1 Department of 
Nephrology, Division of 
Paediatrics, University 
Medical Centre Ljubljana 

2 Community Health 
Centre Ljubljana 

Correspondence: 

rina r. rus, e: rina.rus@ 
guest.arnes.si 

Key words: 

Dent disease; proteinuria; 
hypercalciuria; 
nephrocalcinosis 

Dent disease 

Kristina Vogrin,2rina r. rus1 

Abstract 

Dent disease is an x-linked disorder of proximal renal tubules that occurs almost exclusively in 
males. It is clinically characterized by significant, mostly low-molecular weight proteinuria, hyper-
calciuria, nephrocalcinosis, nephrolithiasis, and chronic renal disease. The signs and symptoms of 
this condition appear in early childhood and worsen over time. There are two forms of Dent disease, 
which are distinguished by their genetic cause and pattern of signs and symptoms (type 1 and type 2). 
Dent disease type 2 is characterized by clinical features described above and is also associated with 
extrarenal manifestations, such as mild intellectual disability, hypotonia and cataract. Some researchers 
consider Dent disease type 2 to be a mild variant of Lowe syndrome. 

In this article, a clinical case of a boy with significant proteinuria in the nephrotic range and hyper-
calciuria is presented. Genetic analysis confirmed Dent disease type 1. 

Cite as: Zdrav Vestn. 2017; 86: 131–7. 

Cite as: 

Zdrav Vestn. 2017; 
86: 131–7. 

received: 4. 12. 2016 
accepted: 17. 2. 2017 

Introduction 

Dent disease is an inherited, X-linked 
condition that affects the proximal tubules 
of the kidney. Clinically it is characterized 
by significant proteinuria, with 
mostly low-molecular weight proteins 
excreted in urine. The excretion of albumins 
is increased in glomerular disorder, 
whereas in tubular disorder the 
excretion of alpha-1-microglobulin, 
beta-2-microglobulin, retinol-binding 
protein and N-acetyl glucosaminidase is 
increased. Dent disease is also characterized 
by hypercalciuria, nephrocalcinosis 
and nephrolithiasis. It is a chronic disease 
that can progress to end stage renal 
disease (1-3). It is a very rare inherited 
disease. In literature, the frequency of 
the disease has not been exactly determined: 
250 families with Dent disease 
type 1 and 25 individuals with Dent dis


ease type 2 have been diagnosed worldwide. 
The disease can be fully expressed 
only in males since the inheritance is X-
linked recessive. In females the disease 
is clinically expressed in a mild form. 
Females are carriers of the disease, in 
50% they pass it to sons and in 50% to 
daughters. In 10 % the disease is caused 
by a new mutation. Also in these cases, 
the inheritance of the disease to successive 
generations is X-linked recessive (2) 
and is usually manifested as asymptomatic 
significant tubular proteinuria and/ 
or hypercalciuria in boys older than 10 
years of age. From 30 % to 80 % of affected 
males develop end stage renal disease 
aged 30 to 50 years. In some of them it 
is developed in late adulthood around 
the age of 60 years (1). It is often accompanied 
with rachitis, osteomalacia, and 


Metabolic anD horMonal DiSorDerS 

poor growth. It can be inherited in two 
ways. The first and more common one 
is Dent disease 1 with mutations in the 
CLCN5 gene, the second one is Dent disease 
2 with mutations in the OCRL gene, 
which is additionally associated with ex-
trarenal abnormalities (mild intellectual 
disability, cataract and hypotonia) (1-5). 

We present a case of a boy with significant 
proteinuria in the nephrotic 
range who started being treated at the 
age of three years. The determination of 
the type of proteinuria revealed a mixed, 
glomerular proteinuria in combination 
with abundant tubular proteinuria. 
Proteinuria in the nephrotic range was 
caused mainly by albuminuria, as tubular 
proteinuria usually does not exceed 
the nephrotic threshold. The boy also 
had a pronounced normocalcemic hypercalciuria. 
Genetic analyses confirmed 
Dent disease type 1. 

Case presentation 

A 3-year-old boy was referred to the 
Department of Nephrology at the University 
Children’s Hospital from a regional 
hospital due to proteinuria in the 
nephrotic range in 2008. 

