Concept Map: Thiazide induced hyponatremias(TAH)

We see this form of hyponatremia in several cases, but recently there has been some newer findings on the mechanisms of TAH(*).  In one study published in JCI in 2017, Ware et al showed that there is a subset of patients with a genetic baseline( SLCO2A1 mutation) decrease in prostaglandin(PGE) transport activity which then becomes a risk factor for TAH.  So these patients have increased urinary PGE2 and low AVP levels leading to a pure "nephrogenic" cause of tubular water absorption and dilution hyponatremia. PGE2 is critical in insertion and removal of AQP2 channels in the apical membrane. Increased PGE2 signaling leads to insertion of AQP2 channels into membrane and increase water absorption in an ADH independent manner. This is fascinating. Perhaps then mechanism in NSAIDS as well?
Check out this amazing review in AJKD on this topic. 

Topic Discussion: Zytiga (Abiraterone) induced hypernatremia, and HTN

Zytiga (Abiraterone) is a hormonal chemotherapy agent used to treat prostate cancer. It selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.

Interestingly. it has a high rate of hypernatremia as a known renal complication. In several studies, hypernatremia (33%), hypokalemia (17% to 30%) were reported as known complications. Why? It is postulated that it can increase mineralocorticoids due to CYP17 inhibition may result in hypertension, hypokalemia, and fluid retention (including grade 3 and 4 events) and perhaps some component of hypernatremia as well- almost like a Cushing's state. Per package insert, concomitant administration with corticosteroids reduces the incidence and severity of these adverse events.

In the LATITUDE trial, which used prednisone 5 mg daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 10% of patients on the zytiga arm and 1% of patients on the placebo arm, grades 3-4 hypertension were observed in 20% of patients on the zytiga arm and 10% of patients on the placebo arm. Grades 3-4 fluid retention occurred in 1% of patients each arm.

It is recommended that patients get monitored for hypertension, hypokalemia, and fluid retention at least once a month. Treatment of hypertension is recommended, choice of drug is not defined.

This is an interesting toxicity that as nephrologist seeing prostate cancer with CKD and perhaps new onset hypertension, hypokalemia or hypernatremia should consider in the differential diagnosis.

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	https://www.ncbi.nlm.nih.gov/pubmed/29203585
Phase 2 in MM	22%(80mg)	6% got salt tablets, Dose reduction	Yes, reduced Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/29381435
Phase 1 in solid tumors	13%	Not mentioned	Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/26926685
Phase 1 in sarcomas	7%	Not mentioned	Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/27458288
Phase 1 in Non Hodgkin lymphomas	10%	Not mentioned	Resolved	https://ashpublications.org/blood/article/129/24/3175/36283/Selective-inhibition-of-nuclear-export-with

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. 

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.

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.