Alemtuzumab for Induction- the 2011 update

A recent NEJM May 2011 article has one article that compares use of Alemtuzumab and early steroid removal to Basiliximab and Thymo.  Its a nicely done randomized controlled trial that is multi centered.
On face value:- appears that rate of biopsy confirmed acute rejection was lower in the alemtuzumab group in the low risk patients when compared to basiliximab and similar to thymo when compared in high risk groups.

Few points from the trial:
1. All were steroid sparing making things not standard around all programs
2. The infection events were statistically more higher in the Alemtuzumab group especially in the low risk population
3. WBC count was also <3000 in the treatment arm
4. Cancer, renal injury other complications were similar
5. Rate of late rejection (after 12 months) was higher in both low and high risk groups compared to standard treatment
6. If steroids were withdrawn, and infections were more in the alemtuzumab group, wonder what the rate of infection would have been with steroids!

Till further studies, looking ahead. Awaiting to see what the transplant community thinks

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21591943
http://www.ncbi.nlm.nih.gov/pubmed/21591949

Dichotomous Effects of Rapamycin

A recent review in AJT 2011 April issue reviews this concept nicely.

Rapamycin has many faces and many different effects on different cells. Lets summarize
1. Suppression of CD4 T+ differentiation
2. Increased T reg development
3. Decreased response to skin graft
4. Decreased dendritic cell maturation
5. Increased CD8 + T cell  memory differentiation
6. Increased CD8 T cell activation
7. Increased response to pathogen
8. Increased IL-12 production

Commonly noted side effects:- hyperlipidemia, thrombocytopenia, decreased wound healing
Ref and information obtained from:
http://www.ncbi.nlm.nih.gov/pubmed/21446969

Arteries and Kidney Transplant

http://consumer.healthday.com/Article.asp?AID=651907
Check out the news release from JASN

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

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

Kidney transplant and donation cancer risks

What are the risks of getting cancer from the donor?
Check out this report from UK regarding a recent case.

http://www.guardian.co.uk/society/2011/mar/22/kidney-transplants-donated-organs-cancer-risks

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

Elimination of anti rejection medicaitons

ASN news recently reported a study that is ongoing using specially processed stem cells from the same kidney donor being transplanted along with the kidney to that recipient, allowing that to continue in chimerism leading to an early presumed tolerance and hence no anti rejection medications for long term.
This concept is not new and has been attempted in the recent past. In 2008, NEJM paper by David Sachs et al showed that 5 patients could come off all immunosuppresion after a combined stem cell and kidney transplantation. This theory is used in myeloma treatment as well when patients get an allogenic and kidney transplant at the same time allowing to help both the organs of treatment.
A similar concept was presented recently in CJASN Feb 2011 issue about using autologous  mesanchymal stromal cells during kidney transplants. They showed that in two patients, this allowed engraftment of T regs in the peripheral blood and control memory CD8 T cells function.  In vitro studies have shown that mesenchymal stromal cells abrogate allo immune response  and could function as anti T cell agents in a "different" manner.


here is some older data on this topic:
http://www.ncbi.nlm.nih.gov/pubmed/18216355
http://www.ncbi.nlm.nih.gov/pubmed/20605588
http://www.ncbi.nlm.nih.gov/pubmed/20930086

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

Skin cancer and Transplants

Talking to your patients and just educating them regarding regular skin cancer screening might be just enough to raise awareness and prevent skin cancer. Regular yearly dermatology visits for skin check ups are essential for prevention. Check out this latest healhday article.

http://consumer.healthday.com/Article.asp?AID=650075

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

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

At the ASN 2010, there was an abstract regarding the role of fibrosis and inflammation at one year to predict transplant survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation.

A group of patients with their biopsies were studied. Over-expression of toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon production and cytotoxic T lymphocyte-associated and acute rejection-associated genes were noted more in the ones with increased fibrosis. Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes.

The abstract can be found at Nephrology Now as well

http://www.nephrologynow.com/publications/fibrosis-with-inflammation-at-one-year-predicts-transplant-functional-decline

Quiz 9 Answers

Which of these statements is TRUE regarding living donor related transplantation in Fabry's Disease?

Renal Transplantation from a heterozygote female relative into a patient with Fabry is risky as globotriaosylceramide accumulation might be present in this donor, without clinical symptoms ( is a true statement)

The measurement of Alpha galactosidase A activity in a potential female living related donor for a patient with Fabry's is not sufficient as a normal value cannot exclude a random X chromosome inactivation( is a true statement as well)
Living related transplantation is possible in donors who do not have the mutation.( this is true)

One has to be careful with male donors as late onset Fabry's disease exists in males and they 

develop proteinuria and renal failure after age of 25 years.( this is true)

Demonstration that the recipient's gene mutation is absent in the potential female relative donor is required before living related transplantation is performed in a patient with Fabry's ( also true)

Hence the answer is all of the above

Check out the Nature Review Nephrology Dec 2010 edition for Kidney Transplantation evals in Hereditary Nephropathies

http://www.ncbi.nlm.nih.gov/pubmed/20877305

http://www.ncbi.nlm.nih.gov/pubmed/3120588

Can Alcohol Consumption be protective post transplant?

One study presented at the recent ASN 2010 at Denver found that alcohol consumption in moderation was indicative of lesser incidence of post transplant diabetes (NODAT). The investigators argue that the belief of interactions with medications might be false and without evidence. Not only did they show that it was a decreased NODAT risk but also decreased risk of death post transplant.  So kind of similar to the general population.  

