Friday, November 15, 2019

In the News: Selinexor induced hyponatremia

A new drug just got approved for treatment for myeloma. It is called selinexor. The correct localization of molecules between nucleus and cytoplasm is fundamental for cellular homeostasis and is controlled by a bidirectional transport system. Exportin 1 (XPO1) regulates the passage of numerous cancer-related proteins. The development of a novel class of antitumor agents, known as selective inhibitors of nuclear export (SINEs) have shown good results in studies and clinical trials in multiple myeloma, non-Hodgkin lymphomas, lymphoblastic leukemia, and acute and chronic myeloid leukemia, sarcomas, and gastric cancer. Selinexor is one of the first to be approved in this class of drugs. In a recent NEJM trial published this year, Chari et al showed that oral selinexor- dexamethasone worked well for  triple class refractory multiple myeloma(MM). We wrote a letter back to the authors published in NEJM few weeks later noticing that  one of the most common grade 3 or 4 adverse event was hyponatremia(<130mmol/l) ( 22%).  In reviewing the prior studies( table below), this is a class effect of selinexor as other trials with the use of this agent had similar rates of hyponatremia ranging from 7%-26%. 
Table: Summary of major trials that led to Grade 3,4 hyponatremia

Phase trial
Incidence of hyponatremia
Intervention
Dose modifications
Reference 
Phase 1 in MM
25%(40mg/m2),
47% (60mg/m2)
Not reported
Not reported
Resolved in most cases
Phase 2 in MM
22%(80mg)
6% got salt tablets,
Dose reduction
Yes, reduced
Resolved in most cases
Phase 1 in solid tumors
13%
Not mentioned
Resolved in most cases
Phase 1 in sarcomas
7%
Not mentioned
Resolved in most cases
Phase 1 in Non Hodgkin lymphomas
10%
Not mentioned
Resolved 

The rates of hyponatremia are higher in the MM studies compared to solid tumor studies.  No workup or cause was found in many of the studies. Another recent study in AML ( phase 1) has close to 70% incidence of hyponatremia. Likely this could be related to the GI effects such as severe nausea leading to an ADH release causing hyponatremia or could this be a direct effect of the mechanism of this agent. Could this drug effect the AQP channels or V2 receptor- not sure as mechanism has not been worked out. A serum osmolarity testing along with urine studies can answer this question. As the drug enters clinical practice, It is very possible that we shall see an even increased incidence given other confounders patients might be on such as thiazides, and or increased free water intake.  Involvement of nephrology consultation in the trials ongoing might be essential to investigate the mechanism of this toxicity. Serum and urine studies would help in assessment of the cause and pathophysiology of the hyponatremia. This will then allow for preventive strategies in further trials and clinical practice. Once out in the real world, it will be more important as lot of our patients could be on thiazides, SSRi and drinking a lot of water and then are given this agent. While most cases the hyponatremia might be asymptomatic, subtle symptoms and appropriate early management can prevent seizures and complications of hyponatremia.
As nephrologists, we need to be aware of this drug as we usually see myeloma patients. 

Wednesday, November 13, 2019

Topic Discussion: Interferons and kidney disease


Interferons usually have been linked with kidney damage with forms of podocytopathies. CJASN paper from 2010 from CUMC described these lesions. Collapsing FSGS may occur after treatment with IFN-alpha, -beta, or -gamma and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions.
Following that series of 11 patients showing Collapsing GN, few cases reports were published in 2016 showing FSGS as well. Another large series by Markowitz et al in 2015 of 32 patients also showed podocytopathies but this time also MCD and FSGS along with collapsing GN. The MCD patients had complete and partial remission but the FSGS and collapsing GN had <50% complete or partial remissions.

But the most common lesion that is hidden in the heme literature is TMA but many being renal limited. There are now over 80 cases described of TMA , AKI and HTN related to interferons. Outcome analysis revealed complete remission in 27 (40%), persistent chronic kidney disease (CKD) in 28 (42%) and fatality in 12 patients (18%). (10) Treatment with corticosteroids, plasma exchange and rituximab resulted in durable responses.

