Paricalcitol and CNI injury?

The most recent issue of Kidney International talks about an animal model that showed that paricalcitol attenuated cyclosporine induced kidney injury. This is interesting to note.
First, why do we get CNI related toxicity. CNI exposure leads to increased inflammatory response in addition to its beneficial effects and as a result increased TGF-B expression and fibrosis and nephropathy.
Also the renal vasomotor impairment leads to RAAS activation and oxidative stress and nephropathy.
The trial shown in the issue is an excellent start of a set of trials that might follow in animal models and hopefully this will one day make it to clinical world.

Reference
http://www.ncbi.nlm.nih.gov/pubmed/20237458
Image source
http://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=1741&type=img&name=zemplar-injection-structure.jpg

Nephrology Crosswords

Check out the next in series of the crosswords in KI

http://www.ncbi.nlm.nih.gov/pubmed/20508666

TOPIC DISCUSSION: Shock wave lithotripsy for kidney stones

Shock wave lithotripsy has been used for many years now for treatment of kidney stones. This might be old news to some people but i learned about this recently that around 2006-2007, there was a big debate about SWL causing DM and HTN.  Results from a retrospective study of 630 patients by researchers at the Mayo Clinic showed a more-than-threefold increased risk of diabetes and a 1.5-fold increased risk of hypertension among patients who underwent SWL 19 years previously compared with a cohort of matched, conservatively treated, nephrolithiasis patients. This was published in the Journal of Urology.
Another study showed the opposite in 2008.
The mechanism of this is unclear, but one possibly is direct toxicity from damage of islet cells from the shock.
The HTN is likely from the scarring and intrinsic kidney damage. 
This is still controversial and under debate in the medical community.

Some good references:

http://www.ncbi.nlm.nih.gov/pubmed/16600747
http://www.ncbi.nlm.nih.gov/pubmed/18387387
http://www.ncbi.nlm.nih.gov/pubmed/18423676

Role Playing in Transplant Teaching

Today at our transplant conference we did something fun.
A month ago, each fellow in training was assigned a transplant drug( MMF, imuran, cyclosporine, prograf, sirolimus, steroids and belatecpt).
In the one hour, each fellow had to play a role of the drug and stay in character. Initial rounds were introduction rounds and then followed debate rounds where major debates between Steroids vs no steroids, CNI vs belatecept, Cyclo vs prograf, sirolimus vs CNI and Imuran vs MMF happened.
It was tons of fun and fellows enjoyed it. Role playing of drugs taught them the strengths, mechanism of actions and their weaknesses.

Hoping to use tools like this to teach nephrology as we more forward; and make it lot of fun!!

Role Playing in Transplant Teaching

Today at our transplant conference we did something fun.
A month ago, each fellow in training was assigned a transplant drug( MMF, imuran, cyclosporine, prograf, sirolimus, steroids and belatecpt).
In the one hour, each fellow had to play a role of the drug and stay in character. Initial rounds were introduction rounds and then followed debate rounds where major debates between Steroids vs no steroids, CNI vs belatecept, Cyclo vs prograf, sirolimus vs CNI and Imuran vs MMF happened.
It was tons of fun and fellows enjoyed it. Role playing of drugs taught them the strengths, mechanism of actions and their weaknesses.

Hoping to use tools like this to teach nephrology as we more forward; and make it lot of fun!!

The SPLEEN in ANTIBODY MEDIATED REJECTION

The recent AJT May 2010 issue has a nice histopathology and immunotyping of the spleen in a case of renal allograft antibody mediated rejection. Splenectomy is done in rare cases to treat ABMR.  What this case illustrates is what they found in the spleen that might have been causing the damage.
The spleen biopsy was abundant with clusters of CD 138+ plasma cells.  This can explain the rapid response that we see once the spleen is removed.  They postulate that the spleen might be a reservoir for converting CD 20+ B cells to antibody secreting CD138+ plasma cells at the time of stress.
The HLA antibody is specific. Is the spleen really producing that specific antibody is unclear.
But this staining showed something novel about the plasma cells.
It has been noted that the kidney biopsy that is rich in plasma cells and ABMR has a worse prognosis.
It might be coming in bursts and splenectomy might help. Anti Plasma cells agents like Bortezomib might also be possible options in a case like this. I think it might worked as well as the splenectomy.

