Virtual Grand Rounds in Nephrology- E nephrology

As we are seeing, there is a blossoming of E -Nephrology tools and one such is the Pediatric Nephrology website and what they refer to as Grand Rounds. It is a fascinating feature of their blog and we have been pasting links of their ongoing grand rounds that helps not only the pediatric but adult nephrology field as well.  Take a look a fascinating article on this very concept.

http://www.springerlink.com/content/h523q12p6t1r8265/

ASN's review on the ESRD bundling

The ASN has created a special website and a pdf summary of the ESRD bundling and will continue to review the 900+ article.

http://asn-online.org/policy_and_public_affairs/esrd-bundling.aspx

Please have a look at the website. The summary is helpful.

TOPIC DISCUSSION: EFFECT OF PROTEINURIA on combination treatment

The role of combination blockade has been now come to question at least in the non nephrotic proteinuria world.
But there were some simple questions we wanted answered?
When you have someone on ACEI, and you add an ARB, what additional reduction in proteinuria do you get?
--> It actually is around 25% more reduction or 0.5g/dl additional reduction in proteinuria. This was extensively studied in one paper listed below. In another study, it was around 39% compared to ACEI monotherapy.
What about the effect on GFR?
--->Usually the fall is 4 ml/min
What about the effect on SBP and DBP?
--->Usually fall of 5mm/hg in both with the addition.

http://www.ncbi.nlm.nih.gov/pubmed/17367311
http://www.ncbi.nlm.nih.gov/pubmed/16797382
http://www.ncbi.nlm.nih.gov/pubmed/18468748

Poem from Pediatric Nephrologist

Check this out on CKD

https://www.pediatric-nephrology.com/daily-updates/2010/07/30/252-ckdpoem1.html

TOPIC DISCUSSION: ACE induce angioedema replaced by an ARB

Th e questions stems from the fact that many of us struggle to use or refrain from using an ARB in patients who have ACE induced allergic reaction specifically angioedema. Here is the data with references --

1) http://www.ncbi.nlm.nih.gov/pubmed/15111379 - Arch Intern Med. 2004 Apr 26;164(8):910-3. "Only a small percentage of patients with ACE inhibitor-related angioedema continue with this symptom when switched to an ARB."

2) http://www.ncbi.nlm.nih.gov/pubmed/17225721 - Ann Allergy Asthma Immunol. 2007 Jan;98(1):57-63. " The mean time to onset of angioedema after initiation of therapy in 51 patients was 1.8 years. Also, none of the 6 patients, whose angioedema was attributed to an ACE-I who then received an ARB, developed recurrent angioedema in more than 8.1 patient-years of follow-up. "

3) http://www.ncbi.nlm.nih.gov/pubmed/19055203 - Ann Allergy Asthma Immunol. 2008 Nov;101(5):495-9. This is the meatanalysis I was referring to - " Any article that described a cohort of patients who had angioedema after taking an ACE-I, were subsequently exposed to an ARB, and were followed for a least 1 month were included. The risk of angioedema was 9.4% (95% confidence interval, 1.6%-17%) for possible cases and 3.5% (95% confidence interval, 0.0%-9.2%) for confirmed cases. CONCLUSIONS: Limited evidence suggests that for patients who develop angioedema when taking an ACE-I, the risk of development of any subsequent angioedema when taking an ARB is between 2% and 17%; for confirmed angioedema, the risk is 0% to 9.2%. This information will aid clinicians in counseling patients regarding therapy options after development of angioedema due to ACE-Is."

Please feel free to share or comment if you have some other ideas or data to share.

Thanks,

Arun Chawla, MD

Nephsap review: Chronic Kidney Disease : CKD patients are more likely to have proximal coronary lesions???

Did you know that patients with CKD are more likely to have proximal coronary lesions on coronary angiography? This is well summarized in Charytan,et al study in KI 2008. This is in comparison to distal lesions
the pathogenic mechanism behind it might the time that is not enough to form collaterals, uremic mileau, and perhaps other unknown reasons.

Interesting

http://www.ncbi.nlm.nih.gov/pubmed/18818684

Nephsap review: Chronic Kidney Disease: Troponin T vs I in CKD

On review of Nephsap 2009 CKD, here is an interesting topic of discussion that came up after a question we reviewed.
Hayeshi, et al studied the utility of using cardiac troponin t as a tool for predicting asymptomatic coronary artery stenosis in CKD patients on renal replacement therapy. The primary finding was that cardiac troponin t was a more potent independent predictor of asymptomatic multivessel coronary artery disease in late stage CKD patients. This raises an important point and makes us wonder will we be using troponin t as a screening tool for asymptomatic coronary artery disase in the future? Further studies are needed to help us with this.
First we need to understand the different troponins in the picture.

Troponin is a component of thin filaments and is the protein to which calcium binds to accomplish this regulation. Troponin has three subunits, TnC, TnI, and TnT. 

• Troponin C binds to calcium ions to produce a conformational change in TnI
• Troponin T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
• Troponin I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place.

Some centers use Tropnin I and some T, both are very sensitive and specific for cardiac events.

The question is which one is better in CKD patients.

Another study by Fehr et al in Clinical Nephrology showed that for diagnosis of ACS in HD patients, a combination of cTnT and cTnI may be used, since the former has higher sensitivity and the latter higher specificity. A higher threshold value for cTnT in HD patients could further increase its diagnostic accuracy.