The family history revealed that the 
grandfather had chronic chronic kidney 
disease. Due to severe significant pro-
teinuria at the age of 18, he underwent 
renal biopsy that showed a segmental 
sclerosing glomerulopathy. At the age of 
44, the grandfather had end stage renal 
disease; currently he has a transplanted 
kidney. The grandfather’s mother had 
renal disease as well. The boy was born 
as the second child after his mother’s 
second, normally progressing pregnancy, 
with normal measurements at birth. 
The period after birth was uneventful. 
For frequent respiratory infections he 
received beta-lactam antibiotics many 
times. Until hospitalization at the De


partment of Nephrology he recovered 
from infectious mononucleosis and had 
surgery due to phimosis and testicular 
retention. He recovered from streptococcal 
tonsillitis, two middle ear inflammations, 
gastroenteritis with paralytic 
ileus and atypical pneumonia. He had 
no allergies, was vaccinated according to 
the vaccination schedule, and had chicken 
pox. 

At his health check when he was 3 
years old, he was diagnosed with protein-
uria. His parents had been noticing for 
some time that his morning urine was 
cloudy without macrohaematuria. The 
boy looked healthy and had no swellings. 
In a regional hospital the proteins in the 
24-hour urine were in the nephrotic 
range (0.64 g/day = 40 mg/m2/h). Urine 
sediment and creatinine (44 µmol/L) 
were within the normal range. 

At the first check-up at our clinic, 
quiet systolic murmur 2/6 was heard 
but otherwise the clinical examination 
was uneventful. The growth was appropriate 
for the age. His blood pressure 
was normal. Laboratory examinations 
showed slightly elevated sedimentation 
values (30 mm/h) and mild thrombocytosis 
(thrombocytes 425). Acid-base 
status showed mild compensated metabolic 
acidosis. Serum creatinine (47 
µmol/L) and urea (3.5 mmol/L) values 
were normal, including creatinine clearance 
(116.8 ml/min/1.73 m2) and serum 
electrolytes. Native urine results showed 
proteinuria (2+) and microscopic haematuria 
(32 erythrocytes), urine pH was 

7.The 24-hour urine collection showed 
proteinuria in the nephrotic range (1.7 g 
= 107 mg/m2/h). The determination of 
the type of proteinuria in urine revealed 
a mixed, selective glomerular protein-
uria with an elevated albumin excretion 
(albumin/creatinine 104.38; normal up 
to 2.26 g/mol) and IgG (IgG/creatinine 
20.0; normal up to 1.13 g/mol) accompa

nied with abundant tubular proteinuria 
with a higher excretion of alpha-1-microglobulin 
(alpha-1-microglobulin/creatinine 
72.19; normal up to 1.58 g/mol). 
The ratio of IgG to albumins (IgG/alb) 
was 0.19. Beta-2-microglobulin value in 
serum was normal, however it was significantly 
elevated in urine (94.6; normal 
up to 0.3 mg/l). CRP, haemogram, hepatogram, 
serum protein electrophoresis 
and lipidogram were normal as well. 

The fractional excretion of electrolytes 
in urine was determined, and elevated 
potassium excretion and hyper-
calciuria were established (11 mg/kg/day; 
upper level 4 mg/kg/day). Fractional excretions 
of other electrolytes were normal. 


The values of complement, anti-neutrophil 
cytoplasmic antibodies, antinuclear 
antibodies and cytoplasmic antigens, 
anti-DNA and anti-cardiolipin 
antibodies were negative. 

Abdomen and urinary tract ultrasound 
scans were normal, without signs 
of nephrocalcinosis or kidney stones 
(Figure 1; A). 

Renal biopsy which was performed 
at the beginning of 2009 showed that 
the boy had inherited nephropathy with 
prevalent chronic striped tubulointerstitial 
histopathological changes and with 
nonspecific chronic poorly active fibrosing 
(50–60%) tubulointerstitial nephritis 
in striped pattern with extensive secondary 
changes in Malpighian bodies with 
pericapsular fibrosis at interstitial events. 
Glomerular changes were mild, collapsing 
with accompanying hypertrophic 
podocytes; they resembled a collapsing 
type of focal segmental glomerulosclero-
sis (FSGS). The aforementioned changes 
were most possibly the secondary, and 
tubulointerstitial events the primary 
cause of their occurrence. Renal biopsy 
in 2009 showed no signs of microscopic 
nephrocalcinosis.A je to ista biopsija kot 

Short Scientific article 

na začetku odstavka, ali je bila narejena 
še ena v istem letu? 

