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!

Topic Discussion: Ever changing FSGS classifications

FSGS is a tough diagnosis and often confusing to the Nephrologist. Classifications in FSGS also have been very confusing and challenging. Several years ago, the pathology based classification had entered all textbooks. 

Is this classification clinically useful? Not sure it is to most nephrologists? If I have a tip variant FSGS, or Perihilar, does it tell me anything re the cause and outcome? Maybe- but mostly not.

In 2007, there was a movement towards changing the concept to more podocytopathy based. ( see below- recreated using biorender). 

Not sure if this is useful either but it really asked a fundamental question re how we are seeing these spectrum of diseases we term FSGS.

The most useful to me personally is classifying the FSGS presentation into 

1) primary vs secondary cause

2) nephrotic syndrome vs nephrotic range proteinuria

While not 100% in most cases, nephrotic syndrome and FSGS usually is going to have a primary cause( sparing some genetic causes and viruses). In addition, what is also helpful from a pathology standpoint is not the LM, but the EM-- 

3) Is there diffuse or partial foot process effacement?- Usually the former responds to treatment better with steroids or other immunosuppression and later is more likely a secondary cause. It may also aid in looking for a secondary cause.

This figure from a JASN paper by De Vriese et al is very helpful indeed. 

So FSGS really should be described more in terms of primary vs secondary causes and EM findings to help in treatment decisions. Classically, your "permeability or immune mediated" FSGS should respond to treatment and would fit under nephrotic syndrome, diffuse foot process effacement and classically your primary FSGS.  Secondary FSGS from various causes like low nephron mass, obesity, viral , meds- all classically would have nephrotic range proteinuria and sporadic foot process effacement on EM. That being said, some genetic causes of FSGS would be seen to have diffuse foot process effacement as well. Genetic FSGS is an important one to keep in mind and screening for genetic causes should be done: young patient, family hx, resistant to treatment, aiding in post transplant risk. etc.

KDIGO GN 2021 guidelines summarize this nicely

APOL-1 plays an important cause and role here and this slide can summarize the primary and the second hit concept with APOL-1 related FSGS

We should not forget --nonspecific scarring on renal biopsies. FSGS should also be differentiated from focal segmental scarring that develops in immune-mediated GN (e.g., Membranous Nephropathy, IgA Neph, ANCA-associated GN, and lupus nephritis) as a result of post-inflammatory scarring of necrotizing or proliferative lesions. This happens a lot and this should not be treated as FSGS. 

In summary, FSGS has come a long way and finally we are seeing some changes in the way we are describing it.. Best 3 ways to categorize FSGS is clinically and EM based.

1. Primary vs Secondary

2. Nephrotic syndrome vs nephrotic range proteinuria

3. Diffuse foot process effacement vs partial foot process effacement 

Detective Nephron: Next Venture

 Check out the next electrolyte venture of Detective Nephron in Kidney News