirish Huprikar, MD
Mount Sinai School of Medicine
AST Education Committee Member
Q: If both parents have type 2 diabetes, should the living donation be allowed if oral glucose tolerance test is normal?
Thank you for your excellent question:
I have actually expanded your question into two...
Thank you for your excellent question:
I have actually expanded your question into two parts:
1) What information does an oral glucose tolerance test provide compared to fasting glucose?
2) Can a current normal oral glucose tolerance test in the setting of a patient with other risk factors help refine the future risk of diabetes?
1) The determinants of elevated fasting glucose and 2-h plasma glucose in an oral glucose tolerance test (2-HPG) levels differ.
Raised hepatic glucose output and a defect in early insulin secretion are characteristic of the former, and peripheral insulin resistance is most characteristic of the latter.
Therefore, concordance between the categories of IFG and IGT is limited. About half or less of people with IFG have IGT, and even a lower proportion (20-30%) with IGT also have IFG. In the majority of studies, IGT is more prevalent than IFG, and there is a difference in phenotype and gender distribution between the two categories. IFG is substantially more common amongst men and IGT slightly more common amongst women. The prevalence of IFG tends to plateau in middle age whereas the prevalence of IGT rises into old age.
Both IFG and IGT are associated with an increased risk of developing diabetes, with the highest risk in people with combined IFG and IGT. Because IGT is commoner than IFG in most populations it is more sensitive (but slightly less specific) for identifying people who will develop diabetes. The OGTT is also less reproducible than the fasting glucose test.
In most studies, 60% of people who develop diabetes have either IGT or IFG 5 years or so before, with the other 40% having normal glucose tolerance at that time.
2) Although research protocols for estimating the future risk of diabetes have primarily depended upon identification of impaired glucose tolerance through a 2 hour oral glucose tolerance test, other clinical, historical and laboratory measures are known risk factors for diabetes. There are no studies to my knowledge that compare risk of diabetes in patients with risk factors (such as parental history) but current normal laboratory tests. Most studies predict risk of progression to diabetes in patients with impaired glucose tolerance ( Edelstein et al).
A recent study in the Annals of Internal Medicine (Khan et al) Compared two risk scores for predicting future diabetes in adults aged 45-64 years. The first risk score was based on clinical and historical criteria only (diabetes in mother, father, sex, smoking history, hypertension, Black race, waist circumference, height, pulse, weight), while the second score also included laboratory tests including fasting glucose, triglycerides, and uric acid. NOte both scores included maternal and paternal history of diabetes.
The risk scores had reasonable sensitivity and specificity for development of diabetes over the next 10 years ( AUC 0.71 and 0.79). These risk scores could be applied to your patient.
Once the risk in your patient is determined, it is important to note that numerous studies have shown that diabetes can be prevented by lifestyle modification and potentially by the use of medications (metformin).
Your final decision to move forward should consider the baseline risk in your donor and your assessment of whether your donor can implement lifestyle changes to modify this risk.
References:
Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse
GK, et al. Predictors of progression from impaired glucose tolerance to NIDDM:
an analysis of six prospective studies. Diabetes. 1997;46:701-10.
Khan et al Ann Intern Med. 2009;150:741-751.
-John Gill
Q: Mycophenolate mofetil is available now as a generic alternative to Cellcept. I'm finding that many physicians are opposed to the switch. Why is this if bioequivalence has been established by the FDA?
In order for a generic drug to be approved by the FDA, it needs to demonstrate bioequivalence with the reference drug. In other words, the rate and extent of absorption of the generic drug can not be significantly different from the reference drug when given at the same molar dose under the same conditions. Bioequivalence for the generic drug is established in a single study of 24-36 healthy volunteers. It is determined by determining the mean AUC and Cmax for the generic drug and comparing it the reference drug. The ratio of bioavailability of the generic drug to the reference drug (T/R ratio) must fall between the confidence interval of 80-125% for the generic drug to get FDA approval.
The FDA does not usually require manufacturers of generic drugs to perform safety or efficacy studies in humans or in this particular case, transplant patients. For this reason, some transplant physicians are reluctant to use generic mycophenolate mofetil since no efficacy studies were perform in transplant patients prior to the release of these drugs into the market.
-Diane Cibrik
Q: I am working in Hong Kong. I recently encountered a case who is a cadaveric organ donor and his family only consent to donate provided that one of the kidneys must be given to the brother-in-law of the deceased patient. Is there any rule/ policy/ guideline in US or other place in the world that the donor can assign the destination of the donated organs? The family claimed there is no financial incentives in this donation but how can we assure this?
Directed donations challenge the traditional construct of altruistic donation
In your...
Directed donations challenge the traditional construct of altruistic donation
In your case, I am not sure how the deceased individual provided consent for this (was this part of a living will?).
In any regard there is policy in the United States regarding directed deceased donation.
The following in formation is taken directly from UNOS.
