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NELL-1 associated membranous nephropathy linked to skin fairness cream useinsights from an Indian case series
Ranjit Narayanan, DM, DNB, Sajeesh Sivadas, DM, Anila Abraham Kurien, MD
PII:
S0085-2538(24)00263-1
DOI:
https://doi.org/10.1016/j.kint.2024.03.025
Reference:
KINT 3810
To appear in:
Kidney International
Received Date: 7 December 2023
Revised Date:
28 February 2024
Accepted Date: 19 March 2024
Please cite this article as: Narayanan R, Sivadas S, Kurien AA, NELL-1 associated membranous
nephropathy linked to skin fairness cream use- insights from an Indian case series, Kidney International
(2024), doi: https://doi.org/10.1016/j.kint.2024.03.025.
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Copyright © 2024, Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
NELL 1 associated membranous nephropathy linked to skin
fairness cream use : Insights from an Indian case series
Autoimmune,
infection, basic
malignancy workup
Chemical analysis
of creams
Jul 2021-Sep 2023
Biopsy proven NELL1 MN
Fairness cream
use
Narayanan R et al, 2023
Visual abstract by Sajeesh Sivadas.
@drsajeesh1
13/15 NELL1MN
used fairness
creams
Mercury > 104 times acceptable
limits on cream analysis
Median age 30y
(14-44 y)
6
&7
High levels of mercury
in blood &/or urine in
9/11 patients
Subtle symptoms
Fatigue, frothuria
Partial or complete remission in
all with cessation of usage of
cream & RAAS inhibition
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Ambispective
analysis
15/22 MN were NELL1 positive (68%)
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Heavy metal
screening in
blood &/or urine
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All biopsy proven
PLA2R negative
NELL1 positive MN
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Single Centre
Outcomes
Methods
Cohort
Clinical features
and outcomes
CONCLUSION
Mean proteinuria
13.3g (6.5-22.1 g)
GFR preserved
Mean time to partial remission 4.8
months and complete remission
10.3 months
Increasing incidence of NELL1 MN linked to use of fairness creams with high mercury content
Cessation of cream usage without immunosuppression has favourable clinical outcomes
Enhancing public awareness, physician sensitization and regulatory authority alertness is crucial
NELL-1 associated membranous nephropathy linked to skin
fairness cream use- insights from an Indian case series
Ranjit Narayanan DM,DNB1, Sajeesh Sivadas DM1, Anila Abraham Kurien MD2
1
2
Department of Nephrology, Aster MIMS Hospital, Kottakkal, Kerala, India
Renopath, Center for Renal and Urological Pathology, Chennai, India
Running title: NELL1 membranous nephropathy linked to fairness creams
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Keywords: Membranous nephropathy, NELL1, Renal Biopsy, Fairness creams, Mercury
toxicity, Nephrotic syndrome
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Corresponding Author:
Ranjit Narayanan
Department of Nephrology, Aster MIMS Hospital, Kottakkal, Kerala PIN:676501
Office: +91-483-2807000 Mobile: +91-9446517629
ranjitnarayanan@gmail.com
twitter handle: X@ranji72
1
INTRODUCTION
Neural epidermal growth factor-like protein 1 (NELL-1) is an autoantigen associated with
both primary and secondary membranous nephropathy (MN) and is described with
malignancy, autoimmune diseases, lipoic acid and traditional indigenous medicines (TIM).1-6
We noticed NELL1 positive MN being disproportionately reported in our biopsies since 2021
without any discernible secondary cause. In early 2023, four consecutive cases of MN were
reported NELL1 positive. All four admitted to actively using skin fairness creams prior to
their symptoms, prompting us to prospectively evaluate all patients with MN for their use
while also revisiting all our NELL1 MN cases over the past 2 years.
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Use of skin fairness creams is widespread with a lucrative market in India and is fuelled by
the societal obsession with fair skin. Skin whitening creams with high mercury content have
been associated with MN.7-9,S1-S2 The putative antigen is unclear although a recent report
has linked NELL1 MN to skin creams in a single family.S3
We report an ambispective series of 15 patients with NELL1 MN, from our hospital over the
past 2 years, 13 of whom gave a history of using unlicensed skin fairness creams.
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METHODS
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RESULTS
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All patients diagnosed to have NELL1 MN between July 2021 and September 2023 at Aster
MIMS Hospital, Kottakkal were studied. Lupus MN was excluded. Those with history of
fairness cream use underwent heavy metal screening in blood and/or urine. The fairness
creams were sent for chemical analysis (detailed methodology in Supplementary Methods).