Interesting the differences in the studies, one with CKD and other with ESRD.

http://www.ncbi.nlm.nih.gov/pubmed/18403432

http://www.ncbi.nlm.nih.gov/pubmed/12572929

Bundled Payment for ESRD

Check out the latest blog by Bill Peckham regarding the release by CMS on the dialysis payment schedule

http://www.billpeckham.com/from_the_sharp_end_of_the/2010/07/cms-releases-final-dialysis-payment-rule.html

2010 North American Dialysis and Transplantation (NASDAT) Meetings — Highlights

2010 North American Dialysis and Transplantation (NASDAT) Meetings — Highlights

Hematuria and Donation?

Donating a kidney is a very noble thought.  We usually screen for hematuria in the donors.  Aysmptomatic hematuria is 13% in general population.  Are donors with asymptomatic hematuria safe to donate?
This question is a tough one with no specific answers.  A recent study in AJT July 2010 tries to answer this question in a retrospective study.  8.3% of kidney donors in 8 years of their evaluation had persistent hematuria pre donation that increased to 15% after donation and when persistent was associated with hypertension, proteinuria and renal damage.  The authors go ahead and conclude that donation of someone with persistent hematuria is not ideal. What is persistent? Months or Years? Its usually on repeated testing at this point. Can be more than 2-3 tests in a short period of time or long period of time.


An editorial in the same issue takes a look at this question of possible donation in such cases.
An approach is suggested( no evidence but just opinion)
1. Repeat testing , assess for proteinuria and a 24 hour CRCL to make sure there is no renal damage. any indication of the above two would halt the donation
2. Nephrology assessment independent of the transplant center as a donor advocate.
3. Role of kidney biopsy might be helpful to help discern an occult IgA Nephropathy or genetic diseases such as Alport's Disease. Family members who have hematuria who are donating should raise concerns of potential genetic causes that might be the same cause in the recipient.  
Living donor Transplants from relatives in Alport families is an ambivalent option. Based on one study in NDT 2009, proteinuria should be an exclusion criterion. Even in these donors with isolated hematuria, families and their physicians should be aware of an increased risk of renal failure in donor and recipient. Careful donor evaluation with a potential need of kidney biopsy might help make the decision easier.


This is a tough question that is hard to answer with any hard data. If there is alternate donor with NO hematuria, that would be ideal.


Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20353466
http://www.ncbi.nlm.nih.gov/pubmed/20642672
http://www.ncbi.nlm.nih.gov/pubmed/19028755

TOPIC DISCUSSION: Do Peritoneal Dialysis patients sleep well?

A question was raised regarding the sleep quality in PD patients --
So here is what I found-

1) Sleep disturbances occur in 45% to 88% of patients on peritoneal dialysis.
2) Incidence/prevalence is no different from there peers on HD.
3) OSA needs to ruled out on most of these patients.
4) Most common reported symptoms are daytime sleepiness, fatigue, sleep latency and frequent nighttime awakenings.
5) Most common causes are - OSA, machine related prob & alarms, difficulty finding comfortable position, depression, psychosocial factors, marital status and abnormal melatonin release and sleep-wake cycle. Most of the above reasons are common to both HD and PD patients.


References:http://www.ncbi.nlm.nih.gov/pubmed/12092125
http://www.ncbi.nlm.nih.gov/pubmed/7579084
http://www.ncbi.nlm.nih.gov/pubmed/10832657
http://www.ncbi.nlm.nih.gov/pubmed/17984430
http://www.ncbi.nlm.nih.gov/pubmed/18427944
http://www.ncbi.nlm.nih.gov/pubmed/19596605

At least from the above information I feel confident about a patient's sleep quality and concerns would be no different weather they choose HD or PD.


Arun Chawla, MD

Renal Fellow Network: Deciphering the pathologists secret code!

A nice post from a pathologist tip on the RFN

Renal Fellow Network: Deciphering the pathologists secret code!: "I will share with you some of the tips I learned from my pathologist friend Ibrahim Batal. When evaluating an allograft kidney biopsy for ac..."

TOPIC DISCUSSION: TIDAL PD

Tidal Peritoneal dialysis introduced in 1990 is a technique in which an initial infusion of solution into the peritoneal cavity is followed after a short dwell time with drainage of only a portion of the dialysate.Part of the dialysate also referred to as the "reserve volume" remains in constant contact with the peritoneal membrane.Rationale to introduce this technique was to improve dialysis efficiency by reducing time lost during inflow and outflow of dialysate and to improve clearances because of the constant contact between dialysate and peritoneal membrane although no study has shown any conclusive evidence to support or refute above due to numerous variables that affect dialysis efficacy and small sample size in each study.
Tidal volume during this modality should be kept as high as possible especially in those with low average peritoneal transport rates.
Its role may be limited in the present time to provide comfort to the patient owing to fewer alarms and less pain during inflow and outflow with the significant drawback of need for higher dialysate volumes and therefore higher incurred costs.
References
Tidal peritoneal dialysis:comparison of different tidal regimens and automated peritoneal dialysis.KI,Vol 57(2000),2063-2607
The role of tidal peritoneal dialysis in modern practice:A european perspective KI Suppl.2006 Nov;(103):S96-S103

TOPIC DISCUSSION: DEXA SCAN in TRANSPLANT PATIENTS?

Osteoporosis is a disease that is devastating especially if someone gets a fracture from it. Being on steroids is considered a risk factor for development of osteoporosis.  What are the recommendations for DEXA scan for transplant recipients? Are they different from general population and are they different if you get a steroid sparing protocol?

