TOPIC DISCUSSION: The BAMBI tale of the Kidney

What is BAMBI? and why is that important for Nephrology?

BAMBI (BMP and Activin Membrane Bound Inhibitor) is considered to influence TGFβ and Wnt signaling, and thereby fibrosis.  Recent basic science studies have shown that this molecule might be important in the role of fibrosis and how can manipulate fibrosis. In zebrafish a role for BAMBI was identified in platelet-endothelial interaction and thrombus formation after endothelial injury. Prior studies in liver cirrhosis and connection with TGF-B, studies have shown that BAMBI downregulation leads to enhanced profibrotic effects of TGF-B. So in other words, BAMBI is a check point and perhaps a gatekeeper for TGF-B'd pro fibrosis.  

One recent study found that BAMBI localizes to endothelial cells in the kidney and that it was a protein that is regulated by lysosomal and autolysosomal degradation. BAMBI expression restricted to vascular compartments, such as the glomerulus and renal blood vessels in the kidney, and mostly all in endothelial cells.

This might lead to potential ongoing studies that might shed some light on the brakes and acceleration that might be seen with TGF-B and why some people have extensive fibrosis and some don't. Besides that, perhaps the role of this entity in thrombotic microangiopathy and other endothelial cell related diseases might be interesting to see as well.

For a full ref check out: 

http://www.ncbi.nlm.nih.gov/pubmed/20886049 

http://www.ncbi.nlm.nih.gov/pubmed/17661381

IMMUNOSUPPRESSION IN THE ELDERLY: WHATS THE BEST INDUCTION AGENT???

The incidence of elderly patients with ESRD is increasing, as is the number of elderly listed for kidney transplantation. In fact, we are transplanting more and more elderly patients over the age of 70. Studies suggest that the elderly have excellent graft survival, possibly due to a less robust immune response, but unfortunately still have a higher mortality than younger patients. This dichotomy led me to wonder what the best immunosuppression is for the elderly. Logic would suggest they need less intense induction immunosuppression to avoid infectious complications. At the same time however, perhaps more intense induction can reduce the incidence of rejection and allow reduced maintenance immunosuppression (such as steroid free or low CNI) improving both infectious and cardiac outcomes. Reviewing the literature led me to 3 interesting papers on induction immunosuppression and outcome in the elderly.

Two studies were registry analysis^1,2 and one was a single center study³. The registry analysis compared 3 agents: IL-2 inhibitors (anti-CD25), antilymphocyte globulin (thymoglobulin), and alemtuzumab. They suggested worse outcome with alemtuzumab compared to thymoglobulin or anti-CD25. Although outcomes with thymoglobulin and anti-CD25 were similar, thymoglobulin had a lower incidence of rejection and surprisingly revealed a trend to better patient survival! This was especially prevalent in high risk recipients whom also enjoyed better graft survival. It is possible that this effect is due to less maintenance immunosuppression and less requirement for high doses of immunosuppression to treat rejection. The single center study evaluated different cumulative doses of Thymoglobulin and outcome within different age groups. What they found was elderly (age > 60) patients had a reduced survival if they received > 6mg/kg of Thymoglobulin.

Looks like low dose thymo induction wins again!

References:

1. Clin J Am Soc Nephrol 2011;6: 1168-1178 PMID:21511836

2. Am J Nephrol 2011; 34:534-541 PMID:22104284

3. Clin Transplant 2011;25:E250-E256 PMID:21231963

Nephro-Pathology.com

Nephropathology is a topic that is dear to all nephrologists. A good website just appeared that might be a good resource to help us all get better at it.

http://www.nephro-pathology.com/index.html

take a look

CLINICAL CASE 50: Answers and Summary

WHICH OF THE FOLLOWING ARE POTENTIAL CAUSES OF DEATH IN DIABETIC KETOACIDOSIS(DKA?)

