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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 1117-1124
A Modified Regimen of Methylprednisolone, Cyclophosphamide, and Mycophenolic Acid for Severe IgA Vasculitis with Nephritis in a Child

1 Department of Child Health, Faculty of Medicine, Universitas Indonesia – Cipto Mangunkusumo Hospital, Central Jakarta, Special Capital Region of Jakarta, Indonesia
2 Department of Pathology Anatomy, Faculty of Medicine, Universitas Indonesia – Cipto Mangunkusumo Hospital, Central Jakarta, Special Capital Region of Jakarta, Indonesia

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Date of Web Publication21-Nov-2020


IgA vasculitis with nephritis (IgAVN), which was formerly known as Henoch–Schonlein purpura nephritis, commonly manifests with mild symptoms. However, in rare circumstances, IgAVN in children can progress to kidney failure. Despite the successful treatment of severe IgAVN with a combination of immunosuppressive medications including corticosteroids, no consensus has been established for IgAVN treatment. Here, we present a case of severe IgAVN in an eight-year-old Indonesian boy who was treated with simultaneous methylprednisolone, cyclophosphamide, and mycophenolic acid. He experienced recovery of kidney function within one month, while proteinuria resolved in five months, and hematuria resolved within a year after treatment initiation. No recurrences were noted during the two-year follow-up. Although our immunosuppressive regimen may seem very potent, it was shown to have tolerable side effects and could be beneficial for kidney recovery. Importantly, they have also been shown to prevent progression to chronic kidney disease in children with severe IgAVN.

How to cite this article:
Pardede SO, Grace A, Saraswati M, Ambarsari CG. A Modified Regimen of Methylprednisolone, Cyclophosphamide, and Mycophenolic Acid for Severe IgA Vasculitis with Nephritis in a Child. Saudi J Kidney Dis Transpl 2020;31:1117-24

How to cite this URL:
Pardede SO, Grace A, Saraswati M, Ambarsari CG. A Modified Regimen of Methylprednisolone, Cyclophosphamide, and Mycophenolic Acid for Severe IgA Vasculitis with Nephritis in a Child. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2022 Aug 10];31:1117-24. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1117/301180

   Introduction Top

IgA vasculitis with nephritis (IgAVN), which was formerly known as Henoch–Schonlein purpura (HSP) nephritis, is found in 30%–50% of patients with IgA vasculitis (IgAV). This condition commonly presents with microscopic hematuria with or without mild proteinuria.[1] The pathophysiology of IgAV primarily involves IgA1 immune deposits in small vessels, and therefore, many believed that the term HSP should be changed to IgAV to more accurately reflect the basis of the disease.[2] Although the majority of IgAVN cases demonstrate mild symptoms, 20% of pediatric IgAVN patients present with nephritic or nephrotic syndrome, and 1%–7% of pediatric IgAVN patients progress to kidney failure, which is less common than that in adults.[1],[3]

The use of steroids in the early stages of disease remains controversial. However, successful treatment of severe IgAVN with a combination of immunosuppressive medications including corticosteroids has been reported. However, no consensus on the treatment of patients with IgAVN has been established.[3] Here, we present a case of severe IgAVN in a child treated with simultaneous methylprednisolone (MP), cyclophosphamide (CPA), and mycophenolic acid (MPA), which resulted in a good outcome, as demonstrated by the recovery of kidney function after one month, resolution of proteinuria in five months, and resolution of hematuria a year after treatment initiation. Furthermore, the patient has not experienced recurrence as of the two-year follow-up.

   Case Report Top

Written informed consent for the publication of this case report and accompanying images were obtained from the patients’ guardian and the copy of the written consent is available for review from the editor of this journal. Further institutional approval is not required to publish de-identified case information.

An eight-year-old Indonesian male presented to our tertiary referral hospital in October 2017 after experiencing generalized edema for two weeks. A month before (September 2017), he had palpable purpura on his legs, arms, cheeks, and ears [Figure 1], which was accompanied by moderate abdominal and joint pain. Upon admission to a local private hospital, he was normotensive, and all laboratory tests were normal except for an increased immunoglobulin A level, an elevated erythrocyte sedimentation rate, and microscopic hematuria [Table 1]. The examining general pediatrician prescribed 50 mg oral prednisolone daily (2 mg/kg BW/day).
Figure 1: Palpable purpura on his legs (a), arms (b), cheeks (c), and ears (d).

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Table 1: Initial laboratory results.

