In the News: Vonoprazan and the Kidney

A new agent has been found to cause AKI and AIN—Vonoprazan.  A recent paper in Kidney International is the first to describe this from Japan. The authors used the National reporting database of drug toxicities in Japan to assess this and compared it to PPIs—JADER database.  See visual ab from the recent paper. 

What is vonoprazan? 

Vonoprazan, a potassium-competitive acid blocker possessing a new mechanism of action. Vonoprazan inhibits acid secretion in the cells of the gastric wall. The inhibitory effect of vonoprazan on H+, K+-ATPase is perhaps over 300 times greater than that of lansoprazole. 

In Japan, this drug was approved for use for acid reflux in 2015. In the US, this drug has been FDA approved for esophageal esophagitis in association with H pylori recently in May 2022.  A recent meta-analysis also found that vonoprazan is non inferior to PPIs as therapy for GERD but in the subgroup for severe erosive esophagitis- it was more effective.

In this recent study in KI, authors compared PPI related renal adverse events to this new agent. The total numbers of renal adverse events associated with PPIs and vonoprazan were 14149 and 2465, respectively. Surprisingly, a safety signal for vonoprazan and a drug associated AIN —was detected, which was similar to that obtained for PPI. Interestingly. a safety signal for AKI caused by PPIs and vonoprazan were not detected.

The mechanism of action of vonoprazan is that it competes with potassium ions for the reversible inhibition of H+- K+-ATPase, whereas PPIs act by binding covalently to the gastric H+, K+-ATPase via disulfide bonds.  Having a H+, K+-ATPASe in the kidney have any impact? Not sure?

Another interesting finding from another study showed increase tacrolimus levels when this agent is used- a caution in our GN and transplant patients.

As we learn more about this agent in the US, we need to be vigilant!

In the NEWs: Hydralazine and the Kidney

Hydralazine- you can love or hate as a nephrologist. Hydralazine is used a lot for both inpatient and outpatient setting my several internists, cardiologists and nephrologists for management of blood pressure. In clinical practice, many times we have noticed vasculitis from hydralazine : both of the lupus or the ANCA kind. Drug induced kidney diseases are important to keep in mind when the clinical picture doesn't make any sense. 

See this exhaustive table from Izzedine and Ng in the recent Kidney News issue on drug induced glomerular diseases. 

A recent study in KI just focused on hydralazine induced ANCA vasculitis and looked at 80 patients.
As suspected, the clinical clues are: many have low complements, +ANCA( both p and c in some cases- 40%), ANA and anti histone positive and even dsDNA positive. When you see several auto antibodies come back positive- think drug induced. Treatment is cessation of the agent and treat like regular vasculitis. 

Check out an old detective nephron from 2013 on this topic.

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. 

Consult Rounds: Novel Sofosbuvir based Hep C agents and AKI

Can the novel agents used to treat hepatitis C cause AKI?

Most of the novel agents used to treat Hep C now in the current era are Sofosbuvir based. It has low rate of drug-drug interaction but kidney excretes over 70% of it’s major metabolite. This metabolite know as GS-331007 increases by ten fold in patients with renal dysfunction.

To my knowledge, no initial trials had any cases of AKI reported with this agent. Based on some recent trials using this agent, AKI might happen in 1-15% of patients treated with this agent.  Higher incidences were seen ( 45%) in liver transplant patients getting this agent. 

https://www.ncbi.nlm.nih.gov/pubmed/26923436

https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14117

When?- 9-22 weeks of treatment.
Risk factors:- CKD, NSAID use, other nephrotoxic agent, DMII and ascites

Pathology:- what is the mechanism? There are only 4 published cases of kidney biopsy findings. We had published the first case of this in 2016 that showed AIN.  Subsequently, 3 other cases with AIN have been published and in one case ATN was also reported. It appears that the most likely mechanism is interstitial disease. In 2 of the 4 cases, 8 weeks was the time frame of injury, in remaining was 14 and 22 weeks of injury. It seems to be reversible in most cases.

https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.1803

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496585/

https://europepmc.org/abstract/med/28656492

This is an interesting trend to watch. As we see less and less of Hep C induced renal disease, it is more likely we may see more treatment induced renal disease now.

A recent review of this topic is a good read.

Consult Rounds: High Dose IV Insulin and new avenues of treatment..

Traditional therapies for beta-blockers or calcium channel blocker toxicity are:
Glucagon, Calcium, Atropine and Vasopressors.

What I learned is that now high-dose insulin therapy has emerged as a preferred treatment of cardiogenic shock induced by calcium channel blockers or beta blockers. When used at doses 10 times that of the normal antidiabetic dose, insulin has positive inotropic effects even in the presence of beta-blocker or calcium channel blocker toxicity. What insulin dose at these high doses is improve hemodynamic stability and improve response to pressors. This takes almost 30 min to take effect.

