Pediatr Nephrol DOI 10.1007/s00467-014-2848-x
ORIGINAL ARTICLE
Early and frequent development of ocular hypertension in children with nephrotic syndrome Emi Kawaguchi & Kenji Ishikura & Riku Hamada & Yoshinobu Nagaoka & Yoshihiko Morikawa & Tomoyuki Sakai & Yuko Hamasaki & Hiroshi Hataya & Eiichiro Noda & Masaru Miura & Takashi Ando & Masataka Honda
Received: 20 September 2013 / Revised: 24 April 2014 / Accepted: 1 May 2014 # IPNA 2014
Abstract Background Prednisolone, the first-line treatment for children with nephrotic syndrome, causes severe side effects. One of these side effects is ocular hypertension, which can result in severe and permanent visual disturbance. However, the exact prevalence, severity and timing of development of ocular hypertension have yet to be fully explored in this pediatric patient group.
E. Kawaguchi Division of General Pediatrics, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan E. Kawaguchi : K. Ishikura (*) : R. Hamada : H. Hataya : M. Honda Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai Fuchu, Tokyo 183-8561, Japan e-mail: [email protected] E. Kawaguchi : Y. Morikawa : M. Miura Clinical Research Support Center, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Y. Nagaoka Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan T. Sakai Department of Pediatrics, Shiga University of Medical Science, Ōtsu, Japan Y. Hamasaki Department of Pediatric Nephrology, Toho University Faculty of Medicine, Tokyo, Japan E. Noda Division of Ophthalmology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan T. Ando Japan Clinical Research Support Unit, Tokyo, Japan
Methods In this retrospective cohort study, children with nephrotic syndrome treated with prednisolone for their first episode were analyzed. Intraocular pressure was screened with an iCare® tonometer and confirmed with Goldmann applanation tonometry before the initiation of prednisolone treatment and at 1 and 4 weeks thereafter. Results A total of 26 children with nephrotic syndrome were included in this study, of whom eight (30.8 %) required treatment with eye drops for ocular hypertension. The median time interval between the diagnosis of ocular hypertension and start of treatment was 9 (range 5–31) days. At relapse of nephrotic syndrome, all children who had undergone treatment for ocular hypertension in their first episode again required treatment for ocular hypertension. Conclusions Routine ophthalmologic examination should be conducted from the early phase after the start of prednisolone treatment. In addition, children with episodes of ocular hypertension may be at greater risk of its reappearance with relapse of the nephrotic syndrome. Keywords Intraocular pressure . Children . Prednisolone . Nephrotic syndrome . iCare tonometer . Goldmann applanation tonometry . Side effect
Introduction Corticosteroid medications, such as prednisolone, play a fundamental role in the treatment of children with idiopathic nephrotic syndrome. Approximately 80–90 % of children respond to prednisolone [1], and its introduction has dramatically reduced mortality rates [2]. However, about 30 % of children experience frequent relapses [3–5], and they may also develop severe side effects to prednisolone, including Cushing’s disease, growth failure, hypertension, gastrointestinal effects,
Pediatr Nephrol
musculoskeletal effects, susceptibility to infections and ophthalmologic diseases [6]. The ophthalmologic side effects associated with corticosteroid use are particularly severe and sometimes cause permanent visual dysfunction. Prednisolone induces an elevation of intraocular pressure (IOP) via increased aqueous outflow resistance owing to an accumulation of extracellular matrix in the trabecular meshwork [7], and subsequent ocular hypertension affects visual function. Steroid-induced ocular hypertension and permanent visual disturbances have been reported in children with nephrotic syndrome and other diseases [8, 9]. Prompt treatment prevents retinal nerve fiber layer damage and visual acuity loss [10, 11], but the exact prevalence and severity of this condition have yet to be fully explored in these children. In addition, the precise time during the management of nephrotic syndrome when there is a risk of progression to increased IOP is unknown. Here, we report the results of our retrospective cohort study in which we investigated the prevalence and course of steroidinduced ocular hypertension in children during their first episode of nephrotic syndrome and its reappearance at relapse.