“Directed donation is a request made by a donor or donor family to transplant a specific recipient. This practice is legally authorized by the Uniform Anatomical Gift Act (UAGA) and by most state anatomical gift laws, which use the UAGA as a guide. (A few state laws are silent on directed donation but do not specifically disallow the practice.)
The policy of the national Organ Procurement and Transplantation Network (OPTN), operated by United Network for Organ Sharing (UNOS) under federal contract, recognizes directed donation as long as the agencies involved take steps to verify the medical suitability of the organ offer for the specified recipient. The Federal regulation that guides the OPTN (the OPTN Final Rule) expressly allows directed donation to a named individual.
In recent years, at least 100 deceased donor transplants each year have occurred through directed donation. Such requests occur most frequently when the donor or donor family either are related to the recipient or know the recipient personally. Past instances of directed donation that have resulted in media coverage include a daughter-to-father heart transplant and a heart transplant from a church member to the church’s pastor. In many instances, only one organ from a deceased donor is directed to a specific recipient; other organs from the donor are allocated according to OPTN policy."
In England, Wales and Northern Ireland, the Human Tissue Act 2004, and in Scotland the Human Tissue (Scotland) Act 2006, are both silent in this regard. Although so-called conditional donation, donation to (or perhaps withheld from) a specific class, has been outlawed as a product of guidance issued by the Secretary of State for Health issued in the wake of the controversial incident occurring in the North of England in 1998, its intended application to ‘directed’ donation is less certain.
In Canada, there are very few examples of directed deceased donation that I am personally aware of.
Most of the American cases appear to have a clear relationship between the donor and the recipient. Although establishing the nature of a relationship can be very difficult, it is clearly desirable. Any suggestion of either coercion or payment should preclude a directed donation.
-John Gill
Q: I would appreciate the expert opinion on current CMV prophylaxis strategies in SOT. In particular, I would like to know what does he think about low-dose valganciclovir (450 mg/day) vs. full-dose (900 mg/day). What's the trend in terms of dosage in most US Transplant Centers nowdays (for example, Kidney Tranplant programs)? What about universal vs. only high-risk recipients prophylaxis? If a Kidney Transplant program does experience a very high rate of significant leukopenia implementing 900 mg/day as standard CMV prophylaxis (3-month course), should it be the next step switching to low-dose valganciclovir?
No randomized studies directly comparing 450mg and 900mg of valganciclovir exist to the best of my knowledge. However, there is data supporting the efficacy of both doses which suggests that the lower dose is probably sufficient in most situations. At our institution, we provide 900mg only to our D+R- liver transplant recipients. All other liver and kidney recipients (except D-R-) receive 450 mg (or adjusted for renal function). Clinicians should be aware of two issues. First, late-onset CMV disease after prophlyaxis has been discontinued is a signficant problem in D+R- patients. Second, dosing of valganciclovir should be readjusted in renal transplant recipients with fluctuating renal function. Most importantly, as renal function improves the dose should be increased to avoid suboptimal prophylaxis and breakthrough CMV disease. Leukopenia can be addressed by either decreasing the dose or providing GCSF.
-Shirish Huprikar
Q: A generic version of prograf came to the market. Will doctors be willing to use this drug on patients as it is much cheaper?
The use of generic tacrolimus poses an interesting dilemma to the transplant community. As opposed to mycophenolate, a non-nephrotoxic drug with excellent and for most predictable bioavailability, tacrolimus has a narrow therapeutic window, and a more variable pharmacokinetic profile. In contrast to some generic preparations of cyclosporine – no pharmacokinetic studies of generic tacrolimus have been carried out in American transplant patients. Since the Food and Drug Administration only requires testing of generic drugs in healthy subjects for approval, performance of clinical pharmacological studies in our transplant patients will not happen.
The paucity of data upon which to base a safe decision making is particularly concerning in the light of a post-hoc analysis of a 3-year randomized, open-label controlled study conducted in Mexico and presented at the 22nd International Congress of the Transplantation Society in August 20081. In this study, primary kidney transplant recipients treated with a generic tacrolimus preparation (Tenacrine) had a greater incidence of acute rejection than their counterparts treated with Prograf®. Mean tacrolimus blood levels were lower in patients treated with the generic form at 3, 6, and 9 months post-transplant when compared with baseline (P < 0.05)1.
Notwithstanding our trepidation, in the current environment of health care reform and cost-containment, private insurance companies will soon impose high co-pay rates on Prograf thereby limiting its access to our patients, and physicians will be left with few options other than a close follow-up of those patients switching agents and hope for the best possible outcome.
Reference:
1)Holm Corzo A et al: A Post-Hoc Analysis of the Safety and Efficacy of Tacrolimus (Prograf) Versus a Generic Formulation of Tacrolimus (Tenacrine) as Primary Immunosuppressive Therapy in LRD and CAD Adults and Pediatric Renal Transplant Recipients [Mini-Oral Session 18 WMO18]
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Q: What's your opinion about initiate treatment with anti CD20 antibody (rituximab) and immunoglobulins on the basis of histopatology only, not having performed immunohistochemistry seeking for C4d either investigation of HLA antidonor antibodies?
