Friday, February 17, 2017

Topic Discussion: Linear staining on IF and the differential diagnosis

Linear Staining in IF on renal pathology differential diagnosis

Image result for linear staining IF

Classically the linear staining in taught in medical schools to be associated with anti GBM disease.

On a recent discussion on ASN-Communities on this topic by many glomerular experts led to generating a differential on other causes of IF linear staining when anti GBM serologies are negative.

Dr. Richard Glassock summarized the other causes on the forum as listed below with a few references:

1)    Atypical anti-GBM disease- This entity recently described by Nasr et al in 2016 is a more indolent form of Anti GBM disease where there are no serological markers for anti GBM and there is linear staining. It’s a slower disease and better renal outcomes compared to classic GBM disease. The light microscopy is variable from MPGN, TMA, to endocapillary proliferation and distinct lack of crescents. Some cases had deposits and some didn’t. 50% of these cases have a monoclonal disorder
2) Fibrillary GN with "pseudo-linear" IgG deposits, often secondary to autoimmunity, infection or cancer
3) IgG4 Anti-GBM disease- most assays do not detect IgG4 anti-GBM antibody 
5) Monoclonal IgG or IgA kappa directed to COLIValpha1/2 chains 
6) Wrong substrate, poor sensitivity, prozone phenomenon  in IF assays
7) "Immune sink" where all circulating antibody is bound to GBM sites in vivo-serial testing will often resolve this
8) Spontaneous decay of circulating antibody levels with persistence of tissue deposited antibody 
9) Diabetic Nephropathy: a physico-chemical alteration of GBM or IgG causing non-specific deposition of IgG (and albumin)

Other references

Saturday, February 4, 2017

Consult Rounds: Thrombocytopenia in ESRD

Thrombocytopenia in a hemodialysis patient can be from multiple reasons

Image result for thrombocytopenia

The top reasons we encounter are:


The most common is heparin and HIT.

A nice review of HIT in the renal patient is here

The other causes can be related to other medical illness not ESRD related. An important but rare cause that can be associated with dialysis associated with thrombocytopenia is a dialyzer reaction. A large systemic evaluation done in Canada suggested that the prevalence of thrombocytopenia associated with dialysis was due to the use of electron beam dialyzers( optiflux) rather than irradiated sterilized dialyzers ( others).  This suggests a relationship of use of the dialyzer sterilization technique causing this.  Exposure to e-beam radiation may change membrane integrity, structure, or physical properties of the dialyzer and could plausibly lead to platelet activation, aggregation, or adsorption and subsequent thrombocytopenia. E-beam sterilization has become a popular method of membrane sterilization recently, because it potentially allows a more focused and precisely delivered dose of sterilization toward the dialyzer membrane. A case report in AJKD had highlighted low platelets as a side effect of dialyzer reaction. Certain membranes due to the many types of hydroxyl groups contained can lead to an active complement system( the older dialyzers).  The degree of complement activation determines the biocompatibility of the membrane. A prior post in RFN also had discussed this phenomenon.
This review from Hemodialysis International is a great one for all to review.

If the patient is inpatient, we might notice that the day after dialysis the platelets drop from 150 to 50 perhaps and then rebound and then again the drop happens on the next set of labs. It is very likely that we are missing this phenomenon on the outpatient and there is ongoing endothelial damage happening chronically due to some of these membranes.  We only check monthly labs in US.  A true incidence of this phenomenon is hard to determine.  

Friday, February 3, 2017

Clinical Case 89: Answers and Summary

Which anti melanoma therapy can lead to immune mediated hyponatremia?

Ipilimumab(CTLA-4 inhibitor) has also been associated with electrolyte disturbances. Two cases of ipilimumab-induced hyponatremia due to panhypopituitarism from ipilimumab related hypophysitis have been reported. The incidence of hypophysitis in patients treated with this agent is close to 17% in clinical trials. Mechanistically, a loss of adrenocorticotrophic hormone-secreting corticotrophs leads to a secondary adrenal insufficiency and loss of regulatory effects of cortisol on arginine vasopressin. This could be the mechanism leading to the hyponatremia. While FDA reporting system has mentioned hyponatremia in PD1 inhibitors(nivolumab and pembrolizumab) and BRAF inhibitors(vemurafenib and dabrafenib), it is at a lower incidence and likely not immune mediated. 

