lupus nephritis ( ln ) is one of the most severe complications of systemic lupus erythematosis ( sle ) . in recent years , the morbidity and mortality of ln
have improved considerably owing to more appropriate use of traditional drugs , such as corticosteroids and cyclophosphamide , and the incorporation of new ones , such as mycophenolate and biologic agents.1 since sle is incurable , medical treatments are lifelong .
the type of drug and intensity of dosing are based on clinical and analytical data.2 adherence , defined as the extent to which patients take medications as prescribed by their health care providers,3 has proven to be a challenging issue in the treatment of sle , and nonadherence is usually associated with poor disease control and increased mortality .
curiously , suitable adherence is far from achievable in many cases , especially in patients at risk for not taking their medication correctly .
the specific physical and psychological characteristics of childhood and adolescence make adherence particularly difficult.4,5 taking into account that approximately 15% of patients with sle develop their disease during this period , detection of nonadherence is worthwhile in clinical practice.6 the enormous psychological and social impact of the disease and its treatment in young patients demand a comprehensive and multidisciplinary approach.7 however , nonadherence in ln can mimic a refractory form of the disease that confuses doctors and leads to inappropriate treatment with severe side effects . to highlight the importance of adherence in this age group , we describe two patients with ln who did not adhere to their drug schedule .
initially , neither patient admitted to nonadherence , and the clinical course was characterized by severe renal and extrarenal flares that were treated using an intensification of immunosuppressive treatment rather than the resumption of the previous regimen .
a 23-year - old spanish woman was diagnosed with sle and ln in july 2004 when she was 15 .
her disease manifested as : nephrotic syndrome ( proteinuria 8 g/24 hours , serum albumin 1.5 g / dl ) ; normal renal function ( serum creatinine 0.7 mg / dl ) ; microhematuria ; high titers of antinuclear antibodies ; and presence of lupus anticoagulant .
renal biopsy revealed class v ln ( membranous , the society of nephrology / renal pathology society classification 2003 ) with neither vascular nor interstitial lesions .
she was treated with oral prednisone ( 1 mg / kg/24 hours ) and cyclosporine a ( 200 mg/24 hours ) for 8 weeks , followed by tapering the doses of prednisone .
although partial remission was achieved , she developed several disturbing side effects , such as cushingoid face and gingival hypertrophy , which affected adherence .
she subsequently presented with symptomatic thrombocytopenia that resolved after resumption of prednisone and cyclosporine a at lower doses .
one year later , after she had achieved complete renal remission , mycophenolate mofetil ( 1,500 mg/24 hours ) was begun to treat proteinuria ( 3 g/24 hours ) .
the patient soon developed severe renal damage ( relapse of nephrotic syndrome and increase in serum creatinine to 4 mg / dl ) associated with anemia and thrombocytopenia .
a second renal biopsy revealed a transformation to class iv ln ( diffuse proliferative glomerulonephritis ) with a high activity index ( austin index , 18/24 ) and a low chronicity index ( austin index , 4/12 ) .
therefore , she received daily pulses of 6-methylprednisolone ( 500 mg intravenous 3 ) , prednisone ( 1 mg / kg/24 hours by mouth ) , and monthly pulses of cyclophosphamide ( 500 mg intravenous 3 ) .
she also required hemodialysis , owing to the presence of anasarca and poor recovery of the renal function .
given the possibility of a refractory form of ln , she received four weekly doses of rituximab ( 375 mg / m ) . in the following weeks , renal function improved , and dialysis was stopped .
after several months with a stable clinical picture and renal function ( serum creatinine 1.41.6 mg / dl and proteinuria 11.5 g/24 hours ) , she experienced a new worsening of renal function with nephrotic proteinuria and was readmitted for treatment . on day 5 of admission , the blood levels of mycophenolic acid , the active metabolite of mycophenolate mofetil , were undetectable ( < 0.8 g / ml ) .
although the patient ( and her family ) initially denied poor adherence , she eventually admitted that she had not taken her treatment correctly , since she was worried about her physical appearance and other troublesome gastrointestinal side effects .
after resumption of prednisone and mycophenolate , renal function improved , and proteinuria decreased to previous levels .
four years after the event , she has not had any further flares of sle - related ln .
