Yonago Acta medica 1999;42:125–130

A Case of Nephrotic Syndrome with Nephrotoxicity Induced by Low-Dose
Cyclosporin Treatment
Yasushi Utsunomiya, Kyoko Konishi, Shin-ichi Okada, Yoshihiro Sasaki, Atsushi
Hayashi, Takako Nakagawa, Tsunakiyo Kasagi* and Kazuo Shiraki
Department of Pediatrics, Faculty of Medicine, Tottori University and *Department of Nursing,
Institute of Medical Care Technology, Tottori University, Yonago 683-0826, Japan
We report a 3-year-old girl with steroid resistant nephrotic syndrome (NS) who developed nephrotoxicity by low-dose cyclosporin (CsA) treatment. Initial prednisolone(PSL) treatment and subsequent additional cyclophosphamide treatment were notsuccessful in leading her into remission. The first renal biopsy finding revealed neither
a glomerular nor interstitial change. CsA therapy was initiated in addition to ongoing
glucocorticoid therapy at 6 months from the time of onset. Proteinuria disappeared 3
weeks later and the patient went into complete remission. After experiencing the first
relapse, the patient was gradually weaned from CsA, and treatment continued with 30
to 50 ng/mL of trough concentration. No elevations of the serum creatinine, serum
urea, serum potassium, excretion of urinary β2-microglobulin, or urinary N-acetyl-βD -glucosaminidase were demonstrated in the follow-up. A second renal biopsy
specimen obtained 1 year later showed a tubulo-interstitial change, containing tubular
atrophy and interstitial fibrosis, both of which are consistent with the morphologicalchange associated with CsA nephrotoxicity. A follow-up biopsy should be done inorder to evaluate the CsA nephrotoxicity, regardless of the treatment dosage.
Key words: cyclosporin; nephrotic syndrome; nephrotoxicity

Cyclosporin (CsA) is a very effective immunosuppressive agent that has been used in thetreatment of steroid dependent or resistantnephrotic syndrome (NS) (Meyrier et al., 1991;
Niaudet et al., 1991; Niaudet, 1992). However,CsA may have adverse effects upon thekidneys, and long-term treatment is associatedwith irreversible renal damage consisting of
focal glomerular sclerosis and interstitialnephritis (Mihatsch et al., 1994). Nephrotoxicity
has occurred in patients following high doses of
CsA, and the likelihood of its occurrence
depends on the trough concentration level of the
drug (Collaborative Study Group of
Sandimmun in Nephrotic Syndrome, 1991). In
this paper we describe a case of a NS patient
suffering from CsA nephrotoxicity though she
was treated with a low blood concentration.
Abbreviations: CsA, cyclosporin; NS, nephrotic
syndrome; PSL, prednisolone

Patient Report
In September 1996, a 3-year-old girl was referred to us from a satellite hospital with symptoms of NS consisting of massive proteinuria,
edema and oliguria, which had begun 4 months
earlier. She had been treated by prednisolone(PSL) and subsequent additional cyclophosphamide treatment but the disease was not resolved by means of these agents. At the time ofadmission to our hospital, she retained symptoms of NS—anasarca, ascites, oliguria (150 to
250 mL/24 h) and hypertension (from 58 to 112
mmHg). Laboratory findings revealed hypoproteinemia (serum total protein: 4.6 g/dL,
serum albumin: 2.3 g/dL) and hypercholesterolemia (serum total cholesterol: 479 mg/dL),though the serum urea level (8 mg/dL) andserum creatinine level (0.2 mg/dL) were nor-125

Y. Utsunomiya et al.

mal. Urinalysis showed massive proteinuria(over 600 mg/dL concentration in the morning
urine and 4.2 g/24 h in urinary protein excretion), but hematuria and abnormal urinary
sediment were not shown (Table 1). On September 25, a needle renal biopsy was performed
from the lower pole of the right kidney. In therenal biopsy specimen, which contained 8
glomeruli, only 1 glomerulus showed global
sclerosis; the other glomeruli and tubulointerstitia did not show any morphologicalchange (Fig. 1). Any depositions of immunoglobulins and components, which were examined by immunofluorescent study, were notobserved in the glomeruli. Beginning on
October 21, CsA was administered at a 50 mg/
day (3.5 mg/kg/day) initial dose in addition tothe ongoing PSL treatment. Blood concentration of the drug was measured regularly twice aweek by fluorescence polarization immunoassay method using monoclonal antibody, andwas maintained in a range of 60 to 90 ng/mL,
and never exceeded 100 ng/mL during theentire period of treatment (Fig. 2). Three weeks
after CsA treatment began, proteinuria appeared to be minimizing and had completely dis-