Dual energy X ray absorptiometry ( DEXA) is recommended in all women that are post menopausal and men with risk factors( age, smoking, so forth).  Treatment is based on number of risk factors and a T score < -2.5.
When I reviewed the Nephsap on transplantation from 2006-2009, DEXA is recommended for transplant recipients on the assumption that they are now a general population.  A study in AJT in 2008 linked here showed that DEXA was useful in predicting fractures in Kidney Transplant patients.  The risk of fractures for those with osteoporosis and osteopenia were three and a half times  and two and a half times respectively  compared to normal Dexa scan patients.  When to do these scans is not really defined.  Should we do one scan prior to transplantation? one right after transplantation and one every 2 years is not really clarified? This needs more work in the field. 


Based on the American College of Rheumatology, patients  begining therapy with glucocorticoid (prednisone equivalent of 5 mg/day) with plans for treatment duration of 3 months should modify risk factors and be on vitamin d and calcium replacement but patients on long term therapy, should do the above plus receive a DEXA and if abnormal, treat and repeat annually or biannually.  Should we be treating our post transplant patients similarly as the ACR recommends? Perhaps so?


The KDIQO recently put out a transplant patient treatment guidelines. Under Chapter 21: Transplant Bone disease, they suggest measurement of bone mineral density in the first 3 months after kidney transplantation if they receive steroids or have risk factors for osteoporosis as in the general population with Grade 2D evidence. They go ahead to mention that if they do have low bone density, to treat with vitamin D, Calcium and possible bisphosphanates( grade 2 evidence).  But treatment decision might depend on pth, 25-oh levels and other parameters that go along with CKD.  Bone biopsy might be considered but not recommended.   The guidelines also mention that there is not enough data to guide treatment after first 12 months.  If the transplant patient is CKD stage IV-V, DEXAs not needed to be performed as this might be different from general population.

So, the bottom line is get a DEXA at least once post transplant and treat like a general population. Follow up scans yearly might be prudent to do but there is no evidence yet.




References:
http://www.rheumatology.org/practice/clinical/guidelines/osteoupdate.asp
http://www.ncbi.nlm.nih.gov/pubmed/18853956


Image source:
https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEilb7pJUOS3xKA-V74lbDmFkCyyiHpcccOr2dTLMZ9exzGWa_PJNTuh0ZcFtRD0icWKFE5znae7mXa_S91Bwm8XDVUGlS3QM9iCcK5I9rSpUXqb_Nlag53nOZ4I4YRjINLp-xVTEUAFnNI/s1600/typical_fractures.jpg

CLINICAL CASE 21, ANSWERS AND SUMMARY

Which solution has the higher osmolality(mmol/L)?

Normal Saline 19%

LR 8%

D5W 5%

D10W 66%

Most of you got it right but it seems that there was some of you thinking of Normal Saline as the higher osmolatlity.  Lets break this down. Let's start with D5W.  D5W contains 5gm of dextrose in 100ml or 50gm in a Liter.  Since the Molecular weight is 180gm, the osmolality is 278mmol/L. This is isotonic to plasma.

Similarly, for D10W, it would turn out to be 556mmol/L. This is relatively hypertonic to plasma.

Normal Saline is 9gm of Nacl in 100ml or 90gm in a liter leading to an osmolality of  308mmol/L which is also isotonic. LR is also isotonic and has an osmolality of 274mmol/L.

So strictly in terms of OSMOLALITY, the highest is D10W.

When you give a dextrose based solution, regardless of the concentration or osmolality of the solution, the distribution of that solution in the body is equal in all compartments. Keeping the 60/40/20 rule in mind of water distribution, only 80 ml of a Liter of the dextrose solution remains in the intravascular space or plasma.

Compared to Normal Saline or LR, when you give a liter of it, 250cc of it remains in the plasma, making it more of a volume expander.

0.45% normal saline will be a mix of both ( 40cc of D5W and 125cc of Normal Saline ) leading to 165cc of it remaining in the plasma.

I would highly recommend the book by Dr. Joel Topf  called The Fluid, Electrolyte and Acid-Base Companion to understand this concept better.  

The basics of chemistry and electrolytes is simplified very well in his book. His blog is at http://www.pbfluids.com/ as well 

Plagiarism In Application Essays????

A recent study in Annals of Internal Medicine noted that 5.2% of a single center application pool was plagiarizing personal statement essays.  The study demonstrated that non US graduates, previous residents or fellows, lack or research experience, lack of volunteer experience and lack of publication, low USMLE step 1 score and non AOA status were all associated with increases chances of students attempting to go to plagiarism.

This is alarming. A lot of this might be as mentioned in the article due to internet boom.  There are many websites that use sample essays for even medical profession and students can be cutting and pasting to their "personal" statement. It isn't personal anymore is it?  Some students don't view using cyber methods as plagiarism but some refer to it as "cyber" plagiarism.  All specialities involved- internal medicine, surgery, ob/gyn, anesthesiology and emergency medicine saw similar findings in this study.

The ACGME views professionalism as one of the core competencies. Plagiarism is not being professional.
Students, residents, physicians, writers should not resort to it.  A personal statement is personal and should come from within you and from your experiences and not of " cyber" experiences. If you need help, there are individuals out there to help you write a statement that reflects yours thoughts and views.  The editorial rightly states in the same journal to be more vigilent about these tactics as program directors and reviewers of applications.

