Post transplant MPGN

A nice recent paper in Kidney International April 2010 edition talks about the examination of MPGN post transplant at a single center.  Few interesting observations they noted:- They found that the risk of recurrence was increased most with patients who had pre transplant low complement levels and elevated monoclonal proteins.  The 29 patients they studied, 5 lost their graft and 2 patients remained on plasmapheresis.  The recurrence rate was low but was important to note few clinical key points.

What does this mean? MPGN is a tough diagnosis to make in my opinion. They ruled out all DDD and fibrillary patients from their study. They did include rare causes like Rheumatoid Arthritis but "clinically" all secondary causes were ruled out. That's my concern as MPGN is one disease that has found to have so many secondary causes.  From infectious to autoimmune diseases, you name it and it can cause MPGN.  Now recently, there has been some suggestion that paraproteins can be related to cause of primary MPGN.  Again, we cannot call it primary if we have found a secondary cause. MPGN like pattern of injury can be seen in TMA, Autoimmune diseases and paraproteinemias. If those are all negative, and there are deposits, perhaps its primary. Also, in post transplant- its even tougher, as immune mediated changes can lead to an MPGN like pattern on the biopsy, CNI induced chronic TMA can look like MPGN as well and transplant glomerulopathy is basically an MPGN pattern of injury. First we need to differential pattern of injury from primary MPGN.
Regardless, the two great points that come up are:
Should we screen everyone with MGPN regularly with complements and if they are low, then their risk post transplant recurrence is high?
Should we screen everyone prior to transplant with serum free light chain assays and if they are present:- not transplant them or consider a bone marrow prior to transplant?
No clear answers but this study raises these important questions!!

Bowel Transplantations, not enough!

Interestingly, just read in AJT that bowel transplantations are not happening as much as they should.
The AJT report summarizes some of the reasons why.
1. Experience of Physicians and surgeons taking care of these patients
2. Knowledge gap and some physicians even not knowing this option exists.
3. TPN might be a better options in some viewpoints
4. There are not enough recipients
5. Some physicians consider this an experimental procedure.

As a Nephrologists, I think that its fascinating that the field of transplantation and immunology has come this far and hopefully in future, bowel transplantation might become a more standard of care option for patients with intestinal failure.

New Agents for renal transplantation

Nature reviews Nephrology has a nice review on the new drugs that have been recently tried and are upcoming for the treatment of rejection or for induction.
To name and summarize a few:-
1. Alafacept  which targets Cd2 is a fusion protein that will delete activated T cells only( apoptosis method)
2. Belatacept which targets Cd80 and cd86 is also a fusion protein and can inhibit the second signal to activate T cells.
3. Sotrastaurin is a protein kinase C target and inhibits it to decrease T cell activation.
4. CP-690,550 is a JAK-3 inhibitor.
5. Eculizimab is a C5 inhibitor and inactivates complement cascade, very good use in ab mediated rejection
6. Bortezomib is a NFkB target and can deplete plasma cells and helps in plasma cell rich ab mediated rejection.
For an excellent summary, look at Figure 1 in the review article in Nature Nephrology.

KIDNEY DONORS have Good Long term survival

A recent paper in JAMA suggests that living donors live normal lives and have good long term survival. Live donors were drawn from a registry and donors between 1984 and 2009 were studied.  A matched cohort of non donors was used for comparison.  Surgical mortality was 3.1per 10,000 donors and did not change during the last 15 years. The long term mortality risk was no higher in live donors than randomly matched participants matched with age and comorbidities.  The median follow up was only 6.3 years, which is long but is it too short for a donor? That we don't know. Physiologic changes do happen in patients when they donate to the other kidney. These findings suggest that epidiemiologically there is no major difference in outcomes to other non donors in the community.
This is one of the largest studies of donors and takes a long period into consideration. It also has a good sample size. Shorter follow up is a major limitation, besides it being a retrospective evaluation.

At least from this study and the recent one in NEJM linked below, long term outcomes of kidney donors are excellent.

Post Transplant Collapsing FSGS: Is it really all Ischemia?

A case report of three cases in AJKD this month reports de-novo post transplant collapsing glomerulopathy(PTCG). Rare cases of de novo collapsing glomerulopathy have been reported during the post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor–dependent podocyte proliferation in HIV-associated nephropathy.This paper nicely shows the immuno-staining of those patients and positive for VEGF at the podocytic injury suggesting that hypoxia induced increased hypoxia inducible factor is leading to increased VEGF for their survival that ultimately leads to the collapse. Other causes that are commonly associated with Collapsing Glomerulapthy are pamidronate use, interferon use, use of sirolimus, parvovirus B19 virus, CMV infection, Renal artery stenosis, SLE, lymphoma, and recently even use of depakote and dilantin. HIV was negative in all patients? It was unclear if parvo virus was checked as post transplant parvo virus B19 cases of collapsing GN has been noted.
It is a devastating disease and something to keep in the differential diagnosis even post transplant in nephrotic range proteinuria.  Ischemia likely from chronic rejection, chronic calcineurin use might be the culprits.
The same causes that lead to Collapsing FSGS in the non transplanted kidney, should also be ruled out in the transplanted kidney. The important major difference is the ischemia as a cause might be more evident in transplanted kidney.
An abstract at ASN showed similar findings as well.


Other references:-
http://www.abstracts2view.com/asn/view.php?nu=ASN09L1_2723a
http://www.ncbi.nlm.nih.gov/pubmed/16705026
http://journals.lww.com/transplantjournal/Abstract/
1998/05150/De_Novo_Collapsing_Glomerulopathy_in_Renal.9.aspx

Belatacept approved by FDA

What is Belatacept and is it going to change the face of transplantation? Its a fusion protein composed of components of  TLA-4, extracellular domain of IgG1.  The drug can selectively block the T cell activation by inhibiting this costimulatory molecule CTLA-4.   From the researchers mainly at UCSF, a landmark paper was published few years ago in NEJM.
They assigned renal tranplant patients to receive an intensive or less intensive of belatacept or cyclosporine. All patients were induced with the same agent of basiliximab. All received steroids and MMF.  At six months, they evaluated that the incidence of acute rejection was no different in two groups. CAN, and decrease in GFR was less common in the belatacept arm.

This drug might show promise. Lets see once more widespread use of it is noted. It might allow us to spare cyclosporine or tacrolimus use in many of our patients. This is important as one of the most common causes of graft loss these days is not rejection but chronic calcineurin toxicity or chronic changes due to medications. The effect on the pancreas by these drugs is also not benign and the most common glomerular disease post transplant still remains to be diabetes.
Lets await and see.