Table 1. Laboratory data on admission
White blood cell(/µL)
Red blood cell(/µL)
Hemoglobin(g/dL)
Hematocrit(%)
Platelet(/µL)
Na(mmol/L)
K(mmol/L)Cl(mmol/L)
Blood urea nitrogen (mg/dL)Cr(mg/dL)
Urea acid(mg/dL)Ca(mg/dL)P(mg/dL)
Serum total protein (g/dL)
Serum albumin(g/dL)
Total cholesterol(mg/dL)Urinalysis
pH
Protein(mg/dL)
GlucoseNegative
Occult blood
Negative
Sediment
Red blood cell(/hpf)White blood cell (/hpf)
U-β2MG(µg/L)U-NAG(IU/L)

12,000455 × 104
13.3
39.3
37.3 × 104
138
4.0
100
8
0.2
4.2
8.6
3.7
4.6
2.3
479
7.0
600 (4.2 g/day)

1–4
5–9
94
8.0

hpf, high power field; U-β2MG, urinary β2 microglobulin; U-NAG, urinary N-acethyl-β-glucoseaminidas.

Fig. 1. Light micrograph of first renal biopsy specimens showing normal tubulointerstitia and glomerulus(periodic acid-Schiff stain × 200).

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CsA nephrotoxicity in nephrotic syndrome

1st biopsy(SEP 25, '96)

'96
JUL

SEP

P

CsA concentration

Urine
volumePSL 25 mg 30 mg
25 mg
CPM
CsA

NOV

P

JAN

25 mg
20 mg/48 h
mg

50

60 mg

Proteinuria(mL/24 h)600

2nd biopsy(OCT 29 , '97) '98

'97
JAN

70 mg

1st relapse

400
200

(ng/mL)

Discharge↑↑ Admission

100

50

TP
(g/dL)
Cr(mg/dL)U-β2 MG (µg/L)

4.0
0.2
160

3.9
0.2
94

5.9
0.2
111

6.7
0.2
112

7.0
0.2
63 160Fig. 2. Clinical course of the present patient. PSL, prednisolone; CPM, cyclophosphamide; CsA, cyclosporin; TP, serum total protein; Cr, serum creatinine; U-β2 MG, urinary β2-microglobulin.

appeared 1 month following administration.
On December 19, when the PSL dose was reduced to 20 mg/48 h every other day, the patient
relapsed with no apparent cause. After the PSL
dose was temporarily raised, the relapse wasresolved, and the patient was discharged on
February 24, 1997. CsA was tapered, and treatment was continued in a range of 30 to 50 ng/
mL of whole blood concentration. The CsA
dose ranged from 1 mg/kg/day to 1.5 mg/kg/day
during the follow-up period. PSL was simultaneously continued in combination with a small
amount of CsA. Blood and urinary analyses
were performed regularly. No elevation of theserum creatinine, urea, and potassium levels
and excretion of urinary β2-microglobulin andN-acetyl-β- D -glucosaminidase were demonstrated during the follow-up period. In order toevaluate the subsequent renal morphologicalchange, a second renal biopsy was performed 1
year later on October 29, 1997. Eighteen glomeruli were obtained, 17 of which showed mild
or moderate mesangial cell proliferation, thoughneither segmental lesion nor global sclerosis wasseen (Fig. 3A). Morphological changes were
unexpectedly found in the tubulointerstitia,
which is regarded as a feature of CsA nephro-

toxicity. Tubular atrophy and interstitial fibrosis were seen focally in some fields by lightmicroscopy (Fig. 3B). Vacuolization in tubularepithelial cells was not identified. No elevationof the serum creatinine (0.2 mg/dL), serum urea
(14 mg/dL), or excretion of urinary β2-microglobulin (63 µg/L) was demonstrated at thetime of the second biopsy. In consideration of
the above histological findings, CsA treatment
was discontinued in July, 1998.

