Kidney Case Conference:
How I Treat
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How I Treat: An Algorithmic Approach to Crystalline
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Nephropathies
Isabelle Brocheriou ,1 Kenar D. Jhaveri ,2 and Hassan Izzedine
CJASN 18: 1369–1371, 2023. doi: https://doi.org/10.2215/CJN.0000000000000236
Introduction
Crystalline nephropathies are an underdiagnosed
cause of kidney disease characterized by the histologic
finding of intrarenal crystal deposition primarily in-
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volving the tubulointerstitium.1 These disorders are
particularly challenging. They require the pathologist
to deduce the nature of the crystals from a variety of
clues (polarization, color, fluorescence, etc.) before a
direct chemical identification.
Clinically, patients may present crystalluria, pro-
teinuria, and cylinduria, while tubulopathies, AKI,
and CKD may also develop. Identification of crystals
within the kidneys on biopsy is definitive for a diag-
nosis of crystalline nephropathy and necessitates eval-
uation of the underlying cause.2
Although excellent reviews summarizing crystal ne-
phropathies have been published,2–4 we propose a
practical and easy approach to guide the diagnosis
on the basis of three steps: examination under polar-
ized light, color of the crystals on hematoxylin and
eosin and periodic acid–Schiff stains, and fluorescence.
Case
A 76-year-old man with dyslipidemia and ischemic
heart disease presented with pancreatic cancer. Treat-
ment with chemotherapy FOLFIRINOX (folinic acid,
fluorouracil, irinotecan, and oxaliplatin) followed by
pancreaticoduodenectomy and consolidation chemo-
therapy by LV5FU2 (fluorouacil and leucovorin) was
proposed. His other medications included atenolol,
acetylsalicylic acid, levothyroxine, paroxetine, pancre-
atic enzyme supplements 75,000 UI/d (since the sur-
gery), and ascorbic acid 500 mg/d, up to 3 days a week
(as needed). The postoperative course was marked
by chronic diarrhea without weight loss and a pro-
gressive decline in kidney function (eGFR/Modifica-
tion of Diet in Renal Disease 90 ml/min per operative
and then 67, 45, and 33 ml/min at 4, 14, and 18
months, respectively, when a kidney biopsy was
performed). Urinalysis revealed no proteinuria, hematu-
ria, or leukocyturia. Kidney biopsy revealed tubulointer-
stitial fibrosis. Examination under polarized light
revealed numerous birefringent and translucent crystals
within the interstitium referring to calcium oxalate, so-
dium urate, or cystinosis crystals and drug-induced
www.cjasn.org Vol 18 October, 2023
3
1
Department of
(acyclovir, indinavir, atazanavir, amoxicillin, and sulfadi- Pathology, Pitie-
azine). Patient’s medical history did not reveal the use of Salpetriere Hospital,
Paris, France;
such drugs nor pathologies, such as HIV or cystinosis. The Sorbonne Université,
diagnosis of oxalate crystal nephropathy is based on a INSERM UMR S1155,
history of duodenopancreatectomy and intake of ascorbic Pitié-Salpêtrière
acid and hyperoxaluria (115 mg/24 hours and an oxalate/ Hospital, APHP6,
Paris, France
creatinine ratio of 78.7 mg/g). Treatment including low 2
Division of Kidney
oxalate diet, calcium and potassium citrate supplementa- Diseases and
tion, and avoidance of ascorbic acid intake resulted in Hypertension, Donald
stabilization of kidney function at 33 ml/min 6 months and Barbara Zucker
School of Medicine,
after the kidney biopsy.
