Nephrology Crosswords: Dyskalemias

Try the next crossword in Kidney International:  The theme this time is Dyskalemias
http://www.nature.com/ki/journal/v81/n8/full/ki20125a.html

In the News: Telomeres and HIVAN

Why is HIVAN or idiopathic collapsing glomerular disease different than standard FSGS? It is more proliferative compared to a podocytopenia seen in other forms of FSGS.  The questions have been thrown out there multiple times.  Studies in past have shown that the podocytes in the collapsing variant are premature form and then proliferate.  Telomerase protein is responsible for aging.  Two components called TERT and TERC are important.  A study showed that transgenic TERT expression in mice induced up regulation of Wnt signaling and leading to disruption of glomerular structure and resulting in collapsing glomerulopathy.  Then they showed that the humans and mice had increased expression of the TERT and activation of Wnt signaling in HIVAN models.   This was inhibited by a Dkk1( inhibitor of the Wnt expression).  The pathology changes were reversible.  Interesting, as this suggests that the process might be reversible.  Perhaps medications that use a Dkk1 might help? This adds to a novel understanding of collapsing GN that was not known before.

Take a look at this paper from Stanford and Columbia group
http://www.ncbi.nlm.nih.gov/pubmed/22138751

History of Erythropoietin development

1878: Bert and Jourdanet described symptoms of anemia and mountain sickness from hypoxia
1906: Carnot and Deflandre observed that serum from an anemic donor rabbit injected in normal rabbits resulted in increased erythropoiesis.  It was initially called hematopoietin: potential circulating factor
1953: Erslev demonstrated that plasma from anemic rabbits contained a factor capable of stimulating erythropoiesis and predicted its potential as a treatment modality. Did a quantitative infusion study regarding this notion as well.
1957: Jacobson and other such as Goldwasser found that the kidney was the source of this hormone that controlled the production via experiments with each organ being removed in animals.
1985: Few milligrams of erythropoietin from over 2.5L of urine of patients with aplastic anemia was collected and purified by Miyake et al
1985: The human erythropoietin gene was cloned
1985: Eshbach et al had the the first treatment of someone with initially just 2.5 units/kg on dialysis followed by no response and then increased dose of 15 units/kg with good response leading to potential treatment success.
1985: Mass effort to large scale production
1989: FDA approves recombinant EPO for use in chronic renal failure patients on dialysis
1990: FDA approves recombinant EPO for use in chronic renal failure without dialysis and other non renal causes.

A good references that summarize as above is
http://www.nephrologyrounds.org/crus/nephUS_0304.pdf

ASN 2012

Bundling and the DOPPS data

Currently as we bundle along the dialysis treatment and anemia treatment along with IV medications and antibiotics needed for dialysis access care, future is looking at 2014 to possibly include sensipar.  It also appears that there might be a switch to giving more PO vitamin D rather than IV Vitamin D during dialysis as well.
How is this going to affect the patients? Most of our dialysis patients take many medications already.  Asking them to take more PO medications will be a concern.  Lot of these questions will arise. Lot of these questions arose when bundling was first proposed.  Did the renal community do ok with the bundling. Recently at a local NKF meet, Dr. Jay Wish presented the DOPPS data that is freely available on their website at http://www.dopps.org/annualreport/index.htm on different parameters.

Some interesting findings in Anemia and bone disease and hospitalization:
1. Average Hgb has decreased in USA after the June 2011 ESA labeling from 11.4 to mean of 11.2.  IN general, the range is narrowing and very few percentages are >12 and <10.  
2. Sharpest decline was in the patients with Hgb greater than 12g/dl
3. Mean epo dose decreased by 15% from 2010 to 2011 August, greatest happening after June 2011.
4. IV Iron use has risen
5. Serum ferritin levels are rising in some cases, >1200 ng/ml in 11%

Pth/Bone disease
1. No major changes in pth levels, continue to increase ( as bar was raised to 600 from 300)
2. No change in use of sensipar
3. Small units using more PO vitamin D rather then IV vitamin D

Hospitalization rates have increased in last one year( cause unknown)

take a complete look at the PDF on their website.

