Hey #NephTwitter #Medtwitter!
⚠️How often do you see a family of cases with nephrotic syndrome?
💭What are your first thoughts when multiple family members present with glomerular disease?
Read along!
Here's an intriguing series of cases we encountered some time ago!👇🏻1/n
⚠️How often do you see a family of cases with nephrotic syndrome?
💭What are your first thoughts when multiple family members present with glomerular disease?
Read along!
Here's an intriguing series of cases we encountered some time ago!👇🏻1/n
2/n
A previously healthy 17-year old young lady ➡️ presented to the clinic with edema feet & puffiness of face for past 4-6 wks
🩺 Normotensive
Unremarkable clinical examination, except for generalised edema
🩸🔬Labs as follows👇
A previously healthy 17-year old young lady ➡️ presented to the clinic with edema feet & puffiness of face for past 4-6 wks
🩺 Normotensive
Unremarkable clinical examination, except for generalised edema
🩸🔬Labs as follows👇
3/n
Diagnosis?
➡️Neural epidermal growth factor-like 1 (NELL1) associated MN
Likely in this young lady?
Observations on demography of NELL1-MN appear contrasting👇
📌Older age group (mean 66.8yrs vs 56.4yrs in PLA2R+)
📌Slight preponderance in males (58.7%)
(PMID: 32828756)
Diagnosis?
➡️Neural epidermal growth factor-like 1 (NELL1) associated MN
Likely in this young lady?
Observations on demography of NELL1-MN appear contrasting👇
📌Older age group (mean 66.8yrs vs 56.4yrs in PLA2R+)
📌Slight preponderance in males (58.7%)
(PMID: 32828756)
4/n
Also, the likely cause in this patient❓
Since its discovery in 2020, well-founded associations of NELL1-MN have been described 👇
💊Lipoic acid (PMID: 34662650)
🎗️Malignancy (PMID: 32828756)
🍶Traditional Indigenous Medicines(PMID: 36096266)
Also, the likely cause in this patient❓
Since its discovery in 2020, well-founded associations of NELL1-MN have been described 👇
💊Lipoic acid (PMID: 34662650)
🎗️Malignancy (PMID: 32828756)
🍶Traditional Indigenous Medicines(PMID: 36096266)
5/n
However, NELL1 appears to be a ubiquitous antigen in MN!
NELL1 can be incited by different mechanisms of injury& is expressed in a variety of conditions causing MN.
👇🏻A recent summary from CKJ, Mar'23📝
academic.oup.com
So what were we dealing with in our case here❓
However, NELL1 appears to be a ubiquitous antigen in MN!
NELL1 can be incited by different mechanisms of injury& is expressed in a variety of conditions causing MN.
👇🏻A recent summary from CKJ, Mar'23📝
academic.oup.com
So what were we dealing with in our case here❓
6/n
Our young lady displayed none of the above associations🔍
She continued to have significant proteinuria➡️ Received Modified Ponticelli regimen, supportive care & thyroxine
🗓️To our surprise few weeks later, patient's mother presented to our clinic with nephrotic syndrome!
Our young lady displayed none of the above associations🔍
She continued to have significant proteinuria➡️ Received Modified Ponticelli regimen, supportive care & thyroxine
🗓️To our surprise few weeks later, patient's mother presented to our clinic with nephrotic syndrome!
7/n
🔬Kidney biopsy👇
LM ➡️Diffuse thickening of basement membrane,no proliferation/sclerosis
IF ➡️IgG1 (3+), IgG2 (1+), IgG4 (3+) & C3 (1+) & NELL1 + in a segmental, granular pattern along capillary walls
➡️Neg for PLA2R/THSD7A/Sema3b/EXT1
NELL1 IF image courtesy: @draalok
🔬Kidney biopsy👇
LM ➡️Diffuse thickening of basement membrane,no proliferation/sclerosis
IF ➡️IgG1 (3+), IgG2 (1+), IgG4 (3+) & C3 (1+) & NELL1 + in a segmental, granular pattern along capillary walls
➡️Neg for PLA2R/THSD7A/Sema3b/EXT1
NELL1 IF image courtesy: @draalok
8/n
➡️Thyroid function tests were deranged
➕Anti-TPO Antibody
Rx: Modified Ponticelli regime, supportive care, thyroxine
🧐We had no clues towards the etiology of MN presenting sequentially in this mother-daughter duo
🌀Another curveball hit a month later!👇🏻
➡️Thyroid function tests were deranged
➕Anti-TPO Antibody
Rx: Modified Ponticelli regime, supportive care, thyroxine
🧐We had no clues towards the etiology of MN presenting sequentially in this mother-daughter duo
🌀Another curveball hit a month later!👇🏻
9/n
The index case's sister presented to us with similar complaints!
🚫This time we did not go for kidney biopsy
💊Treated proteinuria with non-IS measures
💊Treated for antiTPO Ab➕ hypothyroidism
More importantly, what was really going on?
