Immunosuppressive Therapy of Pediatric Lupus Nephritis

 

Aulia Rahmawati Yulistiani*, Risky Vitria Prasetyo, Evi Octavia

Department of Clinical Pharmacy, Universitas Airlangga, Surabaya, Indonesia

*Corresponding Author E-mail: yulistianiy40@gmail.com

 

ABSTRACT:

Lupus nephritis is a disease caused by severe complications of Systemic Lupus Erythematosus which attacks the kidneys. Therapy that is usually given to lupus nephritis patients is immunosuppressants. To determine the pattern of immunosuppressive therapy in pediatric lupus nephritis, the effectiveness and drug interactions that can be generated from these therapies. This study was an observational study with a retrospective method by observing patients’ medical record. This study populations were all pediatric patients ≤18 years old who were diagnosed with late onset of lupus nephritis, being hospitalized at Surabaya Hospital and had an immunosuppressive therapy history. There were 30 patients who met the inclusion criteria in this study. The sample collecting used a purposive sampling technique. The research instrument in this study was the medical record of department of pediatric in hospital of east Indonesia, Namely Dr. Soetomo. From the medical record data, we obtained information regarding the pattern of immunosuppressants administration including dosage, route, frequency of therapy, drug side effects, and drug interactions of immunosuppressive therapy. All patients received Methyl Prednisolone (MP) pulse IV, oral prednisone and Cyclophosphamide (CPA) pulse IV, oral mycophenolatmophetil (MMF), and chloroquine. The individual dosage of treatment was determined according to patients’ individual conditions. Side effects of corticosteroid use were digestive tract disorders in 20% of  patients, hyperglycemia in 10% of patients, hypertension in 67% of patients, and cushingsyndrome in 27% of patients. The side effects of using CPA were leukopenia in 7% of patients, Hepatotoxic in 3% of patients, and cystitishaemorrhage in 47% of patients. Side effects of using MMF were digestive tract disorders in 10% patients and leukopenia in 17% of patients. Drug interactions that found were prednisone-furosemide interactions in 60% of patients, prednisone-metformin in 10% of patients, and cyclophosphamide-allupurinol in 50% of patients. Dosage, route, and frequency of therapy for LN patients in Dr. Soetomo hospital was in accordance with the recommendations of the Clinical Practice Guide which was used as a reference in Dr. Soetomo hospital and several literatures. However, there were some patients with special conditions that requireda dosage adjustment of medication. In addition, it was necessary to monitor patients periodically for the possibility of side effects and drug interactions of immunosuppressive therapy.

 

KEYWORDS: Imunosuppressant, Lupus Nephritis.

 

 


INTRODUCTION:

Lupus nephritis (LN) is a disease caused by severe complications of Systemic Lupus Erythematosus (SLE) associated with kidney1. SLE is a broad spectrum autoimmune disease that can attack many organs and tissues of the body2.

 

SLE has characteristics of several reactive autoantibodies that cause immune complexes and when it is deposited in the kidneys will cause lupus nephritis3. The cause of SLE is multifactorial. One of the dominant factors is genentic factorof immune system abnormalities due to triggered by endogenous and exogenous factors. Thus, there is a formation of pathogenic antibodies that attack themselves.4,5 In SLE patients, the cases of kidney disorders occur in 50% to 75% of patients and most common at the age of 11 and 12 years (rarely under 5 years)6. Lupus nephritis in children with SLE symptoms is more serious, high morbidity, and lower survival rate than adult patients7. Therefore, it needs faster and more appropriate treatment in terms of drug therapy in pediatric lupus nephritis patients.

 

Lupus nephritis can be treated with immunosuppressive therapy. This therapy aims to control symptoms, protect kidney function, reduce kidney flares, prevent complications, and the most important is to reduce mortality8. In addition, this therapy can regulate the immune system. The working mechanism of immunosuppressants is to suppress the immune response. Because in autoimmune diseases there is sensitization of the immune system by endogenous proteins and considers it to be a foreign protein. So it stimulates the antibodies formation or T cells development that can react with endogenous antigens.

