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NDT Advance Access originally published online on February 7, 2008
Nephrology Dialysis Transplantation 2008 23(8):2531-2536; doi:10.1093/ndt/gfn013
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Nephrotic state as a risk factor for developing posterior reversible encephalopathy syndrome in paediatric patients with nephrotic syndrome

Kenji Ishikura1, Masahiro Ikeda1, Yuko Hamasaki1, Hiroshi Hataya1, Gen Nishimura2, Ryugo Hiramoto3 and Masataka Honda1

1 Department of Pediatric Nephrology 2 Department of Pediatric Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo 3 Department of Pediatrics, Matsudo City Hospital, Matsudo, Japan

Correspondence and offprint requests to: Kenji Ishikura, Tokyo Metropolitan Kiyose Children's Hospital, 1-3-1 Umezono, Kiyose-city, Tokyo 204-8567, Japan. Tel: +81-42-491-0011; Fax: +81-42-491-0044; E-mail: kenzo{at}ii.e-mansion.com



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Posterior reversible encephalopathy syndrome (PRES) is a distinctive and potentially serious complication of the nephrotic syndrome. The objective of the present study is to characterize the factors predisposing the development of PRES in paediatric patients with nephrotic syndrome.

Methods. We investigated paediatric patients with idiopathic nephrotic syndrome who developed PRES between 1999 and 2005 in our institution. Patients with steroid-sensitive nephrotic syndrome and those with steroid-resistant nephrotic syndrome that were proven to be idiopathic were eligible.

Results. In total, seven patients ranging in age from 1.5 to 15.1 years old were analysed. At the onset of PRES, six of the seven patients were in a nephrotic state. Various degrees of acute renal insufficiency were shown in four patients. The re-administration of cyclosporine after the episodes of PRES was carried out in four patients. During the observation for 17–51 months after the re-administration, the recurrence of PRES did not develop in these patients.

Conclusions. The development of PRES occurred at the time of moderate to severe nephrotic state in most of our paediatric patients with nephrotic syndrome. Besides the administration of cyclosporine and having hypertension, there appear to be several additive factors predisposing the development of PRES in these patients, namely low serum albumin level, generalized oedema, increase in vascular permeability, unstable fluid status and renal insufficiency. The re-administration of cyclosporine to those patients with anamnesis of PRES may be considered after the management and close monitoring of these factors as well as hypertension.

Keywords: children; cyclosporine; hypertension; nephrotic syndrome; posterior reversible encephalopathy syndrome



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
During the management of paediatric patients with nephrotic syndrome, there are numerous medical complications that deteriorate the disease course [1]. Among them, posterior reversible encephalopathy syndrome (PRES) is distinctive and potentially serious [2–4]. It was first described as reversible posterior leukoencephalopathy syndrome in 1996 [5], denoting a reversible, predominantly posterior leukoencephalopathy in patients who had renal insufficiency, hypertension or were administered immunosuppressants.

In regard to the development of PRES, hypertension and the administration of calcineurin inhibitors including cyclosporine are considered to be the principal risk factors [3,5,6]. In addition, the relatively frequent development of PRES in patients with nephrotic syndrome was shown both in adults [7,8] and in children [9–12], suggesting a consequential relation between PRES and nephrotic syndrome other than the administration of cyclosporine and having hypertension.

To prevent the development of PRES in patients with nephrotic syndrome and to attempt a rational re-administration of cyclosporine to those patients with the anamnesis of PRES, identification of the risk factors for developing PRES would be of great value. The objective of the present study is to characterize the factors predisposing the development of PRES in paediatric patients with idiopathic nephrotic syndrome.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
We investigated paediatric patients with idiopathic nephrotic syndrome (aged <20) who developed PRES between 1999 and 2005 in our institution. Patients with steroid-sensitive nephrotic syndrome and those with steroid-resistant nephrotic syndrome that was proven to be idiopathic nephrotic syndrome by renal biopsies, namely minimal change nephrotic syndrome or focal segmental glomerular sclerosis, were eligible. All patients who satisfied inclusion criteria were analysed. Those with chronic renal failure due to steroid-resistant nephrotic syndrome and renal transplant recipients were excluded. PRES was diagnosed when the patients had neurological symptoms (altered consciousness, seizures, visual disturbances and headaches), positive radiological findings and other neurological disorders were ruled out. Radiological diagnosis was made by the same paediatric radiologist (G.N.).