Regardless a nice read!

Image source: http://www.lifespan.org/tmh/services/surgery/mininvasive/images/spleenlarge.jpg

IN THE NEWS ---> FONT TRIAL

Treating FSGS is tough. It has been a long haul in trying to get the best drug to treat it.
Besides steroids, cyclosporine and scattered literature on cellcept, there is no other magic drug to treat resistant FSGS. Antifibrotic agents are the ones being studied in this study that is still ongoing called the FONT study.
The FONT study describes an ongoing trial that compares anti TNF, anti PPAR and galactose as the modalities to the treatment of FSGS.
Initial Phase 1 trials were produced recently in key journals. The next phase is still on the way.
What is also interesting is that this study has started a network amongst investigators to study diseases, the first of its kind in renal diseases. More studies that form networks should be done and allow more multicenter trials to occur.
Links to the FONT trial papers.
http://www.ncbi.nlm.nih.gov/pubmed/19932542
http://www.ncbi.nlm.nih.gov/pubmed/19932542

IN THE NEWS ---> MCD vs FSGS

A recent study in Kidney International talks about a possible biomarker that might be useful in distinguishing Minimal Change Disease from FSGS.  Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD.  Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS.  A significant increase in urinary CD80, normalized to urinary creatinine, was found in patients with MCD in relapse compared to those in remission or those with FSGS. In seven of eight MCD patients in relapse, CD80 was found in glomeruli by immunohistochemical analysis of their biopsy specimen. No CD80 was found in glomeruli of two patients with FSGS and another MCD patient in remission. 


Given this finding, the authors side the notion that MCD and FSGS are distinct entities and not a spectrum of the same disease.
I think that perhaps in children they might be a distinct different disease, but perhaps in adults still could be the same disease caught at a later time. Perhaps early on in the disease, you shed CD80 and then it decreases due to focal sclerosis. Lets see how the Glomerular world embraces this marker.


http://www.ncbi.nlm.nih.gov/pubmed/20485332
http://www.ncbi.nlm.nih.gov/pubmed/19056875


Image source: http://www.gamewood.net/

Topic Discussion: Aldosterone

Aldosterone, the hormone that seems to be forgotten in the nephrology world with the emergence of ACEI and ARBS and renin inhibitors.  Aldosterone has so many direct actions that having an aldo antagonist as part of your medication regimen is handy. And we have had it for years but its sparingly used partly because of in experience and partly because of better marketing of other drugs.

Well, Nature Review Nephrology this month had a nice review on aldo's mechanisms and effects on the kidney and cardiovascular system.
Few take home points
1. We all know well how aldo effects the salt reabsorption in the distal collecting duct
2. Aldosterone regulates the EnAc channel in the distal duct via a distinct molecular mechanism
3. Aldosterone increases the expression of inflammatory cytokines namely Il-6, Il-1 and MCP-1.
4. Aldosterone via a sgk1 pathway activates NKfB which leads to activation of TGF-B.
5. Due to the above cascade of events, it induces inflammation and fibrosis
6. Aldosterone induces PAI1 expression in mesangial cells and this act can be mitigated using aldo antagonists atleast in a model of radiation injury in rats
7. Aldo can induces fibrosis from a TGF-B independent pathway as well.
8. Aldo can induce mesangial cell proliferation and podocyte injury via reactive oxidative stress and the mTor pathway.
9. Aldosterone can lead to senescence of vascular smooth muscle cells through the ROS and RAS pathways
10. In a setting of high salt diet, the fibrosis or damage is even worse.
11. Too much aldo can lead to endothelial damage - shown in coronary vasculature
12. Large clinical trials such as RALES AND EPHESUS have shown that effects of blocking the mineralocorticoid receptor pathway has good effects on the heart, specifically LVH and reduction in cardiovascular endpoints.
13.We need more large studies in CKD and renal patients of a angiotensin blockade + aldo blockade modality.  We have to keep in mind the Hyperkalemia with those trials; as that's where they ran into problems with the RALES trial

Kidney Autotransplantation

Autotransplantation is something not that talked about. It is mainly used to recover or stabalize renal impairment due to renovascular or ureteric disorders to avoid nephrectomies. Perhaps due to major advances in interventional nephrology and radiology and immunosuppresive agents, this mode of treatment has fallen out of favor. Renal autotransplantation was first performed successfully in 1963 on a patient with severe
ureteral damage.  Bodie et al. reported the longest series of 23 patients who underwent renal
autotransplantation for extensive ureteral injuries, and were followed up for up to 14 years.  