Hyperkalemia	11 (15%)
Aspiration	1 (1%)
Hypokalemia	17 (23%)
Relative hypoglycemia	2 (2%)
Underlying lesion and complications	1 (1%)
All of the above	40 (55%)

Diabetic Ketoacidosis is a common entity that we encounter often leading to ICU level of care.  Standard treatment is usually volume expansion, insulin to stop ketoacid production.  As you give therapy with fluids and insulin, plasma glucose will fall, HCO3 will rise but slowly, ketoacids will decline, anion gap will close, plasma K will decrease, Na will increase and Phos will decrease. 

The five big reasons of complications in treatment of DKA are hyperkalemia that is present during admission and if not treated right away with insulin.  Due to the coma state sometimes, aspiration is likely.  As one starts treating, the K will drop and replacement with IV KCL is important.  6-8 hours later, relative hypoglycemia is also a major contributor and finally making sure the underlying cause of going into DKA is found and treated:- infection perhaps or whatever it might be. So all of the above is the correct answer.

For a good review on this topic: please read the short book:

The ACID Truth and BASIC facts with a SWEET touch, and enLYTEnment by Mitch Halperin, MD
by Rossmark Medical Publishers, 2004, Ontario, Canada.

HISTORY LESSON: Story Behind Central Pontine Myelinolysis

Central Pontine Myelinolysis(CPM) is now well established to be associated with over correction of hyponatremia. It is very interesting to note how that came about. Historically, this is a very fascinating story. Here it is in a bulleted summary.

1959: Adams et al described CPM as a potential disorder. They found it in alcoholics and malnourished and chronically ill individuals. They called it "new disease" and no cases reported prior to those years.
1963:  Aleu and Terry noted that perhaps an iatrogenic agents were involved and that it happened predominately in the hospital setting.
1966: More lesions identified and not localized to the Pons.  It became evident by observation that all had chronic conditions such as liver disease, sepsis, burns, and cancer.
1977: Burcar et al identified 15 cases and 12 had hyponatremia. Overall, 61% of cases of CPM were associated with hyponatremia.
1979: Messert et al made the most important observation that CPM was recognized only after the advent of IV fluids therapy in the late 1950s.  ( reminds us of the MRI and gadolinium association )
1979: Kevin Leslie, a pathology resident was doing an autopsy case of CPM in a jaundiced patient.  He noticed a striking green discoloration in the PONS- likely secondary to breakdown of BBB leading to albumin bound bile pigment to get there.  Review of literature confirmed this in many CPM cases.
1979: Scott Venderberg, pathology resident was reviewing a CPM case.  He mentioned; " could this discoloration be due to osmotic stress?".  This bought to light if the correction of the Na was the factor and not the Na itself.
1980-82: 15 cases of CPM with hyponatremia were reviewed and found that all 15 cases had experienced a 20-30meq/L rise in serum sodium in 3-10 days ( mean of 6 days) before CPM developed.
1982: Similar findings were confirmed in rats made hyponatremic and then given hypertonic saline quickly.
1984: patients with hyponatremia for a short period of time( hours to a few days) did not develop CPM but patients with chronic hyponatremia did.

This is a fascinating history and great discovery. This points to a great observation power of these individuals and putting it together and what is now common knowledge in the Nephrology world.

For a complete reference: http://www.ncbi.nlm.nih.gov/pubmed/20182780

New drug labels for kidney disease patients -- what do they mean?

Check this out on anemia in ckd :New drug labels for kidney disease patients -- what do they mean?

Are dialysis patients at an increased risk of GI bleed? is this the same for PD and Hemo patients

Ju-Yeh yang et al published this study at JASN; titled
"Trends in Acute Nonvariceal Upper Gastrointestinal
Bleeding in Dialysis Patients".
in this study the authors shed some light on why Hemodialysis patients have higher recurrence and 30-day mortality of acute Non-varecial upper Gi bleeding. it's an interesting approach from an epidemiologic point of view where they site Lenient and stringent definitions, and other ways of looking at outpatient management of GI bleed and including those to the total tally. however; they offer some added risk factors that Hemodialysis patients are especially exposed to which may explain the high recurrent and mortality of upper GI bleed that they face. these include; "