Image source: http://sociology.camden.rutgers.edu/jfm/plagiarism/plagiari.jpg

References:
http://www.ncbi.nlm.nih.gov/pubmed/20643991
http://www.ncbi.nlm.nih.gov/pubmed/15726686

Micro RNAs and Transplantation

A novel concept has been emerging in the last few years regarding micro RNAs.  It already has reached some human data in transplant patients.
What is micro RNA?  These are non coding areas of the RNA that play a critical role in regulation of gene expression. They might alter the structure and lead to either expression or regression of the protein in question.
There is mice data that microRNAs play a role in immune response, adaptive immunity, inflammation, fibrosis and epithelial changes.  The role of microRNA will help us understand intracellular signalling, expression of proteins, modulation of cytokines, and graft response better.
Few simple examples are: miR 155 regulates immune response to bacterial infections and viral infections and helps in the crosstalk macrophage becoming an activated macrophage.  Myeloid stem cell goes to becoming a mast cell due to miR 223; and so forth.
What is more fascinating is the role of this in Transplantation.  How can this be useful in transplantation? they can be measured in serum, urine and plasma.  Two studies have now shown that the micro RNA pattern in the in renal allograft biopsies is different in acute rejection episodes vs controls.
The future looks good:- These might be good panel of markers for allograft status.  Therapeutic use of this application in altering the microRNA enviornment might be of advantage to prevent fibrosis or rejection.

Image source:
http://universe-review.ca/I11-38-microRNA.jpg

Good references:
http://www.ncbi.nlm.nih.gov/pubmed/20574417
http://www.ncbi.nlm.nih.gov/pubmed/18346642
http://www.ncbi.nlm.nih.gov/pubmed/19289845

IN THE NEWS: Anabolic Steroids and FSGS

Anabolic Steroid Use can now be considered a secondary cause of FSGS. FSGS can result "from a combination of postadaptive glomerular changes driven by increased lean body mass and potential direct nephrotoxic effects of anabolic steroids." Take a look at the link.

http://www.ncbi.nlm.nih.gov/pubmed/19917783

CLINICAL CASE 20, ANSWERS AND SUMMARY

In this syndrome, kids usually present with neurogenic bladders, severe voiding difficulties, constipation, leading to chronic hydronephrosis and CKD at early age. A characteristic feature is a facial abnormality, they seem to be crying as they smile . 

Dent's Disease  0%

Geller Syndrome 4%

Ochoa Syndrome 52%

Denys Drash Syndrome 14%

Fraiser Syndrome 28%

Lets take one by one. 

Dent's Disease is usually associated with an "electrolyte disorder"

related disease. It is an X linked recessive disease that affects the proximal tubules of the kidney. Kids usually have extreme thirst, nephrolithiasis,and hypercalciuria.  Fanconi syndrome, kidney stones, tubular proteinuria and CKD are hallmarks of the disease. Due to a proxmial RTA, kids get rickets. By mid adulthood, one can get CKD-ESRD.  Amiloride and HCTZ might be beneficial in treating the disease.

Geller Syndrome is an extremely rare disorder that usually presents in pregnancy. It is caused by missense mutation in the mineralocorticoid receptor(MR) leading to severe hypertension with hypokalemic metabolic alkalosis can occur. This entity should be suspected in a previously normotensive patient who develops severe hypertension and hypokalemia during pregnancy, particularly during second and third trimester, when progesterone levels are high. Spironolactone is ineffective as the mutated receptor is not blocked by it. Patients should be managed with antihypertensive agents. Subsequent to delivery, when progesterone level normalizes, patients become normotensive again.

Denys Drash Syndrome is characterized by the following conditions: gonadal dysgenesis,diffuse mesangial sclerosis and FSGS with high risk of Wilm's Tumor. Clinically, they have loss of playfulness, decreased appetite, weight loss, growth delay, abnormal skeletal development, insomnia, abdominal pain, constipation as well. Electron microscopy reveals hypertrophic mesangial cells surrounded by an abundant mesangial matrix, which often contains collagen fibrils. The podocytes are hypertrophied and contain many vacuoles. There is also irregular effacement of foot processes with focal detachment of the epithelial cell from the glomerular basement membrane.

Fraiser Syndrome also causes FSGS. Frasier syndrome presents at birth with male pseudohermaphroditism (the external genetalia have a female appearance despite an XY genotype), streak gonads and progressive glomerulonephropathy (focal segemental glomerulosclerosis). Patients are also at increased risk of genitourinary tumours (usually gonadoblastoma). The glomerulonephropathy presents later than in Denys-Drash syndrome, and the tumour risk phenotype is different - whilst DDS is associated with Wilms' tumour, Frasier syndrome is associated with gonadoblastoma. Most present at puberty.  Phenotypically they are female with amenorrhea, XY karyotype.

The correct answer is Ochoa Syndrome: or Urofacial syndrome.  This is a rare autosomal recessive disorder associated with both lower urinary tract and bowel and a particular facial expression. When they are asked to smile, it appears that they are crying.  They usually have neurogenic bladder or obstructive kidney disease.  Neurological exam is normal.  Its not a muscular thing, its a structural facial defect.  They usually lead to CKD by adulthood.  Most patients are not diagnosed.  Take a look at a recent Make your diagnosis in Kidney international

Image sources:

http://ndt.oxfordjournals.org/content/vol20/issue10/images/large/gfh968f2.jpeg

http://www.vibaku.com/wp-content/uploads/2009/09/hypertension.jpg

http://www.nature.com/ki/journal/v53/n6/thumbs/4490197f4th.gif

http://atlasgeneticsoncology.org/Kprones/Images/FrasierFig2.jpg

http://www.sjkdt.org/articles/2003/14/1/images/SaudiJKidneyDisTranspl_2003_14_1_61_33089_2.jpg

Pediatrics Grand rounds continue

Check out the Pediatric Grand Rounds for this month from Dr.Sethi

https://www.pediatric-nephrology.com/home/2010/07/19/244-pgrx.html

CONSULT ROUNDS: Severe Pre eclampsia

Severe Pre eclampsia and eclampsia can occur post partum leading to severe HTN and intracranial damage. Preeclampsia, the syndrome of hypertension and proteinuria that heralds the seizures of eclampsia, remains one of the great mysteries in the field of obstetrics.

