Impact of COVID-19 on the clinical course of nephrotic syndrome in children: a single-center study

Article information

Child Kidney Dis. 2022;26(2):74-79
Publication date (electronic) : 2022 December 14
doi : https://doi.org/10.3339/ckd.22.035
1Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
2Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Republic of Korea
Correspondence to Min Hyun Cho Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Republic of Korea E-mail: chomh@knu.ac.kr
Received 2022 September 16; Revised 2022 October 29; Accepted 2022 October 31.

Abstract

Purpose

Children with nephrotic syndrome may experience disease relapse or aggravation triggered by various viral infections. Limited studies on the clinical implications of the coronavirus disease 2019 (COVID-19) pandemic in children with nephrotic syndrome have been published worldwide. Therefore, this study aimed to investigate the effects of COVID-19 on the clinical course of nephrotic syndrome in children.

Methods

The medical records of 59 patients with idiopathic nephrotic syndrome who visited our hospital between February and June 2022 were retrospectively analyzed.

Results

Twenty of the total 59 patients with nephrotic syndrome were diagnosed with COVID-19 during the study period. The mean age at the time of the diagnosis of nephrotic syndrome and COVID-19 in all 20 patients was 4.6±3.5 and 8.9±3.9 years, respectively. Three patients (15%) were diagnosed with nephrotic syndrome relapse during COVID-19 and the relapse rate was similar to them without COVID-19 (20.5%, 8/39 patients). At the time of the COVID-19 diagnosis, fever (85%) and cough (40%) were the most common symptoms. After the diagnosis of COVID-19, all patients showed improvement with symptomatic treatment, including antipyretic analgesics and cold medicine. None of the critical patients required hospitalization or oral antiviral medications.

Conclusions

Despite the use of immunosuppressants, the clinical manifestations of COVID-19 in children with nephrotic syndrome were not severe and are expected to be similar to that in the general population. The relapse rate of nephrotic syndrome in children with COVID-19 was also not different from them without COVID-19.

Introduction

Since its first outbreak in 2019, coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, affecting millions of people differently. South Korea has also been heavily affected by COVID-19, with 23.6 million confirmed cases and 27,149 deaths reported as of September 5, 2022. Among the total number of confirmed cases, 5.67 million cases were reported in children aged <19 years, accounting for 24% of the total cases, with 46 deaths, indicating that the severity of COVID-19 in pediatric patients was significantly lower than that in adults [1]. Several reports have described de novo kidney involvement and aggravation of underlying renal diseases due to COVID-19 or vaccination in adult patients [2-6]. Recently, cases of renal complications due to COVID-19 or vaccination have been reported in pediatric patients [7-9]; however, the clinical significance of COVID-19 in pediatric patients with kidney disease is unclear. In addition, although nephrotic syndrome relapse is closely related to various viral infections, there are limited studies on the clinical implications of the COVID-19 pandemic in pediatric patients with nephrotic syndrome. Therefore, this study aimed to investigate the effect of COVID-19 on the clinical course of nephrotic syndrome in children.

Methods

The medical records of pediatric patients with idiopathic nephrotic syndrome who visited our hospital between February and June 2022 were retrospectively analyzed. Patients aged <1 year and >19 years and those with inadequate medical records were excluded. Finally, total 59 patients (20 pediatric patients diagnosed with COVID-19 and 39 pediatric patients who did not have COVID-19) were included in the study. Relapse of the nephrotic syndrome within 2 weeks of COVID-19 was defined as a relapse caused by COVID-19. The diagnosis of COVID-19 was confirmed using real-time polymerase chain reaction or rapid antigen testing performed at a public health center hospital. Student t-test was performed to evaluate continuous variables. Statistical significance was set at a P-value of <0.05. All statistical analyses were conducted using the R software, version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

The baseline characteristics of 59 nephrotic syndrome patients who visited our hospital during the study period are as follows: mean age at the study period, 9.3±3.7 years; mean age at diagnosis of nephrotic syndrome, 4.8±3.1 years; male, 79.7%; steroid-sensitive nephrotic syndrome, 81.4% (Table 1).

