Pediatr Nephrol (2002) 17:290–292
B R I E F R E P O RT
Abdullah Sakarcan · David B. Thomas
Kevin P. O’Reilly · Robert W. Richards
Lithium-induced nephrotic syndrome in a young pediatric patient
Received: 11 June 2001 / Revised: 9 October 2001 / Accepted: 9 October 2001
Abstract Lithium-induced nephrotic syndrome is a rare
complication of lithium therapy and is even rarer in chil-
dren. Most reported cases have been secondary to mini-
mal change disease, which reverses within 1–4 weeks on
discontinuation of lithium therapy. However, focal glo-
merulosclerosis (FSGS) has occasionally been reported
and is not always reversible with discontinuation of lithi-
um. We report an 11-year-old child with lithium-induced
FSGS nephrotic syndrome who went into full remission
after lithium was discontinued.
Keywords Lithium · Focal segmental
glomerulosclerosis · Nephrotic syndrome
Introduction
Lithium, the lightest alkyl metal, is commonly employed
in the treatment of bipolar psychiatric disorders. The
more commonly reported adverse renal effects during
lithium therapy are renal tubular acidosis, nephrogenic
diabetes insipidus, and chronic interstitial nephritis
[1, 2]. An uncommon side effect is lithium-induced
nephrotic syndrome [3].
A. Sakarcan
Department of Pediatrics,
University of South Carolina School of Medicine,
Columbia, South Carolina, USA
A. Sakarcan (✉)
8 Medical Park, Department of Pediatrics,
Division of Pediatric Nephrology, Columbia, SC 29203, USA
e-mail: abdullahsakarcan@hotmail.com
Tel.: +1-803-4342394, Fax: +1-803-4343855
D.B. Thomas
Department of Pathology and Laboratory Medicine,
University of North Carolina Hospitals, North Carolina, USA
K.P. O’Reilly
Division of Nephrology and Hypertension,
University of North Carolina Hospitals, North Carolina, USA
R.W. Richards
Greenville Psychiatry, Greenville, South Carolina, USA
© IPNA 2002
The nephrotic syndrome associated with therapeutic
levels of lithium was first reported by Duflot et al. in
1973 [4]. Since then, 18 adult and 2 pediatric cases have
been reviewed [5]. The purpose of this paper is to report
the youngest patient to develop nephrotic syndrome
associated with lithium.
Case report
An 11-year-old white male with bipolar disorder presented to the
outpatient clinic with proteinuria and hematuria. Current medica-
tions included lithium carbonate 300 mg every 12 h, topiramate
75 mg every 12 h, risperidone 0.5 mg every morning and 1.5 mg
every evening. His psychiatric disorder was under control on this
regimen. He denied gross hematuria, sore throat, polyuria, poly-
dipsia, or edema. Family history was unremarkable. In addition to
his bipolar disorder, he also carried the diagnosis of attention defi-
cit disorder.
On initial examination, his blood pressure was 108/54 mmHg,
heart rate 95 beats per min, and respiratory rate 23 breaths per
min. The remainder of his examination was within normal limits,
including the absence of edema.
Urinalysis showed specific gravity of 1010, pH 6.0, 0 white
blood cells, 20 red blood cells/per high-power field, 4+ protein,
ketones negative, and nitrite negative. Other laboratory findings
included serum sodium 138 mmol/l, potassium 4.3 mmol/l, creati-
nine 0.5 mg/dl, serum albumin 4.0 g/dl, serum calcium 9.3 mg/dl,
blood urea nitrogen 18 mg/dl, and cholesterol 250 mg/dl. Lithium
level was 1.2 mmol/l (therapeutic range 0.8–1.4 mmol/l). C3 and
C4 were in the normal range. Renal ultrasonography was normal.
A 24-h urine collection revealed 3 g of protein. Further laboratory
work-up included negative antinuclear antibody and normal IgA
level. Given the new-onset nephrotic-range proteinuria, a kidney
biopsy was performed.
Tissue was submitted for routine light microscopy, immunoflu-
orescence, microscopy, and electron microscopy. Tissue for light
microscopy was evaluated at five section levels with hematoxylin-
eosin, periodic acid-Schiff, and trichrome stains. There were up to
23 glomeruli per section level. There was no necrosis, no hyper-
cellularity, and no crescent formation. One glomerulus had seg-
mental perihilar sclerosis with adhesion to Bowman’s capsule, and
another glomerulus had focal hilar hyalinosis. Scattered proximal
tubules contained prominent cytoplasmic protein resorption drop-
lets. No significant interstitial fibrosis or tubular atrophy was iden-
tified. There was no evidence of tubulointerstitial disease. Arteries
and arterioles had no sclerosis and no vascular inflammatory
lesions were present. Immunofluorescence microscopy revealed 1

segmentally sclerotic glomerulus with no specific staining for IgG,
IgA, IgM, C3, C1q, kappa light chains, or lambda light chains. No
significant extraglomerular staining was present. The glomerulus
examined ultrastructurally by electron microscopy had no capil-
lary wall or mesangial immune complex-type electron-dense de-
posits. There was variable wrinkling of the glomerular basement
membranes and mild, segmental visceral epithelial foot process
effacement. No endothelial tubuloreticular inclusions were identi-
fied. A diagnosis of focal segmental glomerular sclerosis (FSGS),
perihilar variant, was made.