Advanced age, male sex, and certain medications (such as
antiplatelet or anticoagulant agents".
of note; they mention that some of the reported increased in GI Bleed in these patients may be due to vigilant coding of these occurrence Because of the added financial incentive of reporting GI bleed under the new billing system.
for the full text go to JASN . http://jasn.asnjournals.org/content/early/2012/01/18/ASN.2011070658.full.pdf+html]

IN THE NEWS: LUNAR TRIAL

The LUNAR trial that compared using rituximab to placebo for treatment of Lupus Nephritis is finally in publication.  It was a well designed randomized trial that wanted to show the impact of Rituximab given at 4 doses of 1gm each along with steroids and MMF with Class III and IV compared to a group with no rituximab arm.  At one year, there was no difference in complete or partial remission.  The "lab values" of C4 and C3, and dsDNA were much improved in the rituximab arm but patient outcomes didn't change.
Interestingly, this study suggests that there might be no secondary role for treatment of Lupus with rituximab if MMF and steroids are being used. Steroids were not spared in the rituximab arm, so its hard to see what would have happened if there were no steroids.  Also, authors state that the power was not strong enough for better outcomes.

Judge for yourself. Does anti CD20 agents have a future in Lupus Nephritis?

Ref: http://www.ncbi.nlm.nih.gov/pubmed/22231479

FDA Approves Glucarpidase to Reduce Toxic Levels of Methotrexate

"The FDA has approved glucarpidase (marketed as Voraxaze) to lower toxic levels of methotrexate related to kidney failure. Cancer patients may develop kidney failure when treated with high doses of methotrexate. In a study of 22 patients receiving glucarpidase, 10 patients had methotrexate levels fall below a critical level within 15 minutes and stay low for 8 days. The drug eliminated 95% of methotrexate in all patients."

This should be a resourceful drug for our patients; especially those who receive intrathecall/IV MTX and get kidney injury where we often have to do dialysis due to the toxic levels; so potentially saving patients from dialysis and it's complications.

IN THE NEWS: Soluble FLT-1 and ANCA... Not just pre eclampsia!

A recent study published in the Feb JASN 2012 issue showed that there is an elevated soluble FLT-1 that is inhibiting the endothelial repair of PR3 ANCA vasculitis.  This is very interesting as sFLT-1 now is not just associated with pre eclampsia.  Vasculitis causes endothelial damage. VEGF is a factor that leads to endothelial repair. The authors show that in the PR3 ANCA vasculitis state, the VEGF factors are inhibited by sFLT-1 and leads to decreased endothelial repair and hence worse vasculitis.
sFLT1 are elevated in placental vascular dysfunction and pre eclampsia. sFLT1 is produced by placental cytotrophoblasts but also monocytes and endothelial cells and it inhibits VEGF.  This study is interesting as it showed that sFLT1 was elevated in patients with PR3 ANCA vasculitis and this was due to monocyte activation activating the alternate complement components. They were increased in anti GBM and anti MPO disease but not significantly as in patients with anti PR3 related disease when compared to controls in their experiment. Interestingly, postulated that anti sFLT1 agents might be useful.

Take a look at the full reference
http://www.ncbi.nlm.nih.gov/pubmed/22034638

ANAGRAMS: Secondary causes of ANCA disease

Check out a fun way to learn Nephrology using anagrams on secondary causes of ANCA disease.
Test your knowledge at eAJKD.

eAJKD PODCAST: APOL1 and the Kidney

http://ajkdblog.org/2012/01/12/podcast-genetic-association-and-gene-gene-interaction-analyses-in-african-american-dialysis-patients-with-nondiabetic-nephropathy/

Nephrology Crosswords: Interventional Nephrology

http://www.nature.com/ki/journal/v81/n3/pdf/ki2011373a.pdf

TOPIC DISCUSSION: Atypical ANCA and it's significance?

Three types of positive ANCA are reported: C-ANCA, P-ANCA and atypical ANCA, based on the staining pattern of the neutrophils in the immunofluorescence assay.