Baseline characteristics of patients with nephrotic syndrome

Comparison of the group with and without COVID-19

Twenty of the total 59 patients with nephrotic syndrome were diagnosed with COVID-19 during the study period (Table 2). The mean age at the time of the diagnosis of nephrotic syndrome of 20 patients confirmed with COVID-19 during the study period was 4.6±3.5 years. Their mean age at the time of COVID-19 diagnosis was 8.9±3.9 years, and the mean period from the diagnosis of nephrotic syndrome to that of COVID-19 was 4.6 years. In study population, most COVID-19 cases occurred in April 2022, similar to the general trend of COVID-19 cases in South Korea (Fig. 1). The ratio of patients with steroid-sensitive nephrotic syndrome to those with steroid-resistant nephrotic syndrome was 14:6. All patients visited the hospital for regular follow-up within a month before contracting COVID-19, and the urinalysis results at that time showed no proteinuria. The drugs used for the treatment of nephrotic syndrome during COVID-19 included patients receiving corticosteroid therapy alone (n=5), cyclosporine therapy alone (n=4), corticosteroid and cyclosporine combination therapy (n=3), rituximab therapy within 1 year (n=3), tacrolimus therapy alone (n=1), and corticosteroid and tacrolimus combination therapy (n=1). The mean daily dose for patients receiving steroids was 0.7±0.6 mg/kg. The mean dose of tacrolimus was 0.05±0.01 mg/kg/day, while that of cyclosporine was 5.3±0.4 mg/kg/day. The rate of immunosuppressant use was significantly lower in patients without COVID-19 than in patients with COVID-19 (P<0.01). However, the other baseline characteristics were similar between the groups. At the time of COVID-19 diagnosis, fever (85%) and cough (40%) were the most common symptoms. Other symptoms, such as abdominal pain, diarrhea, and headache were also present. Two of the 20 patients (10%) diagnosed with COVID-19 were vaccinated before diagnosis. Three of the 20 patients with COVID-19 were treated with CD20 monoclonal antibody (rituximab) within 1 year before being diagnosed with COVID-19. In all of them, the administration effect was confirmed by measuring complete depletion of B cells (<1% of lymphocytes) immediately after CD20 monoclonal antibody (rituximab) therapy. However, because they were diagnosed with COVID-19 at the local medical centers and none of them experienced nephrotic syndrome relapse or severe COVID-19 clinical manifestations, they did not visit our hospital and recovered without antiviral medications. After the diagnosis of COVID-19, all 20 patients experienced improvement with symptomatic treatment, including antipyretic analgesics and cold medicine. None of the patients developed critical conditions requiring hospitalization or the administration of oral antiviral medications such as Paxlovid.

Comparison of clinical characteristics between the patients with and without COVID-19

Fig. 1.

Comparison of trends in the cumulative number of confirmed coronavirus disease 2019 (COVID-19) cases in South Korea and our study subjects by month. Data from: Korea Disease Control and Prevention Agency (September 5, 2022) [1].

Clinical characteristics of three patients relapsed during COVID-19

Three (15%) of the 20 patients with COVID-19 were diagnosed with nephrotic syndrome relapse while COVID-19 was ongoing (Table 3). Patients with nephrotic syndrome who visited our hospital during the study period but did not contract COVID-19 had a relapse rate of 20.5% (eight of 39 patients). All three patients diagnosed with nephrotic syndrome relapse complained of fever and abdominal pain during COVID-19, and none of the three patients diagnosed with nephrotic syndrome relapse during COVID-19 were vaccinated. One of the three patients diagnosed with nephrotic syndrome relapse during COVID-19 was not receiving immunosuppressants. Of the other two patients, one received steroids at a dose of 0.4 mg/kg/day, and the other received cyclosporine at a dose of 5.5 mg/kg/day. In these two patients, the dose of immunosuppressants was not higher than that in patients without relapse during COVID-19. All patients who relapsed during COVID-19 responded well to corticosteroid treatment at the time of relapse.

Clinical characteristics of three patients diagnosed with nephrotic syndrome relapse during the COVID-19 illness

