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

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

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

CMV and EBV PCR for 2 years

Check out this interesting post from Dr.Sethi

https://www.pediatric-nephrology.com/home/2010/09/23/300-jasnviremia.html

Infections post transplant

We had a good discussion about infections post transplant yesterday ranging from rare cases of Parvovirus B19 to common bacterial infections
A timeline is important to keep in mind.

<1Month into transplant
Think of the common post surgical fever causes
MRSA, Pneumonias
Wound infection
C.diff
Aspiration
BKV can be seen as early as 2 weeks( depending on net immunosuppression state of the patient)
1-6 months into transplant
BK Nephritis
Adenovirus
CMV, PCP
HCV
MAC
>6 months
Back to normal population infections
But also
Nocardia
Atypical fungi
West nile
JC virus( PML)
CMV can happen here as well
So can BKV

A nice review is listed below from NEJM
http://www.ncbi.nlm.nih.gov/pubmed/18094380

Cidofivir for BK Nephritis

 As we all know that treatment for BK Nephritis is tough. The only thing that really works well is Decreasing immunosuppresion. But as we do that, the risk of mounting an immune response arises and you can start seeing biopsies that look like Acute Cellular Rejection and BK staining Positive.
At that time, most people will treat with IV Immunoglobulins and see if there is some response in terms of preventing rejection and treating BK at the same time.
So far, no drug has directly targeted BK except Cidofivir. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. The dose usually recommended is 0.25mg/kg IV every 2 weeks for 8 doses total. This is a low dose and can be used for someone in already some graft dysfunction as cidofivir itself can causing ATN like injury( same as tenofivir). This low-dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.


http://www.ncbi.nlm.nih.gov/pubmed/18380832
http://www.ncbi.nlm.nih.gov/pubmed/16499584

CMV infection in Kidney Transplantation

Here is a brief presentation by Arun Chawla, MD on CMV in Kidney Transplantation.

CMV in Organ Transplantation

View more presentations from Nephrology, NSLIJ.

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

BKV viral protein-1 mRNA in urinary cells

A noninvasive, accurate biomarker for diagnosis of BKVN is being sought. Recent article in Transplantation reports using the urinary cell mRNA profile at the time of BK Nephropathy diagnosis and compared to risk of graft function.

BK Nephropathy was diagnosed with a sensitivity of 100% and specificity of 97% using the urinary mRNA. Levels of granzyme B (GB) mRNA and proteinase inhibitor (PI)-9 mRNA in urinary cells were higher in BKV patients with a subsequent decline in renal function compared with patients with stable function, and were positively associated with rise in serum creatinine from the time of BK diagnosis to 12 months after diagnosis. 

This confirms the fact that urinary granzyme B and PI-9 could be used as markers of inflammation during any renal episode post transplant. Similar findings were seen in rejection as well. It seems that no matter what causes the inflammation, BK or rejection, a rise in urinary GB and PI-9 suggests a poor prognosis.  

Reference:

http://www.ncbi.nlm.nih.gov/pubmed/20526237

http://www.ncbi.nlm.nih.gov/pubmed/16319383

Leflunomide and liver failure

The FDA just expanded the black box warning on leflunomide( ARAVA), a drug that is sometimes used to treat BK Nephritis in Transplant patients. A recent report showed 49 cases of severe liver toxicity from 2002-2009. Usually the reactions were noted in the first 12 months post use of the drug.  The greatest risk occurred in patients taking other drugs that may cause liver damage while taking leflunomide and in patients with preexisting liver disease. 

This comes as a shock to some of us in the transplant community as we do use this medication for treatment of BK Nephritis. There is so little in the form of treatment available for BK, this black box warning might make leflunomide not a very user friendly drug anymore. 

Risk of PTLD post transplant?

Why and when is someone with a kidney transplant prone to get PTLD?
PTLD is a lymphoproliferative disorder that occurs because of impaired T-cell immunity after solid-organ or allogeneic stem cell transplant. 90% of the time these are EBV associated.