IN THE NEWS: Stem cells and transplantation

Stem cell transplantation and Kidney transplantation has been tried at few centers now as a form to minimize immunosuppression. But inducting with autologous mesenchymal stem cells is a novel thought. A randomized controlled trial just published in JAMA from China and Miami, Florida.  A single center, prospective, open label, randomized study was done from 2008-2009.  The intervention arm had patients inoculated with marrow derived autologous mesenchymal stem cells at the time of kidney repercussion and then 2 weeks later.  They then received either low dose calcinuerin inhibitors or regular dose.  The control group got anti IL-2 induction and standard dose calcineurins inhibitors.
Acute rejection at one year was the major outcome they measured.  At 30 months,the patient and graft survival was same in both groups. Overall, there was less rejection, less infections and better renal function at one year in the stem cell arm compared to standard arm.  Initial recovery of renal function after surgery was also faster in stem cell arm.

This study is a first of its kind and will spark some major centers in US to hopefully consider this modality  to be tested again. Before we move to this as a true replacement for induction treatment, this needs to be reproduced at other centers.

Take a look. Hoping one of the renal journals might have a commentary on this soon
http://jama.ama-assn.org/content/307/11/1169.short

MPGN revisited

This week in the March 2012 issue of NEJM, Sethi and Fervenza discuss a must read article on MPGN. All the recent advances in MPGN and so called C3 glomerulopathy have been reviewed in this article.

Key points
1. EM based approach should be abandoned.  IF based approach seems more logical.
2. Immune complex mediated vs complement mediated MPGN and then looking for secondary causes.
3. Immune complex mediated usually has circulating Immunoglobulin and immune complexes and the big 3 categories are infections, autoimmune disease and MGUS. IF will show C3 and some immunoglobulin.
4. The complement based MPGN usually have capillary wall staining for C3 deposits, then  look at the EM --> if sausage shaped deposits think dense deposit disease and if not then C3 glomerular disease. Both of these are a result of dysregulation of the alternative pathway of complement.
5. Recurrence after transplantation is fair amount, The highest being if this MPGN was associated with MGUS.

Take a look at this nice summary on MPGN
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/22435371

iSediment Feature

Urine microscopy study is very important part of training of residents, and fellows in Nephrology.
The Kidney Doctor website has a nice feature that is worth looking at and here is a collection of all of them so far online on sediment evaluation.

Check out the isediment on the Kidney Doctor.

IN THE NEWS: Hypertension and Kelch like 3 and cullin 3

A recent letter in Nature revealed some interesting findings about Pseudohypoaldosteronism type II (PHAII), a rare syndrome featuring hypertension, hyperkalaemia and metabolic acidosis.  The authors used exome sequencing to identify recessive or dominant mutations in kelch-like 3 (KLHL3) or dominant mutations in cullin 3 (CUL3) in PHAII patients from 41 unrelated families.  KLH3 and CUL3 are expressed in the distal nephron perhaps why this allows for the features we see in this syndrome.  When given thiazides, the disease features were reversed.  
This letter showed that a novel way of exome sequencing could diagnosis new mutations that lead to hypertension.  


Check out the full letter at:
http://www.ncbi.nlm.nih.gov/pubmed/22266938

Acetaminophen and hypertension?

We know about NSAIDS and hypertension. Is there anything about acetaminophen(AT) and hypertension?

One group of researchers looked at this question.

They compared effect of 1gm three times a day of AT to placebo on well controlled HTN with CAD.
2 week follow up was done.  Ambulatory monitoring of BP was done for 24 hours to see changes and endothelial function tests were also done. N =33.  The average BP was higher in AT group with statistical significance b 3/2mmHg.  Heart rate also increased by 2 beats/min.  The biomarkers of endothelial damage, renin and aldosterone levels were unchanged in both groups.

Interesting but so far - only one study, small group of patients, only in one center.  A change of BP doesn't seem that significant. We will have to see what else comes out in the future.

