crescents with fibrinoid necrosis and karyorrhexis of the adjacent lobules. In two glomeruli haematoxylin bodies were present. With trichrome stain, diffuse and.
Nephrol Dial Transplant (2001) 16: 849±852
The Interesting Case
Late recurrence of lupus nephritis after long-term clinical remission Gabriella Moroni, Gustavo C. Greloni1 and Claudio Ponticelli Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore, Milano, Italia
Introduction Diffuse proliferative (class IV) glomerulonephritis is the most frequent and severe form of renal involvement in systemic lupus erythematosus (SLE). The prognosis of patients with class IV lupus nephritis has dramatically improved over the last 30 years w1±3x allowing many patients to survive for decades. Although information on the outcome of patients with a very long-term follow-up is still scanty w4±6x, the available data suggest that after 10 years patients have an increased risk of cardiovascular, cerebrovascular, and neoplastic complications w5,7,8x related either to therapy or to the consequences of SLE damage. In contrast, the activity of the disease seems to quench over time w5x and the risk of renal ¯ares becomes increasingly rare in the long-term w6x. In view of the side-effects of prolonged treatment and of the progressive quenching of SLE over the years, slow reduction of therapy until complete discontinuation has been tried in patients with quiescent SLE w9x. Unfortunately, although some patients may maintain asymptomatic and without signs of active disease for years and even decades, the possibility of a late reactivation of SLE cannot be ruled out. We report here the case of a woman with diffuse proliferative lupus nephritis who, after stopping therapy, enjoyed complete clinical remission of SLE for more than 20 years and eventually developed a nephritic ¯are-up, that could be reversed with appropriate therapy.
Case A 33-year-old woman was admitted to our Unit in September 1975 for an acute nephritic syndrome. Since 1970 she had complained of arthralgias, asthenia, and psychic irritability. In August 1975, after exposure Correspondence and offprint requests to: Gabriella Moroni MD, Divisione di Nefrologia e Dialisi±Padiglione Croff, Ospedale Maggiore IRCCS, Via della Commenda 15, I-20122 Milano, Italy. 1 Present address: Servicio de NefrologõÂa, Hospital Italiano, Buenos Aires, Argentina. #
to sunlight, a malar rash appeared together with fever and oedema. Her body weight increased 12 kg in 2 weeks. At presentation the patient was in good general condition. The physical examination revealed diffuse and marked oedema. Her temperature was 37.88C, blood pressure was 165u105 mmHg, and heart rate was 80 beatsumin. Laboratory tests showed: haematocrit 30%, white cells count 6700umm3 with a normal differentiation, platelet count 180 000umm3, plasma creatinine 1.2 mgudl, plasma urea 58 mgudl, creatinine clearance 56 mlumin, total serum proteins 6.2 gudl, albumin 2.3 gudl, gammaglobulins 2.8 gudl, C3 10% (normal value )80%), C4 5 mgudl (normal value 20±40x, ANA positive (3q) and anti DNA antibodies 84% (normal value -13%). The urinary protein excretion was 1.2 gu24 h. The urinary sediment showed 50 red blood cells and 7 white blood cellsuhigh-power ®eld, together with granular and cellular casts. The patient was submitted to a percutaneous renal biopsy. The specimen contained 20 glomeruli. At light microscopy, all the glomeruli showed diffuse intracapillary proliferation and polymorphonuclear in®ltration. Twenty per cent of glomeruli had segmental epithelial crescents with ®brinoid necrosis and karyorrhexis of the adjacent lobules. In two glomeruli haematoxylin bodies were present. With trichrome stain, diffuse and large subendothelial deposits were seen. No relevant abnormalities were observed in interstitial, tubular, and vascular structures (Figure 1). At immuno¯uorescence, mesangial and parietal deposits of IgA (2q), C3 (2q), C1q (2q), IgG (1q), IgM (1q) and tubular basement membrane deposits of IgM (1q) were found. A diagnosis of diffuse proliferative lupus nephritis was made. The patient was treated with prednisone 1 mgukguday for 1 month, then gradually tapered associated with cyclophosphamide 2 mgukguday for 1 year. The renal function rapidly improved. In October 1975 the plasma creatinine was 0.7 mgudl. Proteinuria and urinary sediment progressively normalized. One year later the patient was in complete remission: plasma creatinine: 0.5 mgudl, normal serum C3 and C4 and negative anti dsDNA antibodies, proteinuria 0.16 gu24 h, with negative urinary sediment. The patient's blood pressure was normal (mean 96 mmHg). Prednisone was
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Fig. 1. First renal biopsy. The glomerulus shows segmental necrotic lesions of the tuft containing fragmented polymorphonuclear leukocytes associated with segmental cellular crescent. The reminder of the glomerular tuft shows mesangial expansion and leukocyte in®ltration. AFOG stain.