It is a diseases of the placenta and the kidney is a major target. Endothelial damage is the hallmark of the disease. Preeclampsia is characterized by a constellation of signs and symptoms, including the new onset of hypertension and proteinuria during the last trimester of pregnancy, usually associated with edema and hyperuricemia.  It occurs only in the presence of the placenta, even when there is no fetus (as in hydatidiform mole) and remits dramatically postpartum. The placenta in preeclampsia is usually abnormal, with evidence of hypoperfusion and ischemia. Severe Pre eclampsia is even more dangerous and it almost leads to termination of pregnancy or delivery. 20% of the cases of both pre eclampsia and eclampsia can be post partum.

Risk Factors :

Nulliparity

Multiple gestation

Molar pregnancies

Older maternal age

Obesity

Family history of preeclampsia (paternal side)

Preexisting hypertension

Chronic renal disease

Diabetes mellitus

Thrombotic vascular disease

Clinical Findings :

The clinical findings of severe preeclampsia are unified by the presence of systemic endothelial dysfunction and microangiopathy, in which the target organ may be the brain (seizures or eclampsia), the liver [the hemolysis, elevated liver function tests, and low platelet count (HELLP) syndrome], or the kidney (glomerular endotheliosis and proteinuria).

Renal dysfunction, proteinuria, and renal pathology

Preeclampsia is associated with a characteristic glomerular lesion, "glomerular capillary endotheliosis” or “bloodless” glomeruli which is a similar lesion seen in Thrombotic Microangiopathy or injury post use of avastin. The pattern of injury is MPGN like, but there are no deposits. Nephrologists have taken an active role in this disease and now we know that the state of this disease is due to decreased VEGF in the body. A factor called placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. Studies now have demonstrated that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia. Also, when you have a VEGF knockout mice, you also get a similar renal pathology as you see in pre eclampsia.

by 

Deepti Torri, MD

http://www.ncbi.nlm.nih.gov/pubmed/17127249

http://www.ncbi.nlm.nih.gov/pubmed/15882253

http://www.ncbi.nlm.nih.gov/pubmed/12618519

Image sources: http://www.nature.com/ki/journal/v71/n10/images/5002318i2.jpg

http://cmbi.bjmu.edu.cn/news/0303/Protein%20for%20High-Pressure%20Pregnancies_files/200330621.jpg

Milk and CKD

Check out this nice blog on Kidney Diet Tip talking about milk substitutes.

http://kidneydiettips.davitablogs.com/?p=716

Transplant/Immunology Quiz 3 answers

Which one of these are risk factors for Post Transplant New Onset Diabetes Mellitus ( NODAT)?
HLA Mismatch 20%
CMV infection 40%
Hep C infection 40%
Sirolimus 40%
Calcium Channel Blockers  10%
Hypomagnesemia 20%
Elevated uric acid 30%
CNI use 70%
Metabolic syndrome 70%



Most of you got it right, all above are risk factors except Calcium Channel Blockers.
NODAT is a common metabolic complication seen in post transplant patients as we are seeing these patients living longer and longer.
It has been linked independently as a risk factor for cardiac disease post transplant.
Lot of research has been done in this field and numerous physicians have done work on identifiable risk factors and hoping to decrease its
incidence.
The list I am going to put below is from a recent review in Nature Review Nephrology and might not be wholesome but covers most of the
known risk factors.
The non modifiable ones are: Age, African american race, Family history of DM, DM as a cause of ESRD. Interestingly, patients with
Glomerulonephritis and ADPKD leading to ESRD had increased risk of NODAT, male gender, HLA mismatch( weak association),
genetic, innate immunity( alteration in it post transplant), cadaveric donor, male donor, education.
The modifiable risk factors are: Previous stress related diabetes, obesity, metabolic syndrome, post transplant high TG level, CMV infection
(affecting the Beta cells directly), Hep C infection, tacrolimus > cyclosporine( direct pancreas effect), sirolimus, steroids, rejection episodes( perhaps
due to more steroid use), anti hypertensives( beta blockers, HCTZ), hypomagnesemia( 2 studies so far), hyperurecemia( one study so far), decreased
GFR.

This is interesting to me personally and we have showed ( in a very small study) that hypomagnesemia might be related to RAPID NODAT, within the
first three months of transplant. There is one large study out of Europe that showed this link before and there is animal and human data on direct
association of insulin resistance and hypomagnesemia as well.

Some good references:
http://www.ncbi.nlm.nih.gov/pubmed/20498675
http://www.ncbi.nlm.nih.gov/pubmed/17198258
http://www.ncbi.nlm.nih.gov/pubmed/20177345
http://www.ncbi.nlm.nih.gov/pubmed/15023151
http://www.ncbi.nlm.nih.gov/pubmed/19624560
http://www.renalandurologynews.com/new-onset-diabetes-linked-to-post-transplant-hypomagnesemia/article/169297/

Rituximab and Cyclophosphamide: A Tale of Two Treatments

Rituximab and Cyclophosphamide: A Tale of Two&nbsp;Treatments

Take a look at this nice editorial on The NEJM blog about the two recent trials that just got published in NEJM this week.

The RAVE and the RITUXIVAS trials, both comparing Rituximab to Cyclophosphamide for treatment of ANCA vasculitis.