Ref:

http://circ.ahajournals.org/content/122/18/1789.long 

CLINICAL CASE 53: Answers and Summary

A 45 Y OLD CAUCASIAN MALE IS SEEN AND YOU DIAGNOSE IDIOPATHIC CALCIUM OXALATE STONE DISEASE. THE STONE FORMATION BEGINS AS SURFACES OF THE RENAL PAPILLAE START COLLECTING SUBUROTHELIAL PLAQUES CALLED RANDALL PLAQUES. WHERE DOES THIS PROCESS BEGIN?

Proximal Tubule  17%
Thin Loop of Henle 30%
Thick Loop of Henle 12%

Distal Collecting Duct 33%

Glomeruli 5%

The correct answer is Thin Loop of Henle.  

http://www.jci.org/articles/view/17038 is the article that made this point with a nice study of biopsies around the plaque sites. They performed intra operative biopsies of plaques in kidneys with calcium stone formers.  They showed this in their paper that the plaques originated in the basement membranes of thin loops of Henle and spread to the interstitum and then the urothelium.  In the patients with obesity related bypass procedures, the stones and plaques were different and instead had intratubular crystals in the collecting ducts.  

The figure 1 and figure 2 from an editorial nicely depicts it.

Topic Discussion: IgM Nephropathy

1. Initial was seen in 1978, 12 cases reported.
2. Pathology findings: mesangial proliferation, diffuse granular C3 and IgM, EM with foot process effacement and mesangial deposits ( exclusion criteria includes FSGS and Lupus Nephritis or systemic vasculitis)
3. Appears like minimal change with mesangial deposits - so steroid resistance is clinical picture as well
4. More common in children than adults
5. There is debate in the literature if this entity is real vs a part of spectrum of minimal change disease or immune complex GN with mesangial deposits.
6. Post transplant recurrent cases have been reported.
7. IgM deposition without accompanying deposits or renal dysfunction or proteinuria has been noted in many cases of donors.
8. Some studies have shown circulating IgM heavy molecules( aggregates and immune complexes ) in the serum in IgM nephropathy.

http://www.ncbi.nlm.nih.gov/pubmed/12552495
http://ndt.oxfordjournals.org/content/19/10/2650.full
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541770/

Detective Nephron strikes again

IN THE NEWS--> Detective Nephron's next venture

Check out the March issue of ASN Kidney News 2012 for the next venture of the detective

http://onlinedigeditions.com/publication/?m=15191&l=1

Take a look at the entire series so far at

http://www.nephronpower.com/p/detective-nephron-seriesasn-kidney-news.html

Topic Discussion: Renin production

The JGA apparatus and renin production in the special smooth muscle cells of the afferent arteriole.
What are the 3 mechanism by which renin production is increased?

1. The Blood pressure monitor in the baroreceptors that notice the decrease in blood flow.
2. The chemo receptors in the macula densa that check for the Na flow in the distal nephron.
3. The baroreceptors in the carotid sinus report back to the nervous system to activate the sympathetic fibers that then activate b1 adrenergic receptors in the JGA to tell the cells to produce renin( hence beta blockers help in renin mediated hypertension)

eAJKD: Nephrology revival

For World Kidney Day: Post your comments on
http://ajkdblog.org/2012/03/08/nephrology-a-revival-for-2012/

World Kidney Day 2012

Today is World Kidney Day.  Lets take this day and pay respect to all patients who are living with kidney disease day and night.  Lets take this time to honor the family members that are also involved in the care of the patient with kidney disease.  In the last 4 decades, the kidney disease community has come a long way. Somewhere along the way, many lives were touched and many lives changed.  The care of the kidney patient is much different now then it was 50 years ago.