There is a toxicology guidelines for this listed below: Consensus recommendations for the management of calcium channel blocker poisoning in adults. There is a  linear dose-response curve where increasing doses of insulin produce increasing positive hemodynamic effects. Goals for treatment can be a heart rate of at least 50 beats per minute and a systolic blood pressure of at least 100 mmHg. Obviously, one has to give dextrose to combat the severe hypoglycemia that might result of this and monitor K and phos levels s well.

Interestingly, this is being used commonly in beta blocker toxicity as well. In one large study looking at using high dose insulin in beta blocker and CCB toxicity, median insulin bolus was 1U/kg and peak infusion was 8 Units/kg/h.  Interestingly and expectedly, hypokalemia occurred in close to 30% of patients and hypoglycemia in 30% of patients.

 This is an interesting concept and a creative use of a common agent.

Concept Map: Drug Induced TMA

In the NEWS: PD-1 inhibitors and ATN, not AIN

Check point inhibitors have been associated with kidney injury. The incidence of check point inhibitor associated renal injury varies widely in the literature. The most common kidney biopsy observed has been acute interstitial nephritis and in a few rare cases- podocytopathies. 

In a recent study from France, the authors report on the incidence of pembrolizumab associated kidney toxicity in a French single-center nephrology referral center and report that renal adverse events occur in 1.77% of patients. A renal biopsy was performed in all 12 patients and acute tubular injury was the most common lesion noted. The most common glomerular pathology in this case series was minimal change disease. In this study, surprisingly, acute tubular injury was the most commonly observed pattern of injury on histology. This is in contrast with other reports that identified acute tubulo-interstitial nephritis as the dominant form of renal injury associated with immunotherapy treatment. A possible explanation is the low threshold to perform a kidney biopsy in this study. 

About half of their patients had ATN. Those patients had more frequently cardiovascular risk factors and marked histological vascular lesions and are more frequently men than AIN patients. Two of them received platinum but at least 1 year before pembrolizumab was introduced. No known mechanism is postulated for the ATN related to pembrolizumab.

This is an important study as this highlights the varied degree of renal toxicities seen with these agents. AIN will respond to steroids and ATN won’t. A kidney biopsy will be important to distinguish that. Empiric steroid treatment by oncologist should not be the gold standard but should be based on kidney biopsies performed and or a nephrology consultation. 

Besides AIN and podocytopathies, it appears that PD-1 inhibitors also can cause ATN.

Topic Discussion: Common Nephrotoxic drugs and their mode of enteries

Common Renal toxic drugs and their mode of entering the tubule and mechanism of toxicity

Drug Name	Mode of entry	Mechanism	Clinical Presentation(s)
Tenofivir(TDF)	Secreted via the basolateral side via OAT and then enters lumen via MRP2 in the urine.	Mitochondrial dysfunction	ATI Proximal tubulopathy Diabetes Insipidus(rare)
Gentamicin(Aminoglycosides)	They are all filtered and they are attracted to negative phospholipids and bind to megalin cubulin receptor and enter the cell.	Lysosomes binding and then cause mitochondrial damage and tubular injury—myelin bodies	ATI Bartter’s syndrome( via activating of the CaSR in the TAHL) Fanconi syndrome(rare)
Polymixin	All filtered, punch holes enter cells via organic cationic transporter(OCT) on apical surface	Apoptosis and necrosis	ATI
Vancomycin	Unclear how it enters	Complement activation Activation of reactive oxygen species Mitochondrial injury Vancomycin cast formations	ATI Worse when combined with Piperacillin / Tazobactam
Amphotericin B	Unclear how it enters	Principal cell defect via holes in the apical membrane	Distal hypokalemic RTA ATI Hypomagnesemia Nephrogenic DI
Heta-Starch, Dextran, Sucrose, Mannitol	Filtered and enter proximal cell – pinocytosis and build up and swell up cells. Cannot be metabolized	Osmotic nephrosis	ATI
Atazanavir	Minimal renal excretion, poorly soluble in urinary ph- leading to crystallization	Crystal formation	Crystal Nephropathy
Cisplatin	Enters via OCT on the basolateral side, enters and activates apoptosis	Oxidative stress	ATI Hypomagnesemia Proximal tubulopathy Salt wasting nephropathy Nephrogenic DI
Ifosfamide	Enters proximal tubular cell via OCT on the basolateral side and then metabolized to its metabolized that causes the damage	Increased oxidative stress and mitochondrial injury	ATI Fanconi syndrome

Concept Map: NSAIDS and their effects on the Kidney

Consult Rounds: Toxic alcohol ingestions

A summary of all potential alcohol toxicities ( Renal perspective)

Name	Metabolic Acidosis	Osmolar Gap	Anion Gap	Ketones	Ca Oxolate Stones	Reduced Vision
Alcohol	Yes	Yes	Yes( lactate also)	Yes	No	No
Methanol	Yes	Yes( earlier on and then disappears)	Yes	No	No	Yes
Ethylene Glycol	Yes	Yes	Yes	No	Yes	No
Isopropyl Alcohol	No	Yes	No	Yes	No	Yes
Propylene Glycol	Yes	Yes(initially)	Yes(converted to lactate)	No	No	No