In the NEWS: Cancer risk after cyclophosphamide use in membranous GN

A common question has always been in our minds – cancer risk after cyclophosphamide use in renal diseases?

Membranous GN has been the landmark GN where cyclophosphamide has been tried. The regimen with alternating months of this agent with steroids is still the standard of care treatment for Membranous GN.  Other therapies have come and stayed or gone, such as CNIs, MMF and rituximab.  They have varied outcomes.

Cancer risk after use of cyclophosphamide recently waslooked at a single center in Europe in this CJASN manuscript.   Over 250 patients were followed over 6 years and 127 patients were treated with cyclophosphamide (CYP).  Cancer risk was 3 fold higher in this cohort compared to ones not treated with CYP. 

Interesting findings:

1.     As one would think, bladder ca would be the highest risk, it was only 2 of the 20 observed

2.     Hematologic malignancies were highest in this cohort

3.     Could some of their cases be secondary membranous and hence had cases of early malignancies?

4.     Table 3 has malignancies listed as Lung, CLL, lymphoma, prostate Ca, colon, AML, bladder and CML

5.     Majority were men

6.     Varied cancers ( 5) of them had membranous GN that was APLAR2 negative but no time correlations was noted

Full paper at http://cjasn.asnjournals.org/content/early/2014/05/22/CJN.08880813.full

Paging Nephrology Fellows: Does it matter to them?

A recent study appeared as an Article in Press on May 2, 2014 in the American Journal of Kidney Diseases (AJKD) entitled “Prospective Analysis of After-Hour Pages to Nephrology Fellows.” This was an audit of the after hour pages received by 6 nephrology fellows at the University of Rochester, lasting for 61 days and recording 615 after hour pages. This study was prompted by the underwhelming interest in nephrology fellowship, as demonstrated by 44% of nephrology programs that participated in the National Resident Matching Program being unmatched in 2014.

The results demonstrated that fellows had to return to the hospital on 64% of overnight calls, most after hour pages did not require any modification of the current patient care plan, and 50% of the after hour pages occurred after 10pm. Only approximately one third of the nights allowed for the ACGME-recommended 5 hour minimum of uninterrupted sleep. 

This study implies that after hour pages are a major deterrent to those that are considering the field of nephrology. Concern over declining nephrology fellowship applicants has been an area of active interest that has been addressed in several studies as well as an American Society of Nephrology task force.  Shah et.al surveyed 204 US adult nephrology fellows and found that the three top reasons why fellows were somewhat, slightly, or not at all satisfied with their career choice included poor income potential after graduation, poor job opportunities after graduation, and long work hours . Jhaveri et.al performed a survey of 714 internal medicine subspecialty fellows and when asked about what they did not like in nephrology, 35% felt that dialysis and transplant patients were too complicated, and another approximately 30% felt they did not have any role models in the field. The burden of after hour pages did not seem to be a factor in either of these studies.

Most other internal medicine high acuity subspecialties likely receive a similar number of after hour pages.  The overnight consults likely involve the cardiology and gastroenterology services as well, since these fields also have urgent procedures and interventions that may need to be performed emergently overnight.  A survey of these fellows may yield the same results with frustration in after hour pages, although in our institution the cardiology fellowship program utilizes an in-house call model, so the frustration with after hour pages is likely to be different. That being said, only 4.6% of gastroenterology programs and 1.6% of cardiovascular fellowship programs went unfilled, compared with the 44% of nephrology programs cited above. Further studies should be performed in order to determine this disparity. 

Dwindling interest in nephrology needs to continue to be investigated.  As the population continues to age and comorbid diseases such as diabetes mellitus and hypertension become more and more prevalent, there will be a rapidly expanding need for nephrologists. Clearly, the lack of fellowship applicants is a multifaceted problem with far reaching effects. Although the burden of after hour pages may play a part in frustration, there are likely to be a number of other factors that play a role in the increasing dissatisfaction within the field. 

Anonymous Fellow in a US based Nephrology Fellowship

Hyponatremia Guidelines Part 5

What to do for over correction?

1.     Prompt relowering if increased >10mmol/L over 24 hours

2.     Stop ongoing treatment

3.     Nephrology or critical care/ endocrine consultation to see if need for starting electrolyte free water or not and monitoring urine output

4.     Expert opinion re the use of ddavp 2ug

Was interesting to note that the new Stern approach of using 3% and ddavp at the same time was not really entertained. It was mentioned in the rationale discussion but more robust trials are needed in that realm.  