Materials and methods Study design and participants This was a retrospective cohort study of children (age range 1–18 years) with nephrotic syndrome who were managed in Tokyo Metropolitan Children’s Medical Center during their first episode between March 2010 and October 2012. The criteria for and definitions of nephrotic syndrome and relapse were in accordance with those of the International Study of Kidney Disease in Children (ISKDC) [12]. Data pertaining to the diagnosis, treatment regimen, ocular management and other complications were analyzed based on the medical records of each patient. The study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki and with the ethical guidelines for epidemiological studies issued by the Ministry of Health, Labour and Welfare in Japan. The study was approved by the ethics board of our institution (ID: H25-24). Due to the retrospective nature of the study (data were collected retrospectively from patient charts), informed consent was not obtained in accordance with the above guidelines. Management of nephrotic syndrome At presentation of the first episode of nephrotic syndrome, all children were admitted to the hospital for 5 weeks. The patients received 60 mg/m2/day of prednisolone during the first 4 weeks of hospitalization, concomitant with blood analyses (complete blood cell count and blood
chemistry) and urine tests (urinalysis and quantitative proteinuria) weekly and daily, respectively, until remission; thereafter, blood analyses and urine tests were performed monthly and weekly, respectively. Prednisolone was administered to the patients with nephrotic syndrome based on the following protocol [13]: for the initial episode of nephrotic syndrome, prednisolone was administered for 4 weeks at a dose of 60 mg/m2/day (calculated based on ideal weight; maximum dosage 80 mg/day) divided into three doses, followed by 40 mg/m2/day on alternate days for 4 weeks. With the occurrence of a relapse, prednisolone at 60 mg/m2/day divided into three doses was given until remission, followed by 60 mg/m2/ day on alternate days for 2 weeks, 30 mg/m2/day on alternate days for 2 weeks and finally15 mg/m2/day on alternate days for 2 weeks. Ophthalmologic management During an initial screening, the IOP of the children was measured using an iCare® tonometer (Icare Finland Oy, Helsinki, Finland). If the IOP as measured with the iCare tonometer was above the normal level (≧30 mmHg), the IOP was measured again by Goldmann applanation tonometry (GAT). Treatment for ocular hypertension was started when the IOP measured with the GAT exceeded 25 mmHg, based on the decision of a pediatric ophthalmologist. The IOP was measured in accordance with standard clinical practice at three time-points: before treatment with prednisolone when available and at 1 and 4 week post-treatment initiation. If the IOP was elevated, the measurement was repeated. Treatment with eye drops was discontinued when the IOP decreased to a normal range, i.e. below 20 mmHg. However, these criteria were modified based on the schedule for reducing prednisolone use. The first treatment of ocular hypertension consisted of eye drops (Timoptol® Ophthalmic Solution; timolol maleate; MSD, Tokyo, Japan) and Xalatan® Eye Drops (latanoprost; Pfizer Japan Inc., Tokyo, Japan). If the IOP could not be controlled, it was treated with oral medicine, such as Diamox® (acetazolamide; Sanwa Kagaku Kenkyusho Co., Aichi, Japan) or surgery. IOP was measured when the patients were at rest, and sedation was not used. Statistical analyses The background characteristics of the patients were analyzed using the mean and standard deviation for the continuous variables, and frequency distribution and percentages for categorical variables. Regression analysis and a Bland–Altman analysis were performed to investigate the linear relationship between IOP measurements made with using iCare® tonometry and GAT. The proportion of those who needed ophthalmologic
Pediatr Nephrol
treatment was calculated using the Kaplan–Meier method using time from the start of prednisolone treatment until ophthalmologic treatment as endpoints for curve generation. A two-sided significance level was set at 0.05. Kaplan– Meier analyses, Student’s t tests and chi-square tests were performed using the IBM SPSS Statistics software package for Windows, release 20.0.0 (IBM Corp.. Armonk, NY).
Results Patients A total of 26 patients (17 boys, 9 girls; mean age 6.8 years) who had experienced their first episode of nephrotic syndrome were included in our study. The background characteristics of the patients, those treated with eye drops for ocular hypertension and those untreated are shown in Table 1. In total, 25 patients had steroid-sensitive nephrotic syndrome and one patient had steroid-resistant nephrotic syndrome at the first episode. Evaluation of IOP measurement The IOP of the children was measured for screening using an iCare® tonometer. The correlation between the iCare® measurement results and those obtained by GAT are shown in Fig. 1a, b. In Fig. 1a, all points but two were included in the 95 % confidence interval (CI), and the IOP values obtained with the iCare® tonometer tended to be higher than those measured with GAT. Bilateral IOP was measured in all patients, and the mean differences between right and left IOP are shown in Fig. 2. Based on the good correlation between right and left IOP measurements, we used the mean bilateral IOP for further analyses in our study. Increase of IOP at the initial stage The initial ophthalmological treatment for ocular hypertension in eight children (30.8 %, 6 boys, 2 girls) was eye drop treatment Table 1 Characteristics of patients
SSNS, Steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; IOP, intraocular pressure a
All data are presented as the mean ± standard deviation (SD) unless indicated otherwise