Given the pathologic diagnosis, the lithium was discontinued.
Three weeks later, there was no evidence of proteinuria. Urinalysis
showed specific gravity of 1020, pH 6.5, blood and protein nega-
tive.
Discussion
Mild proteinuria is a common finding after 2 years of
lithium therapy [5]. However, the nephrotic syndrome is
a rare, idiosyncratic effect of lithium carbonate [3]. It
often resolves following the discontinuation of the medi-
cation when due to minimal change disease [3]. Our pa-
tient is the youngest child to be reported with nephrotic-
range proteinuria and FSGS on lithium carbonate for
bipolar disorder.
Bipolar disorder is an affective and mood disorder that
affects children and adolescents as well as adults. Origi-
nally thought to be rare in childhood, this disorder is
diagnosed in the prepubertal age group. With increased
awareness of this condition, lithium is being used in the
pediatric population with increased frequency [6, 7].
Possible pathophysiological links between minimal
change disease and lithium have been proposed. It has
been suggested that minimal change disease is a disorder
of cell-mediated immunity resulting in the production of
a circulating lymphokine toxic to the podocytes [8].
Tomizawa et al. [9] isolated a soluble glomerular perme-
ability factor from a patient with minimal change dis-
ease. The cytokine profile in patients with minimal
change disease is abnormal [10]. Lithium has been pro-
posed to modulate the T cell-dependent immune system.
Wu and Yang [11] demonstrated that lithium enhances
interleukin-2 (IL-2) production in human T cells. Lithi-
um also augments the IL-1-induced synthesis of IL-6,
GM-CSF, IL-3, and IL-2 in murine T cell hybridoma
cells. In the same model, lithium modulates both tumor
necrosis factor (TNF)-mediated cytotoxicity and TNF-
induced and IL-1-induced cytokine expression [12].
T cell stimulation requires the activation of both the
phosphoinositol pathway as second messenger systems
[13, 14]. Lithium is a well-known activator of the pho-
sphoinositol pathway [15]. Tam et al. [16] showed that
osteoblastic cells, when preincubated with lithium,
showed an amplified response to different stimulators,
such as endothelin-1. Based on these data, it could be
postulated that lithium could lead to enhanced release of
cytokines from T cells, which may increase glomerular
permeability to protein.
There have been only 20 reported cases of nephrotic
syndrome associated with the use of lithium [5]. Only 2
291
of these cases were pediatric patients [3, 5, 17]. One of
these patients, a 19-year-old female, developed the
nephrotic syndrome with a lithium level of 0.8 mmol/l.
The second patient was a 14-year-old female who pre-
sented with nephrotic-range proteinuria (serum albumin
41 g/l) with a nontoxic lithium level. The kidney biopsy
of the second patient revealed minimal change disease,
whereas the first patient did not have a kidney biopsy
performed. In both patients, the nephrotic syndrome re-
solved with the discontinuation of medication. Our pa-
tient had a clinical picture that resembled the younger
patient with one exception – the pathological findings
compatible with FSGS, perihilar variant. In adult cases,
minimal change disease is the most common pathology
seen with lithium-associated nephrotic syndrome. How-
ever, FSGS has been described in a few cases [5]. Pro-
teinuria generally begins 1.5–10 months after starting
lithium therapy [3]. In minimal change disease, the pro-
teinuria usually resolves 1–4 weeks after discontinuation
of the lithium. However, some cases have required treat-
ment with corticosteroids [3]. In several patients, reinsti-
tution of lithium led to recurrence of the nephrotic-range
proteinuria, strongly suggesting an etiological role for
lithium [3]. The relationship with FSGS is less clear. In
some cases, cessation of the lithium did not lead to reso-
lution of the nephrosis, suggesting the patient had either
primary FSGS or a secondary FSGS due to tubulointer-
stitial disease [18]. However, in other cases, as in our re-
port, the proteinuria resolved after discontinuing the lith-
ium [18]. If lithium therapy is to be continued long term,
renal function (i.e., creatinine) should be monitored
every 3–6 months, as 15%–20% of patients on chronic
lithium therapy develop a slowly progressive decrease in
glomerular filtration rate (GFR) [1, 19]. Although GFR
rarely falls below 40–60 ml/min, cases of end-stage renal
disease secondary to lithium have been described. The
greatest risk of this outcome is having a serum creatinine
greater than 2.5 mg/dl at the time of biopsy [20]. It has
been recommended that if the serum creatinine exceeds
2.0 mg/dl, lithium therapy should be discontinued
permanently, given the increased risk of end-stage renal
disease [20].
Our patient is the youngest pediatric patient reported
with lithium-induced nephrotic syndrome and FSGS.
Since bipolar disorder is diagnosed more often in the
pediatric patient population, increased lithium use in
such patients should lead to stricter monitoring with uri-
nalyses and a higher index of suspicion for this associa-
tion.
References
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