C-ANCA: A coarse, clumpy, granular cytoplamic staining of neutrophils, which is usually associated with anti PR3 antibodies

P-ANCA:  A perinuclear staining pattern of neutrophils which is usually associated with anti MPO antibodies. The presence of some anti-nuclear antibodies (homogeneous ANA) may interfere with ANCA testing and invalidate the reporting of P-ANCA. In this situation, an indeterminant result is reported.  However, ANA do not usually interfere with ELISA testing.

Atypical ANCA: Patterns of neutrophil cytoplasmic and / or perinuclear fluorescence  other than the two above, which  occurs when neutrophil antigens other than MPO or PR3 are the antibody target.

Confusion arises when p-ANCA and c-ANCA are negative and so is MPO and PR3 but then you get an atypical ANCA positive. The indirect immunoflourescence (IIF) is the above test used and is not that good as the ELISA.   When the IIF and ELISA are used,  here is a specific things can arise:

1. C-ANCA positive:- suggestive of Wegener's Granulamatosis(WG), Microscopic polyangitis( MPA) or Churg Strauss(CS) - usually ELISA with MPO and PR3 is then performed to confirm

2. P-ANCA positive:- suggestive of MPA, and some times WG and CS. Again ELISA is needed.

3. Atypical ANCA positive:- Not associated with WG, MPA or CS.  Usually seen with chronic inflammation, bowel diseases and other autoimmune diseases. ELISA still needed to make sure no MPO or PR3 positivity is noted

4. ANCA negative:- Treated or inactive WG, MPA or CS. 

5. ANA positive, P-ANCA positive, C-ANCA negative:- Can be secondary due to +ANA. Again MPO and PR3 are needed

6. PR3 negative, MPO negative, +atypical ANCA:- Could be chronic infections, inflammatory bowel diseases, or autoimmune diseases ( usually not ANCA disease)

7. C-ANCA Positive, PR3- ++:- Active WG or MPA or CS
8. C-ANCA Positive, MPO ++:-Active MPA and sometimes CS or WG

9. Atypical ANCA +, PR3 +, MPO +:- Inflammatory bowel disease, doesn't occur in WG or MPA or CS

10. Atypical ANCA+, MPO+++:- Usually not seen except perhaps drug induced vasculitis

Take a look at this special article to get a more complete review of this specific testing.

http://www.ncbi.nlm.nih.gov/pubmed/14502794

eAJKD: Anemia story

Check out the latest commentary by Fishbane and Hazzan on eAJKD.
Also, look at their commentary in Nature Nephrology on similar article.

eAJKD: Interest in Nephrology declining

Interest in Nephrology is declining. Many of us are using new interventions to increase that interest. How do you measure that? Take a look at Tejas Desai et al in eAJKD blog.

IN THE NEWS: Face Transplantation

Many decades ago, the first human kidney transplant was done at BWH Hospital and ever since then multiple organ transplantations have happened- including liver, lung, heart, small bowel and so forth.

The field of transplantation has expanded so rapidly and hard to keep up with the newest developments. 

One of the Indian Hindu Gods, Ganesha can be considered the first xeno transplantation and hence certain books mention his story at the start of the history of transplantation.  Ganesha is the elephant head with the human body who's surgeon was Lord Shiva. Lord Ganesha is considered the God of wisdom and knowledge and good luck. Of all the prayers, a Ganesh Prayer is the first prayer usually performed at most Hindu ceremonies.  

I once read a very interesting interpretation of Lord Ganesha. Of all the Gods in Hindu mythology, he is very overweight. Perhaps he was on steroids for this transplant.  He is always shown in a picture next to his favorite mouse: perhaps a subtle hint of research done even back then on mice on transplantation. Finally, after surgery, Lord Shiva has given elixir drink to Lord Ganesha speculating perhaps that was the ancient version of "thyme" or "simulect"

In the midst of this, last last issue in Dec 2011 of NEJM sheds light on face transplantation. They report a series of 3 patients with complete successful face transplantation.  Similar induction as kidney transplantation was used with thymoglobulin and same triple drug regimen for maintenance regimen.  They present their data case by case with good follow up and steroids withdrawn in all cases.  