What are some of the reasons that leads to autotransplantation of the kidney? at least historically

1. Iatrogenic ureter lesion 
2. Gross hematuria due to kidney vascular abnormalities
3. Renal artery stenosis
4. Long ureteric stenosis
5. Ureteral strictures
6. TCC of upper GU organs
7. RP Fibrosis


Some good references
http://www.ncbi.nlm.nih.gov/pubmed/15134964
http://www.ncbi.nlm.nih.gov/pubmed/13960761
http://www.ncbi.nlm.nih.gov/pubmed/12556645
http://www.ncbi.nlm.nih.gov/pubmed/3534311

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

The Online Transplant Center: Risk of PTLD post transplant?

The Online Transplant Center: Risk of PTLD post transplant?

Size and the Kidney from NephrologyWorld

http://nephrologyworld.blogspot.com/2010/05/size-does-matter-for-renal-transplant.html

TOPIC DISCUSSION: Hyperammonemia and the Nephrologist

Why and when does a nephrologist get called for hyperammonemia? Yes its true, dialysis can be a modality to treat severe high toxic levels of ammonia.

1. Why is it so dangerous?
Cerebral edema and herniation (as well as seizures) are unique to acute hyperammonemia and usually occur only when arterial ammonia levels are > 200 μmol/L.  Chronic brain damage has been noted.


2. What are the treatment choices?
  Treat the intracranial hypertension created and treatment of cerebral edema.
  Hypothermia can help, along with mannitol
  Diltantin and Phenobarbital
  Lactulose
  Treat underlying urea splitting organism if present
  Sodium Benzoate
  IV arginine
  PD/HD and CVVH have been used in the past!! and in most cases as a bridge to liver transplantation.

 3. What are the causes?

     Liver  failure/cirrhosis
     TPN,GI Bleed, Steroid use
     Urea splitting organism infection, herpes infection
     Urinary diversion
     Multiple Myeloma  
     Budd chiari
     Mushrooms/Herbs
     Valproic Acid, carbamazepine, ribavarin, pyrimethamine use
     Urea cycle disorders( usually children)
     idiopathic hyperammonemia

Few interesting points.  

This can be very devastating and we might get called to do dialysis as a final removal of the ammonia. HD removes it the fastest. A nice review is listed below.
Another interesting cause that I learned was Multiple Myeloma and how that might lead to the elevated hyperammonemia syndrome needing dialysis. This might be associated with presence of peripheral blood myeloma cells and a possible MM with a burkitt type translocation t(2,8)(p12;q24)

http://www.ncbi.nlm.nih.gov/pubmed/19373670

http://www.ncbi.nlm.nih.gov/pubmed/11325692?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/19602793

http://www.ncbi.nlm.nih.gov/pubmed/19064403

http://www.ncbi.nlm.nih.gov/pubmed/17934124

     

Cellcept vs Myfortic? any difference!!

We use cellcept often and some centers prefer Myfortic.  A common reason to switch usually is GI side effects more noted in cellcept.  
Is there any difference? otherwise in outcomes of both patients.A retrospective analysis was done of over 45,000 patients from the UNOS database.  They measured graft failure, death with graft, acute rejection, NODAT, and renal function. 
To answer this question, a nice paper in Transplantation talks about this.  A large retrospective trial of 48,000 patients using the UNOS database was done. End points were graft failure, death with functioning graft, NODAT, acute rejection, and renal function.  around 10% were on myfortic and remaining on cellcept.
Propensity score-adjusted regression analysis showed that patients who received myfortic were at increased risk of biopsy proven acute rejection. The adjusted biopsy proven acute rejection rate difference at 3 years post transplant was less than 2% statistically significant due to large number of patients.  There was no difference in graft survival, NODAT, renal function and other measures. 