What are the risk factors for development of PTLD?
1. EBV-negative serostatus at time of transplant
2. Mismatching EBV-negative recipients with EBV positive donors
3. Intestinal Transplants have the highest incidence, then heart-lung, lung, heart, liver and then kidney
4. Children
5. Simultaneous CMV infection within 1 year of transplant
6. Certain HLA subtypes.

http://www.ncbi.nlm.nih.gov/pubmed/12621474
http://www.ncbi.nlm.nih.gov/pubmed/14986084

CMV in organ transplantation

CMV is a hard infection to treat in solid organ transplants. A nice consensus statement came out recently in Transplantation April 2010 issue going over medications. ( similar post on nephronpower for question discussion)
Based on these recs, 
1.IV ganciclovir is " gold standard" for CMV disease
2. The VICTOR trial compared valcyte to ganciclovir and was equally effective ( 900mg PO BID)
3. Do genotype resistance testing for CMV and if it is UL97 major mutation, likely will have ganciclovir resistance. If its a minor mutation or a pol mutation can still use ganciclovir but high doses. A major mutation requires switching to foscarnet.
4. If foscarnet is causing renal damage and or not working, other drugs have been tried.
5. Cidofovir has been tried in adenovirus, bk virus and CMV as well. There is little information on efficacy of cidofivir in single organ transplants but its use in stem cell transplants is also with mixed results.
6. Immunoglobulins containing CMV antibodies or cytogam has been used with good results in Stem cell transplants.  IVIG might have similar effects but no cases that I could find have been documented use of it. This should more likely be reserved for organ damage from CMV( retinitis, pulmonary damage, GI)
7. Leflunomide was reported to clear CMV in one case of Stem cell and one of a renal transplant patient.
8. Other drugs that have shown some anti CMV properties are sirolimus, artesunate and maribavir( experimental)


So the question we have up here, really there is no right answer as all of those drugs have shown some effect on CMV but IVIG is the least evidence about. I am sure its being used for CMV viremia or disease as the concept is the same as cytogam.


Check out the review article with good statements on how to manage difficult CMV viremia and disease patients.

H1N1 and Transplantation

A study at ATC 2010 showed the following

Novel H1N1 caused the 2009-10 pandemic, however the effect on Single Organ Transplants( SOT) is not well known.  The outcomes of H1N1 were reported in a large multicenter study by Kumar et al. from 4/2009 to 11/2009.  115 medically attended H1N1 infections were reported from US and Canada.  61% of patients described were lymphopenic and 65.2% were hospitalized.  Fever and recent ATG use was predictive of requiring hospitalization.  Complications included pneumonia (25.2%), ICU stay and 1 death.  Antiviral therapy was used in 91% of cases predominantly being oseltamivir monotherapy. Patients started on antiviral therapy before 48hrs of symptom onset were less likely to require ICU stay (0% vs. 22.4%).  

Conclusions/ comments:  H1N1 may cause significant morbidity in SOT patients.  If suspected, antiviral treatment should be started immediately and prior to confirmation of H1N1.  Unfortunately the effect of the H1N1 vaccine is not well characterized since the majority of reported cases occurred before vaccine availability.  The optimum dose, course and antiviral therapy remains unknown.  

Reported by Vinay Nair

HIV and the Kidney Transplant

What I learned at the NKF 2010 , some few points.


1. A large NIH sponsored study basically showed that the outcomes of large number of patients when compared to non hiv patients transplanted was no different.
2. The 3 year follow up showed no major difference in graft survival
3. HIV disease didn’t progress either, perhaps because they didn’t get induction therapy or they were carefully selected patients or there is data that almost all immunosuppresive drugs we use has anti HIV viral activity from cellcept to CNI to sirolimus
4. The major problems people run into these transplants are drug toxicities as anti retrovirals have significant effect on CNI levels and high doses of CNI and increased intervals are needed.
5. There is usually more rejection in these patients,perhaps because of point number 5, but also perhaps because they don’t get much induction
6. Some centers are using induction with thymo, but their acute bacterial infection rates are high. Ideally, a anti CD20 induction is a good choice.


A nice website to look at is: hivtransplant.com

New drugs for Hepatitis C

The latest AJT report introduces us to a new line of drugs for treatment of Hepatitis C.  The two drugs that are closest to coming to the market are in Phase 3 trials are will be submitted to FDA soon.  They are telaprevir and boceprevir. Protease inhibitors have been discussed in treating hepatitis C for years now and this brings it to the forefront.
Allowing to treat patients prior to liver transplantation might be the most benefit as the interactions post transplants with immunosuppresive medications is always a challenge. We see that in HIV patients who get kidney transplants.
The article summarizes that the future of treating primary Hep C infection or recurrence in the liver graft is going to be a cocktail of medications that will include standard medications like interferon and ribavarin but also protease inhibitors.  Recurrence of Hep c in the transplanted liver is a commonly encountered problem and this might hopefully help in the near future.
Treatment of Hep C might tag behind how HIV is being treated.