Mesenchymal Stem Cells and Transplantation: Hopeful to Make #NephMadness '17. #TransplantRegion

#NephMadness season is here! The #TransplantRegion has very interesting matchups, but one player that was left out of this contest because is relatively new in the game and relatively unknown, is Mesenchymal Stem Cells (MSCs). In the last few years the transplantation field has struggled to find how to prolong graft survival by inducing tolerance, minimize immunosuppression, inhibit fibrosis and treat rejection episodes. A candidate with all these characteristics are MSCs. MSCs are mesoderm-derived multipotent stromal cells that have high self-renewal and multi-lineage differentiation potential, anti-inflammatory properties, effects in the innate and adaptive immunity and the ability to repair damaged tissue.

 But what exactly makes MSCs attractive to transplantation? First of all, their effectiveness has been reported in the treatment of graft-versus-host-disease (GVHD). MSCs are found in fat, bone, cartilage, umbilical cord, cord blood, synovium, synovial fluid, muscle, skin and pulp and they can also be isolated from those organs, including the kidneys, which could be of major interest due to its repairing properties. MSCs inhibit T cell proliferation via several mechanisms including indoleamine 2,3 -dioxygenase (IDO) activity, production of prostaglandin E2 and transforming growth factor (TGF-β), expression of low levels of major histocompatibility complex (MHC) class II and costimulatory molecules including B7-1 (CD80), B7-2 (CD86) and CD40. They also inhibit macrophages, NK cell proliferation by reducing IFN-γ and dendritic cells (DCs) activity. In experiments, MSCs affect the ability of DCs to prime T cells in vivo. They also have direct effects on the endothelium by enhancing angiogenesis via expression of vascular endothelial growth factor (VEGF) and angiopoietins. The available data on B cells has not been studied extensively but some experiments report that MSCs increase CD4+, CD25+ and FoxP3+ regulatory T cell function (Treg) which may cause arrest of B lymphocytes in the Go-G1 phase of the cell cycle. In addition, MSCs by mediating T cells, inhibit the maturation, migration, proliferation and antibody production of B cells.  Remember that FoxP3+ expression has an important role on Tregs. You can check details here in the #NephMadness Transplant Nephrology Science Region (#TransplantRegion). Although all these properties are exciting there are more questions than answers.

In mouse models of GVHD, MSCs were administered at 3, 8 or 20 days after bone marrow transplantation and other reports have suggested that a better immune suppression can be achieved when they are administered before transplantation, so clearly, there is no evidence for timing of administration. In regards to dosing and frequency, the MSCs proposed dose is 0.4 - 10 x 106 cells per kilogram of body weight in humans but using a high dose has also been reported. The frequency of administration has not been determined.

There are no reports on adverse events related to the infusion itself and long-term effects are not available, however in vitro and in vivo studies have shown that MSCs have the potential to differentiate into neoplastic cells and may promote growth of tumor cells.
In this report with autologous MSCs as induction therapy into living-related kidney transplant recipients, 159 patients were randomized to receive MSCs induction therapy with standard calcineurin inhibitor (CNI), MSCs induction with low-dose CNI or interleukin-2 (IL-2) receptor blocker. The authors reported reduced opportunistic infections in comparison to controls (HR, 0.42; 95% CI, 0.20-0.85; P = .02 ). Rejection episodes with MSCs induction were 8%, compared to 21% in the IL-2 receptor blocker group.

As of today (March, 2016), to my knowledge, there are 13 registered trials of MSCs in kidney transplantation that are currently recruiting patients or have been completed on the clinicaltrials.gov website. Other areas of interest in which MSCs are being used are acute kidney injury, chronic kidney disease and polycystic kidney disease. Most studies have used autologous MSCs since they seem to be more potent than allogeneic MSCs but it requires a long process and time can be an issue if recipients are in need of treatment for rejection. One advantage of allogeneic MSCs is that they can be available rapidly.

In conclusion, I think Tregs would have been a strong competitor in this year’s #NephMadness if MSCs would have qualified. Maybe next year or in the next few years they will be in better shape to compete in #NephMadness. MSCs may have a very important role in kidney transplantation given their immunosuppressive, reparative properties and potential to induce tolerance, however there are several technical aspects that are complex such as isolation, culture, amplification and cost, plus long-term outcomes are unclear at the moment and large clinical trials are needed.

 Don’t forget to fill out your brackets!

Image from: Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nature, Feb 2016. 