We analysed clinical courses and laboratory data, imaging findings, blood pressure and the administrative condition of cyclosporine. The blood concentration of cyclosporine was analysed using fluorescence polarization and was measured as a trough level; hence, the blood samples were taken just before the next administration.

Prednisolone was administered to the patients with nephrotic syndrome based on the following protocol: for the initial episode of nephrotic syndrome, prednisolone at 2 mg/kg/day (calculated on ideal weight) divided into three doses was administered for 4 weeks, followed by 1.3 mg/kg/day on alternate days for 4 weeks. For the relapses, prednisolone at 2 mg/kg/day divided into three doses was given until remission, followed by 2 mg/kg/day on alternate days for 2 weeks, 1 mg/kg/day on alternate days for 2 weeks and 0.5 mg/kg/day on alternate days for 2 weeks.

Cyclosporine was administered to patients with frequently relapsing nephrotic syndrome and steroid-resistant nephrotic syndrome mainly based on the protocols shown elsewhere [12] and in Figure 1. Sandimmune® (Novartis, Basel, Switzerland) was used as cyclosporine before the year 2000; then, this was converted to Neoral® (Novartis, Basel, Switzerland).


Figure 1
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  		Fig. 1 Protocols for patients with frequently relapsing nephrotic syndrome and for patients with steroid-resistant nephrotic syndrome. The protocols of immunosuppressive treatment including cyclosporine for patients with frequently relapsing nephrotic syndrome (A) and steroid-resistant nephrotic syndrome (B) are shown. *For patients with focal segmental glomerular sclerosis proven by biopsy, methylprednisolone pulse therapy is added.

 
The treatment for the patients in the acute phase of PRES comprised the administration of anticonvulsants, control of hypertension and discontinuance of cyclosporine. The re-administration of cyclosporine to the patients with the anamnesis of PRES was attempted when the patients had all of the following conditions: (1) after the discontinuance of cyclosporine, patients experienced frequent relapses of nephrotic syndrome or steroid-resistant nephrotic syndrome that deteriorated the patients’ state; (2) cyclophosphamide was ineffective or the patient had a history of a previous administration of this drug; (3) hypertension was controlled within the normal range and (4) informed consent regarding the re-administration of cyclosporine was obtained from the parents, and patients if appropriate.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
This study was conducted on a total of seven patients (four boys and three girls) ranging in age from 1.5 to 15.1 years (median, 8.4 years). Table 1 shows the clinical characteristics and cranial imaging findings. In total, five patients had steroid-resistant nephrotic syndrome (Patients 1, 2, 3, 6 and 7) and one patient had frequently relapsing nephrotic syndrome (Patient 4).


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  		Table 1 Clinical characteristics and cranial imaging findings of seven patients with posterior reversible encephalopathy syndrome

 
Cyclosporine was administered to six patients (Patients 1–4, 6 and 7). The average trough level of cyclosporine except for Patient 7 was 102.8 ng/ml (71–140). With the exception of one patient (Patient 4), all had mild to moderate hypertension around the time of the episode.

At the onset of PRES, six of the seven patients were in a nephrotic state; the average serum albumin level of these patients was 1.88 g/dl (1.6–2.1) and that of total cholesterol was 614.8 mg/dl (449–909). They showed moderate to severe generalized oedema and most of them required supplies of albumin intravenously. Mild to moderate renal insufficiency was shown in four of six patients with nephrotic state (Patients 3, 5–7), but it was temporary and completely reversible.

The clinical symptoms at the episode were as follows: altered consciousness in six patients, seizures in five patients, visual disturbance in five patients, headaches in four patients and vomiting in three patients. The lesions in imaging findings extended to the grey matter, to the frontal and temporal lobes and to the cerebellum in most of the patients. All recovered both clinically and radiologically within 10 weeks with optimal control of hypertension and seizures, as well as discontinuance of cyclosporine.

The re-administration of cyclosporine after the episodes of PRES was carried out in four patients (Patients 1, 4, 6 and 7). The clinical state of these patients at the re-administration was as shown in Table 2. Blood pressure was maintained within the normal range; fluid status was closely monitored together with retained euvolia. The target trough level of cyclosporine was adjusted based on the aforementioned protocol; however, the dosage of cyclosporine was gradually increased. During the observation for 17–51 months after the re-administration of cyclosporine, the recurrence of PRES did not develop in these patients. After the re-administration of cyclosporine, all four patients experienced remission of the nephrotic state or a significant decrease in the number of relapses.


