Calcium oxalate crystal deposition in the kidney: identification, causes and consequences

Abstract

Calcium oxalate (CaOx) crystal deposition within the tubules is often a perplexing finding on renal biopsy of both native and transplanted kidneys. Understanding the underlying causes may help diagnosis and future management. The most frequent cause of CaOx crystal deposition within the kidney is hyperoxaluria. When this is seen in native kidney biopsy, primary hyperoxaluria must be considered and investigated further with biochemical and genetic tests. Secondary hyperoxaluria, for example due to enteric hyperoxaluria following bariatric surgery, ingested ethylene glycol or vitamin C overdose may also cause CaOx deposition in native kidneys. CaOx deposition is a frequent finding in renal transplant biopsy, often as a consequence of acute tubular necrosis and is associated with poorer long-term graft outcomes. CaOx crystal deposition in the renal transplant may also be secondary to any of the causes associated with this phenotype in the native kidney. The pathophysiology underlying CaOx deposition is complex but this histological phenotype may indicate serious underlying pathology and should always warrant further investigation.

Full text

Vol.:(0123456789)
1 3
Urolithiasis (2020) 48:377–384
https://doi.org/10.1007/s00240-020-01202-w
INVITED REVIEW
Calcium oxalate crystal deposition inthekidney: identication, causes
andconsequences
R.Geraghty1· K.Wood2· J.A.Sayer1,3,4
Received: 23 June 2020 / Accepted: 17 July 2020 / Published online: 27 July 2020
© The Author(s) 2020
Abstract
Calcium oxalate (CaOx) crystal deposition within the tubules is often a perplexing finding on renal biopsy of both native and
transplanted kidneys. Understanding the underlying causes may help diagnosis and future management. The most frequent
cause of CaOx crystal deposition within the kidney is hyperoxaluria. When this is seen in native kidney biopsy, primary
hyperoxaluria must be considered and investigated further with biochemical and genetic tests. Secondary hyperoxaluria,
for example due to enteric hyperoxaluria following bariatric surgery, ingested ethylene glycol or vitamin C overdose may
also cause CaOx deposition in native kidneys. CaOx deposition is a frequent finding in renal transplant biopsy, often as a
consequence of acute tubular necrosis and is associated with poorer long-term graft outcomes. CaOx crystal deposition in
the renal transplant may also be secondary to any of the causes associated with this phenotype in the native kidney. The
pathophysiology underlying CaOx deposition is complex but this histological phenotype may indicate serious underlying
pathology and should always warrant further investigation.
Keywords Calcium oxalate· Oxalosis· Primary hyperoxaluria· Enteric hyperoxaluria
Introduction
Calcium oxalate (CaOx) crystal deposition within the
nephron [1–3], tubular cells [4] or interstitium [5] are
sometimes found by the histopathologist examining a renal
biopsy. CaOx, along with calcium phosphate (CaP) deposi-
tion may lead to nephrocalcinosis [6, 7], although in practice
CaOx crystal deposition is often referred to as renal oxalosis
or oxalate nephropathy. Bagnasco etal. examined biopsies
of both native and transplanted kidneys over the course of
6years [6]. Overall, 1% of native kidney biopsies and 4%
of transplanted kidney biopsies demonstrated CaOx crystal
deposition.
The presence of CaOx crystal deposition within a renal
biopsy may indicate serious underlying pathology and indi-
cate an underlying diagnosis that may not have previously
been considered [7, 8]. Of particular relevance are the pri-
mary hyperoxalurias (PH), which may cause end stage kid-
ney disease and may recur following kidney transplantation.
The diagnosis of PH has potentially life-changing effects
with a broad range of treatment options, up to and including
dual kidney and liver transplant [9, 10].
Crystalluria, although associated with hyperoxaluria [11],
is an uncommon finding [12–14]. There are no descriptions
of the association between CaOx crystalluria and renal oxa-
losis. Here we aim to explore the causes of CaOx crystal
deposition within a renal biopsy and therefore the implica-
tions and future management for the patient. We will review
the histological appearances, the substrates that are most
likely to cause CaOx crystal deposition and the pathophysi-
ology associated with CaOx crystal deposition.
* J. A. Sayer
John.sayer@newcastle.ac.uk
1 Renal Services, The Newcastle Hospitals NHS Foundation
Trust, NewcastleuponTyneNE77DN, UK
2 Histopathology Department, The Newcastle Hospitals NHS
Foundation Trust, NewcastleuponTyneNE14LP, UK
3 Translational andClinical Research Institute, Faculty
ofMedical Sciences, International Centre forLife, Newcastle
University, Central Parkway, NewcastleuponTyneNE13BZ,
UK
4 NIHR Newcastle Biomedical Research Centre,
NewcastleuponTyne, UK
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

378 Urolithiasis (2020) 48:377–384
1 3
Histology ofcalcium oxalate deposition
Oxalate crystals precipitate in renal tubules causing tubular
injury and in the longer term, interstitial fibrosis and tubular
atrophy. They have a clear appearance on light microscopy
[15] (Fig.1a) but are much more easily seen when viewed
under polarised light where they show bright birefringence
(Fig.1b). Particularly abundant crystals are typically asso-
ciated with PH or ethylene glycol ingestion. Lesser degrees
of deposition can be seen in a wide variety of conditions,
which are discussed below. The main pathological differen-
tial diagnosis is 2,8 dihydroxyadenine crystalline nephropa-
thy other cause of polarisable crystals seen in the kidney by
the histopathologist. These patients, with biallelic mutations
in APRT, have adenine phosphoribosyltransferase deficiency
and often develop recurrent nephrolithiasis. Diagnosis can
be challenging but the crystals can be distinguished from
calcium oxalate crystals by their brown colour on haema-
toxylin and eosin staining [16].