Considering the clinical features 
and the laboratory results, Dent disease 
was suspected; however the only way to 
prove it was genetic-molecular diagnostic 
testing, which was performed revealing 
a mutation of the CLCN5 gene; the 
boy had it in hemizygous form as the 
disease is inherited recessively and is X-
linked. 

Due to pronounced hypercalciuria, 
the boy underwent bone density measurements, 
which confirmed osteopoenia; 
upon endocrinologist’s advice, D3 
vitamin and calcium citrate were introduced. 
Increased fluid intake (over two 
litres of liquid a day) and restricted salt 
intake were recommended; additionally, 
the treatment with a combination of 
thiazide and amiloride as well as potassium 
citrate was introduced to decrease 
calcium excretion with urine and equally 
to prevent possible hypokalaemia. As 
proteinuria was mixed, angiotensin-converting-
enzyme inhibitor (ACE inhibitor) 
was introduced to decrease glomerular 
proteinuria. 

The boy is being regularly monitored 
at the Department of Nephrology. He 
has densitometry once a year, his growth 
dynamics is being monitored by endocrinologist. 
Bone density has normalized 
with adequate therapy. Acid-base status 
has been normal. Renal function has 
been normal, with creatinine increase at 
the end of 2016, yet still within the normal 
range. Significant proteinuria persists; 
it has progressed to non-selective 
glomerular proteinuria with abundant 
tubular proteinuria (IgG/albumin ratio 
over 0.2). Calciuria decreased gradually, 
only in the last few months it has slightly 
increased, which can be attributed to 
transitional discontinuance of thiazide 
and amiloride. Over the last few years, 
mild microscopic haematuria has been 


Metabolic anD horMonal DiSorDerS 

20 
40 
60 
80 
100 
120 
140 
0 
10 
20 
30 
40 
50 
60 
2008 2009 2010 2011 2012 2013 2014 2015 2016 
Height H (cm)
Weight W (kg) 
H 
W 
Figure 1: body growth 
and weight in years 

present in urine. Figures 1 and 2 show 

2008–2016 

body growth, renal function, proteinuria 
and calciuria in the boy from 2008 when 
the treatment began until 2016. 

Ultrasound scan in 2016 showed ini


tial signs of nephrocalcinosis (Figure 3; 

B). 

Discussion 

Dent disease is an inherited, X-linked 
recessive renal tubular disease, also called 
X-linked recessive hypercalciuric hypo-
phosphatemic rachitis characterized by 
significant proteinuria (increased low-
molecular weight proteins in urine), hypercalciuria 
and nephrocalcinosis (1-3). 
The disease is almost exclusively found 
in males. A pathological variant in the 
CLCN5 gene accounts for 60 % of people 
suffering from the disease (Dent disease 
1); the other pathological variant is in the 
OCRL gene, and it accounts for 15 % of 
people suffering from the disease (Dent 
disease 2) (1-5). Due to X-chromosome 
inactivation, chronic renal disease rarely 
affects women who are carriers of this 
disease, and in most cases the disease is 
manifested only as hypercalciuria (1,2). 

The disease is suspected when the following 
three criteria are present (1-3,6): 