a 19-year - old spanish woman was diagnosed with sle in january 2008 when she was 17 .
the disease manifested with pericarditis , hemolytic anemia , and high titers of antinuclear and anti - dna antibodies .
she was treated with daily pulses of 6-methylprednisolone ( 1,000 mg intravenous 3 ) , prednisone ( 1 mg / kg/24 hours by mouth ) , and monthly pulses of cyclophosphamide ( 500 mg intravenous 6 ) .
she quickly achieved complete renal remission , and , after receiving the sixth pulse of cyclophosphamide , maintenance treatment was begun with mycophenolate mofetil ( 1,000 mg/24 hours ) .
she subsequently complained that the mycophenolate produced gastrointestinal discomfort , so she reduced the dose on her own initiative .
she agreed to switch to mycophenolic acid ( myfortic , novartis , basel , switzerland ) , which resulted in better tolerance .
the renal response was complete for 2 years , after which time she was admitted with fever , polyserositis , pancytopenia , and increasing proteinuria .
she received three intravenous pulses of 6-methylprednisolone . given her severe leukopenia ( < 200 neutrophils/l ) , she received several doses of a leukocyte - stimulating agent ( filgrastim , neupogen , amgen inc . , thousand oaks , ca , usa ) with a good response .
after her neutrophil count recovered , pulses of cyclophosphamide were administered ( six monthly doses ) , followed by mycophenolic acid .
three months later , she was hospitalized with abdominal vasculitis , increased proteinuria ( 2 g/24 hours ) , and impaired renal function ( serum creatinine , 2.6 mg / dl ) .
she received a further three pulses of 6-methylprednisolone and four weekly doses of rituximab ( 375 mg / m ) . at first , we considered the possibility of refractory ln , and both she and her family claimed that she had taken all the medication correctly .
however , after a detailed interview , the patient admitted that she had often missed taking medication because she was concerned about her physical appearance and weight gain .
indeed , she confessed to having lied as a result of family pressure and had decided to reduce her medication on her own initiative . after resuming her previous medications ,
starting hydroxychloroquine , and receiving psychological counseling , she was discharged and has been in clinical and analytical remission for 2 years .
a 23-year - old spanish woman was diagnosed with sle and ln in july 2004 when she was 15 .
her disease manifested as : nephrotic syndrome ( proteinuria 8 g/24 hours , serum albumin 1.5 g / dl ) ; normal renal function ( serum creatinine 0.7 mg / dl ) ; microhematuria ; high titers of antinuclear antibodies ; and presence of lupus anticoagulant .
renal biopsy revealed class v ln ( membranous , the society of nephrology / renal pathology society classification 2003 ) with neither vascular nor interstitial lesions .
she was treated with oral prednisone ( 1 mg / kg/24 hours ) and cyclosporine a ( 200 mg/24 hours ) for 8 weeks , followed by tapering the doses of prednisone .
although partial remission was achieved , she developed several disturbing side effects , such as cushingoid face and gingival hypertrophy , which affected adherence .
she subsequently presented with symptomatic thrombocytopenia that resolved after resumption of prednisone and cyclosporine a at lower doses .
one year later , after she had achieved complete renal remission , mycophenolate mofetil ( 1,500 mg/24 hours ) was begun to treat proteinuria ( 3 g/24 hours ) .
the patient soon developed severe renal damage ( relapse of nephrotic syndrome and increase in serum creatinine to 4 mg / dl ) associated with anemia and thrombocytopenia .
a second renal biopsy revealed a transformation to class iv ln ( diffuse proliferative glomerulonephritis ) with a high activity index ( austin index , 18/24 ) and a low chronicity index ( austin index , 4/12 ) .
therefore , she received daily pulses of 6-methylprednisolone ( 500 mg intravenous 3 ) , prednisone ( 1 mg / kg/24 hours by mouth ) , and monthly pulses of cyclophosphamide ( 500 mg intravenous 3 ) .
she also required hemodialysis , owing to the presence of anasarca and poor recovery of the renal function .
given the possibility of a refractory form of ln , she received four weekly doses of rituximab ( 375 mg / m ) . in the following weeks , renal function improved , and dialysis was stopped .