Interesting to note this difference. Overall, in terms of graft survival , this RETROSPECTIVE LARGE study showed no major difference. The authors think that due to the large numbers, this difference was less meaningful. 


http://www.ncbi.nlm.nih.gov/pubmed/20445488

EVEROLIMUS FOR KIDNEY TRANSPLANTS

Everolimus, a sister drug of sirolimus; MTOR inhibitor is now FDA approved for use in Transplant patients.
It is commonly used in renal cell cancer patients and in Europe in transplants as well. A phase 3 trial showed that this medication prevented acute rejection and preserved kidney function and it allowed reduction of CNIs. It was promoted as a CNI lowering agent

Using Mtor inhibitors is a topic of discussion at different centers all the time. They might not be that great of immunosuppresive agents as we thought they were initially, they are certainly great antiproliferative agents.
The risk of cancer is likely going to decrease if one of these are used. The use has to be monitored with the baseline proteinuria and renal function.

A nice review is listed below
http://www.ncbi.nlm.nih.gov/pubmed/20155724
http://www.ncbi.nlm.nih.gov/pubmed/20420793

CLINICAL CASE 14 , ANSWER and SUMMARY

Which one is paired incorrectly?

Parvovirus B19- Collapsing FSGS	2 (11%)
BK Nephropathy - Tubulo-interstitial Disease	0 (0%)
Hantavirus- Tubulo-interstitial disease	0 (0%)
Adenovirus - Collapsing FSGS	7 (38%)
Measles- Acute interstitial Nephritis	3 (16%)
Measles- Nephrotic Syndrome	6 (33%)
Hantavirus - Interstitial Hemorrhage	0 (0%

Tough question! Well, few are obvious but some are historical and one is incorrect.

Parvovirus B19 and collapsing FSGS or collapsing Glomeurlopathy(CG) has been reported now by many groups. Initially we thought that all cases of CG were idiopathic but parvovirus has been implicated in causes of CG in both non transplant and post transplant world.  

BK Virus traditionally causes an interstitial tubular disease. We know about that virus from our transplant experience and lately we are seeing cases of BK nephritis and BK cystitis in the Bone marrow transplant world as well.

Hanta virus, usually associated with systemic hemorrhage and even interstitial renal hemorrhage can also cause acute interstitial nephritis.

Measles, is a tough one. It has been associated with acute interstitial nephritis like most viruses are but there is an historical association with nephrotic syndrome as well. Check out some references below.

Adenovirus is not been reported to cause a CG so far. It has a more aggressive variant of acute interstitial nephritis, a necrotic variant usually.  Other viruses that are associated with CG are more of the Hepatitis, CMV and HIV/HTLV family of course.

HEP C is usually associated with MPGN , But IgA, post infectious, Membranous, Immunotactoid and Fibrillary GN has been reported as well

HEP B is usually Membranous GN but mesangioproliferative, MPGN, FSGS, and vasculitis has been reported.

CMV is usually AIN but also CG and TMA 

Mumps, and Dengue have been associated with acute interstitial nephritis

Some nice references for general viral nephropathies and the above mentioned discussion.

http://www.ncbi.nlm.nih.gov/pubmed/18121037
http://www.ncbi.nlm.nih.gov/pubmed/20288668
http://www.ncbi.nlm.nih.gov/pubmed/15393437
http://www.ncbi.nlm.nih.gov/pubmed/16705026
http://www.ncbi.nlm.nih.gov/pubmed/11380814
http://www.ncbi.nlm.nih.gov/pubmed/12455712
http://www.ncbi.nlm.nih.gov/pubmed/15648164

TOPIC DISCUSSION: low K and low Mg??

We always talk about low Mg levels causing low K levels? 
If you replete the Mg, you shall correct the K? Why is this phenomenon happen?