For full review:

http://www.ncbi.nlm.nih.gov/pubmed/24569496

Hyponatremia Guidelines Part 4

Chronic Hyponatremia without severe or moderately severe symptoms              

**Stop non essential offending agents
**Cause specific treatment
**If mild, suggest against treatment with the sole aim to increase the Na( excellent point)
**If moderate to profound, to treat to not more than 10mmol/L over first 24 hours
**Diagnostic workup
**If cause is fluid overload- Fluid restriction is only recommended. They recommend against V2 receptor antagonist and demeclocycline.
**If SIADH, FW restriction as first line treatment.  If profound, suggestion to increase solute intake with 0.25-0.5g/kg/day of urea or a combination of loop diuretics and oral sodium chloride
**If moderate or severe- against demeclocycline.
**If SIADH and moderate, recommend against V2 receptor antagonists( same goes for severe SAIDH)

**If low circulating volume related chronic low Na, use of .9% saline or balanced solutions recommended.

Why V2 receptor antagonists were not recommended in above Volume overload and SAIDH scenerios?

The reviewers of this committee looked at two systematic reviews that compared V2 receptor antagonists to placebo in chronic hyponatremia. The first review had 15 randomized trials and found no significant difference in risk of death and other adverse events although Na did increase by 5mmol/L.  More rapid increases were noted in the V2 arms. The first systematic review did conclude that vasopressin antagonist treatment significantly increased response rate both early (RR, 3.15; 95% CI, 2.27-4.37; 11 trials) and late (RR, 2.27; 95% CI, 1.79-2.89; 4 trials). Response rates were high in trials assessing mostly euvolemic patients and those assessing mostly hypervolemic patients, with greater effect estimate in the former.

The second review was in 2011, eleven trials were identified (1094 patients). Short-term use of VRAs in treating hyponatremia was successful at raising [Na(+)](serum). Additional experience is required to guide their optimal use and minimize safety concerns. There was no change in deaths. 

So if the above two reviews showed positive response- why did they not recommend use of these agents? The authors feel that the quality of evidence was generally reduced by risk of bias due to difficulties with blinding participants, potentially unbalanced use of FW restriction and incomplete outcome reporting in addition to industry sponsorship.  There is also mention in the discussion re the liver toxicities associated with higher doses of these agents when they were studied in ADPKD.  Drug doses administered are lower in hypoantremia management.  Overall, besides all that, the review committee felt that there is a good risk of overly rapid correction of hyponatremia with these agents.  

Interesting thoughts and I commend the reviewers on looking at these agents with an eye of scrutiny. Although the most randomized trials in hyponatremia are with these agents.   

For full review
http://www.ncbi.nlm.nih.gov/pubmed/24569496

William and Sandra Bennett Clinical Scholars Program and Nephrology Education

William and Sandra Bennett Clinical Scholars Program and Nephrology Education

Congrats to the American Society of Nephrology (ASN) on creating the first ever grant for clinician educators and for a career in Nephrology education.  This will inspire more clinicians, Nephrology educators  to complete their scholarly activities and perform research in Nephrology education. It is called the William and Sandra Bennett Clinical Scholars Program. 

ASN and the ASN Foundation for Kidney Research is now accepting applications for the new William and Sandra Bennett Clinical Scholars Program. Applications go live on May 19th 2014. The deadline to apply is Friday, June 27 at 4:00 p.m. ET.

The program provides $50,000 per year for up to two years to support aspiring Nephrology educators to conduct a project to advance all facets of Nephrology education and teaching.

Applicants may submit a proposal that examines any aspect of the Nephrology education, such as curricular reform, innovations in education, new education methods, evaluation of new assessment tools for competency-based learning and assessment, professional development, or professionalism.

Additionally, recipients are encouraged to complete a formal (such as earning a master’s degree in medical education) or semiformal education (such as Stanford University School of Medicine’s Faculty Development Program for Clinical Teaching) during the ASN Foundation funded years.

All interested clinician educators with great ideas- apply for this amazing opportunity to advance your career and the field of Nephrology. 

For more information about this exciting program or to apply, please visit the ASN website. 

Hyponatremia Guidelines Part 3

Hyponatremia with moderately severe symptoms

** Start diagnostic workup
**Stop all meds and contributing factors
** Cause specific treatment(  of course)
**Suggest immediate treatment with bolus of 150ml 3% saline for 20 min( wonder if drip for few hours with equivalent mmol would be good enough as well)- level 2D though
**They suggest aim of 5mmol/l over 24 hours ( not 10, even lesser) level 2D
**The very next suggestion is limiting the increase over 24 hours to 10mmol/L( slightly confusing message)
**Checking serum Na at 1 hours, 6 hours and 12 hours
** This is the category that really needs more research as it’s the gray area. They suggest No suggestions for future research? 