Of the 22 MN reported between July 2021 and September 2023, only four (18%) were
phospholipase A-2 receptor (PLA2R) positive. 15 patients (68.1%) were NELL1 positive
accounting for 83.3% of the PLA2R negative MN. Three were PLA2R and NELL1 negative. The
median age of NELL1 positive patients was 30 years (range 14-75 years) with seven males
and eight females.
Among our NELL1 MN cohort, 13 out of 15 patients admitted using skin fairness creams
prior to their symptom onset. Of the rest, one (57, M) had history of use of traditional
indigenous medicines while the other (75, F) had no identifiable trigger. All were negative
for Hepatitis B and C, autoimmune markers and malignancy. The median age in those who
used skin creams was 30 years (range 14-44 years) with no sex predilection (6 male, 7
female). The median duration of use of the creams was four months (range 2-24 months).
The presenting symptoms were often subtle with fatigue, mild edema and increased
frothing of urine. Only three patients had gross edema though all had nephrotic range
proteinuria (mean 13.33g 4.45g; range 6.5- 22.21 g/day). One patient developed cerebral
vein thrombosis. Renal function was preserved in all (Serum creatinine 0.5-1.1 mg/dL).
(Table 1)
2
On light microscopic examination, all renal biopsies showed normocellular glomeruli
without mesangial matrix expansion. Spike formation was seen on the glomerular basement
membrane in 3 patients (#3, 7, 11). Fuchsinophilic deposits were visualised along the
capillary loops on Masson trichrome stain in the remaining cases. The tubulointerstitial and
vascular compartments were unremarkable. Immunofluorescence study showed segmental
or incomplete bright granular staining for IgG (2–3+/3) and C3 (1–3+/3) along the glomerular
capillary loops in all cases. There was no light chain restriction or significant (>1+) staining
for IgM, IgA or C1q. None showed deposits along tubular basement membranes, Bowman’s
capsule or blood vessels. Immunohistochemical staining for NELL-1 showed granular
staining on the glomerular capillary loop deposits in all patients (Supplementary Figure S1).
Immunostaining for PLA2R was negative in all cases.
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Heavy metal estimation in blood and/or urine was done in 11 patients. 9 showed elevated
mercury levels in blood, urine or both. Those with normal mercury levels presented late
after symptom onset, long after having stopped applying the cream. Two patients in the
retrospective group who were currently not using the creams were not tested. One patient
(#1) with markedly elevated serum mercury level (22.1 mcg/L; normal: 0.46-7.5 mcg/L),
showed reduction in level to 2.42 mcg/L, 3 months after stopping the cream (Table 1).
Analysis of the skin creams revealed high content of mercury (more than 104 times higher
than permissible limits of 1 ppm) (Table 2).
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All patients received RAAS (renin-angiotensin-aldosterone system) blockade with cessation
of cream use. Two patients (#9,13) received empiric steroids before the diagnosis of MN.
One patient (#2) in the retrospective group, received Rituximab in view of persistent
nephrotic state. In the face cream group, 6 patients are in complete remission and 7 are in
partial remission. The mean duration till partial remission was 4.8 ( 3.25) months while
that till complete remission was 10.3 ( 2.73) months in this group. In the overall MN
cohort, the mean time till partial remission was 6.6 ( 4.56) months while that till complete
remission was 11.57 ( 4.11) months. Of the two patients who did not use face creams, one
(#5) needed Rituximab for severe symptomatic nephrotic state and achieved complete
remission after 19 months while the other (#3) is in partial remission (proteinuria <1g) with
RAAS blockade alone. Both took longer (17 and 10 months, respectively) to reach partial
remission. All patients have preserved GFR. (Table 1)
DISCUSSION
The high proportion of NELL1 MN (68%) among our overall MN cohort is unusual compared
to previous cohorts from India (35%) and the West (5-10%).1,3,5,S4 The high prevalence of
NELL1 positive MN (83%) among PLA2R negative MN is comparable to a previous Indian
cohort with TIM use (71%) but much higher than Western cohorts (23%).3,5 In our series, an
association with use of fairness creams was found in 13 out of 15 NELL1 MN cases. The
fairness creams cohort was young, without any sex predilection and had relatively subtle
symptoms despite nephrotic range proteinuria.