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  		Table 2 Clinical state of patients at the re-administration of cyclosporine

 
The representative clinical course and process of the re-administration of cyclosporine are demonstrated below.

Patient 1 is a Japanese girl. In July 2001, when she was 5 years old, she experienced an onset of idiopathic nephrotic syndrome. Initially her nephrotic syndrome was sensitive to prednisolone, then transformed to become steroid-resistant. Histological analysis of the kidney, performed in October 2001, revealed a minimal change in nephrotic syndrome, and the administration of cyclosporine was started. Cyclosporine was effective and resulted in a complete remission. After the discontinuance of cyclosporine, however, she underwent frequent relapses of nephrotic syndrome, followed by peritonitis in June 2004 due to {alpha} haemolytic streptococcus. Her nephrotic state returned to a refractory state with regard to the administration of prednisolone at the same time; cyclosporine was administered again.

Ten days after the administration of cyclosporine for the second time, she experienced a sudden onset of lethargy, seizures, headaches and visual blurring. At the episode, her blood pressure was 156/107, the trough level of cyclosporine was 79 ng/ml, serum albumin was 1.6 g/dl and moderate generalized oedema was shown. In addition to cyclosporine, prednisolone (50 mg/day), mizoribine (250 mg/day) and lisinopril (2.5 mg/day) were also being prescribed. Cranial magnetic resonance imaging (a fluid-attenuated inversion recovery image) revealed hyperintensity lesions in the frontal, temporal, parietal and occipital regions, extending to both the white and grey matter, of the cerebral hemisphere (Figure 2). PRES was diagnosed; cyclosporine was discontinued immediately and the blood pressure was corrected by intravenous nicardipine within the normal range. The neurological findings returned to normal the next day and the follow-up magnetic resonance imaging 2 weeks later was normal.


Figure 2
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  		Fig. 2 Imaging findings of Patient 1. Bilateral, high intensity areas were apparent in the occipital and temporal regions on the second day. These lesions were evident in both the white and grey matter (MRI fluid-attenuated inversion recovery).

 
After the episode of PRES, alternative immunosuppressants comprising high-dose methylprednisolone (30 mg/kg/dose, three times a week) was started; however, the nephrotic state continued to be refractory and generalized oedema deteriorated. Her minimum serum albumin level was 1.0 g/dl and frequent intravenous supplies of albumin were required. Thus, after informed consent was obtained from her parents, we re-administered cyclosporine and discontinued mizoribine. Her albumin level returned to 2.0 g/dl and generalized oedema ameliorated in 6 months after the re-administration of cyclosporine; complete remission of the nephrotic syndrome was achieved in 9 months. She did not experience a relapse of PRES or other major adverse effects of cyclosporine for 18 months after the re-administration.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In this study, the predisposing factors for the development of PRES in paediatric patients with idiopathic nephrotic syndrome were evaluated. The clinical courses after the re-administration of cyclosporine in four patients with the anamnesis of PRES were also shown.

Hitherto, hypertension and the administration of calcineurin inhibitors, including cyclosporine, were considered to be the two principal risk factors for developing PRES [3,5,6]. In most of our patients cyclosporine was administered at the time of developing PRES. Although the neurotoxicity of cyclosporine has been almost established, the relationship between the trough level of cyclosporine and development of PRES remains controversial [13–15]. In our series, three of our patients had trough levels <80 ng/ml and the remainder had trough levels <150 ng/ml; on the other hand, most of the liver transplant patients do not necessarily develop PRES even with trough levels of a much higher degree [15]. Thus, to define a trough level of cyclo- sporine that is absolutely safe appears to be impractical. Instead, other factors that intensify the possibility for development of PRES are to be explored.

In patients with nephrotic syndrome, the administration of cyclosporine and the presence of hypertension frequently co-exist due to the administration of prednisolone or methylprednisolone, renal insufficiency and the adverse effect of cyclosporine itself. In our patients, with one exception (Patient 4), all had mild to moderate hypertension at the time of the episode of PRES. Taken together, when both conditions exist at the same time, the possibility of developing PRES may become higher. Alternatively, even mild hypertension may be detrimental in nephrotic patients receiving cyclosporine [8].