A family with MN??👩👧👧
The index case's sister presented to us with similar complaints!
🚫This time we did not go for kidney biopsy
💊Treated proteinuria with non-IS measures
💊Treated for antiTPO Ab➕ hypothyroidism
More importantly, what was really going on?
A family with MN??👩👧👧
10/n
We probed into the recently emerging evidence for environmental exposures in MN-
1⃣🏭Inhalable particulate matter (PM2.5) (PMID: 27365535)
2⃣👨🏭Occupational (PMID: 36283759)
3⃣⛏️Heavy metals (10.1093/ndt/gfx146.SP343)
4⃣🌿Drugs (NSAIDs, herbal supplements) (PMID: 36096266)
We probed into the recently emerging evidence for environmental exposures in MN-
1⃣🏭Inhalable particulate matter (PM2.5) (PMID: 27365535)
2⃣👨🏭Occupational (PMID: 36283759)
3⃣⛏️Heavy metals (10.1093/ndt/gfx146.SP343)
4⃣🌿Drugs (NSAIDs, herbal supplements) (PMID: 36096266)
11/n
In our cases, we enquired for-
🏭Air/water pollution
🔥Exposure to biomass fuels
🍶Traditional indigenous medicines
💊Drugs
Enquiry about habitually used products led us to a question about the make-up kit.💄🧴
Curiously enough, there was the culprit, hiding in plain sight!
In our cases, we enquired for-
🏭Air/water pollution
🔥Exposure to biomass fuels
🍶Traditional indigenous medicines
💊Drugs
Enquiry about habitually used products led us to a question about the make-up kit.💄🧴
Curiously enough, there was the culprit, hiding in plain sight!
12/n
All 3 ladies were using a 'fairness cream', wildly popular by word-of-the-mouth in their circles.✨
Each used a face serum & cream daily for few months (longest:6-7mo) ➡️ experienced effective skin lightening which prompted further continued use
The real culprit though❓
All 3 ladies were using a 'fairness cream', wildly popular by word-of-the-mouth in their circles.✨
Each used a face serum & cream daily for few months (longest:6-7mo) ➡️ experienced effective skin lightening which prompted further continued use
The real culprit though❓
13/n
🚨Mercury🚨
Inorganic Hg blocks🚫tyrosinase in melanin synthesis by competing with Cu➡️widely used in skin whitening agents since antiquity
⚠️Toxic levels of Hg have been found in up to 50% of these products globally (2022)
eeb.org
👇🏻thegef.org
🚨Mercury🚨
Inorganic Hg blocks🚫tyrosinase in melanin synthesis by competing with Cu➡️widely used in skin whitening agents since antiquity
⚠️Toxic levels of Hg have been found in up to 50% of these products globally (2022)
eeb.org
👇🏻thegef.org
14/n
Minimal change disease & MN resulting from Hg toxicity through skin whitening agents was described as early as the 1970s.
Interesting early observations such as this👇& others explored & established causality.
bmj.com
Minimal change disease & MN resulting from Hg toxicity through skin whitening agents was described as early as the 1970s.
Interesting early observations such as this👇& others explored & established causality.
bmj.com
15/n
Mechanisms behind Hg toxicity & glomerulonephritis are speculative
▪️Anionic charges attract Hg to GBM➡️facilitate crossover to Bowman's space/proximal tubule
▪️Hg binds to -SH ligands➡️disrupts essential cellular enzymes/proteins
▪️Neoantigens➡️autoimmunity (PMID:27666813)
Mechanisms behind Hg toxicity & glomerulonephritis are speculative
▪️Anionic charges attract Hg to GBM➡️facilitate crossover to Bowman's space/proximal tubule
▪️Hg binds to -SH ligands➡️disrupts essential cellular enzymes/proteins
▪️Neoantigens➡️autoimmunity (PMID:27666813)
16/n
🔍Further investigations in our cases established high Hg content in👇🏻
➡️ Skin whitening cream (2,000 & 7,500 times permissible limits of <1ppm)
➡️ Blood
➡️ Urine
Kidney tissue was also examined for Hg content➡️did not reveal high Hg (? relatively shorter exposure times)
🔍Further investigations in our cases established high Hg content in👇🏻
➡️ Skin whitening cream (2,000 & 7,500 times permissible limits of <1ppm)
➡️ Blood
➡️ Urine
Kidney tissue was also examined for Hg content➡️did not reveal high Hg (? relatively shorter exposure times)
17/n
How is NELL1 involved in this❓
NELL1 is a 90 kDa protein expressed in health in osteoblasts
In kidneys, it is located
1⃣Largely in the proximal tubule
2⃣5-25% glomerular cells NELL1mRNA
➡️Can get activated under conditions of injury/epigenetic modifications
PMID33562791👇
How is NELL1 involved in this❓
NELL1 is a 90 kDa protein expressed in health in osteoblasts
In kidneys, it is located
1⃣Largely in the proximal tubule
2⃣5-25% glomerular cells NELL1mRNA
➡️Can get activated under conditions of injury/epigenetic modifications
PMID33562791👇
18/n
Hg is known to give rise to autoimmunity
Crowe, et al (PMID27666813)
Thus, NELL1 may be one of the neoantigens induced by Hg, with consequent complement activation & GBM damage👇
Another autoimmune manifestation notable in all our cases was anti-TPO Ab+ hypothyroidism
Hg is known to give rise to autoimmunity
Crowe, et al (PMID27666813)
Thus, NELL1 may be one of the neoantigens induced by Hg, with consequent complement activation & GBM damage👇
Another autoimmune manifestation notable in all our cases was anti-TPO Ab+ hypothyroidism
19/n
Many kidney diseases appear to have their genesis in a conducive genetic environment exposed to '2nd hit'
The rare familial clustering in our series raises possibility of genetic susceptibility👩👧👧
1⃣Epigenetics-♀️ hormones,autoimmune predisposition
2⃣Environment-Hg exposure
Many kidney diseases appear to have their genesis in a conducive genetic environment exposed to '2nd hit'
The rare familial clustering in our series raises possibility of genetic susceptibility👩👧👧
1⃣Epigenetics-♀️ hormones,autoimmune predisposition
2⃣Environment-Hg exposure
20/n
What is the role of genetic susceptibility in NELL1-MN?