Mg is absorbed mostly in the proximal tubule. The fine tuning is done in the DCT cell with the TRMP6 channel and allows the final exit or entry pathway for Mg. The hypomag-opathies are related to these TRMP6-pathies!
Any defect in the TRMP-6 channel can lead to mg wasting and hypermagnesuria and hypomangesemia.
The place where K and Mg are meeting each other are in the ROMK channel area. Some studies have shown that in the setting of high Mg levels in the cell, the ROMK channel is inhibited and less K is leaked out in the urine. In the setting of low Mg levels, the ROMK channel is more active and more K is leaked out leading to hypokalemia. Another reason that is mentioned is usually in the ascending loop of Henle. The secretion of K channels are ATP dependent( less ATP more open, more ATP less open) and low Mg levels can decrease the amount of ATP production and hence those channels are more open leading to K losses.
Correcting the Mg and fixing the intracellular Mg should fix the hypokalemia.
Other conditions that might be responsible for both losses such as diarrhea, or diuretic use like HCTZ should be considered as well.
Other electrolyte disorder you have to keep in mind is hypocalcemia. If there is severe hypomagnesemia, it is a stimulus for pth and secondary hyperparathyrodism then can lead to hypocalcemia.

Few good references
http://www.ncbi.nlm.nih.gov/pubmed/20395377
http://www.ncbi.nlm.nih.gov/pubmed/8057249
http://www.ncbi.nlm.nih.gov/pubmed/17804670
http://www.ncbi.nlm.nih.gov/pubmed/1444696

IN THE NEWS- VEGF and renal disease

A basic science article in KI 2010 June issue talks about the role of VEGF-A expression in podocytes. The induction of podocyte specific VEGF164 overexpression led to transgenic mice to proteinuria, enlarged glomeruli and mesangial expansion and podocyte effacement. When anti VEGF164 was administered, the effects reversed. This over expression of VEGF164 may be via an autocrine and paracrine VEGF-A signal.
This might be similar to what we see in Diabetic Nephropathy.

Few things.
This attests to the point that too much VEGF is bad for the endothelium and podocyte
Diabetes is a VEGF driven podocytic disease
A fine balance of VEGF ( subtypes unclear) is needed for good podocyte function. Too little might lead to a TMA or pre eclampsia like syndrome and too much perhaps a diabetes like disease or FSGS, more of a collapsing nature.
More of these studies hopefully will help us figure out the final niche of VEGF nephropathology.

The effect of Mycophenolic Acid (MPA) on donor specific Antibody (DSA) strength

The effect of Mycophenolic Acid (MPA) on donor specific Antibody (DSA) strength

The Extra Degrees!!!

The Extra Degrees!!!

CONSULT ROUNDS: CONTRAST and ESRD/CKD

Few things to consider and take home what was talked about at the rounds
The discussion was of contrast load and dialysis patients or CKD patients. Is this a real concern or an old myth now in this era. It was a concern in the days when the dye used was more and the osmolarity of the dye was different. The three reasons perhaps a radiologist might ask you to consult is the concern for fluid overload with the contrast, to prevent residual function in the ESRD patient or to prevent the toxic effects on non renal tissue.

Few take home points and a nice article link.

1. With the common use of low osmolar contrast, the amount of actual contrast entering the ECF is very minimal and studies have disproven the use of it for fluid overload concerns.
2. In terms of residual renal function, it might be an issue with PD as the GFR obtained with PD is 7-8cc.min and the residual function plays a major role. But in HD patients, GFR even if they make urine is around 15-16ccmin making the residual renal function less likely a concern. Post procedure HD was at favor at one time but due to lack of data, it is not routinely recommended at this point.
3. In terms of extra renal side effects, there are few case reports suggesting that but a study of 40 patients showed that there is no major extra renal side effects from contrast in ESRD patients.

Check out this reference:
http://www.ncbi.nlm.nih.gov/pubmed/17244114

TOPIC DISCUSSION: PHEOCHROMOCYTOMA

The case discussion this week in NEJM is renal centric. or one might even say Endo centric or HTN specialist centric!
Pheochromocytoma is a diagnosis that is hard to make, often thought about but never confirmed.
It is a popular diagnosis that medical students talk about , asked on the boards but we never see it
Fortunately, I have seen few cases of it and its clearly a tough diagnosis but the presentation is always different.
This entity can present to you in many shapes and sizes. Be aware and take a look at this nice article that talks about the many facets of a pheochromocytoma!
http://www.ncbi.nlm.nih.gov/pubmed/19242899

