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

Genetic Nephropathies and Kidney Transplantation

A recent article in Nature Review Nephrology reviews the diseases we always get worried if a living donor can be used.
This review outlines the does and don't of hereditary nephropathies and donor evaluation of kidney transplantation. A table in the articles nicely summarizes the disease entity and if the living related donation would be appropriate.
In Finnish type Congenital Nephrotic syndrome, NPHS2 FSGS, NPHS3 FSGS, Pierson Syndrome, Schimke's immunoosseous dystrophy, nephronophthisis, cystinosis and ARPKD and alport syndrome:- it is ok to use living related donation in transplantation.  In Primary Hyperoxaluria and Atypical HUS, one has to be careful in selecting the donor from a living relative.
In general AR type of diseases, the donor can be a relative and most of the time its not a problem. Autosomal Dominant diseases is always a concern. We come across this most in ADPKD and the donor evaluation in that case is so strict and needs careful screening if its a relative.  Atypical HUS should not receive a kidney transplantation from a living donor because it is a high risk for disease recurrence and graft loss.

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

Quiz 9 Answers

Which drug is paired incorrectly with the target molecule?
Rituximab -- CD20
Alemtuzumab -- CD52
Belatacept -- CD198
Belimumab --- TNFSF13B
Atacicept ---TACI-Ig

The correct answer is Belatacept CD198, that is incorrect pairing. Most of you got it right.
We all are familiar with Rituximab which is a B cell antagonist and since all B cells besides plasma cells are CD20 Positive, its an anti CD20. Alemtuzumab(campath) targets cd52 a protein present on the surface of mature lymphocytes. Atacicept(TACI-Ig) is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. The selective inhibitor of T-cell costimulation, belatacept, blocks CD28-mediated T-cell activation by binding CD80 and CD86 on antigen-presenting cells. Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade. Belimumab (registered name Benlysta previously known as LymphoStat-B), is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF).

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