 

Immunosuppressive therapy is divided into two phases, namely the induction phase and the maintenance phase. The induction phase aims to control disease activity by inducing remission of disease recurrence. This therapy phase is given if the disease is life threatening, so patients need an aggressive therapy. While the maintenance phase aims to reduce the long-term risk of flares, reduce inflammation, and prevent further kidney damage.6 In the maintenance phase, immunosuppressant drugs commonly used are mycophenolatmofetil (MMF), azathioprine (AZA), and corticosteroids. Other drugs such as calcineurin inhibitors (cyclosporine, tacrolimus) can be used in special circumstances such as cases of mycophenolatmofetil intolerance (MMF) or azatioprine (AZA) or in patients with severe proteinuria2.

 

However, the administration of other immunosuppressants and glucocorticoids in children give several side effects. The side effects of glucocorticoids are predominantly dominated by genetic mechanisms and depend on the time and dosage of administration. In addition, cyclophosphamide (CYC) with large dosage can cause recycomyelosuppressive disorders, lymphoproliferative disorders, malignancy, pancytopenia, hemorrhagiccystitis, and secondary infertility. in the gastrointestinal (diarrhea, nausea and vomiting) and hematology (leucopenia, red cell aplasia) and also increases the risk of cytomegalovirus (CMV) infection dan leucoencepalopathy multifocal progressive 11.

 

Azatioprin (AZA) can cause bone marrow suppression, including leukopenia (often), thrombocytopenia (rare) and/or anemia (unusual). In addition, Azathioprine can also cause infectious susceptibility (specifically varicella and herpes simplex virus), hepatotoxicity, alopecia, GI toxicity, pancreatitis, and increased risk of resonoplasia11.

 

 

In addition, the treatment given to LN depends on the severity of the disease. Class I and II of LN patients generally have a good prognosis and rarely require aggressive therapy3. Class I and II of LN patients with proteinuria ≥0.5g/day do not need direct immunosuppressive therapy. They are given a maintenance therapy by controlling blood pressure and blocking the angiotensin aldosterone reninsystem12,13. Meanwhile, Lupus Nephritis that progressed to class III and IV has more serious manifestations. Thus, patients need more aggressive immunosuppressive therapy to prevent damage to kidney function and minimize morbidity and mortality3.

 

Based on these statements above it can be concluded that lupus nephritis in pediatric patients has high mortality and morbidity, so that appropriate therapeutic considerations which not affecting the child's growth period are needed. In selection of immunosuppressants, it needs an evaluation of the benefits of therapy and the risks of long-term use due to the high risk of therapeutic side effects14. Therefore, this study focused on the use of immunosuppressants in children with lupus nephritis. The purpose of this study was to determine the pattern of immunosuppressive therapy in pediatric Lupus Nephritis patients, the side effects and drug interactions from these therapies.

 

MATERIAL AND METHODS:

Methods:

This study was an observational with retrospective study. Data collection was conducted retrospectively, then analyzed descriptively. In this study, we did not give treatment or intervention to the sample.

 

Population and Sample:

The population in this study were all pediatric patients diagnosed with lupus nephritis who were hospitalized at the department of pediatric in Dr. Soetomo hospital Surabaya. The samples in this study were 30 patients that met the inclusion criteria in the period of January 2016 - December 2016. The sample collection used the purposive sampling method

 

Sample Inclusion Criteria:

The inclusion criteria in this study were pediatric patients with a final diagnosis of lupus nephritis with or without complications who received immunosuppressive therapy, with complete data related to dosage, route of administration, and frequency of administration in the department of pediatric of Dr. Soetomo Hospital.

 

Location and time of research:

The study was conducted at department of pediatric of Dr. Soetomo Hospital Surabaya. The data collection of patient medical record data was conducted in April - June 2017.

 

Research Instrument:

This study used secondary data. The research instrument in this study was the medical record data of the department of pediatricin Dr. Soetomo Hospital for patients with lupus nephritis who were hospitalized in January 2016 - December 2016. From the medical record data, then information regarding the dosage, route, and frequency of immunosuppressant therapy, drug side effects and drug interactions caused by immunosuppressant therapy were reviewed. From these data, we can determine the pattern of immunosuppressive therapy in pediatric lupus nephritis patients with side effects and drug interactions.