Discussion

The number of COVID-19 cases in the pediatric age group was low during the early stages of the pandemic, but it gradually increased as the unprecedented COVID-19 pandemic continued to spread worldwide [10]. A systematic review published in Pediatric Pulmonology in 2020 reported that >50% of pediatric patients with COVID-19 complained of asymptomatic or mild symptoms, and approximately 1% of patients complained of critical clinical symptoms [11]. The most common symptoms were fever, cough, nasal symptoms, diarrhea, and nausea/vomiting [11-13]. COVID-19 may also cause various pulmonary, gastrointestinal, cardiovascular, neurological, and renal complications [11,14-16]. In addition to possibly increasing risks of new kidney disease, COVID-19 may also worsen the course of patients with underlying kidney disease. Acute kidney injury is an important complication of COVID-19, and several cases of acute tubulointerstitial nephritis and acute glomerulonephritis in pediatric patients have been reported [4,5]. Shah et al. [17] first reported on a new-onset nephrotic syndrome associated with COVID-19 in an 8-year-old boy, followed by Alvarado et al. [18], who reported on a case of COVID-19 associated with the onset of nephrotic syndrome in a 15-year-old boy. COVID-19 has various effects on the clinical courses of patients with underlying diseases. Recently, a number of reports related to nephrotic syndrome relapse have been published, with some focusing on pediatric patients. Moreover, the incidence of nephrotic syndrome relapse is increasing in children with upper respiratory tract infections. According to previous studies, at least 50% of nephrotic syndrome relapses are caused by upper respiratory tract infections [19,20]. The mechanism by which infection leads to nephrotic syndrome relapse is unclear, but it may be related to a non-specific host response, such as cytokine release in response to infection [20]. It has been hypothesized that infection-induced nephrotic syndrome relapse can be caused by podocytopathy based on the concepts of immune dysregulation and increased glomerular permeability [21]. In pediatric patients, the symptoms of COVID-19 vary, and the infection severity is not as high as that reported in adult patients [12,13]. The pediatric patients with nephrotic syndrome included in this study also had various symptoms, and all complained of only mild symptoms that improved spontaneously without hospital treatment. An original article published by Crane et al. [22] and a systematic review published by Morello et al. [23] found that pediatric nephrotic syndrome did not increase the severity of COVID-19 and that the relapse rate of nephrotic syndrome triggered by COVID-19 was low. In the present study, only three of the 20 patients (15%) were diagnosed with nephrotic syndrome relapse due to COVID-19, all of whom responded well to steroid treatment. The long-term use of immunosuppressive agents in pediatric patients with nephrotic syndrome did not adversely affect the severity of COVID-19, consistent with findings of previous studies [23-25]. The association between rituximab and COVID-19, which has a significant effect on immune response, also showed similar results. Recently, the frequency of rituximab administration is increasing for the treatment of pediatric nephrotic syndrome since the public health insurance benefits were applied in South Korea. Although there has been a substantial debate about the administration of rituximab in children concerning infection associated with the COVID-19 pandemic, several studies have demonstrated that rituximab has no significant effect on the incidence, clinical severity, or antibody production in pediatric patients with COVID-19 [26,27]. In the present study, four patients received rituximab treatment 4 to 9 months before the study period, none of whom were diagnosed with nephrotic syndrome relapse or other severe complications of COVID-19. Therefore, pediatric patients with nephrotic syndrome requiring immunosuppressive agents such as rituximab can receive treatment, even in the special situation of the COVID-19 pandemic.

However, this study has some limitations. First, the small number of included patients owing to the short observation period. Therefore, information on later complications could not be confirmed. Second, it cannot be ruled out that patients who were not diagnosed with COVID-19 during the study period had asymptomatic COVID-19. However, to the best of our knowledge, this study is the first study to report the clinical features of COVID-19 in Korean children with nephrotic syndrome. These findings provide valuable evidence for determining the clinical prognosis of pediatric patients with nephrotic syndrome diagnosed with COVID-19.

In conclusion, the clinical manifestations of COVID-19 in children with nephrotic syndrome were not severe in spite of receiving the immunosuppressant medications and are expected to be similar to that in the general population. Further, the relapse rate of nephrotic syndrome in children with COVID-19 was not different from them without COVID-19.

Notes

Ethical statements

This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki. This study was reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital (IRB No. 2022-09-006), which waived the need for written informed consent.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: MHC

Data curation: MJP, JKE

Formal analysis: MJP, JKE

Investigation: JKE

Methodology: MHC

Visualization: MJP

Writing-original draft: MJP, JKE

Writing-review & editing: HSB, MHC

All authors read and approved the final manuscript.