Take a look at the full article

http://www.ncbi.nlm.nih.gov/pubmed/22204672

http://www.iloveindia.com/spirituality/gods/ganesha/legends.html

Detective Nephron: Next venture

Explore the next case of the detective in the Jan 2012 issue of ASN Kidney News

eAJKD: Hypertension, hypokalemia and MPGN

http://ajkdblog.org/2012/01/03/hypertension-and-symptomatic-hypokalemia/

CLINICAL CASE 49: Answers and Discussion

A 45 y old male with Membranous Nephropathy moved to Nepal and started living in a high altitude region. Which of these statements regarding his kidney function at high altitudes are true?

His proteinuria will decrease	4 (6%)
His renal blood flow will increase by 8-20%	24 (39%)
He shall excrete less bicarbonate	17 (27%)
Hypoxia inducible factor 2alpha is stimulated and that leads to decrease erythropoietin production	10 (16%)
He is at low risk for cardiac complications at high altitudes from his CKD	6 (9%)

The only closest correct statement in the above is number 2( renal blood flow will increase by 8-20%). Even that is false if we look strictly at hypoxia vs high altitude. 

The above question refers to the high altitude renal syndrome(HARS).  Over 140 million people live at altitudes >2400ml under hypoxic conditions and that can have physiologic renal effects. 

Subjects that live at high altitudes have increase HIF production that leads to increase erythropoietin production and polycythemia.  Interestingly, as the Hct rose, one study found that proteinuria and microalbuminuria also increased ( perhaps due to increase filtration fraction). Subjects also developed larger glomeruli.  Interestingly, hyperurecemia and hypertension was also noted. Given increased HTN and proteinuria, cardiac complications increase. 

Renal blood flow (RBF) increases 8 to 20% during acute hypoxia, then returns to baseline after several days. The effect on GFR is similar. In high-altitude residents, RBF is decreased 12% and renal plasma flow by 30 to 40% largely as a result of secondary polycythemia. Because the filtration fraction increases by 39%, however, GFR falls by only 12%. In addition, whole organ oxygen delivery, arteriovenous content gradients, and consumption are also maintained at levels equal to sea-level values. 
Acute hypoxia generates acute hypocapnia. Over several days, the kidneys increase bicarbonate excretion to compensate for this respiratory alkalosis, thereby blunting the inhibitory effect of respiratory alkalosis on the hypoxic ventilatory response and improving oxygenation over time at altitude. 


Check out the two really good references:
http://jasn.asnjournals.org/content/19/12/2262.long
http://www.ncbi.nlm.nih.gov/pubmed/21566053

IN THE NEWS: Which glomerular disease is highest risk for venous thromboembolism?

Nephrotic syndrome puts at risk for DVT and Renal vein thrombosis. Data to anti-coagulate is weak and not consistent.  A recent paper in Jan 2012 issue of KI shares some interesting information.

1. 1313 patients were evaluated( different diagnosis- membranous, IgA, FSGS)
2. 63 month follow up was noted
3. The risk of venous thromboembolism was highest in Membranous GN followed by FSGS compared to IgA Nephropathy.
4. Gender, cancer, proteinuria and serum albumin were adjusted.
5. So instead of degree of proteinuria - it was associated with a specific disease type such as Membranous GN.
6. Why is that?  and if so do we need to give anti coagulation?


Interesting study
take a look at the free KI paper for full review:
http://www.nature.com/ki/journal/v81/n2/full/ki2011312a.html

Consult Rounds: Renal disease in Retroperitoneal Fibrosis (RF)

Retroperitoneal fibrosis (RF) is a rare disorder that has many risk factors such as radiation, asbestos and others, but now might fall into a set of diseases called IgG4 related systemic disease. IgG4 has been associated with many organs - mainly RF, autoimmune pancreatitis and skin involvement. Renal involvement is significant as well.  It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. 

