IMMUNOSUPPRESSION IN THE ELDERLY: WHATS THE BEST INDUCTION AGENT???

The incidence of elderly patients with ESRD is increasing, as is the number of elderly listed for kidney transplantation. In fact, we are transplanting more and more elderly patients over the age of 70. Studies suggest that the elderly have excellent graft survival, possibly due to a less robust immune response, but unfortunately still have a higher mortality than younger patients. This dichotomy led me to wonder what the best immunosuppression is for the elderly. Logic would suggest they need less intense induction immunosuppression to avoid infectious complications. At the same time however, perhaps more intense induction can reduce the incidence of rejection and allow reduced maintenance immunosuppression (such as steroid free or low CNI) improving both infectious and cardiac outcomes. Reviewing the literature led me to 3 interesting papers on induction immunosuppression and outcome in the elderly.

Two studies were registry analysis^1,2 and one was a single center study³. The registry analysis compared 3 agents: IL-2 inhibitors (anti-CD25), antilymphocyte globulin (thymoglobulin), and alemtuzumab. They suggested worse outcome with alemtuzumab compared to thymoglobulin or anti-CD25. Although outcomes with thymoglobulin and anti-CD25 were similar, thymoglobulin had a lower incidence of rejection and surprisingly revealed a trend to better patient survival! This was especially prevalent in high risk recipients whom also enjoyed better graft survival. It is possible that this effect is due to less maintenance immunosuppression and less requirement for high doses of immunosuppression to treat rejection. The single center study evaluated different cumulative doses of Thymoglobulin and outcome within different age groups. What they found was elderly (age > 60) patients had a reduced survival if they received > 6mg/kg of Thymoglobulin.

Looks like low dose thymo induction wins again!

References:

1. Clin J Am Soc Nephrol 2011;6: 1168-1178 PMID:21511836

2. Am J Nephrol 2011; 34:534-541 PMID:22104284

3. Clin Transplant 2011;25:E250-E256 PMID:21231963

Advagraf Study

There has been talk about using prograf once a day for quite sometime now.  When it is used once a day its a tacrolimus prolonged use and its called Advagraf.  A recent  multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy of twice a day tacrolimus to advagraf.; combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. 
Per paper:


Biopsy-proven acute rejection rate at 24 weeks  was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment ).
Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. 
Both treatment groups showed equally well-maintained renal function at 12 months  by GFR
Overall, it was not inferior to twice a day dosing.


The original Ref is at:
http://www.ncbi.nlm.nih.gov/pubmed/20840480

Donor Risk Scores?

A recent review in Nature Nephrology discuses this important concept.  A large study out of Finland is discussed in this review and how the donor risk score was developed. What they describe is a donor allograft damage index which involves clinical components as well pathology components.
What constitutes the clinical components are: age >50, smoking, unstable blood pressure, HTN, need for CPR, alcohol abuse, untreated HTN, ischemic heart disease, arteriosclerosis, oliguria and the biopsy component is vascular intimal sclerosis, tubular atrophy, interstitial fibrosis, interstitial inflammation, mesangial matrix increase and glomerulosclerosis.  The Biopsies of the donors were graded with a 0-3 point system with each of the six histological criteria and the higher the points- the worse the kidney was.  The authors showed that the presence of >5 risk factors(clinical) and associated with an increase in mean allograft damage score from 0.5 to 1.4 and an increase in percent glomerulosclerosis from 1.5% to 8.1%.  And eventually higher donor risk scores were associated with long term graft outcomes over 5 years as well.
One of the few large studies to look at histological allograft data and comparing that to the clinical data.  Interesting to see what comes next.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21303414
http://www.ncbi.nlm.nih.gov/pubmed/21522192

Transplant Tourism and Malignancy

Transplant Tourism does still continue and many patients continue to get kidneys from other countries where it could be commercial possible.  A recent study showed that when groups were compared( tourism kidneys to home country based kidneys):- the graft and patient survivals were equal but the 10 year cumulative cancer risk was significantly higher in the transplant tourism kidneys; especially in the older age group.  What might be contributing to this? - immunosuppresive therapy, difficulty in follow ups and were some of the thoughts mentioned in this article. Check it out