Kidney Transplantation in Identical Twins: Do They Need Immunosuppresion?

The first kidney transplant between two identical twins, the Merrick brothers, took place on Dec 23, 1956 in Boston, MA and its is very interesting to read the original article and how Dr. Merril and Dr. Murray concluded that they were identical. They performed a full-thickness skin graft on the recipient and 31 days later a histological examination of the skin graft indicated no rejection and these observations among other clinical findings lead the investigators to conclude that they were monozygous twins and rejection would be unlikely. No HLA typing existed at that time. Surgery was successful and Mr. Herrick lived for 9 years after the transplant without receiving any maintenance immunosuppression. He later died secondary to a myocardial infarction. The side effects of immunosuppression (IS) is a constant battle for nephrologists and finding a sweet spot on maintaining adequate IS to prolong graft survival and avoiding side effects is almost impossible to achieve.

A few days ago we took care of a 72 year-old female that underwent living donor kidney transplantation from her identical twin. Prior to surgery there was a discussion whether the recipient should get any induction and maintenance IS. She was a 0/6 HLA mismatch and genetic testing using PCR-based Short Tandem Repeats (STR) analysis indicated they were identical for the 16 different polymorphic gene loci that were evaluated and because she was elderly and highly functional she was at a low immunological risk. 

Monozygous twins come from a single ovum fertilized by one sperm, and recent studies have shown that monozygous twins are not genetically-related due to the phenomenon of somatic variation, which can arise from three different mechanisms: somatic mosaicism, chimerism and epigenetic drift. Somatic mosaicism occurs in early embryo development and results in tissues having varying genetic expression arising from a single zygote (think about the Rubik’s cube) through numerous mechanisms such as heteroplasmy (unequal division of mitochondrial DNA within the cellular cytoplasm) and uniparental disonomy (where both copies of a chromosome or genomic region are inherited from a single parent) Chimerism arises when new genetic material is introduced from an exogenous source such as maternal cells entering fetal circulation or between two embryos in multiple pregnancies. Epigenetic drift is the result of genetic alterations that have been accumulated throughout life as a result of the interaction of genes and environment (early in utero and lifestyle).

So, should monozygous twins receive any induction or maintenance IS? First of all, there are no randomized controlled trials addressing this question and there have been only a few reports where patients received minimal or no immunosuppression. In this article, the authors reported 194 probable identical twin transplants. Seventy percent of the cases received steroids as induction and 71% were discharged with some form of IS therapy. At one year post-transplant, 21% of recipients were receiving calcineurin inhibitors and 27% were on steroids. By one year post-transplant, 66% percent of recipients were not on any form of IS. Recipients off IS, tended to be younger, White, and had a cold ischemia time of less than 12 hours.

In regards to rejection rates in kidney transplantation in identical twins in the US and United Kingdom during 1988 and 2004, the authors reported 120 cases in the US and 12 cases in the UK and they concluded that there was no significant difference in graft survival between recipients that are received IS and those who did not. In addition, they also reported no differences on cases that had maintenance IS for possible recurrence disease in comparison to those recipients at low risk for recurrence disease. In another series of 5 cases in a single center between 1969 and 2013 in Spain of kidney transplantation between monozygotic twins, the investigators reported good outcomes at one and five years. Recipients received only a single dose of high dose steroids intraoperatively and no maintenance IS. Of this five cases, two recipients died (from cardiovascular disease and melanoma) after 16 and 22.5 years post-transplant, respectively. One patient was lost to follow up and the two remaining were still alive.

DAMPs (damage-associated molecular patterns), among other chemokines, are released during ischemia-reperfusion injury and cellular stress during organ recovery which may modify gene expression after transplant, so using high dose perioperative steroids as induction therapy to suppress this response is a good approach. The somatic variation phenomena described in monozygotic twins should also be considered since they are not strictly identical. In conclusion, once the immune system has been adequately suppressed after the initial inflammatory response related to kidney transplantation surgery, the next step would be to attempt reducing or withdrawing maintenance IS very cautiously considering postoperative course, primary disease and pathological graft findings. Our patient received only high dose steroids as induction IS.