In an elegant experiment by a group published in 2016 in Blood showed that type 1 interferon can induced TMA. They showed that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA with interferon. They then showed that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor. Together their clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. So, this experiment showed that from bedside to bench the clear relationship of interferon and TMA development.
To
So in summary, the renal lesions seen with Interferon should really be TMA, and podocytopathies such as FSGS, collapsing GN and MCD.


Friday, November 1, 2019

In the NEWS: NephSim as an educational tool


Nephrology education related published work is sparse. NephSim, a mobile optimized website tool with cases and interactive approach was developed in 2018. Over 24 cases have been presented and discussed in this tool. Case contents have been amazing. But what the creators of this tool now did is- validate it with a peer reviewed publication. Recently published in JGME, a med ed journal, Farouk et al showcase the NephSim tool and discuss the results of their outreach of this tool and a survey that showed high rate of satisfaction and usability.

Innovation in Nephrology education is extremely important. Case discussions leading to differential diagnosis and then pathology and diagnosis helps in creating and making a Nephrologist a better diagnostician. The NephSim project also showcases the use of website, social media platforms such as twitter and other ways to share information.

This tool can easily be replicated in other fields in internal medicine or medicine. The ease of using and doing the cases makes it very accessible and able to be transformed in all fields in medicine. The drawbacks- survey response was low but enough to make major conclusions. But like most med-ed studies, it touches the first tier of outcomes- medical knowledge (self-assessed) and not addressing other ways of medical knowledge. We hope to see using some of these tools used( perhaps in combo)- such as NephSim, Nephmadness, Whatsapp, blogs, NephJC. Etc—to change practice patterns, behaviors and ultimately effect patient outcomes.

Saturday, October 12, 2019

Topic Discussion: HSCT associated TMA, a renal endothelial variant of GVHD


Kidney injury post HSCT is a mystery. While the initial AKI is from multiple causes, the chronic damage we see in the survivors of HSCT is not well understood. In a recent review in AJKD, we did consider this to be mostly TMA related. But is TMA a form of GVHD ( renal limited) is what some including us have proposed. When one looks at the literature from GVHD and links to the kidney- one thinks of secondary membranous, but perhaps this is a rare finding- endothelial glomerular damage might be more common(TMA).

In a recent mice study, the authors looked at HSCT effect on kidney in various murine models of GVHD. The most common finding was glomerular with classic mesangiolysis, mesangial proliferation and edema with subendothelial widening and microthombi. These are features of HSCT- associated TMA. So, it is very possible that getting a HSCT might be a second hit to several folks who might carry a complement deficiency and perhaps there is some activation of complement system.

Some of the literature proposes that TMA and GVHD are not related but both affect the complement cascade. As clinicians we have seen several cases of TMA and concurrent GVHD and a recent reported case series confirms this. It is intriguing and possible that renal-limited TMA might be a variant of GVHD.  GVHD is usually an epithelial cell disease but having an “endothelial” target might be possible in the kidney. In most cases, when TMA is diagnosed in a patient with HSCT, the knee jerk response is to discontinue CNIs. Whether this is of potential benefit or harm is not clear.

Tuesday, September 17, 2019

Concept Map: Polyuria



A solute diuresis is defined -- urine osmolality >600 mosmol/kg and a total daily osmolar output >1000 mosmol (calculated as the urine osmolality multiplied by the 24-hour urine output).

A water diuresis is defined with a urine osmolality <600 mosmol/kg and often <300 mosmol/kg and a total daily osmolar output <900 mosmol.


Another way to look at it from pure Uosm perspective is U osm <100mOsm/kg is generally a water diuresis from polydipsia or DI.  

Uosm between 100-300 mosm/kg is usually a mixed polyuria( either a central and nephrogenic partial DI and maybe simultaneous water and solute intake and CKD)


U Osm >300 is generally solute diuresis 

Thursday, September 12, 2019

Topic Discussion: Do Renal consultations matter in surgical and cardiac ICU patients