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21270768

IVIG - how does it work from the Immunology blog?

http://allergynotes.blogspot.com/2011/04/intravenous-immune-globulin-ivig-in.html

Neutropenia from Tacrolimus

Post transplant neutropenia has many causes.  Etiology is usually medications, infections, cancer.
In a retrospective evaluation, 28% neutropenia was noted after first year of transplantation.  Most of this was sought to be from MMF-tacrolimus combination.
The drugs we usually consider are: MMF, azathioprine, acyclovir, gancyclovir, bactrim, valcyte.
A recent review on CJASN 2011, presents three patients with pure tacrolimus induced neutropenia and the mechanism behind it. All improved after they were switched to cyclosporine.

Why does it happen?
1. Direct inhibition of myeloid cells
2. effect of the drug on mononuclear accessory cells
3. pharmacokinetic interaction between MMF and tacrolimus
4. autoantibodies against myeloid precursors or mature neutrophils

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21258040
http://www.ncbi.nlm.nih.gov/pubmed/19538494

Hematuria Post Kidney Transplantation

An entity often not talked about and not much out there in the literature. a nice review below by Dr.Krish.

Hematuria post transplant

View more presentations from Nephrology, NSLIJ

Bortezomib for desensitization!

Donor specific alloantibody producing plasma cells might be a good target for proteosomic inhibition by bortezomib. Bortezomib has some data in case series and reports of treating antibody mediated rejection. A recent study published in Transplantation 2011 discussed case series of 4 patients with extremely high DSA and couldn't just get apheresis alone.  They received 4 doses of bortezomib alone in one group and other 4 received 16 doses and  plasma exchange.  The response of these 8 patients was compared to 8 patients with plasma exchange alone.  Bortezomib alone didn't do much but bortezomib + plasma exchange did better than just plasma exchange alone in terms of DSA decrease.  This might lead to more protocols that might develop using this agent for treatment of desensitization.
This study is small and not well designed. IVIG has been used in many centers and Anti CD20 agents as well. Is it bortezomib alone that is doing the magic or is it that we just need two agents along with plasma exchange.  So plasma exchange + IVIG pr plasma exchange + rituximab or plasma exchange + bortezomib.

Have a look

http://www.ncbi.nlm.nih.gov/pubmed/21283064

http://www.ncbi.nlm.nih.gov/pubmed/20121729

Risk factors for post transplant Hypertension

Here are a list of factors that contribute to post kidney transplant development of Hypertension.
1. Pre existing HTN
2. Body Mass Index
3. Native Kidney disease
4. Donor age
5. Donor sex
6. Donor Hypertension
7. Longer Cold Ischemia time
8. Delayed graft function
9. Steroids
10. CNI( cyclosporine>tacrolimus)
11. Acute rejection
12. Anti body mediated rejection
13. Chronic Allograft Nephropathy
14. TMA
15. Recurrent glomerular disease
16. Transplant renal artery stenosis
17. Lymphocele leading to obstruction
18. Ureteric stenosis

Take a look at the more comprehensive article in AJKD
http://www.ncbi.nlm.nih.gov/pubmed/21251543

Male Fertility and Transplantation

Male fertility has not been studied in detail in transplantation.  Does immunosuppresive therapy have impact on sperm production or motility?
Most reports suggest that male transplant recipients have successfully fathered healthy kids.
The one drug that might have led to problems is sirolimus: On observational study showed that sperm count was decreased in the sirolimus arm of the study and that could affect pregnancy outcomes.  No data exists on other agents at this point.