 

RESULTS:

Clinical Manifestations and Lab Data Related to Lupus Nephritis Patients:

Clinical manifestations can be identified from the patients’ complaints. The results showed that the patients' clinical manifestations varied. There were 18 patients experienced swelling. There were 18 patients who had hematuria.

 

Other clinical manifestations that commonly found and the presence of SLE were found in 14 patients. 11 patients experienced a joint pain. There were also 5 patients who had a malar rash and 8 patients had a discoid rash. There were 6 patients experienced oral ulcers. 4 patients experienced seizures and 2 patients experienced photosensitivity. These manifestations were clinical manifestations in SLE that triggered from immune complex deposits in other organs.

 

In addition, based on the patient's laboratory data, 19 patients had low Hb values (anemia). There were 11 patients with GFR ≤ 90ml/minute. In addition, there were 10 patients with low C3 titers. There were 7 patients with positive ANA titers and there were 3 patients with positive anti ds-DNA titers. There were also 12 patients who experienced proteinuria and 11 patients had hypertension.

 

Immunosuppressant Therapy Profile:

The use of immunosuppressive treatment of pediatric lupus nephritis is to suppress immune system dysregulation. This is because in autoimmune diseases there is an abnormality of the immune system which causes the formation of pathogenic antibodies that attack themselves. The therapy regimen for pediatric lupus nephritic patients was accordance to the "Clinical Practice Guide" of Surabaya Hospitals by 2014. Immunosuppressants used are corticosteroids, cyclophosphamide, mycophenolatmofetil, and chloroquine. Results showed that the distribution of the use of immunosuppressant types in patients with pediatric lupus nephritis varied. There were 30 patients who were given MP Pulse IV, Oral Prednisone, and Cyclophosfamid Pelve IV. Some Oral MMFs are only given to 5 patients. While Chloroquine was given to 29 patients.

 

Profile of Immunosuppressant Use Regarding dosage and condition in Lupus Nephritis patients:

There are two patterns of immunosuspension therapy in pediatric lupus nephritis patients. Method I patients were given MP, C, and CPA. In method I, treatment consists of 2 phases. The induction phase was carried out for 6 months. There were 25 patients who received treatment at this phase. During the induction phase, patients are given MP Pulse IV at a dosage of 10-30mg/kg/day for 3 days each month. In addition, patients are also given Oral Prednisone 0.5-1mg/kg/day every day after being given MP Pulse. Patients are also given a CPA Pulse IV at a dosage of 500-1000mg/m2 after being given MP Pulse. Every day, patients are also given Oral Chloroquine at a dosage of 3mg/kg/day.

 

The next phase in method I is the maintenance phase. This phase was carried out for 24 months. The results showed that there were 17 patients who could reach this phase. In this phase, patients are given Oral Prednisone at a dosage of 0.5-1mg/kg/day every day. In addition, patients are also given a CPA Pulse IV at a dosage of 500-1000mg/m2 every 3 months. In this phase, patients are also given Oral Chloroquine at a dosage of 3mg/kg/ day every day.

 

Another method for immunosuppressive therapy is method II. The results showed that there were only 5 patients who got this treatment. Similar to method I, there are also two phases in method II. The first phase is the induction phase. This phase lasts for 6 months. Unlike method I, in method II, patients are given MP, P, and MMF. In this phase, patients are given MP Pulse IV at a dosage of 10-30mg/kg/ day for 3 days each month. Patients are also given Oral Prednisone at a dosage of 0.5-1mg/kg/day every day after being given MP Pulse. In addition, patients are also given Oral MMF at a dosage of 15-23mg/kg daily. In this phase, patients are also given Oral Chloroquine 3mg/kg/day every day.