(Table 1). The initiation of treatment in all patients was based on the IOP; all patients required bilateral treatment, and all were asymptomatic at the first episode of nephrotic syndrome. Timolol maleate and/or latanoprost were used in the eye drop treatment. During their first episode of nephrotic syndrome, no patient received surgical management for ocular hypertension. The mean age of the treated and untreated patients was 5.5± 2.2 and 7.3±5.2 years, respectively (p=0.378). With the except of maximum IOP, there were no significant differences between the characteristics of patients treated and untreated with prednisolone (i.e. age, sex, steroid-sensitive or -resistant, serum albumin, serum creatinine, urine protein/creatinine). The ophthalmological treatment-free period for all patients is given in Fig. 3. Of the eight patients who received treatment for ocular hypertension, treatment was initiated in seven of these before day 15 from the start of steroid treatment. Among those who needed ocular hypertension treatment, the median time until start of treatment for ocular hypertension was 9 (range 5–31) days. The change of IOP during prednisolone treatment is shown in Fig. 4. IOP increased after the start of prednisolone treatment (days 1–28), then decreased during dose reduction of prednisolone (days 29–56), and converging on the normal range thereafter (Fig. 4). The number of days until remission of the nephrotic syndrome was not significantly different (p=0.575) between the two groups. Two patients had primary ophthalmological illness, namely myopia, before treatment. Increase of IOP at relapse Nine patients experienced relapse of nephrotic syndrome during the observational period; of these, three had undergone treatment for ocular hypertension at the first episode of nephrotic syndrome, and all required treatment at relapse. The remaining six patients, who did not have ocular hypertension at the first episode did not need treatment at relapse (p=0.012, Fisher’s exact test). One patient who developed frequently relapsing nephrotic syndrome required surgical treatment at his sixth relapse. He presented with headache and blurred vision, and his maximum IOP was 46 and 19 mmHg in the
Patient characteristicsa
Total (n=26)
Treated (n=8)
Untreated (n=18)
Age (years) Sex (male/female) (n) SSNS/SRNS (n) Maximum IOP (mm Hg)
6.8±4.7 17/9 25/1 26.0±8.5
5.5±2.2 6/2 7/1 34.5±7.0
7.3±5.2 11/7 18/0 22.5±6.6
Serum albumin (g/dl) Serum creatinine (mg/dl) Urine protein/creatinine (g/g) Days until remission
1.4±0.6 0.41±0.28 13.9±13.2 11.7±4.9
1.4±0.4 0.34±0.13 18.0±14.1 12.8±8.0
1.3±0.7 0.44±0.33 12.1±13.3 11.1±2.9
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Fig. 2 Difference in intraocular pressure (IOP) between the right and left eyes. Mean difference in IOP between the right and left eyes was −0.05 mmHg (±2.59 standard deviation; range −13 to 7 mmHg). The Pearson product–moment correlation coefficient was 0.934
Fig. 1 Correlation between intraocular pressure (IOP) measured with the iCare® tonometer and by Goldmann applanation tonometry (GAT). a Bland–Altman plot showing the differences between IOP measurements with iCare® and those with GAT. The 95 % confidence interval (solid horizontal lines) of the differences was 0.27–14.33. b A scattered plot of the results of iCare® and GAT measurements. The linear regression between iCare® and GAT is shown
right and left eye, respectively (measured by GAT). This patient underwent trabeculotomy, and the IOP was successfully controlled without visual disturbance thereafter. Including this patient no children had nearsightedness or glaucomatous changes of the optic disk at the last ophthalmologic examination.
Discussion In this retrospective cohort study of children who received prednisolone for their first episode of nephrotic syndrome, we
found that IOP increased in about one-third of children during steroid treatment. Furthermore, most of the children with ocular hypertension were treated within 2 weeks from the start of prednisolone treatment. To our knowledge, this is the first cohort study to identify the frequency and timing of ocular hypertension in children with nephrotic syndrome treated with prednisolone. Among our patient cohort, approximately 30 % of the children with nephrotic syndrome who received prednisolone for their first episode required treatment for ocular hypertension. Ocular hypertension is known as an important side effect of prednisolone, which ultimately results in visual disturbance. Ophthalmalgia, headache, blurred vision and visual field defect are known symptoms of ocular hypertension, but sometimes no symptoms appear at all [14, 15], as was also noted in our study. Once the visual functions are impaired, they never recover [14, 16]. The Japan Glaucoma Society recommends early intervention because delay of treatment may result in greater visual impairment [14]. Therefore, to detect ocular hypertension and provide early treatment, routine ophthalmologic examination for children with nephrotic syndrome is strongly recommended. Among the patients enrolled in our study, approximately 75 % of those with ocular hypertension were treated within 2 weeks from the start of prednisolone treatment, which is earlier than has been reported in previous studies [17–19]. Early evaluation with the iCare® tonometer, a suitable modality for routine use in children, may have resulted in early detection in our study: the median duration from start of prednisolone
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Fig. 3 Timing of start of treatment for ocular hypertension Follow-up phase was 60 days, and the last day of consultation was determined as the censored case
treatment to ocular hypertension was 9 days, and the earliest case was detected on the day 5. These findings suggest that IOP should be measured at the very least by approximately 1 week after the start of prednisolone treatment and that measurements should be repeated if the IOP tends to be high. Our findings show a relationship between IOP increase and prednisolone treatment in children with nephrotic syndrome. To exclude the effect of treatment with eye drops, we also conducted a mixed model analysis and found that the degree of increase in IOP was significantly related to prednisolone dose (data not shown). Furthermore, none of the factors, including age, gender and hypoalbuminemia, were significantly associated with ocular hypertension in the multiple
logistic analyses (data not shown). These findings also support the routine examination of IOP in all children with nephrotic syndrome who receive prednisolone. As mentioned above, treatment with systemic steroids is a risk factor for ocular hypertension and, therefore, other inflammatory diseases that are treated with prednisolone, such as Kawasaki disease, ulcerative colitis and juvenile rheumatoid arthritis, may predispose to ocular hypertension during the early stages of treatment. All of the children in our study who were treated for ocular hypertension during their first episode were treated again during relapse. Approximately 30–40 % of the general population are considered to be potential “steroid responders” (i.e.