Image from Bioinfoworld

Clinical Kidney Transplantation Course

The Universiteit Leiden and Medical University Medical Center in the Netherlands recently launched an open online course in Clinical Kidney transplantation. This course is endorsed by the European Society of Organ transplantation (ESOT) and it is divided in five modules that you have to complete in 5 weeks, although turning off deadlines is optional:

1- Before the transplant.
2- The surgical procedures and the challenged patient, including the patient with diabetes
3- Early challenges
4- Late challenges after transplantation
5- Final Quiz

The modules include videos, 3D movies, interactive patient cases and a forum for discussions. You can add subtitles to the videos as well. Signing up is very easy (and free!) and you can watch the videos on your desktop or laptop or using your mobile device (I suggest to install the app Coursera for easy access)

For further details, please go to: https://www.coursera.org/learn/clinical-kidney-transplantation

Enjoy!

Donor smoking and recipient outcomes in kidney transplantation

I evaluated a young kidney donor candidate in clinic a few days ago and although he did not have any obvious medical issues and was an excellent candidate, he has been smoking half-a-pack a day of cigarettes for the last 10 years. I recommended that he needed to quit smoking, not only for his health, but also the recipient’s. For kidney transplant candidacy, recipients are strongly encouraged to stop smoking before and after transplantation. there is data that recipients with a history of smoking have a 2.1-2.3 times greater risk of poor graft survival . 

Different guidelines have different recommendations on how to manage tobacco use prior to transplantation on donors. This is what the living donation guidelines around the world state about managing smoking on donors prior to donation:

-In the Unites States, the most recent OPTN/UNOS guidelines from 2014, recommend only assessment for smoking but they don’t make any recommendations in regards to management prior to transplantation. No source of evidence is given.
-The Consensus Statement on the Live Organ Donor state that smokers can be considered if they are tobacco free for 6 months prior to donation; no smoking history is preferable.
-The 2013 ERBP (European Best Practice Guidelines) recommends to patients to stop smoking prior to transplantation (1C level of evidence)
-The 2011 British Transplantation Society guidelines state that donors should be encouraged for smoking cessation (B1-moderate quality of evidence, “we recommend”), frequent exercise and weight loss.
-The 2005 Amsterdam Forum Guidelines advices smoking cessation at least 4 weeks before donation, based on expert opinion.
-The 2010 Spanish Society guidelines, SEN-ONT recommend smoking cessation 4 weeks prior to surgery and patients are encouraged to stop smoking definitely. No level of evidence is given.

A 2007 survey of 132 U.S. kidney transplant programs found that 80% of programs have a smoking policy when evaluating living donors. 35% of programs accept current smokers as living donors, and 36% require donors to commit to quitting before surgery. 20% of programs do not have a smoking policy and only 7% routinely exclude smokers. Only 2 programs perform toxicology screens to verify smoking cessation.

Furthermore, in this paper the authors performed a retrospective study of kidney donors in a single center. They included 100 donors and 100 recipients; they found 29 donors with smoking history (16 with previous tobacco exposure but quit at the time of donation and 13 active smokers at the time of surgery) and 71 non-smoker donors. They also reported that donor’s smoking status has an effect on creatinine change at 1 and 6 months; for instance, recipients who received kidneys from donors with history of tobacco use had lower cGFR at one year, 44.1 mL/min per 1.73 m2 in comparison to recipients’ cGFR of 54.7 m mL/min per 1.73 m2 who received grafts from non smokers. In regards to graft survival, although not statistically significant, recipients with grafts from smokers had a higher rate of graft failure in comparison to the other group (6/13, 46% versus 5/30, 17%). No DGF was reported. The authors also reported the most recent followup for donors and found out that smokers had a greater change in creatinine than non-smokers (57% vs 40%) and there was not a significant difference even if smokers quit smoking prior to surgery. No donors had hypertension at the most recent follow up (approximately 144 days after surgery, for both groups)

In a most recent paper, the authors compared donor and recipient outcomes from kidney donors with active smoking history. They included 602 living donors (156 patients with active smoking) and they found out that smoking did not affect graft survival at the time of evaluation (HR = 1.19, P = 0.52) and was not associated with perioperative complications, but it had an impact on recipient’s survival at 10 years (HR = 1.93, p <0.01 vs HR = 1.74, p = 0.048). The authors acknowledge that recipient smoking was not examined in detail.

Smoking cessation is difficult for patients and generally the success rate is about 5% at any given attempt. In one of our paired kidney exchange (PKE) meetings, we were reviewing a case about a donor from another program in whom smoking cessation was not strongly advised. It’s important to know that complete smoking cessation is not a requirement for donation and recipients enrolled on a PKE program should be well informed about donor’s smoking status as well, especially if the recipient’s donor is healthy. Regardless, living donation is far superior and given the available evidence (or lack of it), transplant centers should strongly continue to advise smoking cessation to living donor candidates. Larger studies need to be done to establish a definitive link between living donor smoking and recipient graft and survival outcomes.