References

1. Korea Disease Control and Prevention Agency. Coronavirus (COVID-19) [Internet]. Cheongju: Korea Disease Control and Prevention Agency; c2022. [cited 2022 Sep 5]. Available from: http://ncov.mohw.go.kr/en/.
2. Lebedev L, Sapojnikov M, Wechsler A, Varadi-Levi R, Zamir D, Tobar A, et al. Minimal change disease following the Pfizer-BioNTech COVID-19 vaccine. Am J Kidney Dis 2021;78:142–5.
3. Klomjit N, Alexander MP, Fervenza FC, Zoghby Z, Garg A, Hogan MC, et al. COVID-19 vaccination and glomerulonephritis. Kidney Int Rep 2021;6:2969–78.
4. Kudose S, Batal I, Santoriello D, Xu K, Barasch J, Peleg Y, et al. Kidney biopsy findings in patients with COVID-19. J Am Soc Nephrol 2020;31:1959–68.
5. Batlle D, Soler MJ, Sparks MA, Hiremath S, South AM, Welling PA, et al. Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology. J Am Soc Nephrol 2020;31:1380–3.
6. Bomback AS, Kudose S, D’Agati VD. De novo and relapsing glomerular diseases after COVID-19 vaccination: what do we know so far? Am J Kidney Dis 2021;78:477–80.
7. Bjornstad EC, Krallman KA, Askenazi D, Zappitelli M, Goldstein SL, Basu RK, et al. Preliminary assessment of acute kidney injury in critically ill children associated with SARS-CoV-2 infection: a multicenter cross-sectional analysis. Clin J Am Soc Nephrol 2021;16:446–8.
8. Serafinelli J, Mastrangelo A, Morello W, Cerioni VF, Salim A, Nebuloni M, et al. Kidney involvement and histological findings in two pediatric COVID-19 patients. Pediatr Nephrol 2021;36:3789–93.
9. Hanna C, Herrera Hernandez LP, Bu L, Kizilbash S, Najera L, Rheault MN, et al. IgA nephropathy presenting as macroscopic hematuria in 2 pediatric patients after receiving the Pfizer COVID-19 vaccine. Kidney Int 2021;100:705–6.
10. Kim L, Whitaker M, O’Halloran A, Kambhampati A, Chai SJ, Reingold A, et al. Hospitalization rates and characteristics of children aged <18 years hospitalized with laboratory-confirmed COVID-19: COVID-NET, 14 States, March 1-July 25, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1081–8.
11. de Souza TH, Nadal JA, Nogueira RJ, Pereira RM, Brandao MB. Clinical manifestations of children with COVID-19: a systematic review. Pediatr Pulmonol 2020;55:1892–9.
12. Badal S, Thapa Bajgain K, Badal S, Thapa R, Bajgain BB, Santana MJ. Prevalence, clinical characteristics, and outcomes of pediatric COVID-19: a systematic review and meta-analysis. J Clin Virol 2021;135:104715.
13. Parcha V, Booker KS, Kalra R, Kuranz S, Berra L, Arora G, et al. A retrospective cohort study of 12,306 pediatric COVID-19 patients in the United States. Sci Rep 2021;11:10231.
14. Valverde I, Singh Y, Sanchez-de-Toledo J, Theocharis P, Chikermane A, Di Filippo S, et al. Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation 2021;143:21–32.
15. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017–32.
16. Basalely A, Gurusinghe S, Schneider J, Shah SS, Siegel LB, Pollack G, et al. Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19. Kidney Int 2021;100:138–45.
17. Shah SA, Carter HP. New-onset nephrotic syndrome in a child associated with COVID-19 infection. Front Pediatr 2020;8:471.
18. Alvarado A, Franceschi G, Resplandor E, Sumba J, Orta N. COVID-19 associated with onset nephrotic syndrome in a pediatric patient: coincidence or related conditions? Pediatr Nephrol 2021;36:205–7.
19. MacDonald NE, Wolfish N, McLaine P, Phipps P, Rossier E. Role of respiratory viruses in exacerbations of primary nephrotic syndrome. J Pediatr 1986;108:378–82.
20. Uwaezuoke SN. Steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis. Ital J Pediatr 2015;41:19.
21. Zhang H, Wang Z, Dong L, Guo Y, Wu J, Zhai S. New insight into the pathogenesis of minimal change nephrotic syndrome: role of the persistence of respiratory tract virus in immune disorders. Autoimmun Rev 2016;15:632–7.
22. Crane C, Bakhoum C, Ingulli E. Rates of idiopathic childhood nephrotic syndrome relapse are lower during the COVID-19 pandemic. Pediatr Nephrol 2022;37:2679–85.
23. Morello W, Vianello FA, Proverbio E, Peruzzi L, Pasini A, Montini G. COVID-19 and idiopathic nephrotic syndrome in children: systematic review of the literature and recommendations from a highly affected area. Pediatr Nephrol 2022;37:757–64.
24. Angeletti A, Drovandi S, Sanguineri F, Santaniello M, Ferrando G, Forno R, et al. COVID-19 in children with nephrotic syndrome on anti-CD20 chronic immunosuppression. Clin J Am Soc Nephrol 2020;15:1494–5.
25. Marlais M, Wlodkowski T, Al-Akash S, Ananin P, Bandi VK, Baudouin V, et al. COVID-19 in children treated with immunosuppressive medication for kidney diseases. Arch Dis Child 2020;106:798–801.
26. Sinha R, Marlais M, Sarkar S, Obukhova V, Lucchetti L, Vasudevan A, et al. Impact of COVID-19 pandemic on use of rituximab among children with difficult nephrotic syndrome. Pediatr Res 2022;92:3–5.
27. Angeletti A, Bruschi M, Bigatti C, Palmeri S, Lugani F, Verrina E, et al. An update on COVID-19 in paediatric and young adults with nephrotic syndrome, receiving chronic immunosuppression during the Omicron pandemic. J Nephrol 2022;35:1775–6.