Fig. 4 Change of intraocular pressure (IOP) after treatment with prednisolone Dots on solid smooth lines IOP measurements, dots on broken lines IOP after eye drop treatment. Red lines Patients treated for ocular hypertension, purple lines untreated patients
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more likely develop steroid-induced ocular hypertension) [20, 21]. Our results show that approximately 30 % of children in our study required treatment for ocular hypertension and also suggest that children are potential “steroid responders.” About 30 % of children with nephrotic syndrome experience frequent relapse, and these patients are treated repeatedly with prednisolone [3]. Therefore, they are exposed to the risk of complications with prednisolone [3, 13], and the possibility of ocular hypertension is also increased. The IOP of one patient in our study increased continuously and could not be controlled medicinally; consequently, this patient had to undergo surgical treatment. Children who have experienced ocular hypertension with prednisolone treatment may frequently require treatment for ocular hypertension during relapse. Therefore, we suggest that children who have previously undergone prednisolone treatment should be carefully observed. Although GAT is a standard means to measure IOP [22], in our study we used the iCare® tonometer for the screening test for IOP. In our dataset, the IOP measurements with the iCare® tomometer were higher than those obtained with GAT, and the correlation between the two modalities was only moderate (R2 =0.477). However, compared to GAT, the iCare® tonometer is painless, requires no drops or topical anesthetic before examination and measurements are obtained in only a fraction of a second [23, 24]. As the use of iCare® tonometer is easy and simple, IOP can be measured frequently, without any burden on children. Also, several studies have shown the utility and good correlation between iCare® and GAT [24–28]. Therefore, we consider the iCare® tonometer to be suitable for use in screening for IOP in children. Several limitations to our study warrant mention. First, the duration of the observation period was confined to the time period of prednisolone use. In our study, we therefore assessed IOP until the end of prednisolone treatment. We suggest that the long-term outcome of visual function should be evaluated in other studies. Second, prednisolone was administered for 8 weeks (60 mg/m2/day for 4 weeks, followed by 40 mg/m2/ day on alternate days for 4 weeks) for the initial episode of nephrotic syndrome, based on the ISKDC regimen [29]. Recently, however, several guidelines have been recommending longer protocols [3, 12]; for example, in the Children’s Nephrotic Syndrome Consensus, prednisolone was administered for 12 weeks (2 mg/kg/day for 6 weeks, followed by 1.5 mg/kg/day for an additional 6 weeks). Children treated in accordance with these protocols may have a higher risk of ocular hypertension. Third, since our study was retrospectively conducted, IOP measurements were performed based upon current clinical practice. Consequently, the IOP was measured before treatment with prednisolone whenever possible, and when the measurements were not available, they were performed as soon as possible after the initiation of treatment. The time to increased IOP could have been biased because of these limited measurements, and IOP may have increased earlier
than we found. Moreover, we may have overlooked patients who developed increased IOP after the early phase examination. However, even patients who had a mild increase of IOP were followed and examined repeatedly in order to maximize our sensitivity of detection. In conclusion, among our patient group the IOP increased in approximately 30 % of the children with nephrotic syndrome treated with prednisolone, mostly within 2 weeks from the start of administration. We recommend that routine ophthalmologic examination from the early phase should be conducted in these children, since early intervention and treatment of ocular hypertension improves outcome of visual function. Acknowledgments Financial declaration Kenji Ishikura has received lecture fees from Novartis Pharma and Asahi Kasei Pharma. Yuko Hamasaki has received research grants from Novartis Pharma, and lecture fee from Novartis Pharma and Astellas Pharma. Hiroshi Hataya has received lecture fees and travel expenses from Asahi Kasei Pharma, Astellas Pharma, Baxter, JMS, and Meiji Seika Pharma Co. LTD. Masataka Honda has received lecture fees from Novartis Pharma and Asahi Kasei Pharma.
References 1. [No authors listed] (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98: 561–564 2. Barnett HL (1979) International study of kidney disease in children. Nihon Jinzo Gakkai Shi 21:1141–1144 3. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1997) Prognostic significance of the early course of minimal change nephrotic syndrome: report of the international study of kidney disease in children. J Am Soc Nephrol 8:769–776 4. [No authors listed] (1984) Minimal change nephrotic syndrome in children: deaths during the first 5 to 15 years’ observation. Report of the International Study of Kidney Disease in Children. Pediatrics 73: 497–501 5. Lewis MA, Baildom EM, Davis N, Houston IB, Postlethwaite RJ (1989) Nephrotic syndrome: from toddlers to twenties. Lancet 1: 255–259 6. Seth A, Aggarwal A (2004) Monitoring adverse reaction to steroid therapy in children. Indian Pediatr 41:349–357 7. Jones R 3rd, Rhee DJ (2006) Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol 17:163–167 8. Yamashita T, Kodama Y, Tanaka M, Yamakiri K, Kawano Y, Sakamoto T (2010) Steroid-induced glaucoma in children with acute lymphoblastic leukemia: a possible complication. J Glaucoma 19: 188–190 9. Kanei M, Ito T (1993) Effects of systemic corticosteroids on the crystalline lens and intraocular prssure. Jpn Rev Clin Ophthalmol 87: 312–318 10. Brito PN, Silva SE, Cotta JS, Falcao-Reis F (2012) Severe ocular hypertension secondary to systemic corticosteroid treatment in a child with nephrotic syndrome. Clin Ophthalmol 6:1675–1679 11. Mohan R, Muralidharan AR (1989) Steroid induced glaucoma and cataract. Indian J Ophthalmol 37:13–16