AHA moment arrived when I saw this article in AJKD on interdisciplinary collaboration of nephrology with surgical and cardiac surgery ICUs. It was a qualitative study highlighting some of the conversations that happen in the CTICU with the nephrologists and what is “felt” about renal consultations.
This is an important topic that we encounter as consultants. Often, we get urgent calls from the ICU, for example CTICU , “ Doc, we need an urgent consult, this patient post CABG is oliguric now and crt rose from 1 to 1.4mg/dl and we need urgent CRRT, and we placed the dialysis catheter already for you…”
Now this situation is not uncommon… how does one respond to that..
Either you say, “ gee. Thanks for that and I will come evaluate and decide if I even need to use that catheter as they might not need dialysis..”  What is the role of the Nephrologist in some of the surgical run ICUs.? Are we seen merely as technicians or truly thoughtful physicians that make decisions that will or not alter the care of the patient..
The article really highlights this very important issue. Some of the major themes highlighted are listed below
1.      There was almost an absent influence of renal decisions in some of the surgical and CTICUs; this stemmed from many surgeons and intensivists not sure of the renal fellows decisions not going along with attending nephrologists decisions. In my opinion, many times and at many centers-they bypass fellow based consult services and call attendings only for that reason.
2.      Nephrology fellows and attendings found it hard to communicate to CTICU staff as the PA or NP would not really be making that decision and the final decision came from the surgical head of that patient ( who often is not in the unit)
3.      Nephrology fellows might not realize the hierarchy noted in some of the surgically based ICUs compared to MICUs.  This is interesting as the first time we encounter surgical culture in depth is during renal fellowship( 3 years in medicine- we usually are kept away from SICU, CTICU and NSICU)
4.      What I found totally astonishing was one of the comments made in box 2 by an NP that was interviewed is that “renal was the only service we had to call to get something done as We can’t just order dialysis” – and hence making us seem like just a dialysis ordering physician
5.      It also goes into details on who manages the fluid removal once CRRT has been started. It is an ongoing battle. Often this leads to conflict and at many centers, Nephrologists have given up CRRT ordering and management to ICU intensivists( sad but true)
6.      Due to our consult note and recommendations have no value- many times- there was early signing off of the consult- as “ if they are not listening to our recommendations anyway – why bother writing a note everyday…” Not uncommon to see in this unit.
7.      While Nephrologists thought they were best valued to understand AKI and noted a good nephrologist is a good internist. Meanwhile, surgical staff didn’t believe that and felt nephrologists were mostly dialysis gatekeepers and didn’t feel we understood AKI in the overall ICU status and ordering tests of diagnostic significance were not very valuable.
8.      The role of nephrologists being dialysis proceduralist clashed nephrologists value of preventive medicine mainly in the CTICU. From a surgical perspective, a consultation that doesn’t offer any valuable intervention such as dialysis to help the acutely ill patient is useless. – heard that one before many times
9.      The most common disagreements were on when to do dialysis, timing of initiation and managing fluids—the most common we see in practice anyway. It is not uncommon where I have written “ stop diuretics” but they are continued and then days later I am starting them on RRT.  But there have been also times where I have said “ stop diuretics” and they continued and they did better by not listening to me.  So in general, does our opinion matter?
10.   Interesting, surgical and CT ICU staff viewed dialysis as a tool to get rid of the kidney problem whereas we see it as a last resort before trying all medical maneuvers.  One comment was really funny, In box 3, one of the nephrologists interviewed said “ they view most of us as technicians. Just like anesthesia can just put the person to sleep, just put a tube and no big deal- anyone can do it, you can slap someone on dialysis, no big deal.”.  My favorite one I get called is “ can you come and spin him”
11.   Finally, due to history of these interactions, nephrologists and nephrology fellows avoided the controversial issues. Many times, this led to resignations from the case.
12.   Lot of these changes are due to different medicine vs surgical cultures.

How do we fix this? Can we fix this? The authors describe this is discipline siloing leading to ineffective collaboration amongst fields of medicine. This is important to break and learn. This will be critical as it can harm patients if gets escalated and neglect ensues. We need to understand the other persons perspective and realize that all physicians have one medical school, residency and fellowship—we all bring in some value to the patient. We need to respect and honor each other’s fields of medicine.
When I showed this article to one of our CT surgeons, his/her reaction was merely to dismiss it. My fellow and I were hoping for more of a conversation to improve this encounter.
Then the next day, in the CTICU, we see that the curtains are closed and one of the rooms was having open heart surgery happening in the middle of the ICU – for an urgent mater.  We were just amazed at the life saving nature of their field in medicine… it is just amazing what they can do. And I told my fellow, “ if they can make the ICU bed an OR instantly, their assumption is that dialysis can happen instantly and at any place- even in the OR..” We have to understand that they come from a different perspective.  Once we start understanding that, we may be more welcoming of their way of thinking. Similarly, at some point, perhaps they can understand our physiological approach to certain things and preventive nature of AKI and that dialysis is a procedure and not the first thing we should be doing..”