In the current age, the empiric treatment of acute rejection – that is without the...
In the current age, the empiric treatment of acute rejection – that is without the benefit of the gold standard: kidney transplant biopsy – is not optimal standard of care with the exception of situations in which the risk-benefit ratio is deemed to be unacceptable.
The diagnosis of antibody-mediated rejection (AMR) requires the presence of light microscopic changes that are well characterized, evidence of antibody activation – C4d deposition in the peritubular capillaries, and detectable donor specific antibody in the recipient serum.
Although one can argue that these criteria need not to be present concomitantly for a patient to have AMR, pursuing the accurate diagnosis is essential to guide therapy appropriately; and empiric therapy should be discouraged.
Rituximab is an expensive chimeric antibody, which efficacy in the treatment of antibody-mediated rejection remains to be proven, and with potentially severe side-effects including infection, prolonged late hypogammaglobulinemia, and neutropenia among others. Thus while using rituximab in AMR can be argued in terms of efficacy, its use without a proven diagnosis is not acceptable.
Q: I have a question about preservation solution in regards to the type of solution utilized. In many transplant centers Wisconsin Solution or Custodiol (HTK solution) are used for kidney preservation. Nevertheless, in the absence of one of these standard preservation solutions, some peple use Hartman Solution (Lactated Ringer) adding to it some electrolytes such as potassium, and other substances as manitol, lidocaine, etc. Is it justified to use the handly prepared preservation solutions with Hartman and other electrolytes?
The principles of organ preservation are flushing, cooling, and pharmacologic intervention....
The principles of organ preservation are flushing, cooling, and pharmacologic intervention. University of Wisconsin (UW) solution is currently considered the standard preservation solution for livers, kidneys, and pancreases. The osmotic concentration is achieved by the administration of metabolically inert substrates like lactobinat and raffinose. Other components include hydroxyethylstarch as a colloid carrier, oxygen radical scavengers, glutathione, allopurinol, and adenosine. Histidine-Tyrptophan-Ketoglutarate (HTK) solution is another option which has shown similar safety and efficacy at least for lower cold ischemia times. Its contents include histidine, mannitol, tryptophan and alpha-ketoglutaric acid. It also contains low concentrations of sodium, potassium, and magnesium. Histidine serves as a buffer, and tryptophan, histidine, and mannitol act as oxygen free-radical scavengers. There is some evidence that using cold lactated Ringers with additives can be safely used for short-term cold preservation of kidneys from living renal donors and is a cost-effective option but only in that circumstance.
-Susan Lerner
Q: What is the current state of the art for immunosuppression for pediatric renal transplantation? Induction, Maintenance Immunosuppression, Duration of prophylactic medication usage, etc? Any authoritative references (which also talk about protocols) would be greatly appreciated. Thanks
I don’t believe that there is any one immunosuppression protocol that would be considered a “state of the art”. As with any other organ transplant and age group, many combinations are utilized currently. Most programs in the USA use some form of induction for children receiving a kidney transplant. The induction agent varies widely; rabbit anti-thymocyte globulin and basiliximab are probably most common, with very specialized centers using alemtuzumab (source UNOS database; www.unos.org). More than 80% of centers use tacrolimus and more than 90% use mycophenolate as part of maintenance immunosuppression in new transplants. Steroid use has dropped considerably, probably only 50-60% of new transplants now receive (source: NAPRTCS database; www.naprtcs.org). Anti-infective prophylaxis has become increasingly important, given the emergence of infections as an equal or bigger problem than acute rejection (1). Most centers will use some form of anti-fungal prophylaxis (nystatin or clotrimazole) for 3 months, anti-bacterial prophylaxis for 3-6 months (also covers pneumocystis) and anti-viral prophylaxis (typically valganciclovir) for 3-12 months. See the recently published KDIGO guidelines for recommendations (2). Published protocols are from specific research centers such as Pittsburgh and Stanford (3-6); they represent specialized protocols unique to those centers or consortia, not necessarily what the majority of centers currently do.
1. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant. 2004 Mar;4(3):384-9.
2. Chapman JR. The KDIGO clinical practice guidelines for the care of kidney transplant recipients. Transplantation. Mar 27;89(6):644-5.
3. Li L, Chang A, Naesens M, Kambham N, Waskerwitz J, Martin J, et al. Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits. Am J Transplant. 2009 Jun;9(6):1362-72.
4. Tan HP, Donaldson J, Ellis D, Moritz ML, Basu A, Morgan C, et al. Pediatric living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy: 4-year experience. Transplantation. 2008 Dec 27;86(12):1725-31.
5. Harmon W, Meyers K, Ingelfinger J, McDonald R, McIntosh M, Ho M, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol. 2006 Jun;17(6):1735-45.
6. Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, et al. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. Jan;10(1):81-8.
-Vikas Dharnidharka