 

The next phase in method II is the maintenance phase. The results showed that there was only 1 patient who can reach this phase. In this phase, patients are given Oral Prednisone at a dosage of 0.5-1mg/kg/day every day. Patients are also given a CPA Pulse IV at a dosage of 500-1000mg/m2 every 3 months. In addition, patients are also given Oral MMF at a dosage of 15-23mg/kg/ day every day. Patients are also given Oral Chloroquine at a dosage of 3mg/kg/day every day. As for LN patients who relapse in the middle of administration of therapy protocol, a reinduction phase will be carried out, but it will be repeated starting from the beginning of the induction phase in each method. The profile of immunosuppressants use related to dosage and conditions in pediatric lupus nephritis patients can be seen in Table 1.

 

 

Table 1 Profile of the Use of Immunosuppressants Related to Dosage and Conditions in Pediatric Lupus Nephritis Patients

Patient Number/ BW/BH/

LP

Initial Contidion of Patient

 

 

Dosage are given

Urine

Blood

MP

PulseIV

CPA

PulseIV

Klorokuin Oral

Prednison Oral

1

15 kg

100 cm

0,628 m2

Erit (+)

Prot

(+1)

Hb 12,4

GFR 26

GDA 80

C345,2

ANA22

375 mg

350 mg

1 x 50 mg

Morning 6 tablet

(Gradually reduced)

2

17 kg

105cm

0,7m2

 

Erit (+2)

Prot (low)

Hb 10

GFR 23 HD GDA109

C398,2

ANA22

 

 

450 mg

 

 

500 mg

 

 

1 x 50 mg

 

Morning 3 tablet (Gradually reduced)

3

18 kg

101cm

0,69m2

 

Erit (+1)

Prot (+3)

Hb 8,2

GFR 3,3 HD ANA10

C363,1

Anti ds-DNA 51

 

 

450 mg

 

 

450 mg

 

 

1 x 60 mg

 

Morning 3 tablet (Gradually reduced)

4

20 kg

116 cm

0,802 m2

Erit(-)

Prot(-)

Hb 9,2

GFR 120

C3 33

 

600 mg

 

500 mg

 

1 x 60 mg

Morning 4 tablet (Gradually reduced)

5

21 kg

117 cm

0,682 m2

Erit (+3)

Prot (+2)

Bil (+2)

Ket(+1)

Glu(+1)

Hb 8,2

GFR 71,5

C3 25

500 mg

350 mg

1 x 75 mg

Morning 4 tablet

(Gradually reduced)

6

22 kg

120cm

0,85m2

Prot(+3)

Erit(+3)

Hb 9

GFR 13,4

HD

Anti ds- DNA

157,57

ANA 4,49

 

750 mg

 

500 mg

 

1 x 75 mg

Morning 5 tablet (Gradually reduced)

7

24 kg

127cm

0,93m2

Prot (-) Erit (+2)

Hb 12,2

GFR 122

ANA 40

,37

C3 139

 

250 mg

 

450 mg

 

1 x 75 mg

Morning 4 tablet (Gradually reduced)

8

25 kg

113cm

0,85m2

Prot (+3)

Eri (+2)

Hb 12

GFR 107

 

500 mg

 

450 mg

 

-

Morning 5 tablet (Gradually reduced)

9

26 kg

132 cm

0,976 m2

Prot (+3)

Hb 10,5

GFR 161

C3 27,4

Anti ds-

DNA 1171

 

750 mg

 

500 mg

 

1 x 75 mg

Morning 5 tablet (gradually reduced)

10

28 kg

135 cm

1 m2

 

 

Prot(-)

Erit(-)

Hb 12,5

GFR 123

C3 116

ANA 112

Anti ds- DNA 39

 

 

750 mg

 

 

500 mg

 

 

1 x 100 mg

 

Morning 6 tablet (Gradually reduced)

11

28 kg

127cm

1,01m2

Prot

(+1)

Erit (-)

Hb 9,9

GFR 97

Anti

dsDNA

30,03

C3 98,2

ANA 49,5

 

 

500

mg

 

 

600

mg

1 x 80 mg

 

 

Morning 11 tablet (Gradually reduced)

12

29 kg

133cm

1,03m2

 

Prot(+3)

Erit (+2)

Hb 8,5

GFR50

GDA89

C3 85

 

1000mg

 

600mg

 

1 x 100mg

 

Morning 8 tablet (Gradually reduced)

13

30 kg

138cm

1,07m2

 

Prot (-) Erit (+)