Hypoxia Inducible Factor and Anemia.

Several new therapies to treat anemia in patients with CKD and ESRD have recently been launched that will likely expand the treatment options. For the last few weeks I have been hearing frequently about Hypoxia Inducible Factors (HIFs) and anemia.

First of all, what are HIFs? They are transcriptional activators that function as master regulators of oxygen homeostasis and play an important role in the body’s response to hypoxia. HIF-1 was discovered in 1992 and purified in 1995. In the original research, the authors reported that HIF-1 activates EPO gene transcription in Hep3B cells that are exposed to hypoxic environments. HIF-1 is a heterodimer, consisting of alfa (HIF-1α, HIF-2α and HIF-3α) and a beta subunit which has three isoforms (Arnt1, Arnt2, Arnt3). Under well-oxygenated conditions, HIF-1α is expressed and bound to Von Hippel-Lindau (VHL) protein and is rapidly degraded via hydroxylation at proline residues (PHD2). PHD2 uses oxygen as substrate and its activity is inhibited under hypoxic conditions which causes accumulation of HIF-1α. This process increases vascularization (angiogenesis) in hypoxic states such as ischemia, tumors, immunological responses, homeostasis and anaerobic metabolism. It also has an important role in tumor proliferation as it has been found that the HIF-α levels are increased in certain types of tumors. In chronic kidney disease, the lack of EPO expression causes anemia which typically is treated with recombinant human EPO (rhEPO). This topic has been covered extensibly at the RFN here, here and here.

This month in JASN, a phase II study was published about an investigational drug for the treatment of anemia, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (GSK1278863). In this research, 73 patients with CKD not on dialysis and 83 patients on hemodialysis were enrolled to receive the experimental drug at different doses (0.5 mg, 2 mg and 5 mg) compared to a control group (placebo for patients not on dialysis and patients on hemodialysis receiving recombinant human erythropoietin -rhEPO-) The results were quite surprising: In the nondialysis group, the experimental drug increased the hemoglobin levels at week 4 (average of 1 g/dl). In the hemodialysis patients that were switched from rhEPO to the experimental drug (5 mg), an increase in maintaining a mean hemoglobin concentration was achieved only in the high-dose group, but not in the lower-dose group. These results suggest that this drug may be a good alternative to rhEPO. Theoretically, high EPO concentrations achieved during rhEPO treatment, contribute to the cardiovascular effects in patients with CKD.

Although this study was short, it brings to light the importance of finding good alternatives to treat anemia in patients with CKD and on hemodialysis. Given the reported adverse events with rhEPO treatment and the promising results of this trial, a phase III trial, a larger population study and longer duration is required to test the safety and efficacy of this drug. Keep your fingers crossed.

Figure from: The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. V H Haase. Kidney International (2006) 69, 1302–1307

Eculizumab dosing in aHUS patients undergoing kidney transplantation

Hemolytic uremic syndrome is a thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia and renal impairment. Most cases (90%) are secondary to infections, such as E. Coli (serotypes O157:H7, O103:H2). For a more comprehensive review about aHUS, check this paper. The rest of the cases are classified as atypical uremic syndrome (aHUS), which is typically associated with a poor prognosis. There is a previous post about Eculizumab and renal transplantation on the RFN.

The majority of the patients with aHUS are affected during childhood and teenage years to the point of developing kidney failure. When kidneys are severely involved the best treatment option is kidney transplantation. These patients are at high risk for recurrence of the disease after transplantation and a high percentage of these patients lose their kidney allografts. In patients with mutations in Factor H and Factor I, recurrence occurs in about 70-80% of the cases. Other less common mutations associated with recurrence, are C3 and FB. Furthermore, it has been reported that mutations in the MCP (membrane associated regulator, CD46) gene are less likely to be associated with recurrence, because the mutation affects the endothelial cells and renal transplantation would restore normal endothelial MCP function in the kidney. 

Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria and aHUS. It is also used in ABO-incompatible living donor kidney transplantation and antibody mediated rejection. This monoclonal antibody binds the complement protein C5, blocking its cleavage into C5a and C5b, hence preventing the formation of MAC. The authors of this paper concluded that eculizumab was effective in patients with aHUS and native kidneys. I found approximately 15 adult cases reported in the literature that received prophylactic eculizumab to prevent post-transplant aHUS suggesting that this approach is effective. However there are no standardized protocols for administration of the drug preoperatively. In these cases, patients received a dose of eculizumab 1,200 mg IV 24 hours prior to transplantation, and after transplantation 900 mg IV weekly for 4 weeks started on post-operative day 1, and then 1,200 mg IV bi-weekly afterwards. This is based on the manufacturer’s recommendations. There are also pediatric cases and the majority of them have had successful transplantation without recurrence of aHUS. All of these case reports, have used different pre-emptive protocols. In one case , the patient was started on eculizumab 7 months prior, receiving 600 mg as the initial dose, followed by 300 mg every two weeks thereafter. In another case, eculizumab was given 2 hours prior to kidney transplantation and in other case, it was given 6 hours prior.

The University of Iowa has developed a protocol aimed for the pediatric population. Additionally, an aHUS longitudinal study is currently underway by the Molecular Otolaryngology and Renal Research Laboratories lead by Dr. Richard Smith, that will follow up biomarkers to assess what happens to patients with aHUS over time. This data-gathering is mostly because eculizumab has changed the survival curve and it is important to know the long-term outcomes.

Unfortunately, there is no data in regards to treatment withdrawal, but it is clear that single doses of eculizumab are ineffective and discontinuing the medication is associated with risk of recurrence in the first 3 months, hence treatment should be life-long. In regards to maintenance therapy, it has been reported that although tacrolimus and cyclosporine are associated with TMA (data is conflicting), tacrolimus is the first choice due to lower rates of TMA. Additionally, plasma exchange was also reported to be effective in some patients prior to the introduction of eculizumab as reported by Zuber et al. Furthermore, liver- kidney transplantation could be a potential cure for aHUS as the authors concluded in this paper. Also, it’s important to point out that patients require meningococcal vaccination prior to eculizumab administration

Zuber et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012 Nov;8(11);543-57

Eculizumab is expensive. I checked different sources for costs; a 300-mg vial costs around $7,500; consider the fact that this drug needs to be given life-long on a bi-weekly or monthly basis. Some sources consider it the most expensive drug in the world. Finally, eculizumab has protected rights until 2017 and until then, biosimilars would have the potential to reduce treatment costs. In conclusion, given the rarity of this disease it would be difficult to have a large randomized control trial, but given the available evidence, it appears to be effective in preventing the recurrence of the disease after transplantation.
(A warm thank you to Dr. Smith, Dr. Haririan and Dr. Thomas for their support and guidance)

Precision Nephrology

One of our attendings, Dr. Sylvia Betcher, PhD, MD gave an excellent presentation at our renal conference about genetic testing in renal diseases that she learned about at #KidneyWeek2015. There were so many good things I liked about her talk, that I want to share what I learned. On January 30th 2015, President Obama announced in his State of the Union address a Precision Medicine initiative. This will provide researchers in the biomedical field with the necessary tools to define preventive measures and treatment of disease by examining variability in genes, environment, and lifestyle of each patient. Precision Medicine relies on specific molecular and genetic information to classify a certain disease into subsets that allow consideration of focused therapies, which is currently being accomplished through GWAS (Check the #NephMadness genetic nephrology region bracket on GWAS here), whole gene sequence analysis via next generation sequencing (NGS) and VAAST (Variant Annotation, Analysis and Search Tool) which is used to identify damaged genes and their disease-causing variants in genome sequences. The president’s 2016 budget will provide $215 million to the various agencies including the NIH and FDA to accomplish his goals. The objectives of such initiative can be found here.

Most of the budget will go to cancer research and there is no mention of rare diseases or any particular hereditary or genetic disease. In the Nephrology world, are there any diseases in particular that need to be addressed? Yes, for instance Steroid Resistance Nephrotic Syndrome (SRNS), among many others. In this paper, a single-gene cause of SRNS was detected in 526 out of 1,783 families (29.5%), by examining 21 genes. The authors mentioned that screening of these genes is cost-effective and may avoid the undesirable side effects of steroids when a mutation is detected and potentially offer targeted therapy (for example with Coenzyme Q10 in cases of COQ2 nephropathy)

According to the NCBI Genetic Testing Registry as of August 2014, there were approximately 4,500 conditions for which genetic testing is available, many of which will have renal manifestations. Advantages to testing include providing specific therapies, allowing family counseling and to evaluate kidney donors in family members. Diseases that are being considered in Nephrology for genetic testing include: rare autosomal dominant interstitial nephropathies (UMOD, MUC1, REN), Syndromic and Polycystic Kidney Disease, Alport Syndrome and Congenital Anomalities of the Kidney and Urinary Tract (CAKUT). Additionally, I want to emphasize the fact that Genomics England (a company owned by the UK Department of Health) and Illumina (an American biotechnology company based in San Diego, California) have launched a $524M project to create a large genome database. Their plan is to sequence 100,000 whole genomes by 2017 focusing on rare diseases, cancer and infectious diseases. A nephrology consortium has been set up to provide renal patients for this ambitious project.