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Three weeks after the first presentation (September 2017), his mother noticed that gradually, he passed less urine that was dark red in color and that he had developed edema over his face and legs. He was then brought to another local private hospital where he was seen by a general pediatrician and underwent additional laboratory tests [Table 1], which revealed anemia, declining kidney function, hypoalbuminemia, proteinuria, and worsened hematuria. He was advised to see a pediatric nephrologist in a different city due to the lack of a nearby pediatric nephrology service.

On admission to our hospital (October 2017), he had high blood pressure (Grade II hypertension), generalized edema, moon face, and oliguria (diuresis 0.3 mL/kg/h). However, his purpuric lesions, abdominal pain, and joint pain were resolving. His laboratory results, as shown in [Table 1], showed that his anemia and hypoalbuminemia had worsened and that his kidney function had further impaired, which was related to acute kidney injury. Intravenous (i.v.) albumin 1 g/kgBW/day was given for two days. In addition, continuous i.v. furosemide, which was increased gradually until a dose of 0.5 mg/kgBW/h, was administered, which resulted in an improvement of edema and oliguria. A kidney biopsy was performed, and while awaiting the results, under the presumptive diagnosis of severe IgAVN, we promptly initiated MP pulse therapy (30 mg/kg/day, maximum 1000 mg/day) for three consecutive days per month, followed by 50 mg oral prednisolone (2 mg/kgBW/day).

The kidney biopsy revealed the appearance of mesangial proliferative glomerulonephritis, focal segmental glomerulosclerosis, and segmental hypercellularity; three glomerular crescents out of 33 glomeruli were visualized by light microscopy [Figure 2]. These results were consistent with the International Study of Kidney Disease in Children Class IIIa disease.[4] Immunofluorescence (IF) microscopy showed IgA (+3) and C3 (+3) deposits. However, inspection by electron microscopy (EM) could not be performed due to unavailability of an EM technician. This result supported a diagnosis of IgAVN.

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Considering the severity of kidney involvement, the presence of glomerular crescents, and persistent severe proteinuria, i.v. CPA pulse therapy was administered (500–1000 mg/m2). Previously, other centers reported i.v. MP pulse therapy for three consecutive days per week for three to four weeks.[5],[6] By contrast, we decided to administer i.v. MP pulse therapy over three consecutive days per month and continued with oral prednisolone 1.5 mg/kgBW/day on alternate days, considering the formation of striae as a significant side effect of high-dose steroids after the end of the 1st series of MP pulse initiation. In addition to the monthly i.v. MP pulse therapy, i.v. CPA was given every month for seven doses. He was also prescribed 5 mg oral ramipril as the antihypertensive medication and anti-proteinuric agent.

After he received two IV MP series and two doses of i.v. CPA, his kidney function normalized [estimated glomerular filtration rate (eGFR) 97.6 mL/min/1.73 m2], but the severe proteinuria persisted. Mycophenolate mofetil at a dose of 300–600 mg/m2 every 12 h was added (750 mg in the morning and 500 mg in the evening). He then experienced side effects of mycophenolate mofetil, namely nausea, bloating, and decreased appetite, which subsided by changing mycophenolate mofetil to mycophenolate sodium (Myfortic®) at a dose of 540 mg in the morning and 360 mg in the evening.

During his 4th regimen cycle, his urinary albumin-to-creatinine ratio (ACR) was 1,134.8 mg/g and his serum albumin was 25 g/L. His urine protein became negative and serum albumin level returned to normal after his 6th regimen cycle, although he still had microscopic hematuria. His blood pressure also normalized, but he continued ramipril treatment due to its antiproteinuric effect. At this point, we discontinued the oral prednisolone. He was noted to experience hair loss because the first i.v. CPA was given, which resolved one month after completion of all CPA cycles. His hematuria completely disappeared a year after disease onset, and thus, we discontinued the MPA. Two years following his treatment initiation, his laboratory results remain normal (eGFR 107 mL/min/1.73 m2, serum albumin 36.3 g/L, and urine ACR 10.1 mg/g) without symptom recurrence.

