Paired Donor Exchange Programs

At the ATC 2010, Speakers from the Alliance for Paired Donation, and other paired exchange programs reported their experience with paired exchange for ABO incompatible and HLA incompatible donor recipient pairs.  They spoke about shipping living donor kidneys; currently there does not seem to be a increase risk for DGF or graft dysfunction up to a CIT of 15 hours.  However they only reported short term results.  All groups agree that a national level paired exchange program needs to be created and apparently UNOS is attempting to do so.  Finding a way to organize such a project and work out financial agreements and oversight will be challenging.

by
Vinay Nair

Bortezemib and highly sensitized patients

Another fascinating study at the ATC 2010 talked about the role of bortezomib in decreasing HLA

Bortezomib is a proteosomal inhibitor shown in small studies to have a pronounced effect on decreasing HLA-antibodies post transplantation.  Previously it has been studied in patients with humoral rejection and coupled with other treatments including plasmapheresis, steroids, and rituximab.  The mechanism of antibody reduction is depletion of long lived plasma cells which are very difficult to eradicate by conventional therapy.  The abstracts presented in the ATC revealed Bortezomib to have some effect on both anti HLA antibodies and plasma cells pre-transplant; as a method of desensitization.  Unfortunately neither abstracts revealed hard endpoints such as percentage of patients transplanted or comparison to a control group.  In addition both studies had relatively small numbers and were single center studies.  The most common side effect seems to be peripheral neuropathy however most cases were mild and at least partially reversible.  

Conclusions/ Comments:  Expert opinion seems to be that the optimal use and effect of bortezomib is currently unknown.  It does have some effect on HLA antibodies but will not magically decrease PRA to 0%.  It may also work better with concurrent plasmapheresis, as stimulated plasma cells are probably more susceptible to proteosomal inhibitor induced apoptosis.  Large multicenter studies need to be performed in sensitized patients with bortezomib.  Some type of control group needs to be employed and hard endpoints (transplantation) will be needed.  The use of proteosomal inhibitors at this time should remain in a properly conducted study.

by Vinay Nair

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

Complement activation and Antibody mediated rejection

Recently at the ATC 2010, there was a presentation about Terminal Complement Inhibition Decreases Early Acute Humoral Rejection in Sensitized Renal Transplant Recipients.

Transplanting highly sensitized patients remains a significant problem in kidney transplantation.  Methods of decreasing alloantibody include plasma exchange, IVIG and Rituximab, however the effect on HLA-antibodies are limited.  Eculizumab inhibits the complement cascade at C5 and therefore may be able to block the effector pathway of antibody mediated rejection.  A study presented at ATC 2010 had 17 incompatible (B flow cytometry crossmatch median channel shift > 340) highly sensitized recipients of living donor allografts received eculizumab post transplant and were compared to 51 historic controls treated with plasmapheresis and IVIG.  Patients received weekly doses of Eculizumab post transplant until they had a spontaneous decrease in donor specific antibody (B flow crossmatch <200 channel shift).   1 of the 16 patients treated with Eculizumab experienced antibody mediated rejection (6.25%) compared to 40% of the historic controls.  However, in the relatively short f/u period (1-17 months) four patients developed signs of chronic injury including 2 with transplant glomerulopathy.  

Conclusions/ comments:  Terminal complement inhibition significantly reduces humoral rejection.  However, the optimum dosing is unknown and long term graft survival may be jeopardized by chronic antibody mediated damage.  Long term f/u will be needed in these patients and a trial evaluating it in sensitized waitlisted patients would also be useful.

Reported by Vinay Nair

ATC Conference highlights 2010

The Renal and Urology News website has nicely summarized some good work from this ATC 2010
Check it out!

http://www.renalandurologynews.com/conference-highlights/section/809/

CONSULT ROUNDS: Distal RTA

Renal tubular acidosis was our discussion today. Always fun to discuss.
Hard to diagnose. Proximal vs dital RTA is sometimes a hard diagnosis to make.
Few take home points from today's discussion

1. Urine Ph is a good marker to see how well the kidney is doing. If you have a metabolic acidemic state with low ph and low bicarbonate and there is no Anion gap, the urine ph appropriately should be low around 5-5.5 to get rid of that acid. If that's the case, the kidney is safely acidifying the urine.  Hence the defect is either GI or proximal tubule( one caveat that you are giving bicarbonate and there is a thrushold reached and you are spilling the bicarb in the urine and make the ph alkaline)
2. There are many mechanism involved in the defects in a distal RTA( or acidification defect). Some people might even say, the problem starts in the proximal tubule since the ammonium genesis is happening there. Then the ammonium is transported to the distal tubule intercalated cells for removal in the urine. so the defect can be in any of these processes.
3. Distal RTA classically presents with low K, and nephrolithiasis(ca phos stones) since there is hypocitraturia and alkaline ph
4. There are three main types of distal RTA
     **Secretory defect:-This is probably the commonest defect and is due to an inability to create and maintain a H‡ gradient across the luminal membrane. The cause is unknown but likely defect in the H/K ATPase transported in the luminal side.This is usually referred to as the CLASSIC distal RTA, usually caused by Sickle cell disease, Sjorgen's syndrome, lupus. etc
     ** back leak:-The ability to secrete H‡ is retained, but the gradient is not maintained due to back diffusion.
 associated with amphotericin B therapy as the drug makes holes in the cell and back diffusion happens
     ** hyperkalemic voltage defect:-This is due to an inability to maintain a negative intraluminal voltage and thus promote H‡ (and K‡) secretion. Voltage-dependent dRTA has many features in common with type IV RTA, most notably the association with hyperkalaemia: the key difference between these two forms of RTA
is that patients with voltage-dependent dRTA cannot lower urine pH in response to systemic acidosis.

Causes are listed below

*** Hypokalaemic (classic dRTA)
Marfan syndrome/EDS
Fabry disease
Wilson's disease
Dysproteinaemia
Amyloidosis
Primary hyperparathyroidism
Vitamin D intoxication
Chronic pyelonephritis
Interstitial Nephritis
Lupus
Renal transplant rejection
Sjorgen's syndrome
Lithium
Analgesic abuse
Toluene
Sickle Cell disease
Calcineurin Inhibitors

*** Hyperkalaemic (voltage-dependent dRTA)
Urinary tract obstruction
Sickle cell disease
Amiloride
Triamterene
Calcineurin inhibitors

Are Generics trustworthy?

This month on AJT report, there was a discussion that might be very important.. can generics be trusted?
Some physicians have concerns about the efficacy and safety of many generic immunosuppresive agents for our transplant patients.  The small article in AJT nicely points out few important points: we need more data to show to FDA that generic drugs might not be working as well or are working equally well.  Name brand drugs go through much more of a validation process.  Bio equivalence might vary as high as 40% based on this summary.  
Its an important topic that needs further prospective trials in this field.