Both trials were of different protocols and time lengths, but included both p and c ANCA disease.
It comes to many as a surprise that Rituximab is not as promising as we thought once it might be. It is if not at least equal to standard of care cyclophosphamide therapy in this case. Rituxivas found rituximab was not superior to its counter part and had the same adverse degree of events. The RAVE found that rituximab was not inferior but atleast equal to its counterpart.

Take a look at the editorial as well

http://content.nejm.org/cgi/content/full/363/3/285?ijkey=V4BEGNbUdj5pY&keytype=ref&siteid=nejm

CONSULT ROUNDS: HUS/TTP During Pregnancy

Is there evidence that Plasma Excahnge or pheresis works in HUS/TTP or TMA of pregnancy?
This is hard to define as TMA during pregnancy can be from many causes, APLAS syndrome, ADAMTS 13 inhibitor mediated, pre eclampsia, HELLP syndrome and Severe HTN mediated.
First and foremost, 20% of it can happen Post partum, need to rule out APLAS syndrome as well


Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome complicating pregnancy is associated with high maternal mortality and long-term morbidity. Preterm delivery and intrauterine fetal death are frequent complications of these pregnancies. Improved survival after this disorder has been attributed to aggressive treatment with plasma transfusion or plasmapheresis.If one knows that the ADAMTS13 inhibitor is positive, TPE will be of some help. Otherwise what is the evidence for the rest. well, there is only one paper( case series that looks at this). It talks about  pre and post partum TTP and its a case series of 11 patients and TPE did show some survival benefit. I have listed the reference below.
So at this point, one would treat with TPE and send of ADAMTS 13 levels and inhibitor levels and continue TPE if there is an inhibitor for sure. But do we continue TPE if this is severe HTN or pre eclampsia induced TMA, probably not?
At this point, don't think there is much evidence for TPE but that's all we have. More work needs to be done in this area.




Reference
http://www.ncbi.nlm.nih.gov/pubmed/8885753c

IN THE NEWS: FACTOR H REPLETION in Atypical HUS

Deficiency of Factor H can lead to two diseases that we can think of : Dense Deposit Disease and Atypical HUS.
As Nephrologists, we share a lot with the immunology and the hematology world and have to know basics of those disclipines to understand certain diseases.
Factor H is a regulator of the alternative pathway.  If deficient, one can have uncontrolled C3 activation and leading to secondary C3 deficiency and C3 deposition in the kidney as well. When Factor H knockout mice were developed, they got secondary C3 deficiency, and a renal disease that showed massive accumulation of C3 along the glomerular basement membrane.  A recent mice study in Kidney international( link below) showed that when these knockout mice were given infusion of factor H, there was rapid normalization of the C3 levels in the plasma and resolution of the renal disease.  
Interestingly, they couldn't treat the mice long term as they developed an immune response to the factor H itself.  
This is a nice study that showed a proof of concept of replacing just Factor H in these patients.
Take a look at the Pediatric Nephrology Blog regarding another review on current available therapies and all updates from Dr.Sethi( HUS expert)
https://www.pediatric-nephrology.com/home/tag/hus.html

References:


http://www.ncbi.nlm.nih.gov/pubmed/20445496
http://www.ncbi.nlm.nih.gov/pubmed/20606628

Leflunomide and liver failure

The FDA just expanded the black box warning on leflunomide( ARAVA), a drug that is sometimes used to treat BK Nephritis in Transplant patients. A recent report showed 49 cases of severe liver toxicity from 2002-2009. Usually the reactions were noted in the first 12 months post use of the drug.  The greatest risk occurred in patients taking other drugs that may cause liver damage while taking leflunomide and in patients with preexisting liver disease. 

This comes as a shock to some of us in the transplant community as we do use this medication for treatment of BK Nephritis. There is so little in the form of treatment available for BK, this black box warning might make leflunomide not a very user friendly drug anymore. 

TOPIC DISCUSSION: Gadolinium and NSF- How to image high risk patients

NSF caught the nephrologist community by surprise with its initial identification in 1997 and had a formal description as a unique entity in 2001. The cause of NSF eluded diagnosis, but it happened only in patients with kidney disease and the culprit was the magnetic resonance contrast enhancing imaging agent. Gadolinium(Gd) has paramagnetic properties that disturb relaxation of water protons and by shortening relaxation it increases signal intensity, making it an excellent contrast agent. For safe use of the contrast-enhancing benefits of Gd, the metal must be sequestered by an organic ligand. In general, there are two major categories of ligand, linear and macrocyclic, are based on biochemical structure. And based on the animal data, linear based agents tend to have significantly higher tissue concentration and hence long term retention in comparison to macrocyclic based agents. Renal clearance of Gd approximates creatinine clearance in normal individuals. and have a terminal half life of 1.3 to 1.6 hours. The terminal half life increases in patients with CKD stage 3 (4-8hrs) and stage 4(18-34hrs). Agents with a component of liver clearance have a terminal half life of 6.1 to 9.5 hrs with stage 3 and 4 CKD respectively.