Rituximab for recurrent idiopathic Membranous GN

A recent article in CJASN 2010 talks about the role of anti CD20 agent in treatment of recurrent membranous GN. The article is a retrospective review and more of a case series of 4 patients that responded to rituximab for recurrent idiopathic GN.
Its a small group of patients as most of them that they had responded well to just anti proteinuric agents.
This is not unusual to see a small number of patients with recurrence of such diseases as some of the drugs we are using for rejection are also controlling the autoimmune disease.  But then why do some patients get it and some don't get recurrence. Perhaps it might have to do with compliance, the nature of their membranous disease or their age perhaps. When they compared the patients with recurrent membranous to ones without recurrence, nothing was significant( nor progression to ESRD, age, BUN, GFR, TP, proteinuria amount) except for albumin.
Interestingly, 3/4 patients with recurrent membranous that got rituxan also were on steroid sparing protocol.
Also, interesting to note, 10/15 that were recurrent were LRRTx and only 60% of them received induction treatment. I think even though those didn't meet significance,( perhaps due to small numbers), matter a lot.
Related relatives, steroid sparing and no induction could be possible risk factors for recurrence in any autoimmune disease, perhaps!
Something to ponder on

CD4 T cell lymphopenia is bad!

A recent article in JASN 2010 May edition talks about the prolonged CD4 T cell loss seen with thymoglobulin.
They studied the mortality and morbidity associated with this prolonged effect.  They evaluated >300 patients and found that if after 1 year the CD4 T cell lymphopenia was present, it was an independent risk factor for death in these patients. They suggest evaluating pre transplant thymic function and identifying these high risk patients.
If you now look at the the KDIGO transplant guidelines, that came out late last year, anti CD20 are the standard and first line choice to be used for induction and not thymoglobulin. Perhaps centers who use thymo for all their patients should re consider this. It should be from a case by case base and not just a protocol of a center.
As we are seeing more and more long survivors of transplant, things like infection and cancer have to be kept in mind and avoid the imbalance to shift.

Nice article

Nephrology Crosswords

Check out my first in series of Nephrology Crosswords. Fun way of Learning Nephrology!

http://www.nature.com/ki/journal/v77/n11/abs/ki201045a.html

CONSULT ROUNDS: Peritonitis

Peritonitis is a tough complication to deal with when someone is on PD. It is becoming rare as good practices are being done.
Few things we learned at consult rounds that are not any thing new but good points to keep in mind
1. Always get a PD fluid cell count, culture, gram stain
2. Don't forget, if frequent peritonitis patient:- get a fungal culture as well, check an amylase level
3. Think of perforation if multiple organisms are noted and pain is unbearable
4. Keep in mind catheter position. it might have moved??
5. In the right context, TB peritonitis is possible
6. Start standard gram positive( more common) than gram neg coverage. Choice of antibiotics can be based on the incidence of enterococcus and MRSA at your institution. Cephazolin + Ceftazadime or Vanco + ceftazadime  are good combinations
7. Gent can be used ONLY in patients with NO residual function
8. Heparin 500Units or 1000Units/ Liter bag for prevention of fibrin formation as well
9. Tailor your antibiotics to the culture results

A nice set of guidelines are set by the PD society
Check it out at http://www.ispd.org/lang-en/treatmentguidelines/guidelines

Drug coverage for transplant from Nephrologyworld blog

http://nephrologyworld.blogspot.com/2010/05/blog-post.html

Topic Discussion: ANCA Disease

The current JASN 2010 issue  has a special article on ANCA disease. A nice historical notation of the disease and where it stands currently
Few things I learned from this article
1. It was first mentioned in 1982
2. Awareness of Friedrich Wegener's connection to the Nazi has prompted efforts to remove his name from the disease entity. Initially, this disease used to be called Rhinogenic granulomatosis
3. Churg Strauss used to be called allergic granulomatosis
4. What activates the neutrophils by ANCA? A theory of second hit is thought about.  You have these antibodies ( ANTI PR3, ANTI MPO) and they are just floating around. A second hit, perhaps an infection or alteration in the immunologic mileau might trigger the ANCA disease.  
5. ANCA causes disease but what produces ANCAs? There  are three theories regarding this topic
           ---> Theory of autoantigen complement theory: the protein complementary to the autoantigen initiates an immune response and leading to increased risk of thrombosis
          ---> LAMP 2 theory: Patients with anti PR3 and MPO have been noticed to have antibodies to another neutrophil protein , lysosome associated membrane protein 2 or LAMP-2 ( analogous to fimH peptides on bacteria). So anti LAMP-2 antibodies could result from molecular mimicry and lead to anti PR3 and MPO antibodies. 
           ----> Neutrophils are surrounded by neutrophil nets and perhaps the MPO and PR3 may be available on the net for initiating an autoimmune response.
6. Summary of some major trials