Hb 11,7

GFR 151,8

C3 42,7

 

375mg

 

550mg

 

1 x 120mg

 

Morning 6 tablet (Gradually reduced)

14

31 kg

129 cm

1,05 m2

Prot(-)

Erit(-)

Hb 12

GFR 97

750mg

500mg

 

1 x 90 mg

Morning 6 tablet (Gradually reduced)

15

43 kg

157cm

1,39m2

 

 

Erit(-)

Prot(-)

Hb 13,2

GDA 90

GFR 101

Anti dsDNA1051

C3 24,6

ANA 508

 

 

1000mg

 

 

650mg

 

 

1 x 120mg

 

 

Morning 8 tablet (Gradually reduced)

16

33 kg

149cm

1,18m2

 

Prot(+3)

Erit (+2)

Hb 11,2

GFR 33

GDA 155

Anti dsDNA537,72

C3 33,3

ANA 267

 

 

1000mg

 

 

590mg

 

 

1 x 100mg

 

 

Morning 12 tablet (Gradually reduced)

17

34 kg

140cm

1,15m2

 

Prot(+3)

Erit (+)

Hb 8,84

GFR 154

C3 107

ANA 169

Anti ds- DNA 74

 

 

1000mg

 

 

500mg

 

 

1 x 100mg

 

 

Morning 7 tablet (Gradually reduced)

18

36 kg

150cm

1,25m2

 

Prot(+2)

Erit (+1)

Hb6,1

GFR7

GDA 119

HD

 

1000mg

 

600mg

 

1 x 100mg

 

Morning 7 tablet (Gradually reduced)

19

 

37 kg

123cm

1,09m2

Prot (low) Erit (+2)

Hb 13,6

GFR 150

C3 103

ANA 33,36

750mg

600mg

1 x 140mg

Morning 8 tablet (Gradually reduced)

20

40 kg

150 cm

1,291m2

 

Prot(+1)

Erit (+1)

Hb 8,6

GFR 21,7

HD

C3 174

ANA 5,01

1000mg

700mg

1 x 140mg

 

Morning 9 tablet (Gradually reduced)

21

41 kg

155cm

1,34m2

Prot

(+2)

Erit (+)

Hb 10

GFR 108

ANA 13

 

1000mg

 

670mg

 

1 x 125mg

Morning 8 tablet

(Gradually reduced)

22

43 kg

153cm

0,25m2

 

Prot(+2)

Erit (+2)

 

Hb 9,3

GFR 194 ANA (+)

 

1000mg

 

700mg

 

1 x 150mg

 

Morning 9 tablet (Gradually reduced)

23

44 kg

144cm

1,3m2

 

Prot(+3)

Erit (-)

Hb10,7

GFR80

ANA 30,9

Anti dsDNA208

 

 

1000mg

 

 

725mg

 

 

1 x 125mg

 

Morning 8 tablet (Gradually reduced)

24

46 kg

157cm

2,03m2

Prot

(+4)

Erit (+3)

Hb 11,4

GFR 20,2

HD

C3 85,9 ANA 11,94

Anti dsDNA 38

 

 

1000mg

 

 

1000mg

 

 

1 x 150mg

 

Morning 9 tablet (Gradually reduced)

25

50 kg

145cm

1,4m2

Prot(+4)

Erit (+2)

Hb 16,5

GDA109

GFR89,6

C3 129 ANA 12,54

 

750mg

 

700mg

 

1 x 125mg

 

Morning 12 tablet (Gradually reduced)


Profile of Oral Prednisone Usage:

The use of oral prednisone is after the patient has metilprednisolonpulse IV. This treatment was for maintenance, so that a recurrence does not occur. Oral prednisone is given every day and tappering off is performed to prevent withdrawal of effects from steroids. Oral administration of Prednisone begins with a dosage of 0.5-1mg/kg/day. Then, the dosage is reduced gradually 5mg/day within 1 month after MP pulse administration and depends on disease activity.