Gd serum elimination using hemodialysis is approximately 74% with 1 treatment, 92% with 2 treatments and 99% after 3 treatments. PD is relatively ineffective in Gd removal

Who is at Maximum risk? - Notably, no cases in stage 1-3 CKD have been confirmed in the published literature so far. In the HALT-PKD and CRISP studies, patients with ADPKD stages I through 3 CKD underwent 1111 Gd exposures with no occurrence of NSF. A total of 592 patients who had stages 3 through 4 CKD were exposed to Gd also did not develop NSF. 88 patients who had stages 1 through 4 CKD underwent 94 Gd exposures, including 34 patients with stage 4 CKD did not develop NSF. Finally, none of 2053 patients ( Stage 3 44.7%, stage 4 23.9%, stage 5 5.7%) who were exposed to 2278 MRIs developed NSF during 29 months of follow-up. The literature suggests that dialysis dependent patients with ESRD, stage 5 CKD and AKI maintain the highest risk.
Imaging with Gadolinium of high risk patients. On the basis of current knowledge, the following statements on patient risk for NSF can be made:
1. Use only macrocyclic gadolinium based contrast agents.
2. Use the lowest dosage required to obtain quality images.
3. Avoid IV iron and high dose ESA's before and after anticipated exposure.
4. Patients with stages I through 3 CKD do not seem to maintain risk for NSF after gadolinium exposure.
5. Patients with stage 4 CKD maintain modest risk and the risk increases in the presence of other factors like pro-inflammatory states, metabolic acidosis, hypercalcemia hyperphosphatemia and liver failure. Hence optimize metabolic status before anticipated exposure.
6. Arrange HD for patients with CKD stage 5, AKI and those dependent on dialysis.

Lupus Nephritis Post Transplant

We have asked this questions many times? Every center gives different answers. Some people have different experiences about this topic. When a lupus nephritis associated ESRD patient gets a kidney transplant, what is the risk of recurrence of lupus in the transplanted kidney?
Well, the recent issue of JASN highlights this question.  From the UNOS database, 6850 patients who had lupus induced kidney diseases and then a transplant was done were reviewed. Only 167 of them had recurrent lupus.  The amount is very small. Three risk factors were identified:
1. African American Recipients.
2. Female recipient.
3. Younger recipient.
As we all think, most of the low numbers of recurrence is likely because we use the same medications that we use for transplant, also to treat and keep lupus under control.

Take a peek at this paper.
http://www.ncbi.nlm.nih.gov/pubmed/20488956

Why do Internal Medicine Residents Choose Nephrology Survey results

The Renal Fellow's Network Blog had this recent survey where people voted online.
A very good and interesting question.
Have a look at the results at the following website:
http://renalfellow.blogspot.com/2010/07/why-do-medicine-residents-specialize-in.html

TOPIC DISCUSSION: TTP/HUS

Old article, but nice review:
NEJM 2006;354:1927-1935

Key Points:

-90% mortality of TTP if untreated
-Pentad not needed for dxn, only MAHA and low plts along with appropriate clinical setting
-Childhood HUS with diarrheal prodrome (Shiga toxin/E.Coli O157:H7) treatment is only supportive care and antiobiotics should be withheld intially unless toxic/bacteremic since it may release more Shiga toxin and exacerbate the HUS
-ADAMTS13 deficiency (cleaving ulVWF) NOT seen in diarrheal prodrome HUS
-Neuro symtpoms more with TTP, renal more with HUS
-Distinguish TMA due to other disorders incl malignant HTN and autoimmune disorders
-LDH levels will be sky high often, schistos, polychromatophilic red cells, indirect bili, neg direct Coombs
-Acute flares may or may not have low levels of ADAMTS13, so cannot go by this, it only tells you risk of relapse
-PEX!!!! If delay, can use plasma infusion but not as effective. Steroids maybe
-Causes: Idiopathic (rare to have renal manifestations), pregnancy, autoimmune d/o, diarrheal prodrome (HUS), immune mediated and dose dependant drug toxicity, HST (TMA usually limited to kidney, unlikely to benefit from PEX)
-PEX works even if no severe ADAMTS13 deficiency

CONSULT ROUND: Hypercalcemia and Lithium

Lithium can manifest in renal disease in many forms. From Tubular interestitial disease to Nephrogenic DI to hypercalcemia to Glomerular disease.
Hypercalcemia and Lithium directly can lead to a Nephrogenic DI.

What are the reasons lithium causes hypercalcemia?
I thought there was only one reason
But there are three:
1. It directly causes a increase in parathyroid production.
2. It raises the threshold for the calcium sensing of the PTH gland
3. It directly inhibits calcium transport across cells
References
http://www.ncbi.nlm.nih.gov/pubmed/17060004
Image source:
http://www.irishhealth.com/clin/depression/images/lithium.jpg

CONSULT ROUND: ATHEROEMBOLIC DISEASE

RENAL ATHERO EMBOLIC DISEASE







We discussed Renal Athero embolic disease
We are referring is to Cholesterol Emboli: Key Take home points:
RISK FACTORS:
Severe vascular disease
Recent manipulation of large arteries ( angio, surgery) but some cases are without manipulation
Cardiac Cath
Age
Anticoagulation use ( coumadin, heparin)
Perhaps even Renal Artery Stenosis( could just be part of severe vascular disease)

Clinical/Lab Clues:
4-6 weeks post procedure rise in crt , and rapid
Hypocomplementemia
Eisonophilia and philuria
Usually a bland sediment in the urine but sometimes blood is noted
Extra renal atheroembolic signs ( cyanosis, gangrene, "blue toes", livedo reticularis with good pulses)
Hollenhorst Plaques on eye exam

CONSULT ROUNDS:Rare and Interesting Cause of Hypertension and Hypokalemia in Pregnancy - GELLAR SYNDROME

It is an extremely rare disorder that usually presents in pregnancy. It is caused by missense mutation in the mineralocorticoid receptor(MR). Under normal circumstances the MR is not activated sufficiently by progesterone. However, this missense mutation in the MR alters its binding affinity and in the setting of elevated plasma progesterone, as in pregnancy, severe hypertension with hypokalemic metabolic alkalosis can occur. This entity should be suspected in a previously normotensive patient who develops severe hypertension and hypokalemia during pregnancy, particularly during second and third trimester, when progesterone levels are high. Spironolactone is ineffective as the mutated receptor is not blocked by it. Patients should be managed with antihypertensive agents. Subsequent to delivery, when progesterone level normalizes, patients become normotensive again.