Calcium andoxalate: atale oftwo substrates
Hypercalciuria and hyperoxaluria are both known to cause
crystal deposition within the kidney [17]. In patients with
hypercalciuria, the primary crystal deposited is CaP [2],
this nidus may form the focus of aggregation for either CaP
or CaOx [18] This variable aggregation has been demon-
strated invitro [19], in rat models [17, 20], and observed
in humans [2]. However, in patients with hyperoxaluria the
predominant crystal type is CaOx [21]; this has again been
demonstrated in a rat model [17], invitro [4, 5, 22] and in
humans [2].
Crystal type and the components of subsequent aggrega-
tion are dependent upon specific locations along the nephron
and degrees of supersaturation. In the urinary space, it seems
that a CaP nidus initiates subsequent CaOx aggregation in
the invitro model [19], as in nephrolithiasis.
In the kidney, the type of crystal deposition appears to be
different dependent on the location along the nephron. CaP
crystals have been observed in the interstitium surrounding
the ascending thin limb of the loop of Henle [2], in stone-
forming patients with hypercalciuria. CaOx crystal deposi-
tion is typically seen more distally, having been observed
within the collecting duct and the interstitium surrounding
it [1, 14].
The situation therefore appears that in hypercalciuria,
CaP crystals are deposited within and around the nephron,
especially near the loop of Henle. By contrast, in hyperox-
aluria, CaOx crystal deposition is found within collecting
duct nephron segments. To test this hypothesis, Khan and
Glenton examined hypercalciuric mice with increasing lev-
els of oxaluria [20]. They demonstrated that in the genetic
hypercalciuric stone-forming (GHS) rat model before die-
tary manipulation, only CaP crystals were formed. However,
as the oxalate precursor hydroxyproline was added to their
diet, CaOx crystals were observed. As hydroxyproline con-
centrations increased, inducing a hyperoxaluria, the crystal
type switched to become entirely CaOx. This suggests that
intrarenal CaOx crystal formation is dependent upon hyper-
oxaluria rather than hypercalciuria.
The mechanism of CaOx deposition within the kidney
is subject to several factors. These include supersatura-
tion and precipitation, crystal aggregation and deposition
within the tubule/epithelium/interstitium. Several studies
have demonstrated that hyperoxaluria induces intratubular
precipitation of CaOx crystals located in the collecting duct
[1, 23]. There are two potential mechanisms by which crys-
tal passage through the tubule is inhibited (crystal reten-
tion). They have either aggregated and become too large [24,
Fig. 1 a = Oxalate nephropathy. A transplant kidney biopsy show-
ing calcium oxalate crystals in dilated tubules. The crystals are clear
with a refractile quality on routine microscopy (haematoxylin and
eosin × 400). b = Oxalate nephropathy. The same calcium oxalate
crystals exhibit bright birefringence when viewed under polarised
light (polarised haematoxylin and eosin × 400)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

379Urolithiasis (2020) 48:377–384
1 3
25], or they have adhered to the epithelium [26]. Following
either of these mechanisms, CaOx crystals then migrate
into the epithelium [27] and interstitium [5]. The process
behind this migration is unclear. However, crystal contain-
ing macrophages have been observed in both animal [28,
29] and human [30] epithelium/interstitium. Therefore active
removal by macrophages is a possible mechanism for this
observation, although this has yet to be demonstrated.
Pathologies associated withcalcium oxalate crystal
deposition
CaOx crystal deposition may be noted in both native and
transplanted kidneys, as a consequence of hyperoxalu-
ria. Oxalate has both endogenous and exogenous sources
[31, 32] and both are equally able to induce hyperoxalu-
ria (defined as > 40–45mg per 24h or > 0.45–0.5 mmol
per 24h). Tubular CaOx deposition leading to acute or
chronic tubular injury, interstitial fibrosis and progressive
renal insufficiency is termed oxalate nephropathy or renal
oxalosis.
Both native and transplanted kidneys are susceptible
to hyperoxaluria and subsequent oxalate nephropathy and
the causes for hyperoxaluria and crystal deposition differ
(Table1).
On light microscopy 2,8-hydroxyadenine crystals may
mimic CaOx crystals under polarized light, because of
their high birefringence [15]. However, the finding of
2,8-hydroxyadenine crystals mimicking CaOx crystals can
lead to a rare, often missed and important genetic diagnosis
being made. Likewise, genuine CaOx deposition can lead
to other important diagnoses being made and should never
be ignored.
Diabetes mellitus is a common cause of nephropathy
and it is unclear whether it is associated with renal oxa-
losis. Diabetics have demonstrably higher urinary oxalate
concentrations than healthy patients [33]. They have also
been observed to develop oxalate nephropathy in several
case reports [34, 35]. However, in these case reports, the
patients had independent risk factors for renal oxalosis
including Roux-en-Y bypass and increased dietary oxalate.