Ref
http://www.ncbi.nlm.nih.gov/pubmed/18510638
http://www.ncbi.nlm.nih.gov/pubmed/17714220
http://www.ncbi.nlm.nih.gov/pubmed/19601935

The Kidney Transplant in HIV patients- the NEJM study

Kidney Transplantation was rare in HIV+ cases few years ago and now many centers have developed protocols that have allowed this to happen with relatively good outcomes.
No prospective studies were ever done in this matter for rejection rates, outcome measures and so forth,
This month in NEJM 2010, a nice multi center study takes a look at this particular question. The investigators evaluated 150 patients for close to 2 years, multicenter fashion, non randomized prospective fashion.
The mean graft survival was 90% at one year and 3 years was 73.7%.  The ones that didn't do well were the ones with rejection episodes, use of thymoglobulin, and non living donors.  The rejection rate was higher than expected, close to 31% at 1 year and 41% in 3 years.

This study shows that graft survival is good but the rejection rates are high still and needs some work. Perhaps the drug interaction with HAART therapy play a role in the fluctuation of perhaps CNI levels and higher rejection risk or the immunosuppresive agents we have now are not the ideal ones for an immunodeficiency diseases model?


ref:
http://www.nejm.org/doi/full/10.1056/NEJMoa1001197
http://www.ncbi.nlm.nih.gov/pubmed/19776780

Wait list and desensitization?

Two landmark papers have discussed using potential agents for potential patients who are on wait list for a kidney but have a very high PRA or now one might use a cPRA. 

The first paper is from 2004 titled was using IVIG.  A rare treat to find a randomized double blind placebo controlled trial in transplant literature, this is one of them. 101 patients ESRD with PRA>50% randomized to getting placebo vs 2g/kg monthly for 4 months of IVIG. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Both groups had equal 2 year graft survival.  

The second was  in 2009, the use of rituximab and IVIG  for desensitization during renal transplantation. A total of 20 highly sensitized patients with known DSA + this time were enrolled and received treatment with intravenous immune globulin and rituximab. The authors noted the rates of transplantation, panel-reactive antibody levels, cross-matching results at the time of transplantation, survival of patients and grafts, acute rejection episodes, The PRA decreased post treatment, significantly. Time to transplant also decreased to 5-6months.  Sixteen of the 20 patients (80%) received a transplant. At 12 months, the mean survival rates of patients and grafts were 100% and 94%, respectively. 

So the only data we have on what to use in highly sensitized DSA+ patients on the WAITING list is IVIG and rituximab perhaps? ( smaller study).

References:

http://www.ncbi.nlm.nih.gov/pubmed/15579530

http://www.ncbi.nlm.nih.gov/pubmed/18635429 

Role Playing exercise in Transplant Education

We did another session of role playing with the fellows and transplant medicine
Each fellow was assigned a "cell" that is an active playing in Immunology. Then they were asked to describe themselves in Homeostasis and then a state of Immunosuppression. A nice discussion and arguments ensued and a live display of the immune reaction was done.  The teaching of basic immunology for transplantation was mediated via this teaching method.
The cells the fellows' role played were: NK cell, macrophage, CD4+ T cell, CD8+T cell, DC, B effector cell, T Reg cell, B reg Cell.

Transplant Glomerulopathy

Transplant Glomerulopathy(TG) is a common biopsy finding that we see in kidney biopsies for proteinuria workup.The causes of TG are usually of similar to what causes secondary MPGN. Most of the time it turns out to be chronic antibody mediated rejection process. Pathologically, it is  defined by glomerular basement membrane duplication with peritubular capillary basement membrane multilayering (PTCML), and associated with anti-human leukocyte antigen antibodies and C4d. 
A recent study in Transplantation 2010 issue talks about possible predictors of long term outcomes of pure TG cases. 36 cases were noted. Only 33% were c4D positive. but the  C4d-positive cases also showed a trend toward rapid graft loss. Interstitial fibrosis, PTCML, and arteriolar hyalinosis were significant predictors of graft survival in TG. C4d positivity was associated with a more rapid rate of function decline. eGFR slope data showed significant deterioration in graft function well before the diagnostic biopsy.