 

Profile of Mycophenolate Mophetil Oral Usage:

Mycophenolatmofetil (MMF) is an alternative drug to replace CPA pulse when induction therapy is carried out. Based on the research that has been done, MMF has the same effectiveness as CPA pulse in the induction phase and lower side effects compared to CPApulse15. The administration of MMF starts with MP pulses at a dosage of 600mg/m2/dosage every 12 hours. The maximum dosage is 1 g every 12 hours. MMF is given to patients every day.

 

Profile of other drug therapies:

The use of other drugs is given to deal with comorbid diseases and for supportive therapy in pediatric lupusnefritis patients. Other drugs given consist of several types of drugs. The types of drugs are Captopril, Lisinopril, Amlodipine, Nifedipine, Losartan, Furosemide, KSR, Calcium Lactate (Calc), Ceftriaxone, Ampicilin, Paracetamol, Metformin, and Allupurinol.

 

Immunosuppressant Side Effects Profile:

Side effects are a drug problem that is often experienced by patients with pediatric lupus nephritis who get immunosuppressivet therapy. Immunosuppressants side effects are seen from clinical data or laboratory data after the drug administration. However, not all data was written in the medical record. The long-term effectiveness of corticosteroids such as adrenal suppression and growth restriction cannot be observed because it requires considerable time of observation and other supporting instruments and/or examinations. All side effects that occur can overlap with the activity of lupusnefritis. So that further research on side effects is needed. The results showed that side effects due to Methylprednisolone or Prednisone were 6 patients who had GI disorder (gastric irritation, pepticulcer, pancreatitis). There were 3 patients experiencing hyperglycemia. There were 20 patients experiencing hypertension. And there were 8 patients experiencing Cushing 's syndrome (moonface).

 

The side effects due to Cyclophosphamide were 2 patients experiencing Leukopenia. There were 3 patients experiencing Hepatotoxicity. There were 14 patients experiencing Cystitishaemorrhage. While the side effects due to mycophenolatophyte were 3 patients experiencing gastrointestinal disorder (nausea, vomiting, diarrhea) and there were 5 patients experiencing Leukopenia.

 

Profile of Potential Drug Interactions:

Patients with pediatric lupus nephritis who have an underlying disease need drug therapy other than immunosuppressants to improve their life quality. The results showed that there were 18 patients who were given Prednisone-Jurosemide drug therapy. The mechanism of the drug interaction is synergism, pharmacodynamics, causing the loss of the caliphia (recikohipokalemia). In addition, there were 3 patients who were given Prednisone – Metformin drug therapy. The mechanism of drug interactions is the effect of antidiabetic decrease due to corticosteroids which cause hyperglycemia. There were also 15 patients given cyclophosphamide-Allupurinol drug therapy. The mechanism of the drug interaction is Allupurinol which decreases metabolism of cyclophosphamide. Thus, cadcarcophosphorus increases.

 

Profile of Outcome Therapy:

The results showed that 19 patients had decreased urinary erythrocytes. There were 23 patients experiencing a decrease in urine protein. There were 7 patients experiencing decreased urine sediment. There were 26 patients experiencing an increase in GFR. Serological data (ANA, levels of C3 and Anti ds-DNA) at the end of the observation were not seen because not all patients performed the test.

 

DISCUSSION:

Our findings show that the pattern of immunosuppressive therapy given to pediatric patients is in accordance with the Clinical Practice Guide (CPG) of Surabaya Hospital by 2014. All patients received MP pulse IV, oral prednisone and CPA pulse IV and 17% of patients received oral MMF and 97% of patients get oral chloroquine. Giving various dosages to each patient was according to their individual conditions.

 

Patients diagnosed with LN must undergo two phases of therapy, namely the induction and maintenance phase. Induction phase therapy aims to induce complete emission and prevent flares. In this phase, aggressive terapisteroid is given, because LN is a life-threatening disease and can cause fatal death if the therapy isinadequate6. Inflammatory lesions in LN are acute and have the potential to return to normal with immunosuppressant therapy16. If LN patient experiences mid-lapses running the therapeutic protocol, then induction must be done, namely repeating the therapy protocol from the start.

