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

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

B cells in Transplantation

Recently at the ATC 2010, a nice abstract was presented regarding Regulatory B cells. They are coming!!!
T cell immunglobulin and mucin -1 or TIM-1 is a costim molecule that controles T effector cells.
The listed abstract below showed that Tim-1 is more highly expressed on naive B cells than on T cells.
Depleting B cells led to Tim-1 accelerated islet cell rejection in these mice.  Re constitution of B cells led to prolonged graft survival and and transfer of Tim-1 + B cells prolonged allograft survivial suggesting that Tim-1 + b cells could be B regulatory cells like Foxp3+ T reg cells.
Again, no human data yet. more studies to come!
Exciting stuff!

Reference:
Ding Q, Yueng M, Najafian N, et al. Regulatory B cells are identified by TIM-1 and can be induced through TIM-1 ligation to promote allograft survival. ATC 2010, San Diego, Calif, Abstract 167.

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

Quiz 6 answers

Which is true? 1.The incidence of Kaposi Sarcoma is most highest in liver transplants of all solid organ transplants
2.Females are more of risk than males get Kaposi Sarcoma in Renal transplant patients
3.It is caused by Human Herpes virus 6 4.Most cases of Kaposi's Sarcoma occur in individuals of Mediterranean or Arabic origin 5.Most cases of Kaposi Sarcoma are visceral in nature in Transplant recipients. The correct answer is 4. Kaposi Sarcome- can be seen in transplant patients. In general few observational findings It is three times more common in males than females It is caused by HHV 8, not 6 Most cases of this virus occur in individuals of Mediterranean or Arabic origin Risk factors are usually levels of CNIs Usually presents as a cutaneous lesion in legs and lymphedema.  Skin involvement is most common Visceral involvement is rare in transplant patients, <10 % Most cases of HHV 8 related KS have been seen in cardiac and renal transplants.

Renal Fellow Network: Doc, I am very sensitized! (part 2)

Renal Fellow Network: Doc, I am very sensitized! (part 2): "Let’s continue our discussion from our last blog about sensitized kidney recipients. In summary, we have this 60 yo man interested on a seco..."

Renal Fellow Network: Doc, I am very sensitized!

Renal Fellow Network: Doc, I am very sensitized!: "Another day of transplant clinic… I heard from my attending that a couple is here for a second opinion about a kidney transplant. The husban..."

Concept Map of Treatment of BK Nephritis

Here is a concept map of BK Nephritis Pathology and Treatment options

Can BK Virus serum PCR be a good marker for Net immunosuppression?

In the field of transplantation, we are struggling to figure out is the patient on which end of the spectrum, too little immunosuppresion or too much immunosuppression.  Markers for rejection have been studied extensively and based on Luminex DSA one can monitor early signs of impending antibody rejection.  But many centers are also developing aggressive screening strategies for BK Nephritis.  This entity is usually seen as early as 2 weeks post transplant to as late as 7 years post transplant but usually in the first year or so.

I think that A BK serum PCR might be a good marker for NET immunosuppression. Someone who has lupus and has been treated with Cytoxan, Cellcept, Rituxan and has failed kidneys recently and then gets a transplant for the kidney and gets inducted with more immunosuppression might be the highest risk for BK Nephritis much earlier on due to their NET immunosuppresion being the highest. No one can really measure NET immunsuppression.  There is a test available called " Cylex" or ImmuKnow . This  is the physiology behind it:  

"Phytohemagglutinin (PHA) is a non‐specific mitogen which can be used to stimulate cell division in CD4 T‐ lymphocytes regardless of their antigenic specificity or memory status. Therefore, PHA is considered to be a “global” stimulator of the immune system. The production of intracellular ATP is one of the first steps in cellular activation following stimulation with mitogens such as PHA.  ATP is a multifunctional nucleotide which plays an indispensible role in the transfer of intracellular chemical energy. The amount of ATP generated can tell us the amount of CD4 T cell activation and the overall immune status of the patient( over or under immunosuppressed). " -from the cylex website( summarized) 

But a cell activation can occur in setting on an infection as well and a similar down stream effect on the kidney. Steady monitoring of infectious agents like BKV might be the BEST marker we have to date to tell us " Hey there is too much immunosuppression on board" !

But might not be as simple as that...

Lets see what future studies hold...

http://www.ncbi.nlm.nih.gov/pubmed/20723175

http://www.cylex.net/

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

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

Histopathology Kidney --Chronic transplant rejection

Histopathology Kidney--Acute transplant rejection

Quiz 5 Answers

Which one of the following is not a risk factor for PTLD
EBV status of donor/recipient 2 (16%)
Prior malignancy 1 (8%)
"Net" immunosuppresion 1 (8%)
Prior BK Virus infection 6 (50%)
Age 2 (16%)

Most of you got this one right away!
All except Prior BK infection has been associated to be a risk factor for PTLD In kidney transplant recipients
Please review the recent updated PTLD presentation by Arun Chawla for further clarification

http://onlinetransplantcenter.blogspot.com/search/label/presentations

Immune System - Natural Killer Cell - The Formulation

The Complement System

Cell Mediated Immune Response

Antibody Mediated Immune Response

Immunology Review

Post Kidney Transplant Renal Injury!

A Short Reminder!

We encounter acute renal failure always in the post transplant period
Besides the traditional pre renal, renal and post renal way of looking at the causes of renal injury post transplant, a mnemonic I learned from my mentors was : SCRI
or short for serum creatinine.

S- STRUCTURAL CAUSES
C- Calcineurin Toxicity
R- Rejection, any type/ Recurrence of primary disease
I- Infection, usually BK

The causes of proteinuria post transplant( major causes)
Rejection
Recurrence
De novo Glomerular Disease
Transplant Glomerulopathy
Post Transplant Collapsing FSGS