Majority of patients tested showed elevated levels of mercury levels in blood or urine . The
degree of elevation varied depending upon whether or not the product was being actively
used at the time of testing. Chemical analysis of the creams revealed mercury content more
than 10,000 times higher than the 1 ppm limit set by the Minamata convention.S5-S6
3
Contamination with heavy metals can occur due to improper purification or during the
production of the cosmetic products.S6
Membranous nephropathy is the most common renal manifestation due to mercury
toxicity8-9 and is well described with topical cosmetics.8-9,S1-S2 Mercury with its high affinity
for sulfanyl groups on the GBM acts as hapten eliciting antibodies targeting antigens on the
GBM, including possibly NELL1, leading to immune complex deposition.8-9 Mercury
accumulates in the proximal convoluted tubule where NELL1 is abundant, potentially
contributing to autoantibody formation.7-9 Genetic susceptibility may explain why not
everyone using these creams develops kidney toxicity.S7 It may be postulated that genetic
polymorphisms could underlie susceptibility to mercury associated MN and that mercury
exposure by face cream use could serve as a “second hit” to this underlying predisposition.
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The key to limiting further kidney damage is to recognise the use of these agents by diligent
history taking, followed by their immediate withdrawal. Most of our patients responded
well to RAAS blockade after discontinuing the inciting creams and did not need
immunosuppression. Fortunately, our patients were identified early when renal function
was preserved. Our patients did not have critical mercury levels to warrant chelation
therapy which has been used previously in mercury toxicity.S8
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NELL1 MN in association with facial whitening cream use was recently reported in three
patients from the same family presenting with nephrotic syndrome, 2 of whom had biopsy
proven NELL1 MN.S3 Our observations regarding a linkage of fairness cream use with NELL1
MN over the past 2 years were made independently. The incriminated creams are
unregulated, widely available and are hugely popular among the youth.S9 Given the societal
obsession with fair skin, this could portend a widespread problem, potentially of epidemic
proportions. Studies from Asia and Africa show that this practice extends beyond India
implying global public health significance.S10 Subtle clinical features at presentation coupled
with lack of awareness among physicians regarding the link between fairness creams and
nephrotic syndrome and failure to obtain a positive history of the same, may explain why
this problem has not been identified on a larger scale. To curb further use, it is essential to
educate the general public and sensitize physicians about the health hazards posed by
contaminated skin creams and alert regulatory authorities to curtail their availability.
However, changing societal attitudes to natural skin tone will pose a greater challenge.
Our study's strengths include a temporal relationship between skin cream use and NELL1
MN, documented high mercury levels in blood and/or urine of patients and in the creams,
and the clinical response upon cream cessation. This represents the largest series of NELL1
MN with a clear link to skin whitening creams with high mercury content. Our study,
however, is limited to a single centre experience.
CONCLUSIONS
We propose that the target antigen linking mercury containing fairness creams and MN
could be NELL1. Most cases resolve on cessation of use of the inciting creams. This poses a
potential public health risk, and it is imperative to spread public awareness about hazards of
using such products and alert health authorities to curb this menace.
4
DISCLOSURES
None of the authors has any conflict of interest to declare.
DATA SHARING STATEMENT
All the data in the study is included in the manuscript.
LIST OF SUPPLEMENTARY MATERIALS
Supplementary Methods
Supplementary Figure S1
Supplementary References
REFERENCES
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1. Sethi S, Debiec H, Madden B, et al. Neural epidermal growth factor-like 1 protein
(NELL-1) associated membranous nephropathy. Kidney Int. 2020;97:163–174
2. Sanjeev Sethi. The Many Faces of NELL1 MN. Clinical Kidney Journal. 2023; 16 (3):
442–446
3. Ronco P, Plaisier E, Debiec H. Advances in Membranous Nephropathy. Journal of
Clinical Medicine. 2021; 10(4):607.
4. Caza TN, Hassen SI, Dvanajscak Z, et al. NELL1 is a target antigen in malignancyassociated membranous nephropathy. Kidney Int. 2021 ; 99(4):967-976.
5. Kurien AA, Prema KS J, Walker PD, at al. Traditional indigenous medicines are an
etiologic consideration for NELL1-positive membranous nephropathy. Kidney Int.
2022;102(6):1424–6.
6. Spain RI, Andeen NK, Gibson PC, et al. Lipoic acid supplementation associated with
neural epidermal growth factor-like 1 (NELL1)-associated membranous
nephropathy. Kidney Int. 2021; 100(6):1208-1213.
7. Li SJ, Zhang SH, Chen HP, et al. Mercury-induced membranous nephropathy:
clinical and pathological features. Clin J Am Soc Nephrol. 2010 ;5(3):439-44.
