In this retrospective descriptive cohort study, we report the evaluation of INS in children from a single tertiary center. Nephrotic syndrome is one of the most common glomerular disease in children showing a higher incidence in boys with a male:female ratio of 2:1 [1, 15]. Similarly, the male:female ratio was 1.8:1 in our study. We also found the ratio of the affected boys to that of girls decreased to 1.2:1 as the age of onset increased above 12 years. Gender disparity disappears by adolescence, making the incidence in adolescents and adults equal among males and females. This is also consistent with the lack of a significant effect of gender on steroid resistance, as seen in our results.
The most common age of INS at presentation is younger than 6 years in 70–80% of the children. There is an increasing trend in the incidence of SRNS with increasing age . In our study, the peak incidence of INS was at four years of age, with SRNS patients showing a higher median age than the patients with SSNS. Logistic regression analysis showed that older age was significantly related to SRNS. The late onset still appears to be one of the most important factors predicting steroid resistance.
On the basis of the International Study of Kidney Diseases in Children ISKDC), almost 80% of children diagnosed with NS entered remission within initial 4–8 weeks of CS therapy. Approximately 10–20% of children with NS do not enter remission . Similarly, 17.8% of our patients were SRNS. The characteristics of children with INS have changed over recent decades and it’s reported that the incidence of FSGS is increased in NS patients . However, we did not find any difference in terms of steroid resistance in patients with NS between decades of 1998–2008 and 2009–2018. The fact that there was no increase in SRNS patients in our study may be due to regional and ethnic differences or the fact that we are a tertiary care center that referral of SRNS patients are always high.
Hypertension and hematuria are not common findings in INS. Elevated systolic and diastolic blood pressures are initially present in 5–20% of the patients . We found hypertension in 13% of the patients being significantly higher in SRNS. Therefore, we suggest keeping in mind that hypertension is a remarkable finding for SRNS. However, we could not demonstrated hypertension as an independent predictive factor in our study.
Macroscopic hematuria occurs in 2–3% and microscopic hematuria in 20% of children with NS [18, 19]. None of our patients with SSNS was presented with macroscopic hematuria. Despite the limited number of patients, we may predict that the NS patients initially presented with macroscopic hematuria mostly are SRNS. We also found microscopic hematuria more frequently in SRNS patients and logistic regression analysis showed that microscopic hematuria was significantly related to steroid resistance.
Steroid resistance is an important risk factor for ESRD and less than 5% of children with SSNS progress to ESRD, inversely . None of our patients with SSNS had chronic kidney disease (CKD) but 25% of SRNS patients had CKD and also 71.4% of them reached ESRD drawing attention to this important issue.
Kidney histology provides an important contribution to the management of SRNS patients. The most common histopathological finding in SRNS is FSGS . Ibrahim-Seif and Pilania reported FSGS and MCD as the most common histopathological findings, respectively [21, 22]. Conversely, the most common histopathological finding was MPGN in a retrospective study including 392 Turkish children with NS and it was stated that it might be due to unidentified causes such as infectious agents or environmental factors that can trigger MPGN . In our study, the most common histopathological findings were FSGS, followed by MCD and MPGN respectively. Contrary to the observations published in recent years showing an increased incidence of FSGS in NS, we did not find an increase in the number of FSGS patients and SRNS patients between two decades in a homogeneous population of Caucasian children. Most of the studies reporting high FSGS frequency include patients of different ethnic origins which may effect the results [4, 5, 17]. However, increased incidence of FSGS was also reported in Caucasian children with INS . Further studies with larger numbers of children are still necessary to reach more accurate results about the change of the frequency of several histopathological subtypes by time.
Focal segmental glomerulosclerosis is not a disease but only a histopathological diagnosis. Patients with FSGS on biopsy may have mutations in COL4A3–5 genes and suggested to be classified and treated as Alport syndrome [25, 26]. Four of our patients with FSGS by light microscopy on biopsy diagnosed as Alport syndrome with electron microscopic findings and confirmed by genetic tests later. Our limited number of cases suggest that genetic–pathologic correlation improves diagnostic accuracy in FSGS. Besides, three of the patients who had a diagnosis of MPGN previously were re-diagnosed as C3 glomerulopathy by new insides to MPGN.
Children with NS may develop a number of life-threatening complications during their disease course, including venous thromboembolic disease. This complication arises in approximately 3% of childhood NS cases . Despite our center is a tertiary care center, we observed only one venous thromboembolic complication in our NS patients which is less then general. The incidence of deep vein thrombosis and pulmonary embolisms has been reported much lower in Asians, and this has been attributed to ethnic diversity and genetic background. [28, 29].
The most frequent and important adverse effects of CS therapy are Cushing-like appearance, obesity, hypertension, growth retardation, ophthalmologic disorders including posterior subcapsular cataracts and raised intraocular pressure, behavioral changes and osteoporosis . In our patients the most common side effects were Cushing-like appearance, osteopenia, obesity, and hypertension. In particular, bone mineral density may not be evaluated regularly in SSNS patients even those who had used long-term CS therapy. In our study, 18 of the 28 patients with low bone mineral density were SSNS patients who used CS longer than six months. We may suggest the evaluation of bone mineral density in patients who have received CS therapy longer than the standard protocol.
Our study has some limitations. The number of patients with SRNS and FSGS per 10-years periods between 1998 and 2018 was relatively small. We do not know whether there will be a difference in FSGS patients between the decades with a larger number of patients. Since our study includes a homogeneous population of Caucasian children, we do not know the trends of SRNS and FSGS in other ethnic groups. Because of the retrospective design of the study, some minor complications may not have been recorded in the medical files of the patients and triggers of the relapses been assessed. However, our study is important in terms of determining the factors that predict steroid resistance and stating that the frequency of SRNS and FSGS in 10-years periods is not different in a single tertiary center.
As a conclusion, the late onset is still an important marker for steroid resistance. The fact that microscopic hematuria was significantly related to steroid resistance and macroscopic hematuria was observed completely in SRNS patients gives a hint for potential steroid resistance at the beginning of the disease. In addition, hypertension should also be considered as an important finding in terms of steroid resistance. Focal segmental glomerulosclerosis is not a disease but a histopathological diagnosis leading to different entities. Alport syndrome should also be kept in mind in patients with FSGS to avoid potentially toxic effects of immunosuppressive treatment.