continued at a dose of 10 mg per day and was eventually stopped in November 1981 after a slow tapering. In the following years she was well with the exception of recurrent arthralgias treated with non-steroidal anti-in¯ammatory drugs. Laboratory tests remained normal. Since January 1991 decreased levels of serum C3 and positive values of anti dsDNA antibodies were observed without any clinical symptom or sign of SLE. Since that time on, the patient was more closely examined, but renal function and urinalysis remained normal for the following 9 years. In November 1999 she developed skin purpura on her legs, diffuse oedema, dyspnoea, arterial hypertension, and severe myoarthralgias. The patient was admitted to our Unit in December 1999. At presentation she looked pale and ill. The arterial blood pressure was 150u100 mmHg, with a heart rate of 90 beatsumin. The physical examination revealed diffuse oedema, with purpuric lesions on legs and hands. Laboratory tests showed plasma creatinine 1.9 mgudl, blood urea 80 mgudl, creatinine clearance 32 mlumin, haematocrit 28%, white blood cells 10 000 mm3, platelets 217 000 mm3, total serum proteins 6.4 gudl, albumin 2.8 gudl, C3 complement fraction 48 mgudl (normal value 90±180) and C4 3 mgudl (normal value: 10±40), and positive anti dsDNA antibodies. The urine examination revealed proteinuria 6.7 guday, severe microscopic haematuria
()100 red blood cellsuhigh power ®eld), leukocyturia, and granular and cellular casts. The patient was submitted to a second renal biopsy. The specimen contained 20 glomeruli, none of which was sclerotic. All the glomeruli showed mild to severe increase of mesangial and endothelial cells together with in®ltration of mononuclear and polymorphonuclear leukocytes. Five glomeruli showed a small area of ®brinoid necrosis and karyorrhexis surrounded by segmental epithelial crescents. At trichrome stain mesangial, intramembranous, and subendothelial deposits were seen. Focal areas of mild tubular atrophy and interstitial ®brosis were present (Figure 2). At immuno¯uorescence a full-house pattern of immune deposits was observed: C1q 3q, IgG 2q, IgA 2q, IgM 1q, C3 1q in parietal and mesangial distribution, ®brin 3q in necrotic areas and C1q 2q, IgM 1q along tubular basement membranes. A diagnosis of diffuse proliferative lupus nephritis with high activity index was made. The patient was treated with three intravenous pulses of methylprednisolone 1 g each every 24 h followed by prednisone 0.5 mgukguday for 2 months, then gradually tapered, associated with cyclophosphamide 2 mgukguday. After 2 months, cyclophosphamide was stopped and cyclosporin 3 mgukguday was added. Renal insuf®ciency rapidly reversed and proteinuria slowly remitted. At the last observation in June
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Fig. 2. Second renal biopsy. Global intracapillary proliferation of the glomerular tuft with in®ltration of mononuclear and polymorphonuclear leukocytes. Increase of mesangial matrix associated with mesangial deposits and segmental wire loops. AFOG stain.
2000 plasma creatinine was 0.8 mgudl, proteinuria 0.37 gu24 h, while microscopic haematuria (50 red blood cellsuhigh-power ®eld) and arterial hypertension (blood pressure 150u92 mmHg) persisted. The patient is continuing treatment with prednisone 0.3 mgukguday, cyclosporin 2 mgukguday, and antihypertensive therapy.
Discussion Little information is available about the possibility of late ¯are-up in patients with long-term quiescent lupus nephritis w5x. To the best of our knowledge it is exceptional that a patient who has maintained complete remission of lupus nephritis for an extremely long time can develop a renal ¯are. After such a long period of clinical remission we believed that the disease had been de®nitively beaten in our patient. Nevertheless she continued to be regularly checked in our Unit. After 14 years, serum levels of C3 decreased and anti-dsDNA antibodies became positive, but no other clinical sign of SLE reappeared and renal disease remained silent for the following 9 years. At our surprise, however, a nephritic ¯are developed without identi®able causes after 23 years of clinical quiescence. As the patient was in good general condition, the therapy was vigorous. Six months later she went again into remission.
The activity of SLE seems to reduce over time. In our previous experience the incidence of renal and extrarenal ¯ares signi®cantly decreased after the 10th year of the disease w6x. Although one cannot exclude that this reduced clinical activity may be induced by previous corticosteroid and immunosuppressive therapy, it is also possible that it re¯ects a spontaneous remission of the disease. At any rate, it must be pointed out that even patients with prolonged inactive disease may develop ¯ares of activity. Therefore patients with lupus nephritis should undergo regular checkups after years of complete remission, particularly when previously negative serological markers become positive. This attitude may allow an early diagnosis and an appropriate treatment of renal ¯ares, which is a paramount prerequisite for therapeutic success. This case demonstrates that there is no such thing as `burnt-out lupus', any more than there are extinct volcanoes: the possibility of further eruption is always present.
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