Let’s say we have screened our patients for congenital kidney diseases. Now what? We have to consider whether the results will influence any change in management, or perhaps we need to screen for extra-renal manifestations. I think that providing family counseling will definitively be helpful. It will also influence the decision on safety of kidney donation. Urine could be an excellent source of genetic information through DNA fragmentation which is a normal process in apoptotic cells to eliminate mutated, damaged or infected cells and is usually highly fragmented whereas in cancer cells the DNA maintains its integrity. So in conclusion, these are exciting times in Nephrology with precise genetic testing now a diagnostic option. Do you see yourself practicing Precision Nephrology in 10-20 years? Let us know what you think!

Is there a benefit in pre-transplant weight loss? #NephMadness

To complement the NephMadness Nutrition in Nephrology obesity match-ups, we thought a post on pre-transplant weight loss was timely. According to a recent report published in JAMA, more than one third of the US population are obese (BMI>30) with an estimated medical annual cost of $147million in 2008. Obesity causes heart disease, stroke, type 2 diabetes mellitus and certain types of cancer. According to a recent policy statement of ASCO, obesity is predicted to overtake tobacco as the leading modifiable cause of cancer in the United States in the near future.
In the Nephrology world, we are all aware of the survival advantage of obesity in dialysis patients with the so-called “reverse epidemiology” or “obesity paradox” (While obesity, hypertension and hyperlipidemia are indicators of high cardiovascular risk in the general population, in dialysis patients these conditions are associated with a survival advantage). This was demonstrated in several well-conducted studies (ref, ref, ref) in the United States and Europe.

But is there any survival advantage for obese patients while they are waiting for a kidney transplant? Obesity is not an absolute contraindication for transplant listing although some transplant centers do not evaluate patients with BMI >30-35 kg/m2. At our center, we recommend patients should aim for a BMI < 35kg/m2; however we have performed kidney transplants in patients with higher BMIs. Approximately 60% of kidney transplant recipients are overweight, which represents a 116% increase from 1987. But is BMI an accurate reflection of obesity in adults? The answer is no. The accuracy is limited and although a BMI cutoff of >30 kg/m2 has good specificity, it misses more than half of people with excess fat. Newer techniques to evaluate obesity include abdominal circumference, waist to hip ratio, hydrostatic weighing and body fat measuring.

There are concerns about allograft survival, weight gain after kidney transplantation and wound healing. Two retrospective analyses in obese patients undergoing kidney transplantation reported higher rates of delayed graft function, acute rejection, peri-operative complications and worse renal function with higher BMIs.
On the other hand, there is evidence that higher BMIs do not influence outcomes. A study of >164,000 patients demonstrated that low pre-transplant BMI, low pre-transplant serum creatinine (which could be due to sarcopenia), were associated with worse post-transplant outcomes. Bariatric surgery is becoming more popular prior to kidney transplantation and according to this study of USRDS data that evaluated the safety of the procedure, bariatric surgery provides substantial weight loss to kidney recipients. However, it also reported more peri-operative complications and increased mortality in comparison to patients undergoing the same procedure without kidney disease. Significant pre-transplant weight loss (>10kgs) may be a risk factor for peri-operative complications, particularly wound problems. Another study reported that weight loss during transplant listing had no effect on long term outcomes after transplantation and rapid weight loss was associated with subsequent post-transplant rapid weight gain. According to this analysis, the rate of mortality before and after transplantation is unchanged despite weight loss.

In conclusion, there is no evidence that weight loss before transplantation improves long-term outcomes following transplantation although much of the evidence is retrospective and observational in nature. The absence of significant central obesity certainly helps with wound healing and it is intuitive that a ‘healthy weight’ augers well for long term morbidity. How we measure this ‘healthy weight’ however is debatable including where BMI fits into this assessment, if at all.

Hector M. Madariaga,
SUNY Upstate Medical University