Moreover, CaOx crystals are not among the number of his-
tological features of diabetic nephropathy [36, 37]. A large
study of cadaveric renal biopsies examined risk factors asso-
ciated with renal oxalosis [38] Diabetes mellitus was shown
not to be associated with renal oxalosis. Therefore, if CaOx
crystals are seen on renal biopsy of a patient with diabetes,
the likely driving factor is hyperoxaluria. The type and cause
of hyperoxaluria should therefore be investigated as this may
lead to important changes in patient management.
Primary hyperoxaluria
Primary hyperoxaluria is a rare autosomal recessive disorder
associated with renal CaOx crystal deposition. Oxalate is an
end metabolite for glyoxylate and the three types of primary
hyperoxalurias (PH1-3) affect enzymes of glyoxylate metab-
olism. The enzymes implicated are: alanine glyoxylate ami-
notransferase (PH1) [39], glycolate reductase/hydroxypyru-
vate reductase (PH2) [40] and 4-hydroxy-2-ketoglutarate
aldolase (PH3) [41, 42]. These disorders tend to present in
childhood to early adolescence with severe recurrent nephro-
lithiasis, although given some may be asymptomatic (espe-
cially PH3), they may not present until the development of
advanced renal failure. PH may also present in late adult life
with calcium oxalate stone formation or insidious chronic
kidney disease.
Table 1 Causes of Calcium Oxalate crystal deposition within the native and transplanted kidney
Calcium oxalate crystal deposition
Native kidney Transplanted kidney
Primary hyperoxaluria – types 1–3 Causes as per native kidney
Secondary hyperoxaluria: Transient hyperoxaluria due to sudden increase in GFR and
previous systemic oxalosis secondary to end stage kidney
disease
Enteric hyperoxaluria (fat malabsorption) Acute tubular necrosis
High oxalate diet Chronic allograft nephropathy
Ethylene glycol intoxication
Thiamine/Pyridoxine deficiency
Vitamin C overdose (precursor of oxalic acid)
Orlistat use
Alterations in intestinal flora
Genetic variations of oxalate transporters
Acute tubular necrosis
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

380 Urolithiasis (2020) 48:377–384
1 3
The majority of cases are PH1, which have the most
severe disease phenotypes. PH1 and PH2 both cause pro-
gressive nephrocalcinosis, nephrolithiasis and renal dam-
age resulting in early end stage renal failure [13, 26–28].
With the progressive decline in renal function comes rising
plasma oxalate levels. At a glomerular filtration rate < 45ml/
min/1.73m2 plasma oxalate concentrations exceed the
supersaturation threshold leading to systemic deposition of
CaOx (systemic oxalosis) [43]. This leads to early death if
left untreated [44].
It is unclear if patients with PH3 have the same natu-
ral history as PH1/2 given its rarity and recent description.
Recent data has shown children with PH3 show a decline in
renal function [45]. However, there remains a lack of long-
term follow-up data to allow for an accurate description of
its clinical course. It is possible that all types of PH may
present with unexplained chronic kidney disease and CaOx
crystal deposition on renal biopsy.
Secondary hyperoxalurias
Secondary hyperoxaluria may be due to a number of differ-
ent causes. The passage of oxalate through the body helps
illustrate why differing mechanisms cause hyperoxaluria.
There is a large oxalate content in certain foods [46], which
is both metabolized by gut commensals (Oxalobacter formi-
genes) [47] and absorbed into the enterohepatic circulation
[48, 49]. Absorbed oxalate is then filtered and excreted in the
kidney [48, 49] along with oxalate produced as an end-point
of glyoxylate metabolism.
At each of these points, excess oxalate may occur. Case
reports describing high intakes of oxalate containing foods
[46] or vitamin C [50] (which is catabolized into oxalate) are
associated with hyperoxaluria. Deficiencies, dietary or oth-
erwise, in thiamine or pyridoxine [51–54], deliberate inges-
tion of orlistat [55] or ethylene glycol [56, 57] may also lead
to hyperoxaluria. High doses of vitamin C [50], some foods
[58–61], excessive dieting [62] and ethylene glycol [56] have
been demonstrated to induce acute oxalate nephropathy.
The gut commensal Oxalobacter formigenes, catabolizes
oxalate thus diminishing gut absorption [63, 64]. There has
been an attempt to exploit this phenomenon for PH, which
showed initial promise, but unfortunately failed in phase II/
III trials [65]. Although touted as a treatment, there have not
been further studies of its effectiveness to treat secondary
hyperoxaluria.
Several case reports have associated hyperoxaluria with
bariatric surgery [66, 67] as well as chronic pancreatitis
[68, 69], with both conditions associated with acute oxa-
late nephropathy [66, 68]. Increased oxalate absorption is a
function of fat malabsorption (enteric hyperoxaluria). In the
normal state, oxalate is bound to calcium within the gut. Fat
malabsorption leads to free fatty acids binding to calcium,
leaving the oxalate in its absorbable, ionised state [49].
Mice and humans with genetic variations of gut oxalate
transporters have also been demonstrated to have increased
urinary oxalate [70] Deletion of Slc26a6 in mice [71, 72]
along with variants V185M in the SLC26A6 transporter in
humans [73] have both been associated with hyperoxaluria.
None of these studies performed renal biopsies and therefore
further study is required to see if these are risk factors for
oxalate nephropathy and CaOx deposition.
Transplanted kidneys
Around 4% of transplanted kidneys will display CaOx crys-
tals on biopsy [6]. Crystals can be found early or late, dis-
tributed throughout the kidney or only in focal segments.