Article information Continued

Fig. 1.

Comparison of trends in the cumulative number of confirmed coronavirus disease 2019 (COVID-19) cases in South Korea and our study subjects by month. Data from: Korea Disease Control and Prevention Agency (September 5, 2022) [1].

Table 1.

Baseline characteristics of patients with nephrotic syndrome

Characteristic Value (n=59)
Age at the study period (yr) 9.3±3.7
Age at diagnosis of nephrotic syndrome (yr) 4.8±3.1
Male sex 47 (79.7)
SSNS:SRNS 48:11
Frequent relapse 31 (52.5)
Perform a renal biopsy 14 (23.7)
 Minimal change disease 11
 Focal segmental glomerulosclerosis 3

Values are presented as mean±standard deviation or number (%).

SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome.

Table 2.

Comparison of clinical characteristics between the patients with and without COVID-19

Characteristic COVID-19 (+) COVID-19 (–) P-value
No. of patients 20 39
Male sex 17 (85.0) 30 (76.9) 0.47
Age at diagnosis of NS (yr) 4.6±3.5 4.9±2.9 0.71
Age at the study period (yr) 8.9±3.9 9.5±3.6 0.62
SSNS:SRNS 14:6 34:5 0.11
Frequent relapse 11 (55.0) 20 (51.3) 0.79
Performed renal biopsy 5 (25.0) 9 (23.1) 0.87
 Minimal change disease 3 8
 Focal segmental glomerulosclerosis 2 1
History of relapse triggered by URI 13 (65.0) 22 (56.4) 0.52
eGFR at the study period (mL/min/1.73 m2) 117.3±21.9 126.2±20.0 0.12
Period from the diagnosis of NS to study (yr) 4.6±3.1 4.4±3.6 0.83
Drugs being taken at the study period
 Corticosteroid alone 5 (25.0) 3 (7.7)
 Cyclosporine alone 4 (20.0) 8 (20.5)
 Corticosteroid + cyclosporine 3 (15.0) 0
 Tacrolimus alone 1 (5.0) 1 (2.6)
 Corticosteroid + tacrolimus 1 (5.0) 0
 Mycophenolate mofetil + tacrolimus 0 1 (2.6)
 Rituximab (within 1 yr) 3 (15.0) 5 (12.8)
 Rituximab (within 1 yr) + corticosteroid 0 1 (2.6)
 None 3 (15.0) 20 (51.3) <0.01
Patient number with NS relapse during study period 3 (15.0) 8 (20.5) 0.61

Values are presented as number (%) or mean±standard deviation.

COVID-19, coronavirus disease 2019; NS, nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; URI, upper respiratory infection; eGFR, estimated glomerular filtration rate.

Table 3.

Clinical characteristics of three patients diagnosed with nephrotic syndrome relapse during the COVID-19 illness

Characteristic Patient 1 Patient 2 Patient 3
Sex Male Male Female
Age at diagnosis of NS (yr) 3.0 3.3 4.5
Age at the time of COVID-19 (yr) 5.7 10.5 7.8
Steroid responsiveness Steroid-resistant Steroid-sensitive Steroid-sensitive
Frequent relapse No Yes No
Performed renal biopsy (result) No Yes (MCD) No
History of relapse triggered by URI No Yes Yes
Duration from the diagnosis of NS to COVID-19 (yr) 2.7 7.2 3.3
Drug being taken at the time of COVID-19 (dose, mg/kg/day) Cyclosporine (5.5) Corticosteroid (0.4) None
Duration from diagnosed COVID-19 to relapse (day) 5 3 0
Time to remission (day) 9 6 12
Follow-up period after remission (mo) 4 2 4
Relapse during follow-up after remission None None None

COVID-19, coronavirus disease 2019; NS, nephrotic syndrome; URI, upper respiratory infection; MCD, minimal change disease.