Northwell Health,
Hempstead, New York
3
Department of
How to Diagnose Crystalline Nephropathy Nephrology, Peupliers
Crystalline nephropathies are a unique form of kid- Private Hospital, Paris,
ney disease. They are categorized by the cause, namely France
medication induced (sulfa-based medications, metho-
trexate, acyclovir, protease inhibitors, triamterene, ci- Correspondence:
Dr. Hassan Izzedine,
profloxacin, levofloxacin, amoxicillin, ascorbic acid, Department of
foscarnet, and sodium phosphate purgative), parapro- Nephrology, Peupliers
teinemia induced (light chain proximal tubulopathy, Private Hospital, 8
crystalline cast nephropathy, crystalglobulinemia, and Place de l’Abbe
Henocque, 75013
crystal storing histocytosis), and those associated with
Paris, France. Email:
inherited disorders (Dent disease, primary hyperoxalu- h.izzedine@
ria, Lowe syndrome, and cystinosis). ramsaygds.fr
The clinical presentations of the above syndromes
can be variable and cannot provide too much insight
into the cause of the nephropathy. AKI is present in
most of the causes of this syndrome, but in some, there
will also be nephrolithiasis and in some crystalluria.
Fanconi syndrome is more associated with the light
chain–associated crystalline nephropathies and many
hereditary nephropathies (cystinosis, Dent disease,
and Lowe syndrome). High-grade monoclonal pro-
teinuria is a subtle clue in light chain crystalline cast
nephropathy. Diagnosis of medication-induced crys-
talline nephropathies hinges on the knowledge of cul-
prit medications, their clinical syndromes, and urine
microscopic findings.
Urinary examination and microscopy is clinically
useful in diagnosis of crystal nephropathies. The color,
shape, and content of the crystals can be useful in the
clinical diagnosis and clues the clinicians in to the
cause of the syndrome. Figure 1 summarizes the var-
ious urine microscopic findings of drug-induced, light
chain–induced, and genetic causes of this syndrome.
Copyright © 2023 by the American Society of Nephrology 1369
 1370 CJASN

Kidney-related imaging, such as computed tomogra-
phy scan or ultrasound, can help only if there is
nephrolithiasis associated with the syndrome. Pure
crystal-related AKI may not be clinically diagnosed
with imaging techniques.
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1. Crystals with a positive birefringent polarization and
brown, brownish-green, or yellow can lead to metho-
trexate or triamterene, 2,8-dihydroxyadenine deficit, and
foscarnet crystals, respectively, whereas crystals birefringent
and translucent can evoke calcium oxalate, sodium urate,

It is not uncommon that most patients are asymp- or cystinosis crystals and drug-induced (acyclovir, indinavir,
tomatic and only show isolated elevated serum creat- atazanavir, amoxicillin, and sulfadiazine).
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inine. In some cases, if the urine findings are not useful
or are completely benign, kidney biopsy is the gold
standard. If histologic findings are not obvious at the
beginning and in the presence of specific lesions (acute
tubular injury in nonatrophic tubules, interstitial fibro-
sis and tubular atrophy, and mild-to-moderate intersti-
tial inflammation without eosinophilic infiltrate), the
first step that the pathologist should systematically
perform is an examination under polarized light (Fig-
ure 1). If there is a refringence under polarized light, the
second step is to determine the color of the crystals. The
Is1NZ2sSo on 10/18/2023
2. Crystals without polarization and blue colored on
periodic acid–Schiff suggest phosphocalcic crystals. If
crystals are colorless, vancomycin crystals could be
the search (B).
If none of the above methods are successful, the pathol-
ogist should perform immunofluorescence as the third step.