In the initial post-operative period it is thought that, due
to the poor renal function indicating the need for transplant,
there is systemic oxalosis. With the improvement in renal
function attained by transplantation there is rapid excretion
of the excess oxalate. This leads to a transient hyperoxaluria
with a small proportion developing subsequent renal precipi-
tation of CaOx [74]. There is debate as to whether or not this
initial transient hyperoxaluria is pathological, and long-term
outcomes of this have not been proven.
There is more evidence for the implications of CaOx crys-
tals on renal biopsy, albeit conflicting. In the short term, the
presence of CaOx crystals on graft biopsy up to 3months
after transplantation seems to be associated with poorer
longer term graft survival [75]. Although a later study dem-
onstrated that, although graft function at 1year was signifi-
cantly poorer in those with CaOx deposition, there was no
statistically significant difference in renal function at 2years
[6]. In this second study however, there was an overall drop
in both control and crystal graft function in the second year
compared to the first. It is likely that CaOx crystals are a
negative prognostic indicator for long-term graft survival in
the initial period following transplantation. These patients
should be followed-up closely.
Delayed graft function and acute tubular necrosis (ATN)
or acute cell‐mediated rejection is associated with focal
CaOx deposition [76, 77]. The long-term impact of these
acute events is unclear. The majority of transplanted kidneys
demonstrated normal function at follow-up [76]. However,
these observations were underpowered, lacked follow-up
biopsies, and biochemical data for clinical correlation. The
authors postulated this observation was due to high oxalate
excretion using the mechanism previously described. How-
ever, inferring this mechanism from the data is difficult due
to the lack of clinical context and small numbers of patients.
In the longer term, CaOx crystals are seen on biopsy of
those with chronic allograft nephropathy [76]. In the two
patients studied, CaOx crystal deposition was widespread
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

381Urolithiasis (2020) 48:377–384
1 3
in keeping with chronic renal failure (mechanism discussed
below). An earlier study by Memeo etal. of forty allograft
nephrectomies showed 87% had widespread CaOx crystals
[78]. Again, given the low numbers it is difficult to draw con-
clusions from these case reports, but they suggest CaOx crys-
tals, identified at any point in time from biopsy, are associated
with long-term graft failure.
Transplanted kidneys can also be affected by any of the
primary or secondary hyperoxalurias. Failure to diagnose PH
prior to transplantation may result in early graft failure [79,
80]. Likewise for secondary hyperoxalurias, failure to recog-
nise may lead to acute kidney injury [81] or even graft failure.
There have been graft failure case reports for enteric hyperox-
aluria [82, 83] and excessive vitamin C intake [84].
Pathophysiology ofrenal damage associated
withcrystal deposition
Severe hyperoxaluria has been demonstrated to be clinically
associated with acute or chronic renal failure, although it
is unclear which is causative of the other. It is also unclear
whether mild to moderate hyperoxaluria, such as that seen
in PH3, is associated with renal damage, despite evidence of
CaOx crystal deposition in both conditions.
There is a large body of evidence from rat and invitro mod-
els, and human observation that CaOx crystal deposition is
associated with renal epithelial damage [4, 5, 85–89]. Differ-
ing structures of CaOx crystals can damage renal epithelial
cells inducing apoptosis [22]. This body of evidence suggests
that epithelial injury and progressive inflammation is caused
by CaOx crystals, rather than CaOx crystals forming second-
ary to renal damage. This explains the findings in PH and
severe secondary hyperoxaluria.
The observation that CaOx crystals are only found in focal
segments of acute tubular necrosis in transplanted kidneys
[76, 77] however, does not fit with the widespread renal dam-
age and CaOx crystals of hyperoxaluria. It implies that CaOx
crystal deposition seen in this situation is secondary to focal
epithelial damage [4], rather than crystal precipitation and sub-
sequent epithelial damage.
The pathophysiology of renal oxalosis secondary to severe
hyperoxaluria has been described. However, the mechanism
of focal CaOx crystal deposition in acute tubular necrosis
remains unclear. CaOx crystals on renal biopsy should always
prompt investigation for serious underlying conditions in both
the native and transplanted kidney (Table1), that could lead to
progressive renal failure.
Conclusion
CaOx crystals identified histologically on renal biopsy are
indicative of a potential underlying pathology. This finding
warrants further investigation to determine the cause, the
most serious of which is PH. Much of the clinical litera-
ture describing conditions associated with CaOx crystal
deposition are case reports. In the long-term there appears
to be a potential association between CaOx deposition and
increased risk of chronic kidney disease. Larger studies are
needed to examine this association in more depth.
Acknowledgements RG is supported by the National Institute for
Health Research. JAS is supported by the Northern Counties Kidney
Research Fund and Kidney Research UK.
Compliance with Ethical Standards
Conflicts of interest The authors have no conflicts of interest to de-
clare.
Statement of human and animal rights All procedures performed in
studies involving human participants were in accordance with the ethi-
cal standards of the institutional research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards.
Informed consent Informed written consent was obtained for use of
patient biopsy images in this article.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.