Pediatr Nephrol 12. Lombel RM, Gipson DS, Hodson EM (2013) Treatment of steroidsensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol 28:415–426 13. [No authors listed] (1982) Early identification of frequent relapsers among children with minimal change nephrotic syndrome. A report of the International Study of Kidney Disease in Children. J Pediatr 101:514–518 14. [No authors listed] (2012) The Japan Glaucoma Society Guidelines for Glaucoma, 3rd edn. Nihon Ganka Gakkai Zasshi 116:3–46 15. Fitzgerald LA, Dudley J, Inward C, Tizard J (2012) Under pressure: an ocular complication of oral corticosteroid therapy. BMJ Case Rep 2012. pii: bcr2012006955. doi: 10.1136/bcr-2012-006955 16. Lewis JM, Priddy T, Judd J, Gordon MO, Kass MA, Kolker AE, Becker B (1988) Intraocular pressure response to topical dexamethasone as a predictor for the development of primary open-angle glaucoma. Am J Ophthalmol 106:607–612 17. Razeghinejad MR, Katz LJ (2012) Steroid-induced iatrogenic glaucoma. Ophthalmic Res 47:66–80 18. Francois J (1984) Corticosteroid glaucoma. Ophthalmologica 188:76–81 19. Bernstein HN, Sshwartz B (1962) Effects of long-term systemic steroids on ocular pressure and tonographic values. Arch Ophthalmol 68:742–753 20. Sapir-Pichhadze R, Blumenthal EZ (2003) Steroid induced glaucoma. Harefuah 142(137–140):157 21. Fingert JH, Alward WL, Wang K, Yorio T, Clark AF (2010) Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders. Mol Vis 16:596–601
22. Sandhu SS, Chattopadhyay S, Birch MK, Ray-Chaudhuri N (2005) Frequency of goldmann applanation tonometer calibration error checks. J Glaucoma 14:215–218 23. Iliev ME, Goldblum D, Katsoulis K, Amstutz C, Frueh B (2006) Comparison of rebound tonometry with Goldmann applanation tonometry and correlation with central corneal thickness. Br J Ophthalmol 90:833–835 24. Kontiola AI (2000) A new induction-based impact method for measuring intraocular pressure. Acta Ophthalmol Scand 78: 142–145 25. Kim KN, Jeoung JW, Park KH, Yang MK, Kim DM (2013) Comparison of the new rebound tonometer with Goldmann applanation tonometer in a clinical setting. Acta Ophthalmol 91: e392–396 26. Lopez-Caballero C, Contreras I, Munoz-Negrete FJ, Rebolleda G, Cabrejas L, Marcelo P (2007) Rebound tonometry in a clinical setting. Comparison with applanation tonometry. Arch Soc Esp Oftalmol 82:273–278 27. Krzyzanowska-Berkowska P, Asejczyk-Widlicka M (2010) Clinical evaluation of the ICare tonometer in measuring intraocular pressure. Klin Oczna 112:217–220 28. Pakrou N, Gray T, Mills R, Landers J, Craig J (2008) Clinical comparison of the Icare tonometer and Goldmann applanation tonometry. J Glaucoma 17:43–47 29. Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan JD, Wigfall D, Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum LA (2009) Management of childhood onset nephrotic syndrome. Pediatrics 124:747–757
ORIGINAL ARTICLE
Early and frequent development of ocular hypertension in children with nephrotic syndrome Emi Kawaguchi & Kenji Ishikura & Riku Hamada & Yoshinobu Nagaoka & Yoshihiko Morikawa & Tomoyuki Sakai & Yuko Hamasaki & Hiroshi Hataya & Eiichiro Noda & Masaru Miura & Takashi Ando & Masataka Honda
Received: 20 September 2013 / Revised: 24 April 2014 / Accepted: 1 May 2014 # IPNA 2014
Abstract Background Prednisolone, the first-line treatment for children with nephrotic syndrome, causes severe side effects. One of these side effects is ocular hypertension, which can result in severe and permanent visual disturbance. However, the exact prevalence, severity and timing of development of ocular hypertension have yet to be fully explored in this pediatric patient group.
E. Kawaguchi Division of General Pediatrics, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan E. Kawaguchi : K. Ishikura (*) : R. Hamada : H. Hataya : M. Honda Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai Fuchu, Tokyo 183-8561, Japan e-mail: [email protected] E. Kawaguchi : Y. Morikawa : M. Miura Clinical Research Support Center, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Y. Nagaoka Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan T. Sakai Department of Pediatrics, Shiga University of Medical Science, Ōtsu, Japan Y. Hamasaki Department of Pediatric Nephrology, Toho University Faculty of Medicine, Tokyo, Japan E. Noda Division of Ophthalmology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan T. Ando Japan Clinical Research Support Unit, Tokyo, Japan
Methods In this retrospective cohort study, children with nephrotic syndrome treated with prednisolone for their first episode were analyzed. Intraocular pressure was screened with an iCare® tonometer and confirmed with Goldmann applanation tonometry before the initiation of prednisolone treatment and at 1 and 4 weeks thereafter. Results A total of 26 children with nephrotic syndrome were included in this study, of whom eight (30.8 %) required treatment with eye drops for ocular hypertension. The median time interval between the diagnosis of ocular hypertension and start of treatment was 9 (range 5–31) days. At relapse of nephrotic syndrome, all children who had undergone treatment for ocular hypertension in their first episode again required treatment for ocular hypertension. Conclusions Routine ophthalmologic examination should be conducted from the early phase after the start of prednisolone treatment. In addition, children with episodes of ocular hypertension may be at greater risk of its reappearance with relapse of the nephrotic syndrome. Keywords Intraocular pressure . Children . Prednisolone . Nephrotic syndrome . iCare tonometer . Goldmann applanation tonometry . Side effect
Introduction Corticosteroid medications, such as prednisolone, play a fundamental role in the treatment of children with idiopathic nephrotic syndrome. Approximately 80–90 % of children respond to prednisolone [1], and its introduction has dramatically reduced mortality rates [2]. However, about 30 % of children experience frequent relapses [3–5], and they may also develop severe side effects to prednisolone, including Cushing’s disease, growth failure, hypertension, gastrointestinal effects,
Pediatr Nephrol
musculoskeletal effects, susceptibility to infections and ophthalmologic diseases [6]. The ophthalmologic side effects associated with corticosteroid use are particularly severe and sometimes cause permanent visual dysfunction. Prednisolone induces an elevation of intraocular pressure (IOP) via increased aqueous outflow resistance owing to an accumulation of extracellular matrix in the trabecular meshwork [7], and subsequent ocular hypertension affects visual function. Steroid-induced ocular hypertension and permanent visual disturbances have been reported in children with nephrotic syndrome and other diseases [8, 9]. Prompt treatment prevents retinal nerve fiber layer damage and visual acuity loss [10, 11], but the exact prevalence and severity of this condition have yet to be fully explored in these children. In addition, the precise time during the management of nephrotic syndrome when there is a risk of progression to increased IOP is unknown. Here, we report the results of our retrospective cohort study in which we investigated the prevalence and course of steroidinduced ocular hypertension in children during their first episode of nephrotic syndrome and its reappearance at relapse.