1. MEPEX trial: JASN 2007 showed that for patients with ANCA vasculitis and Creatinine > 5.8 and on dialysis, plasmapheresis was helpful in taking them off dialysis and for renal recovery.
2. CYCLOPS trial: Large trial that compared oral vs IV cytoxan in ANCA vasculitis and there was no difference in end points for renal outcomes but there was less cumulative dose of cytoxan in IV dosing and less side effects.
3. CYCAZAREM trial: compared changing to Imuran after 6 months of induction with PO cytoxan to continuing cytoxan PO for 12 months, no difference in remission.
4. RITUXVAS:- RCT (small) IV cytoxan to Rituxan + initial 2 months of cytoxan IV — no difference in remission. More adverse events in rituxan arm
5. RAVE:- Rituxan + azathioprine for maintenance vs IV cytoxan plus azathioprine, induction part completed:- similar rates of remission and no major advantage with rituxan
6. NORAM:- compared Methotrexate in lieu of cytoxan, more relapse with Methotrexate.


In terms of maintenance, two trials, one comparing MMF to AZA showed AZA to be safer and less side effects. 
SO it the best treatment even till date for induction :- cytoxan and maintenance imuran?

IN THE NEWS- AGE and NEPHROSCLEROSIS

A cross sectional study in Annals of internal medicine recently reports the association of age and nephrosclerosis studying a very good population- the donors.
Over 1200 donors were looked at and core needle biopsies done at time of implantation and then medical records reviewed for risk assessment.
They found that the finding of nephrosclerosis was 2.7% in 18-29 years of age
16% for 30-39 and 28% for 40-49, 44% for 50-59, 58% for 60-69 and 73% for 70-77 years of age.
No other factors that are traditional risk factors for kidney disease had significance except age. So they conclude that kidney function and chronic kidney disease risk factors did not explain the strong association between age and their findings in these healthy adults.

A closer look at the study, Few things did predict the nephrosclerosis:- urinary albumin excretion, nocturnal blood pressure and treated hypertension.
Hence, urinary albumin is still a good predictor of kidney function
They speculate that nephrosclerosis may be in part of the underlying pathway by which increased urinary albumin excretion may predict the development of hypertension.
Another important point from this large study:- importance of nocturnal HTN and the non dippers and overall better control of the hypertensive disease.

Check it out

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.

CLINICAL CASE 13

Which is NOT a known treatment for CMV in solid organ transplants?
Valgancyclovir 0%
Gancyclovir 0%
IVIG 50%
Cytogam 0%
Leflunomide 33%
Maribavir 0%
Foscarnet 11%


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.
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.

IN THE NEWS: encapsulating peritoneal sclerosis

We don't talk about PD much. Here is a new PD related study on EPS.
This is the largest incidence and outcomes study on EPS.
Few take home points

1. EPS is rare and the incidence is 4% in 8 years and as low as 0.3% in 3 years
2. The predictors of EPS are younger age, and duration of peritoneal dialysis
3. The death risk is low

Check out this nice study on this enigmatic entity

Check out the Latest from the world of Pediatrics

Pediatric Nephrology Virtual Grand Rounds by Dr. Sethi

https://www.pediatric-nephrology.com/home/2010/05/08/199-pgrviii.html

TOPIC DISCUSSION: Interferon and the kidney

A recent review in KI May 2010 Issue discussed the role of both interferon Aplha and Beta interferon in the role of kidney inflammation. Both of these play a major role in anti viral and auto immunity but their role in the kidney is unknown.  Few points made by this review that were fascinating and shed some thought for research