References
1. Kok DJ (1996) Crystallization and stone formation inside the
nephron. Scan Microsc 10:471–484 (discussion 484–6)
2. Evan AP, Lingeman JE, Coe FL etal (2003) Randall’s plaque
of patients with nephrolithiasis begins in basement membranes
of thin loops of Henle. J Clin Invest 111:607–616. https ://doi.
org/10.1172/JCI17 038
3. Evan AP, Coe FL, Lingeman J etal (2018) Randall’s plaque in
stone formers originates in ascending thin limbs. Am J Physiol
Renal Physiol 315:F1236–F1242. https ://doi.org/10.1152/ajpre
nal.00035 .2018
4. Khan SR (1995) Calcium oxalate crystal interaction with renal
tubular epithelium, mechanism of crystal adhesion and its
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

382 Urolithiasis (2020) 48:377–384
1 3
impact on stone development. Urol Res 23:71–79. https ://doi.
org/10.1007/bf003 07936
5. Water R, Noordermeer C, Kwast TH etal (1999) Calcium oxa-
late nephrolithiasis effect of renal crystal deposition on the cel-
lular composition of the renal interstitium. Am J Kidney Dis
33:761–771. https ://doi.org/10.1016/s0272 -6386(99)70231 -3
6. Bagnasco SM, Mohammed BS, Mani H etal (2009) Oxalate
deposits in biopsies from native and transplanted kidneys, and
impact on graft function. Nephrol Dial Transplant 24:1319–
1325. https ://doi.org/10.1093/ndt/gfn69 7
7. Sayer JA, Carr G, Simmons NL (2004) Nephrocalcinosis:
molecular insights into calcium precipitation within the kidney.
Clin Sci 106:549–561. https ://doi.org/10.1042/CS200 40048
8. Dickson FJ, Sayer JA (2020) Nephrocalcinosis: a review of
monogenic causes and insights they provide into this heteroge-
neous condition. Int J Mol Sci 21:369. https ://doi.org/10.3390/
ijms2 10103 69
9. Watts RW, Calne RY, Rolles K etal (1987) Successful treatment
of primary hyperoxaluria type I by combined hepatic and renal
transplantation. Lancet 2:474–475. https ://doi.org/10.1016/
s0140 -6736(87)91791 -0
10. Kotb MA, Hamza AF, Abd El Kader H etal (2019) Combined
liver-kidney transplantation for primary hyperoxaluria type
I in children: single center experience. Pediatr Transplant
23:e13313. https ://doi.org/10.1111/petr.13313
11. Daudon M, Jungers P, Lacour B (2004) Intérêt clinique de
l’étude de la cristallurie. Ann Biol Clin 62:379–393
12. Winkens RA, Wielders JP, Degenaar CP, van Hoof JP (1988)
Calcium oxalate crystalluria, a curiosity or a diagnostical aid?
J Clin Chem Clin Biochem 26:653–654
13. Robert M, Boularan AM, Delbos O etal (1998) Study of cal-
cium oxalate crystalluria on renal and vesical urines in stone
formers and normal subjects. Urol Int 60:41–46. https ://doi.
org/10.1159/00003 0201
14. Elliot JS, Rabinowitz IN (1980) Calcium oxalate crystalluria:
crystal size in urine. JURO 123:324–327. https ://doi.org/10.1016/
s0022 -5347(17)55918 -2
15. Herlitz LC, D’Agati VD, Markowitz GS (2012) Crystalline
nephropathies. Arch Pathol Lab Med 136:713–720. https ://doi.
org/10.5858/arpa.2011-0565-RA
16. Bagai S, Khullar D, Bansal B (2019) Rare crystalline nephropathy
leading to acute graft dysfunction: a case report. BMC Nephrol
20:428–433. https ://doi.org/10.1186/s1288 2-019-1616-3
17. Evan AP, Bledsoe SB, Smith SB, Bushinsky DA (2004) Calcium
oxalate crystal localization and osteopontin immunostaining in
genetic hypercalciuric stone-forming rats. Kidney Int 65:154–161.
https ://doi.org/10.1111/j.1523-1755.2004.00396 .x
18. Sayer JA, Simmons NL (2002) Urinary stone formation: Dent’s
disease moves understanding forward. Exp Nephrol 10:176–181.
https ://doi.org/10.1159/00005 8344
19. Xie B, Halter TJ, Borah BM, Nancollas GH (2015) Aggregation
of calcium phosphate and oxalate phases in the formation of renal
stones. Cryst Growth Des 15:204–211. https ://doi.org/10.1021/
cg501 209h
20. Khan SR, Glenton PA (2008) Calcium oxalate crystal deposition
in kidneys of hypercalciuric mice with disrupted type IIa sodium-
phosphate cotransporter. Am J Physiol Renal Physiol 294:F1109–
F1115. https ://doi.org/10.1152/ajpre nal.00620 .2007
21. Hoppe B (2012) An update on primary hyperoxaluria. Nat Rev
Nephrol 8:467–475. https ://doi.org/10.1038/nrnep h.2012.113
22. Sun X-Y, Ouyang J-M, Yu K (2017) Shape-dependent cellular
toxicity on renal epithelial cells and stone risk of calcium oxalate
dihydrate crystals. Sci Rep 7:7250–7313. https ://doi.org/10.1038/
s4159 8-017-07598 -7
23. Kok DJ (1997) Intratubular crystallization events. World J Urol
15:219–228. https ://doi.org/10.1007/bf013 67659
24. Kok DJ, Khan SR (1994) Calcium oxalate nephrolithiasis, a free
or fixed particle disease. Kidney Int 46:847–854. https ://doi.
org/10.1038/ki.1994.341
25. Robertson WG (2015) Potential role of fluctuations in the compo-
sition of renal tubular fluid through the nephron in the initiation
of Randall’s plugs and calcium oxalate crystalluria in a computer
model of renal function. Urolithiasis 43(1):93–107. https ://doi.