Nephrotic syndrome itself has been considered to be a predisposing condition for developing PRES in both adults and children [7–11]. Although the precise prevalence is still to be explored, 5.7% of paediatric patients with nephrotic syndrome to whom cyclosporine was administered developed PRES during the observation in our previous series [12]. It is worth noting that most of our patients were in a nephrotic state at the time of developing PRES; consequently, low serum albumin levels requiring occasional administrations of albumin, moderate to severe generalized oedema, increase in vascular permeability [16], unstable fluid status and occasional renal insufficiency [17] were shown. The key pathophysiological process of PRES was identified as vasogenic oedema that denotes fluid extravasation from intracerebral capillaries [5,18,19]. Cyclosporine may induce vasogenic oedema by several mechanisms including the alteration of sympathetic flow [14], cyclosporine-mediated release of endothelin or endothelial dysfunction [13], while hypertension may also induce vasogenic oedema due to autoregulation failure of the cerebral blood flow [19]. Other factors seen in the nephrotic state could induce vasogenic oedema due to decreased intravascular oncotic pressure, increased permeability of intracerebral capillaries and fluid overload. Thus, regarding patients with nephrotic syndrome, a severe nephrotic state may exaggerate the risks of developing PRES, as may administration of cyclosporine and having hypertension.

Among paediatric patients with idiopathic nephrotic syndrome, available strategies are very limited for patients with steroid-resistant and frequently relapsing nephrotic syndrome; for the former, only cyclosporine and methylprednisolone pulse therapy have been barely established [17,20,21] and for the latter, cyclosporine, cyclophosphamide, chlorambucil and levamisole are considered to be effective [22]. Chlorambucil and levamisole are not available in Japan. Besides, the safe dosage of cyclophosphamide is limited to avoid gonadal toxicity [23]; we limited the total dose of cyclophosphamide for those patients up to 210 mg/kg (2.5 mg/kg for 12 weeks). Hence the four patients who experienced the re-administration of cyclosporine in our study had a very limited choice of immunosuppressants that could be used. They were suffering from frequent relapses due to the accumulated adverse effects of prednisolone (Patient 4, data not shown) or a refractory nephrotic state with severe generalized oedema (Patients 1, 6 and 7). Taken together, we decided to re-administer cyclosporine to these patients.

At the time of the re-administration for these patients, postulated risk factors for developing PRES were strictly managed or monitored. Hypertension was controlled with antihypertensive drugs including intravenous nicardipine within the normal range in all the patients. The fluid status and renal function were closely monitored around the time of re-administration and thereafter. In this manner, the nephrotic syndrome in these four patients was managed without major adverse effects of cyclosporine including the development of PRES to date.

With regard to Patient 4, the clinical course as well as imaging findings was distinctive among our patients. The episode developed during the intermittent period, and not at the relapse. Only this patient was free from seizures and altered consciousness at the episode of PRES. Hypertension was not detected throughout the course, the trough level of cyclosporine was the lowest among our patients and he was not nephrotic at the time of the episode. The dominant lesion in the cranial imaging was in the cerebellum, which was relatively an atypical area for PRES. As a whole, other mechanisms that have not been elucidated yet might be involved in the development of PRES in this patient.

Several limitations of our study must be addressed. At the re-administrations of cyclosporine three of our patients were still nephrotic; even with the close management and monitoring, predisposing factors including generalized oedema and increased vascular permeability still existed. Therefore, despite the successful results, risks of recurrence of PRES could not be ruled out. The number of patients investigated was small, and the majority of our patients were resistant to steroid therapy. Thus, there are some difficulties to apply our results to general practice. Also, it is a retrospective study and does not have a control group. Analysis and interpretation for the efficacy and adverse effects of the re-administration of cyclosporine must be prudent.

In conclusion, the development of PRES occurred at the time of moderate to severe nephrotic state in most of our paediatric patients with nephrotic syndrome. Besides the administration of cyclosporine and having hypertension, there appear to be several additive factors predisposing the development of PRES in these patients, namely low serum albumin level, generalized oedema, increase in vascular permeability, unstable fluid status and renal insufficiency. The re-administration of cyclosporine to these patients with anamnesis of PRES may be considered after the management and close monitoring of these factors as well as the hypertension.



   Acknowledgments
 
We thank Kunimasa Yan and Ryouta Kurayama, Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan, for the precise information of the patient.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 5. 4.07
Accepted in revised form: 8. 1.08


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