References:
http://www.ncbi.nlm.nih.gov/pubmed/20838279
http://www.ncbi.nlm.nih.gov/pubmed/19594595

Paired Chain Donation

A nice letter to the editor in NEJM this week Sept 2010 reflects on the Kidney Paired Donation program from San Antonio, Texas. KPD, which matches a living donor with a compatible recipient in a tag-team approach among potential donor–recipient pairs, can achieve compatible transplant combinations.
Based on this letter, if performed at a national level, it would potentially result in approximately 2000 additional live-donor transplantations annually and reduce the number of patients on the waiting list.
This is a growing trend and many transplant centers are reaching out to do this in many different ways. Some via a paired donation and some via a chain that is started by an altruistic donor.

Have a look at the NEJM editorial
http://www.nejm.org/doi/full/10.1056/NEJMc1004959
http://www.ncbi.nlm.nih.gov/pubmed/20061914

Interferon Gamma use in fungal infections in transplant patients

A recent article in AJT reports the use of Interferon Gamma as a salvage and additional therapy for disseminated fungal infections in kidney transplant recipients.
We always get concerned with giving interferons to transplant recipients as it will increase and promote an immune response and pose a risk of rejection.

In the above cases, not only did the patients survived but the graft was not effect in 4/7 cases as well with no consequences of rejection. Why interferon gamma? It is the most important cytokine in communication of T cells to fight fungal and mycobacterial infections.

The idea is novel yet scary. More data and more cases are needed till we think of possibly using this in large clinical settings. Clearly, the concern of activating more crosstalk among T helper cells by using Interferon Gamma is helpful in fighting infection but might have to be the right balance to prevent rejection.

Reference:
http://www.ncbi.nlm.nih.gov/pubmed/20353472
http://www.ncbi.nlm.nih.gov/pubmed/20636453

Post Transplant Lymphoproliferative Disorder (PTLD)

View more presentations from Nephrology, NSLIJ.

B cell and long term graft function

A lot of transplant patients do so well and require very minimal amounts of medications. What is the magic recipe for that? Perhaps it is T regs cells and amount of T regs vs T effector cells. Perhaps it is a subset of B cells.
A recent paper in Kidney International addresses this topic.
The investigators compared B cells of people with stable graft function and ones with chronic rejection and healthy volunteers.  They found that the ones who had stable graft function with minimal drugs had increased B cells of activated, memory and early memory type. They had a enriched transcriptional profiling.  The costimulatory molecules like CD40 and CD80 ligand were upregulated in these B cells.  These cells were also giving out an inhibitory signal for proliferation and a preventive signal for Hyperactive B cell response.  They expressed CD1D and CD5 ( another recent paper had suggested this as well).
This suggests that there a specific type of B cells out there that patients with good graft function and minimal drugs have that might be regulatory in nature and allow long term graft functioning.

More studies should be done to look out for these type of cells
http://www.ncbi.nlm.nih.gov/pubmed/20531452
Also, perhaps using anti co stiumatory blockades might not be all that ideal then? Perhaps. not much data to say yes or no!

Transplantatation of two kidneys in marginal donors

http://nephrohug.com/2010/08/16/greffe-des-deux-reins/

Check out the above French Blog on this topic from Nephrohug.

Low Donor Kidney Weight ? Does it matter?

We have asked this question many times in conferences and especially when a pediatric kidney gets put in an adult recipient? Does it matter if the donor kidney weight is not compatible to the recipient's weight?
There is one study in 2005 that showed that low donor kidney weight to recipient weight ratio did not affect graft survival.  That study only had 2.5 year follow up.
A recent study in JASN looked at >1000 patients for over 10 years and max of 7 year follow up. They found that with a low donor kidney to recipient kidney ratio of <2.3g/kg, initially the GFR increased, plateaued at 6 months but then decreased rapidly after 7 years at a mean rate of 3 ml/min.
With patients with >2.3g/kg, the the GFR after 7 years decreased at a much slower rate- 1.34ml/min.
The proteinuria was also higher in the low ratio group.FSGS was more common in the biopsies of the low ratio group.This is a retrospective analysis with its usual flaws but raises an important point of avoiding kidney and recipient weight incompatibility to avoid late clinical outcomes.

References:
http://www.ncbi.nlm.nih.gov/pubmed/20488949
http://www.ncbi.nlm.nih.gov/pubmed/15563571