This epidemiological study is the first survey of its kind to investigate the characteristics of CNS and INS in Japan. Data obtained from 44 institutions in Japan managing 92 patients with CNS or INS were evaluated. As a result, we identified and analyzed a total of 83 patients with CNS or INS.
In the present study, the disease type was Finnish in 33 patients, non-Finnish without syndrome in 26 patients, and non-Finnish with syndrome in 24 patients. Among patients with Finnish-type disease, the number of male and female patients was similar (15 and 18, respectively). As Finnish-type CNS is inherited in an autosomal recessive manner, the incidence in both sexes tends to be similar .
The most frequent syndrome was Denys–Drash syndrome in 70.8% of patients (17/24) in the present study. Denys–Drash syndrome is characterized by nephrotic syndrome owing to diffuse mesangial sclerosis, male pseudohermaphroditism, and predisposition to develop Wilms tumor and gonadoblastoma .
Patients with Finnish-type disease were diagnosed the earliest compared with those with non-Finnish-type disease. It is likely that these patients were diagnosed first because of the clinical manifestations of the disease, such as the enlarged placenta, and the massive edema that becomes evident shortly after birth in most patients with Finnish-type CNS. In fact, an enlarged placenta was frequently reported among patients with Finnish-type disease in the present study. This is consistent with the previous descriptions of patients with Finnish-type disease, in which the weight of the placenta is approximately 25% of the birth weight .
Renal biopsy was more frequently performed among patients with non-Finnish-type disease, while genetic testing was more frequent among patients with Finnish-type disease and non-Finnish-type with syndrome. The Finnish-type CNS does not have characteristic pathologic findings and the diagnosis is usually based on the clinical manifestations along with the results of genetic testing. Several genes (e.g., NPHS1, NPHS2, PLCE1, and WT1) involved in the etiology of CNS and INS have been discovered so far [13-17], and these are useful in the diagnosis of Finnish-type CNS and non-Finnish-type with syndrome . Finnish-type CNS is often associated with mutations in the NPHS1 gene , whereas mutations in the NPHS2 gene are linked to non-Finnish steroid-resistant INS . In 20% of cases of non-Finnish CNS, Machuca et al were not able to identify the underlying genetic alteration .
In the present survey, positive extra-renal symptoms were reported in 36.4%, 19.2%, and 79.2% of patients with Finnish-type disease and non-Finnish-type without and with syndrome, respectively. Mental retardation (21.2%) was the most frequent extra-renal symptom in patients with Finnish-type disease; in patients with non-Finnish-type disease with syndrome, urogenital symptoms (54.2%), mental retardation (29.2%), and other (29.2%) were the most frequent extra-renal symptoms. The presence of urogenital symptoms in patients with non-Finnish-type disease with syndrome may be a useful characteristic for the diagnosis of Denys–Drash syndrome. In a study that evaluated 1655 patients with steroid-resistant nephrotic syndrome from 21 countries , extra-renal symptoms were reported in 17.3% of patients, with short stature (n=84, 5.1%) and mental retardation (n=65, 3.9%) being the most common extra-renal symptoms. A higher incidence of extra-renal symptoms was found in the present study compared with the previous study; however, this may be because of the methodological differences between the studies.
In the present study, steroids and immunosuppressants were used more frequently in patients with non-Finnish-type disease without syndrome compared with patients with Finnish-type disease and non-Finnish-type disease with syndrome, and complete remission was only reported among patients with non-Finnish-type disease without syndrome. Generally, patients with Finnish-type and non-Finnish-type with syndrome do not respond to steroids or immunosuppressants. The pathogenesis of Finnish-type CNS is non-immunological; thus, patients with this disease tend to be resistant to treatment with corticosteroids and immunosuppressive drugs . In contrast, patients with non-Finnish-type disease without syndrome are among the INS cases that respond to steroids or immunosuppressants. Interestingly, the present results indicate that most pediatric nephrologists in Japan are aware of such treatment outcomes, and that the patients in this sample were treated in accordance with the recommendations of the Japanese clinical practice guidelines for nephrotic syndrome .
Thrombosis and infection are known to be common complications of CNS patients . A single-center study conducted in Jordan reported 25 episodes of serious bacterial infections in 18 out of 30 infants with CNS, most of whom had Finnish-type disease . A retrospective study of 21 infants with Finnish-type CNS conducted in Finland reported 63 verified and 62 suspected episodes of sepsis . In the present study, thrombosis and infection were reported in all groups, but the frequency was particularly higher in patients with Finnish-type disease. The high frequency of infection among patients with Finnish-type disease in the present study is consistent with that reported previously in the Jordanian and Finnish studies [20,21].
The number of patients who underwent unilateral nephrectomy was higher than that of patients who underwent bilateral nephrectomy. The most common renal replacement therapy in all groups was peritoneal dialysis. Although there is currently no guideline for the management of CNS in Japan, unilateral nephrectomy is a more popular approach than bilateral nephrectomy. The main reason for this preference is that the management of patients after unilateral nephrectomy is easier than that after bilateral nephrectomy because dialysis for patients with anuria is more difficult. In a recent retrospective study conducted in Japan, the long-term outcome data from 14 Finnish-type CNS Japanese patients who underwent kidney transplantation showed satisfactory graft survival .
The Kaplan–Meier analysis in the present study showed a slower progression to end-stage kidney disease in patients with non-Finnish-type disease without syndrome. The reason may be that this group was the most responsive to treatment, considering that this was the only group that included patients who achieved complete remission in response to steroids or immunosuppressive agents.
The present study has some limitations, including those inherent to the observational/cross-sectional study design and those related to the use of questionnaires (incomplete/incorrect completion of survey forms). The response rate of the survey was 63.3%, which may have introduced bias or affected the accuracy of our estimates.
In conclusion, the present survey sheds light on the characteristics of children with CNS and INS in Japan. Among the most relevant findings, we observed that children with Finnish-type disease were diagnosed earlier than those with non-Finnish-type disease; the placenta was large mainly among those with Finnish-type disease; in patients with non-Finnish-type disease with syndrome, urogenital symptoms were the most frequent extra-renal symptoms; a high proportion of patients underwent genetic examination; and most patients underwent unilateral nephrectomy followed by peritoneal dialysis before renal transplantation. Ideally, all patients with CNS or INS should undergo genetic testing, which may allow a better evaluation of the distribution of these diseases and a better characterization of patients for early stage disease management. In the future, we plan to evaluate the long-term outcomes of CNS and INS.