Materials and methods Study design and participants This was a retrospective cohort study of children (age range 1–18 years) with nephrotic syndrome who were managed in Tokyo Metropolitan Children’s Medical Center during their first episode between March 2010 and October 2012. The criteria for and definitions of nephrotic syndrome and relapse were in accordance with those of the International Study of Kidney Disease in Children (ISKDC) [12]. Data pertaining to the diagnosis, treatment regimen, ocular management and other complications were analyzed based on the medical records of each patient. The study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki and with the ethical guidelines for epidemiological studies issued by the Ministry of Health, Labour and Welfare in Japan. The study was approved by the ethics board of our institution (ID: H25-24). Due to the retrospective nature of the study (data were collected retrospectively from patient charts), informed consent was not obtained in accordance with the above guidelines. Management of nephrotic syndrome At presentation of the first episode of nephrotic syndrome, all children were admitted to the hospital for 5 weeks. The patients received 60 mg/m2/day of prednisolone during the first 4 weeks of hospitalization, concomitant with blood analyses (complete blood cell count and blood
chemistry) and urine tests (urinalysis and quantitative proteinuria) weekly and daily, respectively, until remission; thereafter, blood analyses and urine tests were performed monthly and weekly, respectively. Prednisolone was administered to the patients with nephrotic syndrome based on the following protocol [13]: for the initial episode of nephrotic syndrome, prednisolone was administered for 4 weeks at a dose of 60 mg/m2/day (calculated based on ideal weight; maximum dosage 80 mg/day) divided into three doses, followed by 40 mg/m2/day on alternate days for 4 weeks. With the occurrence of a relapse, prednisolone at 60 mg/m2/day divided into three doses was given until remission, followed by 60 mg/m2/ day on alternate days for 2 weeks, 30 mg/m2/day on alternate days for 2 weeks and finally15 mg/m2/day on alternate days for 2 weeks. Ophthalmologic management During an initial screening, the IOP of the children was measured using an iCare® tonometer (Icare Finland Oy, Helsinki, Finland). If the IOP as measured with the iCare tonometer was above the normal level (≧30 mmHg), the IOP was measured again by Goldmann applanation tonometry (GAT). Treatment for ocular hypertension was started when the IOP measured with the GAT exceeded 25 mmHg, based on the decision of a pediatric ophthalmologist. The IOP was measured in accordance with standard clinical practice at three time-points: before treatment with prednisolone when available and at 1 and 4 week post-treatment initiation. If the IOP was elevated, the measurement was repeated. Treatment with eye drops was discontinued when the IOP decreased to a normal range, i.e. below 20 mmHg. However, these criteria were modified based on the schedule for reducing prednisolone use. The first treatment of ocular hypertension consisted of eye drops (Timoptol® Ophthalmic Solution; timolol maleate; MSD, Tokyo, Japan) and Xalatan® Eye Drops (latanoprost; Pfizer Japan Inc., Tokyo, Japan). If the IOP could not be controlled, it was treated with oral medicine, such as Diamox® (acetazolamide; Sanwa Kagaku Kenkyusho Co., Aichi, Japan) or surgery. IOP was measured when the patients were at rest, and sedation was not used. Statistical analyses The background characteristics of the patients were analyzed using the mean and standard deviation for the continuous variables, and frequency distribution and percentages for categorical variables. Regression analysis and a Bland–Altman analysis were performed to investigate the linear relationship between IOP measurements made with using iCare® tonometry and GAT. The proportion of those who needed ophthalmologic
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treatment was calculated using the Kaplan–Meier method using time from the start of prednisolone treatment until ophthalmologic treatment as endpoints for curve generation. A two-sided significance level was set at 0.05. Kaplan– Meier analyses, Student’s t tests and chi-square tests were performed using the IBM SPSS Statistics software package for Windows, release 20.0.0 (IBM Corp.. Armonk, NY).