1. Significant tubular low-molecular 
weight proteinuria: characterized 
by 5 to 10 times higher values than 
normal; measurements of proteins 
alpha-1-microglobulin, beta-2-micro-
globulin, retinol-binding protein and 
N-acetylglucosaminidase. 
2. Hypercalciuria: > 4 mg/kg calcium 
in 24 hours (children > 2 years and 
adults) or 0,25 calcium/creatinine 
mg/mg (= 0,57 mmol/mmol) in single 
urine collection (patients over 18 yars; 
for children there are different reference 
tables which are age dependent). 
3. At least one of the following criteria 
is fulfilled: hypophosphatemia, 
chronic renal disease, family history 
of X-linked inherited disease, nephrolithiasis 
(kidney stones: Ca oxalate 
and/or Ca phosphate), haematuria 
(microscopic or macroscopic) and 
nephrocalcinosis (deposition of calcium 
salts in the medulla of the kidney 
or rarely in the renal cortex) (6). 
When ultrasound shows nephrocalcinosis, 
further investigations to determine 
the cause of the disease are 
needed. Electrolytes, including calcium 
and phosphate, urine acidity 
as well as urea and creatinine values 
in serum need to be determined. If 
the aforementioned investigations 
are normal and there are no signs of 
hypercalcemia (exclusion of primary 
hyperparathyroidism, sarcoidosis, vitamin 
D3 treatment,...) and distal tubular 
acidosis, the patient should collect 
24-hour urine, which will be used 
to measure the excretion of calcium, 
phosphate (inherited tubulopathies 
including Dent disease with present 
significant proteinuria), oxalate (primary 
hyperoxaluria), citrate (nephrocalcinosis 
and hypocitraturia can 
show medullary sponge kidney) and 
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0 
40 
80 
120 
160 
200 
0 
3 
6 
9 
12 
15 
2008 2009 2010 2011 2012 2013 2014 2015 2016 
Cl. cr. (ml/min/1,732)
Proteinuria (g/day)
Calciuria (mg/kg/day) 
Cl. cr. 
Proteinuria 
Calciuria 
0 
40 
80 
120 
160 
200 
0 
3 
6 
9 
12 
15 
2008 2009 2010 2011 2012 2013 2014 2015 2016 
Cl. cr. (ml/min/1,732)
Proteinuria (g/day)
Calciuria (mg/kg/day) 
Cl. cr. 
Proteinuria 
Calciuria 
Figure 2: renal function, 
proteinuria and calciuria 

creatinine with renal function assess-

in years 2008–2016 

ment (7). 

Laboratory findings of the boy 
showed moderate to severe proteinuria, 
which was established as mixed, initially 
selective, then non-selective glomerular 
proteinuria with tubular proteinuria. 
Significant tubular proteinuria suggested 
proximal tubule disorder, as in this 
part of a healthy tubule low-molecular 
weight proteins are almost completely 
absorbed. Hypercalciuria also suggested 
proximal tubule disorder, which is typical 
for patients with Dent disease (1-3). 
The boy had glomerular proteinuria, 
which was most likely caused by secondary 
modified Malpighian bodies with 
the signs of collapsing FSGS and peri-
capsular fibrosis. These changes were 
most likely caused by primary tubulointerstitial 
histopathological changes. Also 
according to the literature, renal biopsies 
of patients with Dent disease can show 
changes, such as interstitial fibrosis, 
FSGS and/or focal global glomerulo-
sclerosis (FGGS), and also the signs of 
nephrocalcinosis, which initially was not 
determined in our patient. Renal biopsy 

Short Scientific article 

changes in patients with Dent disease are 
rather non-specific (1,8-10). 

The diagnosis is confirmed by mo-
lecular-genetic investigations, using sequence 
analysis method to prove the mutation 
in the CLCN5 causal gene (Dent 
disease 1) or OCRL gene (Dent disease 
2). In some cases, gene deletion/duplication 
analysis or multiple-gene panel that 
includes other genes besides these two is 
needed (1,2). 

In the present case, genetic laboratory 
of the Faculty of Medicine (mislim) in 
Ljubljana confirmed the diagnosis with 
molecular-genetic investigations. Causal 
gene CLCN5 in hemizygous form was 
determined. The boy has a pathological 
substitution c.1909>T(NM_000084.4) 
that modifies amino acid arginine 
in stop codon at amino acid position 
637 (NP_000075.1:p.Arg637 and 
NP_001121370.1:p.Arg707Ter). The modification 
has already been described (11). 