8. Gao Z, Wu N, Du X, et al. Toxic Nephropathy Secondary to Chronic Mercury
Poisoning: Clinical Characteristics and Outcomes. Kidney Int Rep. 2022;7(6):11891197.
9. Caza TN, Al-Rabadi LF. What Can Mercury Teach Us About Membranous
Nephropathy and Minimal Change Disease? Kidney Int Rep. 2022;7(6):1157-1160.
5
UPCR
(g/g))
DURATION
OF USE OF
CREAM
(mo)
24
MERCURY LEVELS
WHETHER USING
THE CREAM AT
TIME OF BIOPSY
SERUM
CHOLESTEROL
(mg/dl)
SERUM
ALBUMIN
(g/dl)
DATE OF
RENAL
BIOPSY
USE OF
CREAM
YES/NO
UPCR
(g/g)
SERUM
CREATININE
(mg/dl)
1.1
304
3.9
17 Jul
2021
YES
NO
1.0
1.2
3.3
11 Jan
2022
YES
12
NO
-
-
5
YES-RITUXIMAB
0.2
0.8
767
2.3
20 Apr
2022
NO
N/A
N/A
N/A
N/A
10
NO
0.96
0.7
-
-
5
6
NO
0.1
1.0
N/A
N/A
17
19
YES-RITUXIMAB
0.1
0.8
1.3
-
5
14
NO
0.28
0.6
YES
10.0
-
9
12
NO
0.22
0.6
2
NO
4.23
18.46
7
9
NO
0.3
0.6
4
YES
4.71
13.89
3
YES-STEROIDSbefore biopsy
0.79
0.4
YES
2
YES
4.73
13.1
7
NO
0.12
0.9
YES
1.5
NO
3.2
11.53
3
NO
0.81
0.6
NO
2.5
0.4
2
42
M
22.21
3
75
F
19.63
4
30
M
11.04
0.9
339
3.5
28 Apr
2022
YES
6
YES
5
57
M
31.21
0.7
620
2.2
17 Jun
2022
NO
N/A
N/A
6
22
F
6.5
0.6
3.5
19 Aug
2022
YES
6
7
34
F
11.75
0.6
17 Jan
2023
YES
4
8
34
F
16.69
0.7
340
2.6
6 Feb
2023
YES
9
14
F
13
0.5
599
1.8
9 Feb
2023
YES
10
30
M
12.1
1.1
320
2.6
9 Feb
2023
11
29
F
11.96
0.5
263
3.4
23 May
2023
12
26
F
21.98
0.5
544
2.2
13
30
M
12.6
0.9
305
14
36
M
11.02
0.8
15
22
F
11.5
0.7
22.1
2.4
(initial)
(3mths after
stopping
cream)
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NO
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0.7
YES
14
10
f
44
URINE
LEVELS
(0.14-4.2
mcg/L)
-
AT LAST FOLLOW-UP
USE OF
IMMUNOSUPPRE
SION
1
SERUM LEVELS
(0.46-7.5 mcg/l)
TIME TO REMISSION
(in months)
PARTIAL
COMPLETE
REMISSION
REMISSION
SERUM
CREATININE
(mg/dl)
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10.94
FAIRNESS CREAM USE
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M
AT PRESENTATION
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NO
PATIENT
DETAILS
AGE
SEX
11
23 May
2023
YES
3
YES
2.45
15.84
6
1.9
18 Jul
2023
YES
2
NO
4.7
2.61
2
-
YES-STEROIDSbefore biopsy
0.6
0.7
320
3.2
25 Sep
2023
YES
2
YES
10.78
50.46
3
-
NO
2.12
0.85
600
2.5
25 Sep
2023
YES
8
YES
9.18
28.22
-
NO
2.3
0.6
Table 1: NELL1MN cohort -Jul 2021-Sep 2023
6
Arsenic
(mg/kg)
Cadmium
(mg/kg)
Strontium
(mg/kg)
Lead
(mg/kg)
1 ppm
<3
<0.3
<25000
<10
13200
-
0.13
1.44
2.58
10800
-
33.8
195.43
269.27
21900
not detected
-
-
-
10500
0.48
0.75
4.0
0.89
13000
0.14
0.35
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0.5
1.53
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Permissible
limits
Cream 1
(Youth face)
Cream 2
(Unnamed)
Cream 3
(Faiza)
Cream 4
(Aina)
Cream 5
(Luka)
Mercury
(ppm)
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Table 2: Fairness cream chemical analysis
7
8
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