 

Based on CPG, the induction phase is carried out for 6 months with MP pulse IV administration at a dosage of 10-30mg/kg/day (maximum 1 gram) for 3 consecutive days every 2-4 weeks (CPG, 2014). The procedure for making MP pulse IV is MP 500 or 1000mg dissolved in 0.9% NaCl 100cc and given within 1-3 hours. Based on the distribution of glucocorticoid dosages, the MP dosage used included the pulse dosageor supraphysiologic (> 250mg). Pulse dosages are given for the purpose of achieving a rapid therapeutic effect and reducing long-term side effects17. At this dosage, MP can cause immunosuppressant effects through the genomic and non-genomic pathways.

 

After the patient is given MP pulse for 3 days, the therapy is continued with oral prednisone administration with a dosage of 0.5-1mg/kg/day (maximum 80mg) every day. The dosage is reduced gradually 5mg/day within 1 month or depending on activity. This is because corticosteroids that are used for a long time will cause some effective reactions, one of which is Axis adrenal/ HPA suppression18.

 

However, the termination of corticosteroids therapy cannot be done suddenly10. The best way to reduce the high side effects of steroids is by tapperingoff19. Tapperingoff depends on disease activity, dosage, duration of therapy, and clinical response

 

Our findings indicate that the dosage of prednisone tapperingoff has been carried out with the applicable CPG, which reduces 1 tablet of prednisone (5mg) every month. The minimum dosage to maintain remission is also done by alternatedosage (AD). AD is defined as corticosteroids every 48 hours20.

 

After MP pulse IV isas given, the LN patient is also given cyclophosphamide (CPA) pulse IV or mycophenolatmofetil (MMF) as a sparing corticosteroid agent. Giving the Sparing agent aims to facilitate the reduction of corticosteroid dosages and function also to control basic diseases. CPA is given at a dosage of 500-1000mg/m2/day per month in the induction phase.

 

CPA is an alkylating compound. CPA is metabolized in the body to become phosphorusamidard which can form covalent irreversible bonds with nucleophilic substances in DNA. Thus, this can prevent DNA replication and cause cells to experience apoptosis10. Before being given CPA, LN patient is given a premdication in the form of ondansetron or metoclopramide to overcome nausea vomiting associated with CPA side effects. Rehydration is done by giving 5% dextrose or NaCl 0.9% as much as 750cc within 3 hours (250cc / hour).

 

Giving MMF is stated to have lower side effects than CPA. Adult MMF can be given daily starting with MP pulses at a dosage of 600mg/m2/dosage every 12 hours (maximum of 1 gram per 12 hours). MMF is a product that is rapidly hydrolyzed into a selective, noncompetitive active form of mycophenolic acid (MPA). MMF is also a reversible inhibitor of enzyme inemonophosphatedehydrogenase (IMDPH) which functions in guanine nucleotide synthesis via the de novo pathway. When this synthesis line is inhibited, the T lymphocytes and B lymphocytes cannot proliferate so that it will suppress the number of T lymphocytes and B lymphocytes in the body including its function in the formation of antibodies.11

 

MMF used in Surabaya Hospital is Myfortic (Mycophenolate Mophetil) and Cell-cept (Mycophenolate Sodium). These forms are both hydrolyzed into mycophenolic acid which is active in the body. The difference is that the MMF forms more often cause gastrointestinal effects. Whereas, mycophenolate sodium has been modified into entericcoated tablets which have little gastrointestinal side effects21.

 

After the induction phase is completed, therapy is still continued with the maintenance phase. Therapy also uses immunosuppressants. However, the dosage is slowly reduced to achieve a stable state and reduce the risk of recurrence in patients including side effects. This maintenance phase uses oral prednisone which is used every day with dosages that are lowered every month until the lowest dosage can maintain the remission condition.

 

In addition, cyclophosphamidpulse IV is also given every 3 months for 24 months. The recommended initial dosage is 1mg/kg/day (maximum 80mg/day) reduced by 5mg/month every month. Adjuvant therapy such as chloroquine is also recommended by the ACR and European League for Rheumatism (EULAR) for the long-term management of lupus nephritis. Chloroquine reduces the incidence of renal and non-renal flares, reduces the spread of disease activity to other organs, and increases survival of patients with SLE16. In addition, chloroquine also inhibits TLR activation, so the production of proinflammatory compounds such as IFN-α, cytokines and immunoglobulins produced by B cells can decrease22. The chloroquine dosage used is 3 mg/kg/day and can be started from an induction phase therapy.