Currently two forms of Dent disease 
are known: 

DENT 1 (CLCN5 mutation): The 
gene causing chloride channel disorder 
Cl-/H+ – transporter (CLC-5) is located 
on Xp11.22 chromosome and is encoding 
lysosomal transport protein CLC-5. It is 
located together with ATP-proton pump 
on the endosome of proximal tubular 
cells (2,4,12). In most cases it is clinically 
manifested as very severe or mild form 
with hypercalciuria, significant protein-
uria (prevalence of low-molecular proteins), 
nephrocalcinosis and chronic renal 
disease (1,5). Currently, there are no 
known data on the number of patients 
with only mild form of the disease with 
asymptomatic hypercalciuria and/or 
proteinuria without progress to chronic 
renal disease. Some patients develop 
chronic renal disease with proteinuria 
without other typical features, such as 
kidney stones, nephrocalcinosis and 

Dent disease on line edition 


Metabolic anD horMonal DiSorDerS 

Figure 3: a. normal 
sonographic findings 
in the year 2008 b. 
Sonographic findings of 
nephrocalcinosis in the 
year 2016. 

bone disease. Renal biopsy shows FSGS 
and FGGS (1,8,9). 

DENT 2 (OCRL mutation): In this 
form which occurs in only 15 % of these 
patients and is much less common than 
the first one, clinical features are slightly 
different from “classic” Lowe disease (oculocerebrorenal 
syndrome), namely: tubular 
acidosis is rare (actually the main 
sign of Lowe syndrome), the signs of 
Fanconi syndrome (aminoaciduria, glucosuria, 
renal tubular acidosis) are more 
typical of Lowe syndrome than of Dent 
disease type 2; hypercalciuria, nephrocalcinosis 
and nephrolithiasis are typical 
of Dent disease and rare in Lowe syndrome. 
Extrarenal manifestations such 
as mild intellectual disability, hypotonia 
and cataract are typical (13). The gene 
causing this form of disease has locus 
on the X-chromosome Xq25 and is encoding 
phosphatidylinositol 4,5-biphosphate 
5-phosphatase that is involved in 
actin polymerisation and is located in 
trans-Golgi network (2,3,14). 

The primary goal of the treatment is 
to decrease hypercalciuria by increased 
fluid intake, addition of thiazide diuretic 
and potassium citrate in order to prevent 
the formation of kidney stones and 
nephrocalcinosis, and to slow down the 
progress of chronic renal disease (1-3). 


Until now no randomized controlled 
studies on the efficiency of diuretics in 
children have been performed. Thiazide 
diuretics in doses over 0.4 mg/kg/day 
lower calcium excretion in boys with 
Dent disease by 40 %, however their 
use is restricted due to the side effects, 

e.g. hypokalaemia, hypovolemia and 
cramps. Significant proteinuria in Dent 
disease can be treated with ACE inhibitors, 
however their efficiency in preventing 
further decrease in renal function in 
children with Dent disease has not been 
proven (1,10). As the patient had abundant 
albuminuria with pathohistological 
changes in Malpighian bodies with the 
signs of collapsing FSGS, ACE inhibitor 
was introduced. ACE inhibitors have 
been proven to have a nephroprotective 
effect in children with focal segmental 
glomerulosclerosis (FSGS) (1). 
In children with end stage renal disease, 
substitution treatment with haemo-
dialysis, peritoneal dialysis and kidney 
transplantation is necessary. In concurrent 
bone disorders, substitution treatment 
with vitamin D and phosphate is 
necessary. In case of poor growth, treatment 
with growth hormone is described. 
Diet restriction of calcium intake is not 
recommended (1-3). 

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In the present case, ACE inhibitor, 
potassium citrate and a combination of 
thiazide diuretic and amiloride were introduced 
into treatment. The latest bone 
density measurement along with adequate 
therapy was normal. The growth 
is being monitored; currently it is on the 
lower end of normal. 

Conclusion 

We present the case of a 3-year-old 
boy with clinically suspected Dent disease. 
The disease is a very rare, inherited, 
X-linked condition that affects the 

Short Scientific article 

proximal tubules of the kidney, found 
almost exclusively in males. However, 
in case of significant proteinuria, hypercalciuria, 
nephrocalcinosis and/or 
nephrolithiasis it is necessary to think 
of this disease as well. The diagnosis 
is confirmed by proving genetic mutations. 
For a small percentage of patients, 
the mutation of one or the other 
gene cannot be proven, which requires 
the inclusion of other existent genes in 
the testing. The treatment is based on 
symptomatic alleviation and prevention 
of complications. 

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