Discussion
Our patient suffered from nephrotoxicity within
the 1st year of CsA administration, although she
had been treated with a low-dose treatment.
The CsA dose was reduced within the first 2
months, and continued at 30 to 50 ng/mL oftrough concentration during almost all of thetreatment period. CsA nephrotoxicity is characterized as hyalinization of afferent arteries,
tubular atrophy and stripped interstitial fibrosis(Bergstein, 1992); tubular atrophy and strippedinterstitial fibrosis were seen in the present patient. The mesangial proliferation in the present
patient is not considered to be a morphological127

Y. Utsunomiya et al.

A

B
Fig. 3. Light micrographs of second renal biopsy specimens showing mesangial proliferation (A:periodicacid-Schiff stain × 400), stripped interstitial fibrosis and tubular atrophy (B: PAM × 400).

change indicative of CsA nephrotoxicity, but asa glomerular change seen in cases of diffuse
mesangial hypercellularity, which was addressed by the International Study of Kidney Disease in Children (1981).

It has been considered that the deteriorationof renal function depends on the trough concentration level of the treatment drug, and that
long-term use of CsA results in chronic renal injury, which is not corroborated by biochemical

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CsA nephrotoxicity in nephrotic syndrome

laboratory findings (Collaborative Study Groupof Sandimmun in Nephrotic Syndrome, 1991;
Tanaka et al., 1993). In previous literatureauthored by Yoshikawa and colleagues (1995),
7 of 13 patients with steroid-dependent NS,
managed with 100 ng/mL of whole blood levelfor 2 years, suffered subsequent chronic nephrotoxicity, although none of these patientsdemonstrated elevation of both serum creatinine and urinary β2-microglobulin during theadministration period. Other published reports
concerning a moderate dose of CsA treatment
showed a relatively high incidence of morphological change. The reported incidence of nephrotoxicity among patients with NS ranges
from 25 to 63% (Brodehl et al., 1988; Niaudet
et al., 1988; Sieberth et al., 1992). Conversely,a publication by Gregory and colleagues (1996)
describing long-term use has drawn attention toa relatively low incidence; the authors showedthat the incidence of nephrotoxicity in biopsy
specimens obtained after 12 to 41 months oftherapy is 17%.
Based on reported studies, the incidence ofnephrotoxicity in patients with steroid resistantnephrotic syndrome is higher than that in patients with steroid dependent nephrotic syndrome: 22 to 66% versus 0 to 10% (Capodicasa
et al., 1986; Niaudet et al., 1988, 1991; Neuhaus etal,. 1992). However , steroid resistant nephrotic
syndrome itself carries a substantial risk ofchronic renal insufficiency and end-stage renal
disease (Mampaso et al., 1981). Other studies
showed that the risk of CsA nephrotoxicity was
associated with increased patient age, preexisting deteriorating renal function, hypertension
and decreased renal blood perfusion (Thiel etal., 1986; Feutren et al., 1992). We found noevidence, however, to explain why our patient
suffered CsA nephrotoxicity in response to a
relatively small dose. We speculate that thecondition of the patient’s illness at the time ofcommencement of CsA treatment may relate toa increased risk for nephrotoxicity. When CsA
was initiated, she still had symptoms of NS including massive proteinuria, edema, hypertension and oliguria, suggesting the existence ofpoor renal blood perfusion and decreased renal
function which were not associated with detect-able laboratory data. To our knowledge, preexisting renal dysfunction is one of the high risk
factors of increased CsA nephrotoxicity. In
previous studies using ischemic rat kidneys,
poor renal blood perfusion has proven to be oneof the increasing risk factors (Jablonski et al.,
1986; Thiel et al., 1986). We consider that CsA
administration on the hypoperfusion kidney inthe initial presentation might increase CsA intoxication, and result in subsequent tubulointerstitial change. Accordingly, regardless of theproceeding CsA dose, a careful follow-up, including re-evaluation of histological changes bysecond renal biopsy, is warranted in this patient.
Acknowledgments: We thank our many medical andnursing colleagues who have looked after this patient.

129

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(Received November 11, Accepted December 10, 1998)130