What we have now:
1. A much more affordable treatment modality that can sustain life with dialysis in the ESRD patient.
2. Much more successful and sophisticated outcomes of kidney transplantation.
3. More treatment options for glomerular diseases
4. A better understanding of anemia and bone disease in ESRD and CKD

Some Major Breakthroughs in Nephrology in last decade:

1. More dialysis is better and the data keeps pouring in on that.
2. APOL1 gene story for AA and FSGS
3. Membranous Nephropathy is not idiopathic anymore
4. Rituximab for ANCA vasculitis and Lupus Nephritis
5. The knowledge of the T regulatory system in transplantation and glomerular diseases
6. Anemia and the Hgb target changes due to novel findings of CREATE and CHOIR
7. Late vs early initiation of dialysis question perhaps answered?
8. sUpar as the cause of FSGS
9. Pre eclampsia is a VEGF related disease that effects the kidney
10. C3 glomerulopathy and its impact on how we view MPGN pattern of injury

Happy World Kidney day

Image courtesy: as stated above

ASN new podcast for Kidney day 2012

ASN Kidney News Podcast:
Immunosuppressive Legislation

In recognition of World Kidney Day 2012 (Thursday, March 8^th) ASN speaks with Michelle Josephson, MD (Chair, ASN Transplant Advisory Group) and William Applegate (lobbyist for the American Society of Transplantation) about immunosuppressive drugs and legislation to extend anti-rejection drug therapy.

Download Episode

IN THE NEWS: FSP-1

 Urinary FSP1 as a possible acute glomerulonephritis biomarker.  Apparently when you have renal injury, it leads to accumulation of fibroblast specific protein 1 (FSP-1) in the kidney and this could serve as a biomarker. A paper in JASN showed that this urinary FSP-1 was elevated significantly more in crescentic GN and later even became undetectable after treatment.  The authors suggest that it could be screening test for active GN.  Interestingly, the same group had found this elevation in diabetic nephropathy as well,  Take a look at the original paper in JASN.  Is it really? or is it a marker of podocyte damage. Take a look at similar paper now using FSGS showing that it might reflect detachment of foot processes. The same authors have shown that this entity is EMT in tubular interstitial fibrosis.  And HIVAN as well.  Is FSP1 measurement as measuring podocyturia? Or are we truly getting to a potential urinary marker?

Kidney Education- in many Indian Languages( gift for World Kidney Day 2012)

First Kidney Education Website in Indian languages to ANIO Website.

www.KidneyEducation.com - website will be Unique Gift on World Kidney Day.  Brief information about website

·       First kidney website of world in Five Indian languages

·       Most popular medical website of India, 3.6 Million Hits in just 16 Months

·    The website provides facility to read and print 200 paged kidney guides in Hindi, English, Gujarati, Marathi and Telugu language for free. These kidney guides for patients in Indian languages are first and one of its kinds in the country.

·      First kidney website where information about All Major Kidney problems is available at single click.

·      Noncommercial website. No advertisement. No financial support from pharmaceutical companies for website.

 

From,

Dr Sanjay Pandya   

Nephrologist         

Chief Mentor, Kidney Education Foundation , India 

www.KidneyEducation.com

Hypernatremia and Acute Myeloid Leukemia

Electrolyte abnormalities have been seen with AML. Severe hyponatremia associated with SIADH secretion has occurred at presentation. Hypokalemia is a more frequent finding at presentation and is related to kaliuresis. Hypercalcemia can occur. Severe lactic acidosis prior to treatment has been reported. Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur. But hypernatremia secondary to a diabetes insipidus (DI) is rare but has been described. 
Interestingly, this phenomenon( mostly central) has been seen with certain cytogenetics in AML.  
It appears that when you have monosomy 7 variant of AML, it can also lead to in some cases a central DI. Sometimes CDI might be the primary event presenting the AML. Prior literature is not clear the association of this and doesn't appear its CNS involvement but perhaps a genetic association.  Literature reveals many abstracts when you google and pubmed this entity. 
Typically,one would think that the combination of DI and AML is associated with structural abnormalities of the neurohypophysis. But there are cases presenting without any abnormalities of the neurohypophysis on radiological scanning and with normal cerebrospinal fluid examination. AML may directly result in dysregulation of transcription factors resulting in development of DI in AML patients.
One study even compared monosomy 7 with DI and AML and without DI, the group with DI had a 
poorer outcome. 
This association is hard to understand and why this is the case?


Ref:
http://www.ncbi.nlm.nih.gov/pubmed/19380027
http://www.ncbi.nlm.nih.gov/pubmed/3319680
http://www.ncbi.nlm.nih.gov/pubmed/1398517

ASN POLICY PRIORITIES 2012