A. A positive immunofluorescence for kappa or lambda
chains should lead to a search for light chain–restricted
dysproteinemia (light chain cast nephropathy, light chain

color will guide the pathologist toward different cate- proximal tubulopathy, crystal-storing histiocytosis, and
gories of etiology: drug induced, metabolic, genetic, crystalglobulinemia). Electron microscopic analysis is
or others. necessary in these cases. Nevertheless, the topography of

Figure 1. Crystalline nephropathy: an illustrated algorithm approach. In the presence of specific lesions, the first step is an examination
under polarized light. If there is a refringence under polarized light, the second step is to determine the color of the crystals. The color guide
toward different categories of etiology: crystals with a positive birefringent polarization and brown, brownish-green, or yellow can lead to
methotrexate or triamterene, 2,8 dihydroxyadenine deficit, and foscarnet crystals, respectively, whereas crystals birefringent and translucent evoke
calcium oxalate, sodium urate, or cystinosis crystals and drug-induced (acyclovir, indinavir, atazanavir, amoxicillin, and sulfadiazine). Crystals
without polarization and blue colored on PAS are phosphocalcic crystals. If crystals are colorless, vancomycin crystals could be the search. If
none of the above methods are successful, the pathologist should perform immunofluorescence as the third step: a positive IF for kappa or
lambda chains should lead to a search for LC-restricted dysproteinemia (LC cast nephropathy, LC proximal tubulopathy, crystal-storing
histiocytosis, and crystalglobulinemia). Crystal topography aids diagnosis according to the nephron structure affected (tubules, LCPT, LCCN;
interstitium, LC crystalline cast nephropathy, crystal-storing histiocytosis; podocytes/FSGS, LCC podocytopathy; glomeruli and/or vessels,
crystalglobulinemia). Electron microscopic analysis is necessary in these cases. A negative IF indicates phosphocalcic (blue) or vancomycin
(translucent) crystals. CTIN, chronic tubulointerstitial nephritis; EM, electron microscopy; IF, immunofluorescence; LC, light chain; LCCN, light
chain crystalline cast nephropathy; LCPT, light chain proximal tubulopathy; PAS, periodic acid–Schiff.
 CJASN 18: 1369–1371, October, 2023
the crystals helps in the diagnosis. Tubular involvement
suggests light chain proximal tubulopathy (particularly in
the case of Vk1 light chains) and/or light chain crystalline
cast nephropathy (in the presence of phagolysosomes).
Interstitial involvement points to light chain crystalline
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cast nephropathy, particularly in cases of associated
monocytic/giant cell reaction and tubulointerstitial in-
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flammation or crystal-storing histiocytosis in the presence
of numerous histiocytes. Glomerular localization of crys-
tals suggests crystalglobulinemia, particularly in cases of
vascular thrombosis or occlusion and arthralgias and rash
or light chain crystalline podocytopathy in cases of FSGS
often collapsing in association with Fanconi syndrome,
crystalline keratopathy, and kappa light chains.5
B. A negative immunofluorescence indicates phosphocalcic
(blue) or vancomycin (translucent) crystals
Careful clinicopathologic correlation is important in
Is1NZ2sSo on 10/18/2023
the interpretation of crystalline nephropathies. There-
fore, biopsy specimens could be analyzed by Fourier-
transformed infrared spectroscopy to confirm the composition
of crystals (Figure 1).
Disclosures
K.D. Jhaveri reports consultancy agreements with Calliditas,
George Clinicals, GSK, PMV Pharmaceuticals, and Secretome; re-
ports honoraria from the American Society of Nephrology and
UpToDate.com; reports serving on the editorial boards of American
Journal of Kidney Diseases, CJASN, Clinical Kidney Journal, Journal of
Onconephrology, Kidney International, and Nephrology Dialysis Trans-
plantation; and reports serving as Editor-in-Chief of ASN Kidney
News and section editor for onconephrology for Nephrology Dialysis
Transplantation. All remaining authors have nothing to disclose.
Crystalline Nephropathy: An Algorithm Approach, Brocheriou et al. 1371
Funding
None.
Author Contributions
Conceptualization: Isabelle Brocheriou, Hassan Izzedine.
Formal analysis: Isabelle Brocheriou, Hassan Izzedine.
Investigation: Isabelle Brocheriou.
Methodology: Isabelle Brocheriou, Hassan Izzedine, Kenar
D. Jhaveri.
Resources: Hassan Izzedine.
Supervision: Isabelle Brocheriou, Hassan Izzedine.
Validation: Isabelle Brocheriou, Hassan Izzedine, Kenar D. Jhaveri.
Visualization: Hassan Izzedine.
Writing – original draft: Isabelle Brocheriou, Hassan Izzedine,
Kenar D. Jhaveri.
Writing – review & editing: Isabelle Brocheriou, Hassan Izzedine,
Kenar D. Jhaveri.
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Published Online Ahead of Print: June 22, 2023