Wednesday, January 18, 2017

Nephrologist are Incrementalists and Superheros

Image result for incrementalistsDr. Atul Gawande recently wrote this amazing article on amazing heroism on incremental care. 

This article discusses the difference of episodic heroic medicine vs incremental care. Who cares of you when episodes of urgent care and then there is care of chronic illnesses.

Who are the physicians that take care of you "episodically"?- the Er doc, the cardiologist when you have chest pain, the surgeon when you need emergent surgery.  Who are the incrementalists-- the primary care docs, ID docs for HIV patients, family docs, pediatricians.etc...

He makes an amazing argument of payment to those docs as well. He says that the interventionists make most of their income on defined, minutes- hours long procedures such as hip replacements, endoscopies, cardiac procedures. etc.,and then move on.  Hence payment is high for those specialists. On the other hand, the lowest paid specialties such as pediatrics, endocrine, family medicine, ID, and I would add nephrology here as well are incrementalists and are not paid that well.  Almost certainly at the bottom are geriatricians and palliative care specialists. All are incrementalists, they produce value by improving lives long term and over time but not well compensated.

The article does an amazing job describing the two types of physicians and how each type make such an amazing impact on the patient's lives. While some are "acute" life savers; others are "long term" life maintainers.  Both are important to maintain balance in medicine. Nephrologists are not mentioned in the article but I would say they are both episodic care providers and incrementalist.  We have times were we are urgent life savers for taking care of the hyperkalemia and dialysis but then the long term care of the CKD patient, ESRD patient and transplant patient is incrementalist side of the nephrologist.  Yet, we fall in the bottom half of the payment model.  Incrementalists need to be rewarded as well. Being a surgeon, Gawande raises and brings an important issue to the forefront for us internists out there. Bravo for supporting and thinking of us and what we do. We make a difference in incremental ways and it matters!

Worth read in the New Yorker

Sunday, January 15, 2017

IN the NEWS: Vancomycin induced CAST nephropathy

Recent literature has linked AKI with vancomycin and zosyn and it was thought that the higher vancomycin levels might have been the culprit.
It was also assumed that the injury was either AIN or ATN. Few biopsies done in these cases were suggestive of ATN in the past( vancomycin mainly). Personal experience, I have seen ATN from vancomycin as well that is biopsy proven.
In JASN,  Luque et al might have discovered what is the mechanism behind vancomycin toxicity. The biopsy of a single case presented showed tubular casts entangled with uromodulin.  EM showed vancomycin particles in the tubular cast when immunogold labeling was used.  Staining with anti-vancomycin antibody revealed the specific accumulation of vancomycin in the tubular lumen mainly. Similar to myeloma casts, this leads to an intratubular obstructive ATN. A CD68+ macrophagic infiltrate was also observed surrounding the casts and within the kidney’s interstitium, suggesting that pathologic casts might induce an inflammatory process. To further confirm the pathogenicity of vancomycin-associated casts, they  retrospectively examined eight additional renal biopsies with ATN that had been performed in the clinical context of high-vancomycin trough levels preceding AKI. Similar findings were noted in the biopsies.  Vancomycin trough levels ranged from 35-106mg/dl in the 8 patients.  50% of the patients required dialysis. To confirm, they did in studies in mice and injected vancomycin and observed effects in the kidney.Kidney injuries have been visible as early as two days after vancomycin injection.
In summary, this article is the first to describe the novel form of injury an antibiotic can give.This can explain the sometimes noticed rapid rises we noted in some cases of acute ATN with vancomycin and perhaps even other antibiotics.
Should we be giving pre and post hydration like we do for acyclovir when giving vancomycin to prevent AKI?
Check out this amazing paper! Kudos on thinking out of the box and finally giving us a potential mechanism!