The main renal manifestations are:

1. Tubulo interstitial disease. 30% of patients with autoimmune pancreatitis have interstitial renal involvement. Usually have elevated serum IgG4 levels. They have tubular basement membrane deposits. See references below for details. Staining for IgG4 plasma cells might be beneficial in the kidney.

2. Glomerular disease: Usually Membranous GN, IgA Nephropathy

3. Obstructive disease( most common):- due to mass effect of RF.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/17827834

http://www.ncbi.nlm.nih.gov/pubmed/21898030

Kidney Transplantation Induction Quiz Answers

Alemtuzumab	A. This anti CD25 human/ mouse chimeric antibody is almost devoid of side effects. It does not increase the risk for malignancies or infections.
Rituximab	B. This antibody has been used in a recent trial to facilitate positive crossmatch transplantation in living donors by blocking the effector pathway of antibody mediated allograft injury.
Thymoglobulin	C. This agent is used to treat antibody mediated rejection and as induction in sensitized individuals. It decreased the production of anti-HLA antibodies by targeting the CD 20 receptor on B cells and plasma cells.
Daclizumab	D. This antibody targets CD 52. It is FDA approved for the treatment of CLL. It is often used in minimization protocols for kidney transplantation.
Basiliximab	E. This agent when used as an induction agent may increase the risk of cellular rejection.
Atgam	F. This polyclonal antibody preparation targets many different receptors on T cells. It increases the risk of PTLD, and CMV compared to no induction or anti-CD25 induction. However, it has been shown to be a superior agent in reducing rejection episodes and prolonging graft survival especially in high risk individuals.
OK3T	G. This polyclonal antibody preparation came from horses. It has since been largely replaced by another polyclonal T cell preparation.
Eculizumab	H. This agent was a humanized monoclonal antibody that targeted the alpha chain of the IL-2 receptor of T-cells. The manufacturer discontinued its use in January 2009.
	I. This monoclonal antibody against the T-cell receptor was the first such antibody used for any clinical indication in the United States. Its current use has been minimized due to severe adverse reactions including serum sickness and pulmonary edema.

Answers:

Alemtuzumab: D Alemtuzumab is FDA approved to treat CLL. It targets CD 52 and results in B and T cell depletion. It has been used as an agent to facilitate steroid free transplantation, and had similar outcome to Thymoglobulin in the recent INTACT trial (N Engl J Med. 2011 May 19;364(20):1909-19. PMID: 21591943).

Rituximab: E Rituximab is a monoclonal anti-CD 20 antibody that targets B cells. It has been used to treat antibody mediated rejection and in desensitization protocols. It does not however, target plasma cells (which is why answer C is incorrect). In non-sensitized patients, Clatworthy et al. found the risk of cellular rejection to be much higher when using rituximab as an induction agent compared to dacillizumab (83% vs. 14%) (N Engl J Med. 2009 Jun 18;360(25):2683-5. PMID: 19535812).

Thymoglobulin: F Thymoglobulin is the most common induction agent used in the USA. It is created by immunizing rabbits with human thymus. This results in a potent polyclonal T cell depleting agent which reduces the risk of rejection but also increases infectious and malignant complications.

Dacilizumab: H

Basiliximab: A Basilizimab and Daclizumab have been shown to reduce the risk of rejection in the first year post transplant (Lancet. 1997 Oct 25;350(9086):1193-8 PMID: 9652559). The anti-rejection effect is not as potent as anti-lymphocyte globulin however, basiliximab does not increase the risk for infections or malignancy.

Atgam: G Atgam has been largely replaced by Thymoglobulin in the U.S.

OKT3: I

Eculizumab: B A recent trial by Stegall et al. found Eculizumab to help abrogate a positive flow cytometry crossmatch in living donor kidney transplantation(Am J Transplant. 2011 Nov;11(11):2405-13. PMID: 21942930). It is FDA approved to treat paroxysmal nocturnal hemoglobinuria (PNH) and works by blocking complement component C5.