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
Dose modifications
Phase 1 in MM
47% (60mg/m2)
Not reported
Not reported
Resolved in most cases
Phase 2 in MM
6% got salt tablets,
Dose reduction
Yes, reduced
Resolved in most cases
Phase 1 in solid tumors
Not mentioned
Resolved in most cases
Phase 1 in sarcomas
Not mentioned
Resolved in most cases
Phase 1 in Non Hodgkin lymphomas
Not mentioned

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.
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 

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