after several months with a stable clinical picture and renal function ( serum creatinine 1.41.6 mg / dl and proteinuria 11.5 g/24 hours ) , she experienced a new worsening of renal function with nephrotic proteinuria and was readmitted for treatment . on day 5 of admission , the blood levels of mycophenolic acid , the active metabolite of mycophenolate mofetil , were undetectable ( < 0.8 g / ml ) .
although the patient ( and her family ) initially denied poor adherence , she eventually admitted that she had not taken her treatment correctly , since she was worried about her physical appearance and other troublesome gastrointestinal side effects .
after resumption of prednisone and mycophenolate , renal function improved , and proteinuria decreased to previous levels .
four years after the event , she has not had any further flares of sle - related ln .
a 19-year - old spanish woman was diagnosed with sle in january 2008 when she was 17 . the disease manifested with pericarditis , hemolytic anemia , and high titers of antinuclear and anti - dna antibodies .
four months later , she developed nephrotic syndrome with microhematuria and normal renal function . a renal biopsy revealed class iv ln .
she was treated with daily pulses of 6-methylprednisolone ( 1,000 mg intravenous 3 ) , prednisone ( 1 mg / kg/24 hours by mouth ) , and monthly pulses of cyclophosphamide ( 500 mg intravenous 6 ) .
she quickly achieved complete renal remission , and , after receiving the sixth pulse of cyclophosphamide , maintenance treatment was begun with mycophenolate mofetil ( 1,000 mg/24 hours ) .
she subsequently complained that the mycophenolate produced gastrointestinal discomfort , so she reduced the dose on her own initiative .
she agreed to switch to mycophenolic acid ( myfortic , novartis , basel , switzerland ) , which resulted in better tolerance .
the renal response was complete for 2 years , after which time she was admitted with fever , polyserositis , pancytopenia , and increasing proteinuria .
given her severe leukopenia ( < 200 neutrophils/l ) , she received several doses of a leukocyte - stimulating agent ( filgrastim , neupogen , amgen inc . , thousand oaks , ca , usa ) with a good response .
after her neutrophil count recovered , pulses of cyclophosphamide were administered ( six monthly doses ) , followed by mycophenolic acid .
three months later , she was hospitalized with abdominal vasculitis , increased proteinuria ( 2 g/24 hours ) , and impaired renal function ( serum creatinine , 2.6 mg / dl ) .
she received a further three pulses of 6-methylprednisolone and four weekly doses of rituximab ( 375 mg / m ) . at first , we considered the possibility of refractory ln , and both she and her family claimed that she had taken all the medication correctly .
however , after a detailed interview , the patient admitted that she had often missed taking medication because she was concerned about her physical appearance and weight gain .
indeed , she confessed to having lied as a result of family pressure and had decided to reduce her medication on her own initiative . after resuming her previous medications ,
starting hydroxychloroquine , and receiving psychological counseling , she was discharged and has been in clinical and analytical remission for 2 years .
we report two representative cases of renal flare in patients with ln caused by nonadherence to treatment rather than refractory disease .
these cases emphasize that nonadherence in ln is a challenge for clinicians , particularly in young patients for whom suitable treatment is mandatory .
nonadherence is a major problem in the management of chronic diseases , including sle , and should be suspected whenever a patient is receiving home oral medication and not improving as expected .
adherence of more than 80% is currently accepted as sufficient for achieving a therapeutic response in sle.4 however , rates of nonadherence in patients with this disease vary between 10%50% , depending on the evaluation methods used.3,8 despite the importance of adherence for successful medical interventions , no universally accepted measurement criteria have been established .
koneru et al9 reported that the medication - adherence self - report inventory was a reliable measure of adherence in sle . indeed
, very low blood hydroxychloroquine levels are an objective marker of prolonged poor adherence in patients with this disease.10 recently developed methods include self - reported adherence11 and electronic monitoring of medication consumption.12 in the cases we report , we were alerted to poor adherence by the undetectable blood levels of mycophenolic acid , which have proven useful for monitoring activity in other settings.13 in spain , hydroxychloroquine was not included in the standard treatment of ln until recently .
therefore , the patients described did not take this drug during their initial disease . in any case ,
the patients progress would likely have been similar , because nonadherence to hydroxychloroquine could be associated with nonadherence to the remaining drugs.10 it is essential to identify patients at risk for nonadherence.14 as in many chronic diseases , nonadherence is multifactorial .