TOPIC DISCUSSION: URR and Kt/V

Measure of adequacy of dialysis:
Relationship between URR and spKt/V ( single pool Kt/V):
URR (Urea Reduction ratio)= predialysis BUN-postdialysis BUN/ predialysis BUN X 100
spKt/V dimensionless unit- refers to amount of plasma cleared of urea corrected for volume of distribution of urea. K (dialyzer clearence L/hr) X t (duration of dialysis hr)/V (Volume of distribution of urea L).
Relationship between URR and spKt/V:
spKt/V=-ln(1-URR)
so based on above equation, for Kt/V of 1.0 URR should be 0.63 ( i.e. 63% urea extraction) however this equation does not account for urea generation during dialysis ( will increase postdialysis BUN) and ultrafiltration( which will remove urea by convection) so corrected equation is:
spKt/V = -ln(R – 0.008 x t) + (4 - 3.5 x R) x 0.55 UF/V
(where R = 1 – URR, V = postdialysis volume distribution, UF=volume of fluid removed)
0.008 x t is correction for urea generation which is dependent on time and 0.55UF/V is correction for ultrafiltration. Therefore, for Kt/V of 1.0, URR actually is 60% (if there is no ultrafiltration) instead of 63%.
Remember that URR we see, does not account for urea generation and ultrafiltration which can change the amount of dialysis a patient is actually getting.
eKT/V which is equillibrated Kt/V takes into account for rebound. Rebound is seen because of sequestration of urea in muscle which is rich in water and hence urea but has poor blood flow, thereby limiting the extration of urea into blood. At the end of dialysis, this urea is released from the tissues because of concentration gradient causing rebound. Hence eKt/V is lower than spKt/V by 0.21 for each dialysis.
eKt/V=spKt/V-rebound.

Organ Trading Discussion

The Economist is holding a live debate on Organ trading on Facebook.
Check it out with this link On facebook.


Also, the Renal Fellow Network has a recent post on it as well.

Dietary Management of Hypertension

Dietary Management of&nbsp;Hypertension

Chronic Dialysis: Now or Later?

Chronic Dialysis: Now or&nbsp;Later?

Photopheresis therapy for renal allograft rejection?

The technique involves three stages: 1-leucapheresis, 2- photoactivation with photosensitizer plus UV A irradiation, and 3- re-infusion of the buffy coat.

Extra Corporal Photopheresis (ECP) was first introduced for the treatment of Cutaneous T-Cell Lymphoma. Now has been widely used in the treatment of acute allograft rejection; most extensively in cases of cardiac transplant rejection. It has also shown success and high efficacy in reversing renal allograft rejection as well. Only one cohort study has been done by Jardine et al; ECP been used in 10 kidney recipients with therapy resistant rejection, and to our surprise, it showed that rejection has been resolved in all patients treated with ECP!

The exact mechanism of action remains unclear, but believe it has an immunomodulatory rather than immunosuppressive effect: The irradiation therapy induces high rate of apoptosis of the T-cells with sparing of the monocytes, and this eventually creates changes in the patient’s cytokine profile towards “type 2” cytokines; with significant increase of IL-5 and decrease of IFN-Gamma - “which is associated with allograft rejection!” also, it has a stimulatory effect on the T-regulatory cells as well..

Safety profile is excellent with <1% adverse effect, considered more safe than any other modality of apheresis!

ECP been mainly used for CTCL, and GVHD. Also, has been used in other autoimmune diseases including MS, scleroderma, DM-1, RA, psoriasis, Crohn’s, Nephrogenic Fibrosing Dermopathy. ECP is an effective, tolerable, and safe immunomodulatory therapy that can be used theoretically for resistant renal allograft rejection “T-cell rejection”. We still need more data and large cohort trials for this promising technique/therapy.

IN THE NEWS --->google as a diagnostician

As we are becoming all savy with the web, google has become our right hand man for diagnosis.
Check out this article by a nephrologist on google as a diagnostic tool.
One instance that everyone sites is the of the medical student at Harvard who was given a constellation of symptoms and he "googled" it and came up with IPEX syndrome.( FOX P3 T cell deficiency).
We all are guilty of doing that in tough cases. I admit I have used it and it has helped in some cases but not all.
Dr.Google can help us but not as perfect as a good nephrologist's knowledge that one acquires by daily reading and seeing cases after cases.
Check out the last reference: a patients view

Check out these references
http://www.ncbi.nlm.nih.gov/pubmed/18599952
http://www.ncbi.nlm.nih.gov/pubmed/20418338
http://www.ncbi.nlm.nih.gov/pubmed/19304965

Live Donor Nephrectomy with vaginal extraction

Donor nephrectomies are being done in some patients via a different approach at John Hopkins.  A case report was done for a patient presented in AJT July 2010 issue where the donor kidney was removed via vaginal route.  The warm ischemia time was 3 min and the post op pain was less; hospital stay was shorter and the cosmetic outcome was more desirable.  This is a creative approach to a surgical technique.
Lets see where we stand with this in the future.

For now its just one patient and we have to wait and see further work in this field. An editorial along with this case report is a must read as well. It discusses the potential hazards of this type of approach.

http://www.ncbi.nlm.nih.gov/pubmed/20553450
http://www.ncbi.nlm.nih.gov/pubmed/20353482