Sunday, August 25, 2019

Topic Discussion: Artificial Intelligence in Nephrology


Artificial intelligence(AI) is on a rise in science. Using it in medicine and specifically nephrology is sure to come.
According to the dictionary, AI is “the theory and development of computer systems able to perform tasks that normally require human intelligence, such as visual perception, speech recognition, decision-making, and translation between languages.

Dr Eric Topol has been a big proponent of this concept in medicine for years and recently has written a book called “Deep Medicine “ that details the potential uses of this in medicine.
Basically, AI can help in three main ways: 1) diagnosis that is often challenging in various challenging syndromes and even basic common ones. 2) make the physician’s life easier and decrease paper work and finally leading to the third -the most important 3) spending more time at the bedside.

AI is done via creating an  artificial neural network (ANN ) which is simply a collection of artificial neurons organized in layers. In a recent article in AJKD, authors discuss the potential use of this concept in Nephrology. They describe using it for IgA nephropathy(IgAN) as a recognizable cause for AKI. The ability to identify the patients that will progress to ESRD with IgAN would be useful for prognostic and therapeutic reasons. Geddes et al hypothesized that there exists a function that associates clinical and biological parameters measured at the time of IgAN diagnosis (namely age, sex, blood pressure, proteinuria, serum creatinine level, and antihypertensive treatments) to the probability of developing progressive IgAN. The authors designed and implemented an ANN to approximate this function. The results showed that their ANN could predict the occurrence of progressive IgAN more accurately than experienced nephrologists (correct predictions, 87% vs 69.4%; sensitivity, 86.4% vs 72%; and specificity, 87.5% vs 66%). Hmm, now this might be interesting to help guide a lot of therapies in Nephrology. This might be very useful in transplantation and prognosticating even need for dialysis for the elderly CKD patients.

Interestingly, many AI algorithms have been approved by FDA that are used in clinical practice:- some examples are of Atrial fibrillation detection, EF ECHO determination, Coronary calcium scoring, CT brain bleed diagnosis, device for paramedic stroke diagnosis, breast density via mammography to name a few.  No nephrology related such algorithms are approved to my knowledge.
There is an entire journal dedicated for this in medicine now
Nephrologists, let’s get started and catch on!

Monday, August 5, 2019

Topic Discussion: Osmotic Nephrosis

Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells.

What does the pathology show:
Usually there is acute tubular necrosis–like changes. Histologically, osmotic nephrosis is characterized by a focal or, less often, diffuse “clear-cell” transformation of proximal tubular epithelial cells showing isometric fine vacuolization of the cytoplasm . The straight part of the proximal tubule primarily is involved and, in severe cases, also the convoluted part. Severely affected tubules are often seen side by side with normal-appearing tubules. Distal tubules and collecting ducts are more or less unchanged
Classic known causes of this entity are:

Intravenous immune globulin preparation(sucrose based)
Mannitol Dextrans
Contrast media
Hydroxyethyl starch
Glucose



How does one differentiate this from vacuolization seen with tacrolimus and cyclosporine? Is that a form of osmotic nephrosis?

Renal Pathologist Dr Lynn Cornell nicely describes this on twitter with these images. The image below shows isometric vacuolization in CNI toxicity. This leads to have focal tubules with this change( see arrow)



In osmotic nephrosis, tends to show vacuolated cytoplasm in tubules diffusely( see below)
Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells.


In addition, In paraffin sections, the isometric vacuolization seen in patients with calcineurin-inhibitor toxicity may be indistinguishable from osmotic nephrosis. However, electron microscopy shows dilated endoplasmatic reticulum as the cause of vacuolization in the former.  Osmotic nephrosis cannot be differentiated from lipid storage in tubular cells (foam cells), as seen in patients with nephrotic syndrome, liver failure, or intoxication. In such cases, foam cells also are often found in large amounts in the interstitial space. This does not occur in osmotic nephrosis.