interestingly , one of the predictors of nonadherence to clinic visits  and probably to medication  was the presence of renal involvement , because patients may be unaware of active disease in the absence of significant clinical manifestations.15 additional barriers to adherence include financial problems , fear of side effects , depression , emotional stress , psychological factors , perception of treatment as inefficacious , lack of familial support , and lower educational level,11,12,1618 as well as young age , unmarried status , and poor communication between patients and health care providers.4,19 the two reasons for nonadherence we identified were young age and fear of adverse side effects , mainly those related to physical appearance .
we report two typical examples of nonadherence that was discovered after a detailed interview with the patients and their families .
although we did not have any specific tools for detecting nonadherence , we would emphasize the importance of clinical suspicion of nonadherence when caring for young patients with sle .
determination of the levels of mycophenolic acid in blood is also an effective tool for evaluating nonadherence , as in the present report .
treatment of ln in young patients is similar to that used in adults , although it is affected by specific problems stemming from age , psychological adaptation , and exposure to side effects in the long term.6 thus , it is not surprising that nonadherence is one of the most challenging issues when treating young patients with sle .
first , adolescence is a time of profound biological and psychological changes , and a diagnosis of sle with severe organ damage , such as that caused by ln , could have an impact on adaptation to this chronic disease.4 second , many young people find drug side effects almost intolerable and are thus at risk for nonadherence , which can manifest as failure to fill prescriptions , delay in taking medication , omission of doses , failure to follow medical advice , and poor attendance at appointments.5 third , young patients with sle do not admit to their nonadherence so as not to damage their relationship with their family and health care providers.20 in the cases we describe , refractory ln was the first diagnosis , although the true cause of renal flare proved to be nonadherence . therefore ,
if our patients had admitted to their nonadherence , we would have successfully administered a less aggressive treatment regimen comprising corticosteroids , cyclophosphamide , and/or mycophenolate without rituximab or repeated boluses of cyclophosphamide
. once nonadherence has been confirmed , specific interventions tailored to the patient and his / her family can be provided.5,16,21 in our patients , psychological support combined with increased communication between family , patient , and medical staff improved adherence .
we conclude that the frequent and severe relapses of ln observed in young patients may actually be due to nonadherence rather than to refractory disease . this possibility must always be taken into account , especially in teenagers , in whom adherence to chronic treatment is hampered mainly for psychological reasons .
prompt identification of this situation can obviate aggressive immunosuppressive treatment and facilitate psychological and familial support so that the patient can follow treatment and maintain sustained renal and systemic remission .
 purposeadherence is a challenging issue in the treatment of systemic lupus erythematosus . 
 nonadherence has been widely addressed in patients with lupus and must be detected quickly to prevent severe complications . 
 the cases we present illustrate the importance of adherence in young adults.case 1a 23-year - old spanish woman diagnosed with severe lupus nephritis 8 years previously achieved renal remission after immunosuppressive treatment with corticosteroids and cyclophosphamide . 
 three years later , she developed a renal flare . 
 her treatment was intensified , and rituximab and mycophenolate mofetil were added . 
 one year later , she was readmitted for a new renal flare . 
 a blood test revealed no detectable levels of mycophenolic acid , and the patient admitted she had not taken her treatment correctly . 
 treatment was resumed . 
 four years later , the patient remains in remission.case 2a 19-year - old spanish woman was diagnosed with nephrotic syndrome due to lupus nephritis . 
 she achieved complete remission after treatment with corticosteroids and cyclophosphamide followed by mycophenolate mofetil . 
 two years later , she developed a severe renal relapse that was treated with corticosteroids , cyclophosphamide , and rituximab . 
 the response to treatment was good . 
 mycophenolic acid was undetectable in blood . 
 the patient admitted that she had often missed doses before this relapse . 
 the renal response has been maintained since she resumed her previous medications 2 years ago.conclusionwe conclude that the frequent and severe relapses of lupus nephritis observed in young patients may actually be due to nonadherence rather than to refractory disease . 
 our cases are typical examples of nonadherence that were discovered after a detailed interview with the patients and their families . 
 we emphasize the need for clinical suspicion of nonadherence when caring for young adults with lupus . 
Introduction
Case presentations
Case 1
Case 2
Discussion
Conclusion