Results Patients A total of 26 patients (17 boys, 9 girls; mean age 6.8 years) who had experienced their first episode of nephrotic syndrome were included in our study. The background characteristics of the patients, those treated with eye drops for ocular hypertension and those untreated are shown in Table 1. In total, 25 patients had steroid-sensitive nephrotic syndrome and one patient had steroid-resistant nephrotic syndrome at the first episode. Evaluation of IOP measurement The IOP of the children was measured for screening using an iCare® tonometer. The correlation between the iCare® measurement results and those obtained by GAT are shown in Fig. 1a, b. In Fig. 1a, all points but two were included in the 95 % confidence interval (CI), and the IOP values obtained with the iCare® tonometer tended to be higher than those measured with GAT. Bilateral IOP was measured in all patients, and the mean differences between right and left IOP are shown in Fig. 2. Based on the good correlation between right and left IOP measurements, we used the mean bilateral IOP for further analyses in our study. Increase of IOP at the initial stage The initial ophthalmological treatment for ocular hypertension in eight children (30.8 %, 6 boys, 2 girls) was eye drop treatment Table 1 Characteristics of patients
SSNS, Steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; IOP, intraocular pressure a
All data are presented as the mean ± standard deviation (SD) unless indicated otherwise
(Table 1). The initiation of treatment in all patients was based on the IOP; all patients required bilateral treatment, and all were asymptomatic at the first episode of nephrotic syndrome. Timolol maleate and/or latanoprost were used in the eye drop treatment. During their first episode of nephrotic syndrome, no patient received surgical management for ocular hypertension. The mean age of the treated and untreated patients was 5.5± 2.2 and 7.3±5.2 years, respectively (p=0.378). With the except of maximum IOP, there were no significant differences between the characteristics of patients treated and untreated with prednisolone (i.e. age, sex, steroid-sensitive or -resistant, serum albumin, serum creatinine, urine protein/creatinine). The ophthalmological treatment-free period for all patients is given in Fig. 3. Of the eight patients who received treatment for ocular hypertension, treatment was initiated in seven of these before day 15 from the start of steroid treatment. Among those who needed ocular hypertension treatment, the median time until start of treatment for ocular hypertension was 9 (range 5–31) days. The change of IOP during prednisolone treatment is shown in Fig. 4. IOP increased after the start of prednisolone treatment (days 1–28), then decreased during dose reduction of prednisolone (days 29–56), and converging on the normal range thereafter (Fig. 4). The number of days until remission of the nephrotic syndrome was not significantly different (p=0.575) between the two groups. Two patients had primary ophthalmological illness, namely myopia, before treatment. Increase of IOP at relapse Nine patients experienced relapse of nephrotic syndrome during the observational period; of these, three had undergone treatment for ocular hypertension at the first episode of nephrotic syndrome, and all required treatment at relapse. The remaining six patients, who did not have ocular hypertension at the first episode did not need treatment at relapse (p=0.012, Fisher’s exact test). One patient who developed frequently relapsing nephrotic syndrome required surgical treatment at his sixth relapse. He presented with headache and blurred vision, and his maximum IOP was 46 and 19 mmHg in the
Patient characteristicsa
Total (n=26)
Treated (n=8)
Untreated (n=18)
Age (years) Sex (male/female) (n) SSNS/SRNS (n) Maximum IOP (mm Hg)
6.8±4.7 17/9 25/1 26.0±8.5
5.5±2.2 6/2 7/1 34.5±7.0
7.3±5.2 11/7 18/0 22.5±6.6
Serum albumin (g/dl) Serum creatinine (mg/dl) Urine protein/creatinine (g/g) Days until remission
1.4±0.6 0.41±0.28 13.9±13.2 11.7±4.9
1.4±0.4 0.34±0.13 18.0±14.1 12.8±8.0
1.3±0.7 0.44±0.33 12.1±13.3 11.1±2.9
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Fig. 2 Difference in intraocular pressure (IOP) between the right and left eyes. Mean difference in IOP between the right and left eyes was −0.05 mmHg (±2.59 standard deviation; range −13 to 7 mmHg). The Pearson product–moment correlation coefficient was 0.934
Fig. 1 Correlation between intraocular pressure (IOP) measured with the iCare® tonometer and by Goldmann applanation tonometry (GAT). a Bland–Altman plot showing the differences between IOP measurements with iCare® and those with GAT. The 95 % confidence interval (solid horizontal lines) of the differences was 0.27–14.33. b A scattered plot of the results of iCare® and GAT measurements. The linear regression between iCare® and GAT is shown
right and left eye, respectively (measured by GAT). This patient underwent trabeculotomy, and the IOP was successfully controlled without visual disturbance thereafter. Including this patient no children had nearsightedness or glaucomatous changes of the optic disk at the last ophthalmologic examination.