Thursday, January 12, 2017

IN THE NEWS: Preventing rejection while using immunotherapy in organ transplants

Use of immunotherapy such as CTLA-4 and PD-1 inhibitors have been sparingly used in renal transplant patients due to the concern for rejection.  Several cases and one recently published in NEJM last year showed severe acute cellular and antibody mediated rejection with use of PD-1 inhibitor therapy. In the limited number of patients who have received these agents, it appears that PD-1 inhibitors could be more prone than CTLA-4 antagonists to cause rejection in the transplanted kidney. This is especially true when the patients receive anti–CTLA-4 agents before PD-1 inhibitor treatment

We reported now in NEJM a creative solution of preventing rejection in a patient getting nivolumab (PD-1 inhibitor). By using a prophylactic approach of higher doses of steroids and mTOR inhibitors, we were able to successfully prevent rejection along with successful treatment of the cancer as noted in the supplementary files of the letter. Immune check point inhibitors have revolutionized the treatment of many types of cancers.With this approach, it is possible that these agents can be perhaps safely be used in the organ transplant patient.

We recently reviewed entire literature on the use of immunotherapy in the organ transplant world. As stated above, the rejections were mostly seen in PD-1 inhibitor based therapy compared to CTLA-4 therapy. In addition, the 2 cases of liver transplant where these agent were used and 1 case of heart transplant didn’t lead to a rejection episode.  But in the renal transplant patients, 5 cases have now been reported of leading to acute cellular and antibody mediated rejection when PD-1 inhibitor was administered. The above NEJM case suggests a potential treatment strategy.

Renal effects of immunotherapy are not minor.  AIN, podocytopathy and electrolyte disorders have been reported. It is important for the general nephrologists to know about these effects.Two recent reviews discuss this elegantly.

Sunday, January 8, 2017

NKF Spring Meetings: Pre course on Point of Care Ultrasound for the Nephrologist

04/18/2017     7:30 AM

04/18/2017     12:30 PM

Walt Disney World Swan and Dolphin, Orlando, FL
The renal consultant needs knowledge of lung ultrasound to determine volume status, renal and bladder ultrasound to evaluate for obstruction and knowledge of vascular access guidance to assist in placement of catheters. This course will focus on the above elements in point of care ultrasonography. 

  • Image acquisition will be practiced on human models using high-quality ultrasound machines and supervised by experienced faculty. Training sessions give you practical, hands-on training with a 1:3 teacher-to-learner ratio, so you benefit from personal instruction.
  • Image interpretation during group sessions under the supervision of experienced faculty members offers relevant practice. Numerous ultrasound images demonstrating normal and pathologic findings will give you a comprehensive learning opportunity. As you improve your skills, you will be further challenged with unknowns and case-based image sets.
  • Knowledge base will be enhanced with lectures that focus on important aspects of point of care ultrasonography applicable to the renal consultant. Discussions will have immediate application within your practice.

Learning Objectives:
Upon completion of this course, participants will be able to:
  • Discuss how to perform lung ultrasonography and ultrasonography of the renal system.
  • Identify appropriate uses of ultrasonography in renal practice.
  • Demonstrate appropriate image acquisition techniques required for renal ultrasonography.
  • Interpret image-based clinical cases to help identify abnormalities.

Paul Mayo, MD
Mangala Narasimhan, MD,
Daniel Ross, MD
Kenar Jhaveri, MD

Breakfast and Introductions
Lung Ultrasound for the Assessment of Volume Status
Hands on Lung Ultrasound
Image Interpretation Lung Ultrasound
Vascular Access/ IVC Size
Hands on Vascular Access/IVC
Image Interpretation Vascular Access/IVC
Renal Bladder Ultrasound
Hands on Renal Ultrasound
Image Interpretation
Wrap-up and Evaluation
4.25 credits/contact hours

REQUIRED: Separate registration fee of $60 for NKF Members, $75 for Non-Members, $40 for Fellows/Residents. Includes light breakfast, and CME credits. Participation is limited, so register early.  

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