   Discussion Top

IgAV is commonly diagnosed in children and is included as a core competency in general pediatrics. However, when symptoms of further kidney involvement are observed, such as hypertension, edema, proteinuria, or gross hematuria, it is recommended that the patient be referred to a pediatric nephrologist.[7] Despite the possibility that IgAVN can resolve on its own, the prompt treatment IgAVN is recommended, particularly in patients with severe manifestations.[8] In this case, the pediatrician at the first and second hospitals made the correct decision in treating and referring the patient. To date, only less than 50 pediatric nephrologists practice in Indonesia, to serve the nation comprising more than 17,000 islands with a population of over 260 million people.[9]

The initial intervention by the first pediatrician was the prescription of oral prednisolone. However, the effectiveness of steroids in early-phase IgAVN to prevent the progression of kidney involvement is doubtful.[8],[10] Despite the adequate dose of oral prednisolone (2 mg/kg BW/day) given at early disease onset, his kidney involvement progressed significantly (eGFR of 107.4 mL/min/1.73 m2 to eGFR of 45.5 mL/min/1.73 m2 in 3 weeks). This is consistent with The Kidney Disease: Improving Global Outcomes (KDIGO) recommendation, which opposes the use of corticosteroids to prevent IgAVN in children.[10] Furthermore, long-term steroid use (>10 days) was shown to be a risk factor of IgAV recurrence in addition to kidney involvement (nephritis) in the first episode of IgAV.[11] The recurrence rate of IgAV is 16.3%, with an average time to the second episode of 9.21 months in 87.5% of patients.[11]

The disease course in each IgAVN patient is unpredictable, and therefore, a standard therapy for IgAVN in children has not been established. Pediatric nephrologists typically treat IgAVN with immunosuppressive agents, but there are a variety of potential medications, which range from corticosteroids, CPA, and cyclosporine to azathioprine, mycophenolate mofetil, and MPA.[8] Considerations for safety and long-term outcomes also contribute to a difficult decision-making process in pediatric IgAVN patients, especially those with severe manifestations. The recommendation by KDIGO is to treat crescentic nephritis if the percentage of glomerular crescents is >50%.[10] However, a recent meta-analysis stated that even a low-grade crescentic appearance could lead to unfavorable outcomes.[1] In addition, we have been encountering cases with significant clinical deterioration upon admission to the tertiary referral centers due to delayed diagnosis and treatment resulted in poor outcomes.[9],[12] For that reason, we propose prompt treatment of severe IgAVN in children.

A case report in 2013 showed successful treatment of severe IgAVN in a child using IV MP pulse therapy, i.v. CPA, and cocktail therapy (azathioprine, prednisolone, dipyridamole, and enalapril).[5] Unfortunately, azathioprine availability in Indonesia has been unsustainable and has only been provided by principal hospitals in major cities that offer chemotherapy. The shortages of essential medicines have been reported in other middle- and low-income countries including our center.[13]

In this case, we decided to administer i.v. MP pulse therapy over three consecutive days per month and tapered the oral prednisolone dose, considering the appearance of striae as a significant side effect of high-dose steroids. We then added i.v. CPA because of the patient's severe manifestations and the presence of glomerular crescents, which indicate a need for greater immunosuppression, especially because the steroid dose had already been reduced. Later, we added mycophenolate mofetil because his proteinuria persisted despite the addition of an angiotensin-converting enzyme inhibitor, which acted not only as an antihypertensive in this case, but also as an antiproteinuric agent. A study in Iran also reported successful treatment of IgAVN using mycophenolate mofetil, due to its inhibitory effects on lymphocyte and mesangial cell proliferation. In steroid-resistant IgAVN, mycophenolate mofetil seemed to improve the proteinuria.[14]

Although our combination of steroids, CPA, and mycophenolate mofetil may seem excessive, the patient did not develop significant side effects, such as bone marrow suppression, due to the CPA. However, he did experience gastrointestinal side effects from the mycophenolate mofetil, which were resolved by substituting MPA for mycophenolate mofetil. This combination of modified MP pulse therapy, i.v. CPA, and MPA could apparently be used to treat severe IgAVN in children, with consideration of its association with safety and long-term outcome.

In terms of a diagnostic tool, the kidney biopsy specimen in this case was divided into two parts for light microscopy and infrared examination. Although EM analysis is routinely performed on all native kidney biopsies in Western countries, in developing countries such as India, it is not readily accessible and is considered essential in only 20% of cases.[15] In contrast, although an EM unit is available at one of the public universities, Indonesia does not have an EM technician. The lack of diagnostic studies has been a challenge in our country; such a challenge also arises in diagnosing rare diseases, which require that specimens be sent overseas due to the unavailability of supporting laboratories.[12]

It is known that the course of IgAVN in each case is not identical, even when similar treatment is given. Our case demonstrated recovery of kidney function after one month, resolution of proteinuria and hypertension in five months, and resolution of hematuria within a year following treatment initiation. Another pediatric patient with IgAVN who was treated with i.v. MP pulse, i.v. CPA, and a cocktail therapy exhibited normal kidney function within 22 months and had no proteinuria in two months and no hematuria in four months. Unlike our case, this patient did not develop hypertension.[5] A corresponding case of pediatric IgAVN treated with mycophenolate mofetil also demonstrated a different progression than our case, that is, resolution of proteinuria in one month, recovery of kidney function and hematuria in five months, and no hypertension in ten months.[14] Consequently, the prognosis of IgAVN nephritis is unforeseeable and long-term follow-up is advised,[11] requiring patients’ and caregivers’ compliance, which can be problematic in Indonesia.[16] Fortunately, in this case, no recurrence has been noted in our patient as of the two-year follow-up.