Hyponatremia guidelines Part 2:

First set of guidelines are on which parameters to be used for differentiating hypotonic hypoantremia?

**They recommend urine osmolarity of a spot urine as the first step( - to be honest, takes a day to come back sometimes) although level 1D evidence

**If the urine osm is <100, it is thought the diagnosis is due to water excess intake( tea and toast, beer potamania) – level 1D evidence

**If the urine osm is >100, then a urine Na is ordered.

**If Urine Na <30, low effective arterial volume as the cause of low Na

**If Urine Na>30, ECF should be assessed, and if diuretics are involved

**They suggest against measuring an ADH level

  

First hour treatment of hyponatremia of severe symptoms( acute or chronic)

**Prompt IV infusion of hypertonic 3% saline over 20min( 150cc)

**Checking Na levels after 20 min and repeating a second bolus( bolus vs a drip – and bolus was chosen, level evidence 2D)

**Keep repeating till level over 5 mmol/L corrected.

**Consider ICU setting care

Follow up management after 5 mmol/L increase

**Stop IV infusion of 3% saline

**Diagnostic workup

**Limiting the rise to not more than  10mmol/l in first 24 hours( evidence 1D)

**Checking Na levels after 6 and 12 hours daily till stable

If no improvement of symptoms after 5mmol/L increase

**Continue 3% infusion with additional increase for 1mmol/l per hour

**Stopping 3% when symptoms improve or if Na increase by 10mmol

**Additional diagnostic workup

**Check Na q 4 hours till 3% has been stopped.

Full report at http://www.ncbi.nlm.nih.gov/pubmed/24569496

In the News: Hyponatremia guidelines Part 1

The NDT paper on clinical practice guidelines suggests some interesting changes in diagnosis and treatment in hyponatremia.  In the series of posts , we shall highlight the major findings of their report.

Pathophysiology update:

1.       Once the hyponatremia has been deemed hypotonic – the first test recommended is urine osmolarity and the break down after that is interesting.  If urine osm<100Mosm/kg, primary polydipsia and water intoxication is considered a likely potential.  If urine osm>100, we go into our usual categories and then order a urine Na.  If urine Na <30, low effective arterial volume is deemed and volume exam will determine next cause( from volume loss to CHF).  If urine Na>30, one either has kidney disease or diuretic use and or if ECF is reduced could be renal salt wasting or cerebral salt wasting. But if normal ECF- then SIAD.

2.       A nice table on page 21 discusses the much debated SIADH vs cerebral salt wasting.  While uric acid in the serum is same in both, it’s the BUN that is usually low in SIADH.  Urine volume is much higher in cerebral salt wasting.  And patients are usually orthostatic in the later. CVP is also low in the later.

      

    For full details click here

http://www.ncbi.nlm.nih.gov/pubmed/24569496

Consult Rounds: IgA nephropathy and TMA- does it have a connection?

IgA and thrombotic microangiopathy?- is there a link?

Does IgA nephropathy present with biopsy findings  of TMA? A paper in JASN in 2012 looked at this exact question.

1.      They studied over 100 patients retrospectively at a single center and looked at biopsy findings of IgA nephropathy patients with follow up for 44 months

2.      Over 50% had TMA findings on biopsy.

3.      One would presume most of this might be HTN related to the IgA that leads to TMA.  4% were normotensive, 25% had controlled hypertension, and 71% had uncontrolled hypertension.

4.      The biopsies with TMA had most fibrosis and tubular atrophy

5.      TMA with IgA nephropathy also had significant protienuria.

6.      Renal survival was 52.2% at 44 months among the TMA patients versus 93.5% among those without TMA (P=0.00001).

7.      IgAN-associated TMA remains a primarily arterial/arteriolar lesion resembling like scleroderma

8.      What else besides HTN can lead to this in IgA? Endothelial damage is what is presumed to the most likely cause.

9.      Anti-phospholipid syndrome antibodies have also been described in IgAN. In their series, it was no the major cause.

10.  Decreased VEGF and or anti endothelial antibodies are presumed to be other causes

11.  Could this resemble some form of secondary variant of IgA nephropathy perhaps from a virus or infection or other systemic disease?

12.  If the incidence of TMA in Ig A nephropathy is this high, then why is this not part of the Oxford classification?

13.  Other studies that have looked at this

http://www.ncbi.nlm.nih.gov/pubmed/17176910/