GN Chat- a new initiative

 

The Glomerular Center of Northwell now runs a special monthly GN chat to discuss fun and interesting case based discussions of glomerular disease topics. This is on 3rd Tuesday of each month at 8AM EST

Register in advance for this meeting:

https://northwell.zoom.us/meeting/register/tJElf-iqqzgoE9edbml-AI1dNR07Q1LQOL-m 

After registering, you will receive a confirmation email containing information about joining the meeting.

Come learn GN in a coffee style manner with experts in the field- Purva Sharma, Jordan Rosenstock and Kenar Jhaveri

Concept Map: AKI in patients with Chronic Liver Disease

 

Concept map of AKI associated with chronic liver disease. Made using biorender.com 
Inspired by an article in CJASN

New Combined Glomerular Diseases and Onco-Nephrology Fellowship at Northwell

Northwell Nephrology is offering both a traditional two year general nephrology fellowship as well as a new fellowship that includes a third year fellowship specializing in glomerular diseases and onconephrology. The traditional two year fellowship can be applied for through this link

The new expanded third year is through the prestigious Northwell Nephrology Galdi Fellowship in Onconephrology and Glomerular Diseases. This fellowship offer a year of intensive training in these two important subject areas.

A candidate for the Galdi Fellowship will have completed internal medicine residency training, a general nephrology fellowship and demonstrate the highest level of performance and scientific and clinical potential. Candidates for the Galdi Fellowship would be carefully vetted based upon academic and other indications suggesting that advanced training as a Galdi Fellow would enable their ability to become one of a select few international leaders in glomerular diseases and onco-nephrology. The Galdi Fellowship will last for one academic calendar (July through June) year.  A new fellow will be recruited each year.

Training in glomerular kidney diseases is through the Northwell Nephrology Center for Glomerular Diseases directed by Drs. Kenar Jhaveri and Purva Sharma. The fellow will work in the Glomerular Disease Center and be exposed to all aspects of glomerular disease management including a rotation with Division of Rheumatology for extra training in SLE and ANCA vasculitis. The fellow will also have the opportunity to participate in ongoing clinical trials in glomerulonephritis at the Glomerular Disease Center. 

Onconephrology overlaps to an extent with glomerular diseases. Fellows gain experience both in the clinic and hospital with world renowned leaders Rimda Wanchoo and Kenar Jhaveri. Rotations will also include with hematology and oncology teams dealing with multiple myeloma, renal cell cancer and bone marrow transplant services. In addition, the fellow will have rotations with our nephropathologists as well.

 Currently we are accepting applications from current nephrology fellows or recent graduates for the Galdi Fellowship for start date of July 2023. In addition we are accepting applications from internal medicine residents for the general nephrology fellowship starting July, 2023 with a third year Galdi fellowship starting in July, 2025.

For inquiries regarding the advanced fellowship program, please email Dr. Kenar Jhaveri at kjhaveri@northwell.edu 

          Galdi fellowship website 

The application should include
1.      CV of the applicant
2.      Two recommendation letters (one must be from the Nephrology Program Director of Chief)
3.      A Personal Statement on the reasons for joining this fellowship.

Concept Map: Malaria and the Kidney

 

Created using biorender.com
Credit to topic content to Dr. Mythri Shankar and Mala Sachdeva

Opinion- Renal Thrombotic Microangiopathy?- Should we be calling it Renal Limited Endothelial injury or Endothelial Injury of Renal Significance

Thrombotic Microangiopathy- what’s in a name?

This is a common conversation:

“ The kidney biopsy confirms TMA”.  Great- we should ask hematology to help treat..
Hematology—“ but there are no signs of microangiopathic hemolytic anemia.. no schistocytes on smear—no need to treat”

Another conversation

“ The kidney biopsy confirms TMA”.  But there are no micro thrombi on the kidney biopsy. This is likely from HTN—treat the HTN.  “ but the patient has a complement factor H mutation..”.. hmm..

The presentation of TMA can be as mild as HTN only, or AKI on CKD or HTN with CKD or nephritic syndrome or nephrotic syndrome or just nephrotic range proteinuria with AKI. The clinical presentation is very varied. I have seen it all.

The problem with TMA starts with the nomenclature.  Personally, I have a problem with a series of diseases in the kidney called TMA—some have angiopathy only, some have endotheliosis, some have both and some have additional microthrombi but at the end we call all of them TMA.

Most of TMA cases are without thrombosis, only rarely would you see true thrombi.  Frank thrombosis is more common in (catastrophic) APLAS associated TMA in the kidney.

Some TMA tends to be more glomerular  classically in pregnancy related, for example, with endothelial cell swelling = endotheliosis).  And some TMA tends to be more arterial (thrombotic angiopathy rather than microangiopathy). Or we might be catching them at various points in time. A continuous process..

 In my opinion, a better terminology of this entity should be Renal limited endothelial injury or endothelial injury of renal significance. Renal limited TMA without systemic findings is common-- very common than we think and we may be missing to treat as most likely don't get a renal biopsy. Systemic findings of MAHA or other endothelial injury are not required. In several cases- the injury is purely renal limited.  

The pathology is also variable and hence should be considered to be defined perhaps with what is noted on it. 

Endothelial injury with angiopathy
Endothelial injury with micro thrombi
Endothelial injury with endotheliosis predominant

The cause of the injury than can be defined better based on history of the patient and then divided into categories as per the syndromes of TMA or better called “endothelial injury”- such as ADAMTS13 mediated, complement mediated, Drug induced ( immune vs toxic), Shiga toxin mediated, metabolism mediated, coagulation mediated and so forth. This figure is from the classic NEJM article by George et al in 2014.

As we learn more about renal endothelial injury, perhaps a better practical terminology may be useful in defining the disease to help clinicians guide the treatment plan.

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