The above image shows  osmotic nephrosis in a kidney biopsy specimen. (A, B) Tubular cross-section with seemingly no lumen. Epithelial cells are massively swollen, cytoplasm is completely filled by vacuoles of about the same size (isometric vacuoles), and nuclei are displaced to the base of the cells and distorted by adjacent vacuoles( source https://www.ajkd.org/article/S0272-6386(07)01592-2/pdf


Tuesday, July 23, 2019

In the NEWS: The New Kidney Health Order






















Few weeks ago, there was an executive order signed to advance kidney health in the US. This is an historic event for the field of Nephrology and for kidney patients. The above image is a visual abstract that summarizes the changes that might be coming in 2020. This image is courtesy of Dr Tejas Desai @nephondemand

The goal of this order is to increase home dialysis options, increase organ transplantation and promote kidney health and keep patients "away from dialysis".  In addition, several incentives have been built in to allow for improved compensation for physicians and what looks like better options for patients. What does this mean for Nephrology?- Time will tell but this is a huge improvement in terms of patient care and patient choices. Hope this also sparks some more interest in the field of nephrology where we are still struggling for trainees.

Saturday, July 13, 2019

Friday, June 28, 2019

Topic Discussion: Amyloidosis and Renal Infarction


Usually when we think of amyloidosis in the kidney- we think of paraprotein mediated amyloidosis (AL or AH) leading to nephrotic syndrome and in some rare cases- vascular amyloid presenting as AKI.
A recent study published in Mayo Clinic Proceedings suggests that renal infarction might be a common finding in patients with cardiac amyloidosis. Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003).  Renal infarction (defined by defect(s) on the DSMA scan) was reported in 20.7% of patients with and 25% without evidence of cardiac amyloidosis. Prior studies have not really shown any association like this before of amyloidosis and infarction. Renal infarcts were described in an autopsy study in 3 kidneys that had either cast nephropathy, plasma cell nodules, or autolysis but not with amyloid deposits. Dang et al interesting are reporting is a high percentage of abnormal DSMA scans in patients with wild-type transthyretin amyloidosis (wtATTR) and mutant transthyretin amyloidosis (mATTR) amyloidosis.
These findings are intriguing. The 20% to 25% prevalence reported by Dang and colleagues was therefore unexpected. Renal involvement in ATTR is thought to be rare, especially in patients with wtATTR amyloidosis. Recent drugs used to treat this form of amyloidosis might lead to a glomerulonephritis( my recent post). The finding from the current study suggests that we may be vastly underestimating the prevalence of kidney involvement in ATTR amyloidosis. These patients usually don’t present with nephrotic range proteinuria but more with AKI and subacute AKI. Perhaps, instead of labeling all of these as cardio-renal syndrome, we should consider looking for renal infarction in these patients. And as I have always thought about ruling out amyloidosis in young males who present with renal infarction, I usually stop at AL-AH amyloidosis testing. Given the above findings, perhaps an amyloid scan to look for wtATTR and mATTR might be important as perhaps renal infarction could be a potential relationship here. 
Quite an interesting association!!

Thursday, June 20, 2019

Topic Discussion: Tumor Lysis Syndrome with immunotherapy


At this point the nephrology and oncology community is very aware of the AIN, glomerular diseases including vasculitis and ATN seen with check point inhibitors… but we might not be aware of tumor lysis syndrome that this drug can entice in certain patients. 

In the last 2 years, I found several published reports of TLS with check point inhibitors.
Here is a table I created to help with the theme on this one

Immunotherapy
Age
Gender
Cancer type
Time to TLS
Dialysis needed?
Outcome
Reference
Nivolumab
76
Male
Melanoma
5
Yes but declined
Disease progression-death

Atezolizumab
77
Female
GU cancer
14
Yes
Disease progression-death

Atezolizumab
-
-
Solid tumor
-
-
-

Atezolizumab
-
-
Solid tumor
-
-
-

Ipilumumab
73
Male
Melanoma
6
No
Death

Nivolumab
74
Male
RCC
2
No
Death



Based on this, it is seen with PD-1, PDL1 and CTLA4 inhibitors and melanoma and urological cancers. A recent review in JON showed a case of a patient getting TLS with melanoma.  So it’s hard to tell if these agents are causing it or is it the burden of tumor- usually solid tumors in these cases.

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