org/10.1007/s0024 0-014-0737-1
26. Verkoelen CF, Van Der Boom BG, Kok DJ etal (1999) Attach-
ment sites for particles in the urinary tract. J Am Soc Nephrol
10(14):S430–S435
27. Ebisuno S, Kohjimoto Y, Tamura M etal (1997) Histological
observations of the adhesion and endocytosis of calcium oxalate
crystals in MDCK cells and in rat and human kidney. Urol Int
58:227–231. https ://doi.org/10.1159/00028 2989
28. Water R, Noordermeer C, Houtsmuller AB etal (2000) Role
of macrophages in nephrolithiasis in rats an analysis of the
renal interstitium. Am J Kidney Dis 36:615–625. https ://doi.
org/10.1053/ajkd.2000.16203
29. Thurgood LA, Sørensen ES, Ryall RL (2012) The effect of intrac-
rystalline and surface-bound osteopontin on the degradation and
dissolution of calcium oxalate dihydrate crystals in MDCKII cells.
Urol Res 40:1–15. https ://doi.org/10.1007/s0024 0-011-0423-5
30. Kusmartsev S, Dominguez-Gutierrez PR, Canales BK etal
(2016) Calcium oxalate stone fragment and crystal phagocyto-
sis by human macrophages. J Urol 195:1143–1151. https ://doi.
org/10.1016/j.juro.2015.11.048
31. Holmes RP, Goodman HO, Assimos DG (2001) Contribution of
dietary oxalate to urinary oxalate excretion. Kidney Int 59:270–
276. https ://doi.org/10.1046/j.1523-1755.2001.00488 .x
32. Holmes RP, Ambrosius WT, Assimos DG (2005) Dietary oxa-
late loads and renal oxalate handling. JURO 174:943–947. https
://doi.org/10.1097/01.ju.00001 69476 .85935 .e2
33. Eisner BH, Porten SP, Bechis SK, Stoller ML (2010) Uro-
lithiasis/endourology diabetic kidney stone formers excrete
more oxalate and have lower urine ph than nondiabetic stone
formers. JURO 183:2244–2248. https ://doi.org/10.1016/j.
juro.2010.02.007
34. Moutzouris D-A, Skaneli G, Margellos V etal (2011) Oxalate
nephropathy in a diabetic patient after gastric by-pass. Clin Neph-
rol 75(1):16–19
35. Muji A, Moll S, Saudan P (2015) Oxalate nephropathy: a new
entity of acute kidney injury in diabetic patients? Rev Med Suisse
11:493–496
36. Fioretto P, Mauer M (2007) Histopathology of diabetic nephropa-
thy. Semin Nephrol 27:195–207. https ://doi.org/10.1016/j.semne
phrol .2007.01.012
37. Fioretto P, Barzon I, Mauer M (2014) Is diabetic nephropathy
reversible? Diabetes Res Clin Pract 104:323–328. https ://doi.
org/10.1016/j.diabr es.2014.01.017
38. Mori S, Beppu T (1983) Secondary renal oxalosis. A statistical
analysis of its possible causes. Acta Pathol Jpn 33:661–669
39. Danpure CJ, Jennings PR (1986) Peroxisomal alanine:glyoxylate
aminotransferase deficiency in primary hyperoxaluria type
I. FEBS Lett 201:20–34. https ://doi.org/10.1016/0014-
5793(86)80563 -4
40. Cramer SD, Ferree PM, Lin K etal (1999) The gene encoding
hydroxypyruvate reductase (GRHPR) is mutated in patients with
primary hyperoxaluria type II. Hum Mol Genet 8:2063–2069.
https ://doi.org/10.1093/hmg/8.11.2063
41. Williams EL, Bockenhauer D etal (2012) The enzyme 4-hydroxy-
2-oxoglutarate aldolase is deficient in primary hyperoxaluria
type 3. Nephrol Dial Transplant 27:3191–3195. https ://doi.
org/10.1093/ndt/gfs03 9
42. Huang A, Burke J, Bunker RD etal (2019) Regulation of
human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

383Urolithiasis (2020) 48:377–384
1 3
α-ketoglutarate: implications for primary hyperoxaluria type-3.
Biochem J 476:3369–3383. https ://doi.org/10.1042/BCJ20 19054 8
43. Leumann E, Hoppe B (2001) The primary hyperoxalurias. J Am
Soc Nephrol 12:1986–1993
44. Milliner DS, Wilson DM, Smith LH (2001) Phenotypic
expression of primary hyperoxaluria: comparative features
of types I and II. Kidney Int 59:31–36. https ://doi.org/10.104
6/j.1523-1755.2001.00462 .x
45. Allard L, Cochat P, Leclerc A-L etal (2015) Renal function
can be impaired in children with primary hyperoxaluria type 3.