1. All cells produce Type 1 interferons during viral infections but no data in renal cells
2. Type 1 interferons are also central mediators of SLE. Studies are on going to treat lupus with IFN gamma neutralizing antibodies
3. What about in HIVAN, the most widely studied virus and the kidney? Only one study reported increased intrarenal IFN-gamma production in human HIVAN biopsies compared with non HIV FSGS.  This local release is probably what we see as tubuloreticular inclusions in HIVAN biopsies.
4. No data exists in Polyomavirus and such inclusions bodies.
5. Extrarenal viral infections like Hep C can trigger an immune complex GN with increased IFN-gamma production.  What about in other immune complex diseases, some virus instigates an IFN response and triggers IgA and MPGN, no one knows.
6. IFN -alpha has been identified now as a central mediator in lupus. Hence the similarities with viral infections in terms of symptoms such as fever, athralgias might be interferon effect.
7. One way we use to figure out if the membranous or the kidney disease is idiopathic vs lupus is the presence of tubuloreticular bodies( hence an interferon effect)
8. So in summary, little is known about the immunomodulary role in renal inflammation. in some cases, its harmful and in some cases such as Hep C and Renal Cell, it helps. The authors suggest that perhaps measuring urinary interferon levels might shed some light on the extent an interferon mediated process is involved.

Check out some other references

http://www.ncbi.nlm.nih.gov/pubmed/19773191
http://www.ncbi.nlm.nih.gov/pubmed/15320958
http://www.ncbi.nlm.nih.gov/pubmed/11256746

New-Onset Diabetes Linked to Post-Transplant Hypomagnesemia - Renal and Urology News

New-Onset Diabetes Linked to Post-Transplant Hypomagnesemia - Renal and Urology News

New News on Belatacept

Currently calcineurin inhibitors are the gold standard for immunosuppression of solid organ transplant recipients.  Unfortunately long term CNI use is associated with both patient morbidity (HTN, hyperuricemia, hyperlipidemia, diabetes) and renal toxicity. 

Belatacept is a selective co-stimulation blocker (given IV), which binds surface costimulatory ligands (CD80 and CD86) of antigen-presenting cells.  After antigen recognition by the T cell receptor (signal 1), the interaction of CD80 and CD86 with the surface costimulatory receptor CD28 of T cells (signal 2) is required for full activation of T cells. Blockade of signal 2 inhibits T-cell activation, promoting anergy and apoptosis. 

The purpose of this study was to switch patients from maintenance CNI use to belatacept in order to reduce toxicity without compromising immunosuppression. 

Rostaing et al. randomized 173 patients (6-36 months post transplant) to remain on CNI based therapy or switch to belatacept.  Primary endpoint was change in EGFR at 12 months.  Secondary outcomes included rejection and safety outcomes.  At month 12 the belatacept group had an increase in GFR of 7 ml/min while the CNI group had an increase in GFR of 2.1 ml/min.  Patient and graft survival was 100% and 99% in the belatacept and CNI group respectively.  7% of the belatacept group had ACR vs. none in the CNI group (including grade IIa and IIb).  There were 3 cases of BK viremia in the belatacept group but none in the CNI group.  There were more fungal skin infections in the belatacept group.  PTLD was not seen. 

Conclusions/ Comments:  Authors concluded that switching to a belatacept based regimen was safe, associated with low risk of rejection and resulted in improved renal function.  However, there are several concerns with this study.  First, even the CNI group had an increase in GFR which does not occur in clinical practice.  Second, patients greater than 1 yr post transplant had a 7% rejection rate which is significant.  In fact, these rejections were not mild (several vascular rejections, all cell mediated).  BK viremia was also increased in the belatacept group and studies have proven that it has a poor prognosis.  Finally other studies with belatacept have been associated with PTLD and this is still a concern.  Longer term f/u is needed to compare graft survival and safety profile of belatacept compared to CNI’s, however belatacept therapy may be beneficial in a subset of patients.  Of note, several experts believe too high of a dose of belatacept may lead to both overimmunosuppression and rejection by blocking negative costimulatory pathways.  Proper dosing may be key in reducing rates of rejection and opportunistic infections.

By Vinay Nair