Modern day genetic studies👇🏻🔍
1⃣Rare familial clusters have been described in MN
2⃣GWAS has identified highly replicable patterns backed by functional studies in other NELL1 disorders (not MN)
ajp.amjpathol.org
What is the role of genetic susceptibility in NELL1-MN?
Modern day genetic studies👇🏻🔍
1⃣Rare familial clusters have been described in MN
2⃣GWAS has identified highly replicable patterns backed by functional studies in other NELL1 disorders (not MN)
ajp.amjpathol.org
21/n
This observation is not unlike that in PLA2R+ MN, where genetic predisposition likely accounts for 25-32% risk in diverse populations
🧬Implicated genotypes appear to predict response to immunosuppression as well
PMIDs: 21323541,32231244, 29998121, 25187357
This observation is not unlike that in PLA2R+ MN, where genetic predisposition likely accounts for 25-32% risk in diverse populations
🧬Implicated genotypes appear to predict response to immunosuppression as well
PMIDs: 21323541,32231244, 29998121, 25187357
22/n
NELL1-MN has different geographical prevalence🗺️& etiologies as seen in various cohort studies from different populations across the globe.
Can these variations be accounted for by different 2nd hits leading to NELL1-MN?
karger.com
NELL1-MN has different geographical prevalence🗺️& etiologies as seen in various cohort studies from different populations across the globe.
Can these variations be accounted for by different 2nd hits leading to NELL1-MN?
karger.com
23/n
Environmental exposures are an under-recognised cause of glomerulonephritis
⌛️Following is the timeline of our cases with respect to exposure & clinical course. Remarkably, stopping product use led to improvement in proteinuria for all 3, indicating reversible injury.
Environmental exposures are an under-recognised cause of glomerulonephritis
⌛️Following is the timeline of our cases with respect to exposure & clinical course. Remarkably, stopping product use led to improvement in proteinuria for all 3, indicating reversible injury.
24/n
Lesson learnt?
📌Add “use of skin lightening products”to history checklist of MN!🔬
Also, may this serve as a cautionary tale⚠️
➡️Innocuous exposures can harm
➡️Be skeptical,especially if it ‘works like magic’
➡️Insist on accurate product labelling🛒
‘Know thy ingredients’
Lesson learnt?
📌Add “use of skin lightening products”to history checklist of MN!🔬
Also, may this serve as a cautionary tale⚠️
➡️Innocuous exposures can harm
➡️Be skeptical,especially if it ‘works like magic’
➡️Insist on accurate product labelling🛒
‘Know thy ingredients’
25/n
"Dosis sola facit venenum"
-Parcelsus
"Only the dose makes the poison"☣️
Or does it?!
Is susceptibility more important, as in our cases?
📝For more information, check out our paper👇🏻
doi.org
@tukaramj @sultan_amar8 @ameyrojekar
Thank you for your attention!
"Dosis sola facit venenum"
-Parcelsus
"Only the dose makes the poison"☣️
Or does it?!
Is susceptibility more important, as in our cases?
📝For more information, check out our paper👇🏻
doi.org
@tukaramj @sultan_amar8 @ameyrojekar
Thank you for your attention!
Thank you all for going through this tweetorial! All credit goes to brilliant insights from Dr. @tukaramj who led this investigation, Dr. @sultan_amar8 who identified these peculiar cases in his clinic,did initial w/up &management,& Dr. @ameyrojekar who gave valuable🔬insights!🙏🏻
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