Pediatr Nephrol 30:1807–1813. https ://doi.org/10.1007/s0046
7-015-3090-x
46. Noonan SC, Savage GP (1999) Oxalate content of foods and its
effect on humans. Asia Pac J Clin Nutr 8:64–74
47. Stewart CS, Duncan SH, Cave DR (2004) Oxalobacter formigenes
and its role in oxalate metabolism in the human gut. FEMS Micro-
biol Lett 230:1–7. https ://doi.org/10.1016/S0378 -1097(03)00864
-4
48. Hatch M, Freel RW (2003) Renal and intestinal handling of oxa-
late following oxalate loading in rats. Am J Nephrol 23:18–26.
https ://doi.org/10.1159/00006 6300
49. Whittamore JM, Hatch M (2017) The role of intestinal oxalate
transport in hyperoxaluria and the formation of kidney stones in
animals and man. Urolithiasis 45:89–108. https ://doi.org/10.1007/
s0024 0-016-0952-z
50. Wong K, Thomson C, Bailey RR etal (1994) Acute oxalate
nephropathy after a massive intravenous dose of vitamin C. Aust
N Z J Med 24:410–411. https ://doi.org/10.1111/j.1445-5994.1994.
tb014 77.x
51. Tiselius HG, Almgård LE (1977) The diurnal urinary excretion
of oxalate and the effect of pyridoxine and ascorbate on oxalate
excretion. Eur Urol 3:41–46. https ://doi.org/10.1159/00047 2053
52. Hannett B, Thomas DW, Chalmers AH etal (1977) Formation of
oxalate in pyridoxine or thiamin deficient rats during intravenous
xylitol infusions. J Nutr 107:458–465. https ://doi.org/10.1093/
jn/107.3.458
53. Gill HS, Rose GA (1986) Mild metabolic hyperoxaluria and
its response to pyridoxine. Urol Int 41:393–396. https ://doi.
org/10.1159/00028 1241
54. Svedruzić D, Jónsson S, Toyota CG etal (2005) The enzymes
of oxalate metabolism: unexpected structures and mechanisms.
Arch Biochem Biophys 433:176–192. https ://doi.org/10.1016/j.
abb.2004.08.032
55. Solomon LR, Nixon AC, Ogden L (2017) Nair B (2017) Orl-
istat-induced oxalate nephropathy: an under-recognised cause
of chronic kidney disease. BMJ Case Rep 21:6–23. https ://doi.
org/10.1136/bcr-2016-21862 3
56. Ting SMS, Ching I, Nair H etal (2009) Early and late presenta-
tions of ethylene glycol poisoning. Am J Kidney Dis 53:1091–
1097. https ://doi.org/10.1053/j.ajkd.2008.12.019
57. Hanouneh M, Chen TK (2017) Calcium oxalate crystals in eth-
ylene glycol toxicity. N Engl J Med 377:1467–1467. https ://doi.
org/10.1056/NEJMi cm170 4369
58. Syed F, Mena-Gutierrez A, Ghaffar U (2015) A case of iced-
tea nephropathy. N Engl J Med 372:1377–1378. https ://doi.
org/10.1056/NEJMc 14144 81
59. Getting JE, Gregoire JR, Phul A, Kasten MJ (2013) Oxalate
nephropathy Due to “Juicing”: case report and review. Am J Med
126:768–772. https ://doi.org/10.1016/j.amjme d.2013.03.019
60. Lien Y-HH (2013) Juicing is not all juicy. Am J Med 126:755–
756. https ://doi.org/10.1016/j.amjme d.2013.04.007
61. Makkapati S, D’Agati VD, Balsam L (2018) “Green smoothie
cleanse” causing acute oxalate nephropathy. Am J Kidney Dis
71:281–286. https ://doi.org/10.1053/j.ajkd.2017.08.002
62. Khneizer G, Al-Taee A, Mallick MS, Bastani B (2017) Chronic
dietary oxalate nephropathy after intensive dietary weight loss
regimen. J Nephropathol 6:126–129. https ://doi.org/10.15171 /
jnp.2017.21
63. Mittal RD, Kumar R (2004) Gut-inhabiting bacterium Oxalobac-
terformigenes: role in calcium oxalate urolithiasis. J Endourol
18:418–424. https ://doi.org/10.1089/08927 79041 27170 6
64. Hatch M, Cornelius J, Allison M etal (2006) Oxalobacter sp.
reduces urinary oxalate excretion by promoting enteric oxa-
late secretion. Kidney Int 69:691–698. https ://doi.org/10.1038/
sj.ki.50001 62
65. Milliner D, Hoppe B, Groothoff J (2018) A randomised Phase II/
III study to evaluate the efficacy and safety of orally administered
Oxalobacter formigenes to treat primary hyperoxaluria. Urolithi-
asis 46:313–323. https ://doi.org/10.1007/s0024 0-017-0998-6
66. Nasr SH, D’Agati VD, Said SM etal (2008) Oxalate nephropa-
thy complicating Roux-en-Y Gastric Bypass: an underrecognized
cause of irreversible renal failure. Clin J Am Soc Nephrol 3:1676–
1683. https ://doi.org/10.2215/CJN.02940 608
67. Sinha MK, Collazo-Clavell ML, Rule A etal (2007) Hyperox-
aluric nephrolithiasis is a complication of Roux-en-Y gastric
bypass surgery. Kidney Int 72:100–107. https ://doi.org/10.1038/
sj.ki.50021 94
68. Cartery C, Faguer S, Karras A etal (2011) Oxalate nephropa-
thy associated with chronic pancreatitis. Clin J Am Soc Nephrol
6:1895–1902. https ://doi.org/10.2215/CJN.00010 111
69. Demoulin N, Issa Z, Crott R etal (2017) Enteric hyperoxaluria in
chronic pancreatitis. Medicine (Baltimore) 96:e6758. https ://doi.