 

Our findings also showed that immunosuppressant therapy in pediatric LN patients was routinely monitored. This is because the therapy has side effects, especially the corticosteroid used in the long term. The side effects that we found in the removal of Methylprednisolone or Prednisone are GI disorders (gastric irritation, pepticulcer, pancreatitis), Hyperglycemia, Hypertension, and Cushing's syndrome (moonface). The side effects due to Cyclophosphamide are Leukopenia, Hepatotoxicity, and Cystitis haemorrhage. While the side effects due to mycophenolate mofetil are gastrointestinal disorders (nausea, vomiting, diarrhea) and leukopenia.

 

Corticosteroids can cause a negative increase in blood through a mineralocorticoid mechanism that causes the retention of sodium and water. In addition, corticosteroids can increase receptor risk. So, this is dangerous for patients with heart problems because hypocalaemia can increase the effect of cardiac arrhythmias.23 Therefore, to avoid heart-related symptoms, potassium serum levels must be checked first before an MP pulse is carried out. Patients with heart problems should be monitored with an electrocardiogram during infusion and the procedure performed in the peripheral vein for 30-60 minutes19.

 

Long-term corticosteroid use generally causes Cushingsyndrome which is characterized by weight gain, redistribution of adipose tissue, and especially fullmoonface fat. The recommendation to overcome this side effect is to stop corticosteroid use gradually or decrease the dosage of corticosteroids because of the risk of cushing syndrome increases with increasing dosage24.

 

In MMF, side effects that often arise are GIdisorder (nausea vomiting, diarrhea), leukopenia and increased risk of infection (especially sepsis due to cytomegalovirus) (Krenskyetal, 2011). Side effects of GI disorder increase with the magnitude of the dosage given so that it can be overcome by dividing the MMF dosage in a day into 2-3 dosages19.

 

From our findings, it can be seen that there was potential for drug interactions. Prednisone and furosemide, if it used together can aggravate the condition of hypokalemia. Therefore, potassium monitoring even potassium supplementation is needed to keep the body's electrolyte balance balanced25. In addition, the use of Allupurinol simultaneously with cyclophosphamide can reduce metabolism of cyclophosphamide. Thus,  the content of carcophosphorus increases

 

Other interactions occur in the administration of prednisone and metformin. The antidiabetic effect of decreasing blood sugar will be in contrast to the effect of corticosteroids which can increase blood sugar if the two drugs are used together. However, the effects of this interaction depend on the condition of each individual. Patients who get both of these drugs together must monitor blood sugar regularly and if it is needed to increase an antidiabetic dosage25.

 

From our findings it can also be seen that the therapeutic outcome achieved by pediatric LN patients is multifactorial. At the end of the observation it was found that 64% of patients experienced a decrease in urinary erythrocytes. 77% of patients experienced a decrease in urine protein. 24% of patients experienced decreased urinary sediment and 87% of patients experienced an increase in GFR. Serological data (ANA, C3 levels and Anti ds-DNA) at the end of the observation were not seen because not all patients performed the test.

 

CONCLUSION:

From the results above, it can be concluded that the pattern of therapy in pediatric Lupus Nephritis patients in Surabaya Hospital, namely Dr. Soetomo Hospital was in accordance with the recommendations of the Clinical Practice Guidelines that are used as a reference in the hospitals. However, there were some special patients who got the different dosage according to the patient's condition. In addition, there were side effects and drug interactions from the use of immunosuppressants. Therefore, it was necessary to periodically monitor patients to observe the side effects and drug interactions in patients.

 

ETHICAL CLEARANCE:

This research had been approved by the Health Research Ethics Commission of  Dr. Soetomo Hospital and declared "Approved" with Ethical Clearance Letter Number 92 / Panke.KKE / II / 2017

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 15.07.2019            Modified on 03.09.2019

Accepted on 02.10.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(3):1257-1265.

DOI: 10.5958/0974-360X.2020.00232.2