Check out Renal and Urology news's website for a video on the presenter at ASN 2010

http://www.renalandurologynews.com/moderate-alcohol-use-benefits-renal-transplant-patients/article/191147/

Chronic renal allograft dysfunction

This month's Kidney International has a special extra edition on Chronic renal allograft dysfunction.
This supplement has >10 articles that highlights latest development in transplantation on pathogenetic mechanisms of T and B cells in Chronic rejection, IF/TA and then few chapters on fibrosis and genomic studies.
Risk factors, infections and immune monitoring are also discussed.

Few of them are linked below:
http://www.ncbi.nlm.nih.gov/pubmed
http://www.ncbi.nlm.nih.gov/pubmed/21116312
http://www.ncbi.nlm.nih.gov/pubmed/21116316

CMV in solid Organ transplantation!

CMV infections are fairly common in solid organ transplantations.  A nice review in Nature Review Nephrology this month highlights prophylaxis treatment, active treatment and serology testing. What I found very useful wa a table on dosage recommendations for ganciclovir and valganciclovir in varied renal function states. 

A nice section on anti viral resistance also reveals some important data on use of foscarnet and when there is UL97 mutations.  These strains usually have ganciclovir resistance.  The UL54 strain mutation can have resistance to even foscarnet and cidofivir.  The advent of commercially available genotyping allows for rapid results of UL97 or 54 and allow for personalized treatment of CMV viremia or disease.  

Resistant CMV guidelines

1. Increase dose of ganciclovir 

2. Change to foscarnet with or without continued ganciclovir

3. Change to Cidofovir only if pol mutations are not present otherwise it cross reacts with ganciclovir resistance.

4. leflunomide has been tried in few cases.

5. CMV immunoglobulin (IVIG) as a last resort and if there is organ damage happening.

Check it out

http://www.ncbi.nlm.nih.gov/pubmed/20978468

Sirolimus- the Positive aspects

The same issue of KI shares another view- the positive aspects of sirolimus
As we mentioned earlier that this agent was discovered as a cancer drug and has antiproliferative properties

Recent animal data and human data have shown it to be beneficial in preventing cancer post transplant
So the benefits of this agents are:

1. Prevention of cancer, as mTOR is responsible for transcription and translation for cell growth.  Definite evidence against Kaposi, Skin cancers and renal cancers.
2. Increase in T regs
3. Anti viral effects - CMV, BK and EBV viral infections ( still not sure- conflicting data)
4. Tolerance inducing potential
5. Control of fibrotic process - conflicting data when compared to CNI alone

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20981120

Sirolimus - The negative aspects

A recent article in Kidney International discusses the negative and positive aspects of this interesting drug- sirolimus, mTOr inhibitor.  Initially designed to fight renal cancer, fast caught on to treat rejection and be used as an immunosuppression.
1. Six trials so far have randomized sirolimus vs a calcineurin inhibitor that were mentioned in this article. They all had more acute rejection episodes with sirolimus. So graft survival is a concern.
2. Renal toxicity has been described- from TMA to collapsing FSGS and severe proteinuria making it not as promising as CNI. But CNI have a more chronic toxicity to the kidney
3. Dyslipidemia has been noted as well more with this agent. - close to 60% of the patients getting mTor in clinical trials required lipid lowering agents
4. NODAT was also noted to be higher in this group; 25% more chance than CNI
5. Wound healing:- preventing the surgical wound healing or in future if patients need other surgeries makes it tough.
6. Other- mouth ulcers, myelosuppresion and infertility were more common in this agent as well.
7. Finally, they mention the new findings lately described pulmonary toxicities that are leading to a restrictive disease in the lung.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20703217

FGF-23 and PTH and Bone Disease post transplant

Patients with ESRD have bone disease of various types. The three that are commonly seen are adynamic bone disease, increased bone turnover related or a combination of both.
BMD loss is common complication following kidney transplantation.
Few points to take home from a recent paper published in CJASN 2010, October edition.

1. The bone loss is accelerated in the post transplant period- why? Steroids and perhaps CNI worsen the rate.
2. Other risk factors are pre existing renal disease, hypogonadism, and metabolic acidosis.
3. 90% of post transplant patients have hypophosphatemia( CNI related and or tertiary hyperparathyroidism)
4. Renal phosphate wasting has bad effects  on bone
5. The renal phosphate wasting in part might be caused by elevated FGF23 levels or phosphatonin hormone.
6. PTH levels don't return completely to normal in most transplant patients post transplant
7. FGF 23 levels usually return to normal after one year post transplant
8. A recent study found that a high FGF23 level and low pth at time of transplant are the highest risk of developing bone disease post transplant
9. The most common bone biopsy finding post transplant is adynamic bone disease.

Image source: clipartheaven.com
References:
http://www.ncbi.nlm.nih.gov/pubmed/20634326
http://www.ncbi.nlm.nih.gov/pubmed/17359508
http://www.ncbi.nlm.nih.gov/pubmed/16941023

Aspergilloma in the transplant kidney

A recent issue of AJKD talks about a case of aspergilloma in the transplanted kidney. The fact that it affected the kidney is the novelty of the case and the also they used a novel way of treating this patient. Please see the link below.


http://www.ajkd.org/article/S0272-6386(10)01257-6/fulltext