org/10.1097/MD.00000 00000 00675 8
70. Sayer JA (2017) Progress in understanding the genetics of cal-
cium-containing nephrolithiasis. J Am Soc Nephrol 28:748–
759. https ://doi.org/10.1681/ASN.20160 50576
71. Freel RW, Hatch M, Green M, Soleimani M (2006) Ileal oxa-
late absorption and urinary oxalate excretion are enhanced in
Slc26a6 null mice. Am J Physiol Gastrointest Liver Physiol
290:G719–G728. https ://doi.org/10.1152/ajpgi .00481 .2005
72. Jiang Z, Asplin JR, Evan AP etal (2006) Calcium oxalate uro-
lithiasis in mice lacking anion transporter Slc26a6. Nat Genet
38:474–478. https ://doi.org/10.1038/ng176 2
73. Clark JS, Vandorpe DH, Chernova MN etal (2008) Species
differences in Cl− affinity and in electrogenicity of SLC26A6-
mediated oxalate/Cl− exchange correlate with the distinct
human and mouse susceptibilities to nephrolithiasis. J Physiol
586:1291–1306. https ://doi.org/10.1113/jphys iol.2007.14322 2
74. Worcester EM, Fellner SK, Nakagawa Y, Coe FL (1994) Effect
of renal transplantation on serum oxalate and urinary oxalate
excretion. Nephron 67:414–418. https ://doi.org/10.1159/00018
8014
75. Pinheiro HS, Câmara NOS, Osaki KS etal (2005) Early pres-
ence of calcium oxalate deposition in kidney graft biopsies is
associated with poor long-term graft survival. Am J Transplant
5:323–329. https ://doi.org/10.1111/j.1600-6143.2004.00684 .x
76. Truong LD, Yakupoglu U, Feig D etal (2004) Calcium oxalate
deposition in renal allografts: morphologic spectrum and clinical
implications. Am J Transplant 4:1338–1344. https ://doi.org/10.1
111/j.1600-6143.2004.00511 .x
77. Olsen S, Burdick JF, Keown PA etal (1989) Primary acute renal
failure (“acute tubular necrosis”) in the transplanted kidney: mor-
phology and pathogenesis. Medicine (Baltimore) 68:173–187.
https ://doi.org/10.1097/00005 792-19890 5000-00005
78. Memeo L, Pecorella I, Ciardi A etal (2001) Calcium oxa-
late microdeposition in failing kidney grafts. Transplant Proc
33:1262–1265. https ://doi.org/10.1016/s0041 -1345(00)02470 -2
79. Bilgin N, Tirnaksiz MB, Moray G etal (1999) Early recurrence
of oxalate deposition after renal transplantation in a patient with
primary hyperoxaluria type I. Transplant Proc 31:3219–3220.
https ://doi.org/10.1016/s0041 -1345(99)00699 -5
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

384 Urolithiasis (2020) 48:377–384
1 3
80. Riksen NP, Timmers HJLM, Assmann KJM, Huysmans FTM
(2002) Renal graft failure due to type 1 primary hyperoxaluria.
Neth J Med 60:407–410
81. Suneja M, Kumar AB (2013) Secondary oxalosis induced acute
kidney injury in allograft kidneys. Clin Kidney J 6:84–86. https
://doi.org/10.1093/ckj/sfs16 7
82. Cuvelier C, Goffin E, Cosyns J-P etal (2002) Enteric hyperoxalu-
ria: a hidden cause of early renal graft failure in two successive
transplants: spontaneous late graft recovery. Am J Kidney Dis
40:6. https ://doi.org/10.1053/ajkd.2002.33934
83. Rankin AC, Walsh SB, Summers SA etal (2008) Acute oxalate
nephropathy causing late renal transplant dysfunction due to
enteric hyperoxaluria. Am J Transplant 8:1755–1758. https ://doi.
org/10.1111/j.1600-6143.2008.02288 .x
84. Parasuraman R, Zhang L etal (2011) Primary nonfunction of renal
allograft secondary to acute oxalate nephropathy. Case Rep Trans-
plant 2011:876906–876914. https ://doi.org/10.1155/2011/87690 6
85. Lieske JC, Spargo BH, Toback FG (1992) Endocytosis of calcium
oxalate crystals and proliferation of renal tubular epithelial cells
in a patient with type 1 primary hyperoxaluria. JURO 148:1517–
1519. https ://doi.org/10.1016/s0022 -5347(17)36954 -9
86. Khan SR, Shevock PN, Hackett RL (1992) Acute hyperoxaluria,
renal injury and calcium oxalate urolithiasis. JURO 147:226–230.
https ://doi.org/10.1016/s0022 -5347(17)37202 -6
87. de Water R, Boevé ER, van Miert PP etal (1996) Pathological and
immunocytochemical changes in chronic calcium oxalate neph-
rolithiasis in the rat. Scanning Microsc 10:577–587 (discussion
587–90)
88. Umekawa T, Chegini N, Khan SR (2002) Oxalate ions and
calcium oxalate crystals stimulate MCP-1 expression by renal
epithelial cells. Kidney Int 61:105–112. https ://doi.org/10.104
6/j.1523-1755.2002.00106 .x
89. Schepers MSJ, van Ballegooijen ES, Bangma CH, Verkoelen CF
(2005) Crystals cause acute necrotic cell death in renal proxi-
mal tubule cells, but not in collecting tubule cells. Kidney Int
68:1543–1553. https ://doi.org/10.1111/j.1523-1755.2005.00566
.x
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com