To conclude, although simultaneous MP, CPA, and MPA may seem very potent, these drugs have tolerable side effects and can be beneficial for kidney recovery, and importantly, they can prevent progression of severe IgAVN to chronic kidney disease in children.

   Acknowledgment Top

We would like to thank ENAGO (http:// www.enago.com) for the careful reading and editing of this manuscript.

   Declaration of Patient Consent Top

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflict of interest: None declared.

   References Top

Shi D, Chan H, Yang X, et al. Risk factors associated with IgA vasculitis with nephritis (Henoch-Schönlein purpura nephritis) progressing to unfavorable outcomes: A meta-analysis. PLoS One 2019;14:e0223218.  Back to cited text no. 1
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1-1.  Back to cited text no. 2
Chen JY, Mao JH. Henoch-Schönlein purpura nephritis in children: Incidence, pathogenesis and management. World J Pediatr 2015;11:29- 34.  Back to cited text no. 3
Haas M. IgA Nephropathy and IgA Vasculitis (Henoch–Schönlein Purpura) Nephritis. In: Jennette JC, Olson JL, Silva FG, D’Agati VD, editors. Pathology of the Kidney. 7th ed. Philadelphia: Lippincott, Williams & Wilkins; 2015. p. 463-558.  Back to cited text no. 4
Kanai H, Kobayashi A, Matsushita K, Sawanobori E, Sugita K, Higashida K. Methylprednisolone pulse therapy and intravenous cyclophosphamide therapy combined with cocktail therapy in severe pediatric Henoch-Schönlein purpura nephritis patient. CEN Case Rep 2013;2:117-22.  Back to cited text no. 5
Kanai H, Sawanobori E, Kobayashi A, Matsushita K, Sugita K, Higashida K. Early treatment with methylprednisolone pulse therapy combined with tonsillectomy for heavy proteinuric Henoch-Schönlein purpura nephritis in children. Nephron Extra 2011;1:101-11.  Back to cited text no. 6
Christin NM. Identification, management of renal involvement important in Henoch-Schönlein purpura. Am Academy Pediat News 2014;35:11.  Back to cited text no. 7
Pohl M. Henoch-Schönlein purpura nephritis. Pediatr Nephrol 2015;30:245-52.  Back to cited text no. 8
Ambarsari CG, Trihono PP, Kadaristiana A, et al. Five-year experience of continuous ambulatory peritoneal dialysis in children: A single center experience in a developing country. Med J Indones 2019;28:329-37.  Back to cited text no. 9
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139- 274.  Back to cited text no. 10
Lei WT, Tsai PL, Chu SH, et al. Incidence and risk factors for recurrent Henoch-Schönlein purpura in children from a 16-year nationwide database. Pediatr Rheumatol Online J 2018; 16:25.  Back to cited text no. 11
Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: A case report. Ren Fail 2020;42:113-21.  Back to cited text no. 12
Ambarsari CG, Bermanshah EK, Putra MA, Rahman FH, Pardede SO. Effective management of peritoneal dialysis-associated hydrothorax in a child: A case report. Case Rep Nephrol Dial 2020;10:18-25.  Back to cited text no. 13
Nikibakhsh AA, Mahmoodzadeh H, Karamyyar M, Hejazi S, Noroozi M, Macooie AA. Treatment of severe Henoch-Schonlein purpura nephritis with mycophenolate mofetil. Saudi J Kidney Dis Transpl 2014;25:858-63.  Back to cited text no. 14
[PUBMED]  [Full text]  
Kurien AA, Larsen C, Rajapurkar M, Bonsib SM, Walker P. Lack of electron microscopy hinders correct renal biopsy diagnosis: A study from India. Ultrastruct Pathol 2016;40:14-7.  Back to cited text no. 15
Ambarsari CG, Rahman FH, Bermanshah EK, Kadaristiana A. An unusual case of peritoneal dialysis twisted catheter in a child. J Indon Med Assoc 2020;70:27-31.  Back to cited text no. 16

Correspondence Address:
Cahyani G Ambarsari
Department of Child Health, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital, Central Jakarta Special Capital Region of Jakarta
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.301180

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