Discussion In this retrospective cohort study of children who received prednisolone for their first episode of nephrotic syndrome, we
found that IOP increased in about one-third of children during steroid treatment. Furthermore, most of the children with ocular hypertension were treated within 2 weeks from the start of prednisolone treatment. To our knowledge, this is the first cohort study to identify the frequency and timing of ocular hypertension in children with nephrotic syndrome treated with prednisolone. Among our patient cohort, approximately 30 % of the children with nephrotic syndrome who received prednisolone for their first episode required treatment for ocular hypertension. Ocular hypertension is known as an important side effect of prednisolone, which ultimately results in visual disturbance. Ophthalmalgia, headache, blurred vision and visual field defect are known symptoms of ocular hypertension, but sometimes no symptoms appear at all [14, 15], as was also noted in our study. Once the visual functions are impaired, they never recover [14, 16]. The Japan Glaucoma Society recommends early intervention because delay of treatment may result in greater visual impairment [14]. Therefore, to detect ocular hypertension and provide early treatment, routine ophthalmologic examination for children with nephrotic syndrome is strongly recommended. Among the patients enrolled in our study, approximately 75 % of those with ocular hypertension were treated within 2 weeks from the start of prednisolone treatment, which is earlier than has been reported in previous studies [17–19]. Early evaluation with the iCare® tonometer, a suitable modality for routine use in children, may have resulted in early detection in our study: the median duration from start of prednisolone
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Fig. 3 Timing of start of treatment for ocular hypertension Follow-up phase was 60 days, and the last day of consultation was determined as the censored case
treatment to ocular hypertension was 9 days, and the earliest case was detected on the day 5. These findings suggest that IOP should be measured at the very least by approximately 1 week after the start of prednisolone treatment and that measurements should be repeated if the IOP tends to be high. Our findings show a relationship between IOP increase and prednisolone treatment in children with nephrotic syndrome. To exclude the effect of treatment with eye drops, we also conducted a mixed model analysis and found that the degree of increase in IOP was significantly related to prednisolone dose (data not shown). Furthermore, none of the factors, including age, gender and hypoalbuminemia, were significantly associated with ocular hypertension in the multiple
logistic analyses (data not shown). These findings also support the routine examination of IOP in all children with nephrotic syndrome who receive prednisolone. As mentioned above, treatment with systemic steroids is a risk factor for ocular hypertension and, therefore, other inflammatory diseases that are treated with prednisolone, such as Kawasaki disease, ulcerative colitis and juvenile rheumatoid arthritis, may predispose to ocular hypertension during the early stages of treatment. All of the children in our study who were treated for ocular hypertension during their first episode were treated again during relapse. Approximately 30–40 % of the general population are considered to be potential “steroid responders” (i.e.
Fig. 4 Change of intraocular pressure (IOP) after treatment with prednisolone Dots on solid smooth lines IOP measurements, dots on broken lines IOP after eye drop treatment. Red lines Patients treated for ocular hypertension, purple lines untreated patients
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more likely develop steroid-induced ocular hypertension) [20, 21]. Our results show that approximately 30 % of children in our study required treatment for ocular hypertension and also suggest that children are potential “steroid responders.” About 30 % of children with nephrotic syndrome experience frequent relapse, and these patients are treated repeatedly with prednisolone [3]. Therefore, they are exposed to the risk of complications with prednisolone [3, 13], and the possibility of ocular hypertension is also increased. The IOP of one patient in our study increased continuously and could not be controlled medicinally; consequently, this patient had to undergo surgical treatment. Children who have experienced ocular hypertension with prednisolone treatment may frequently require treatment for ocular hypertension during relapse. Therefore, we suggest that children who have previously undergone prednisolone treatment should be carefully observed. Although GAT is a standard means to measure IOP [22], in our study we used the iCare® tonometer for the screening test for IOP. In our dataset, the IOP measurements with the iCare® tomometer were higher than those obtained with GAT, and the correlation between the two modalities was only moderate (R2 =0.477). However, compared to GAT, the iCare® tonometer is painless, requires no drops or topical anesthetic before examination and measurements are obtained in only a fraction of a second [23, 24]. As the use of iCare® tonometer is easy and simple, IOP can be measured frequently, without any burden on children. Also, several studies have shown the utility and good correlation between iCare® and GAT [24–28]. Therefore, we consider the iCare® tonometer to be suitable for use in screening for IOP in children. Several limitations to our study warrant mention. First, the duration of the observation period was confined to the time period of prednisolone use. In our study, we therefore assessed IOP until the end of prednisolone treatment. We suggest that the long-term outcome of visual function should be evaluated in other studies. Second, prednisolone was administered for 8 weeks (60 mg/m2/day for 4 weeks, followed by 40 mg/m2/ day on alternate days for 4 weeks) for the initial episode of nephrotic syndrome, based on the ISKDC regimen [29]. Recently, however, several guidelines have been recommending longer protocols [3, 12]; for example, in the Children’s Nephrotic Syndrome Consensus, prednisolone was administered for 12 weeks (2 mg/kg/day for 6 weeks, followed by 1.5 mg/kg/day for an additional 6 weeks). Children treated in accordance with these protocols may have a higher risk of ocular hypertension. Third, since our study was retrospectively conducted, IOP measurements were performed based upon current clinical practice. Consequently, the IOP was measured before treatment with prednisolone whenever possible, and when the measurements were not available, they were performed as soon as possible after the initiation of treatment. The time to increased IOP could have been biased because of these limited measurements, and IOP may have increased earlier
than we found. Moreover, we may have overlooked patients who developed increased IOP after the early phase examination. However, even patients who had a mild increase of IOP were followed and examined repeatedly in order to maximize our sensitivity of detection. In conclusion, among our patient group the IOP increased in approximately 30 % of the children with nephrotic syndrome treated with prednisolone, mostly within 2 weeks from the start of administration. We recommend that routine ophthalmologic examination from the early phase should be conducted in these children, since early intervention and treatment of ocular hypertension improves outcome of visual function. Acknowledgments Financial declaration Kenji Ishikura has received lecture fees from Novartis Pharma and Asahi Kasei Pharma. Yuko Hamasaki has received research grants from Novartis Pharma, and lecture fee from Novartis Pharma and Astellas Pharma. Hiroshi Hataya has received lecture fees and travel expenses from Asahi Kasei Pharma, Astellas Pharma, Baxter, JMS, and Meiji Seika Pharma Co. LTD. Masataka Honda has received lecture fees from Novartis Pharma and Asahi Kasei Pharma.
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