Relapse of lupus nephritis more than 10 years after complete remission

Ana Carlavilla, Eduardo Gutiérrez, Teresa Ortuño, Enrique Morales, Ester González and Manuel Praga

Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain

Correspondence and offprint requests to: Manuel Praga, Servicio de Nefrología, Hospital 12 de Octubre, Avda. Córdoba, s/n, 28041 Madrid, Spain. Email: mpragat{at}senefro.org

Keywords: lupus nephritis; renal lupus relapses; focal lupus nephritis; mycophenolate mofetil treatment; follow-up of quiescent lupus patients



   Introduction
 Top
 Introduction
 Cases
 Discussion
 References
 
Over the last decade there has been a dramatic improvement in the treatment and prognosis of lupus nephritis, even in its most severe forms. However, most investigations have focused mainly on the initial episodes of lupus nephritis. Information about the treatment of relapses or the correct long-term management of clinically quiescent patients is relatively scarce. These aspects are particularly important because current therapeutic options allow renal survival after the first episode of lupus nephritis in a majority of patients and because clinical studies have shown that recurrent renal flares are common: 37–45% of patients successfully treated at their initial episode have relapses of nephritis later [1–5]. Most of these relapses occur soon after the initial episode, especially when immunosuppressive therapy is reduced.

Since the risk of very late relapses appears to be very low, complete discontinuation of immunosuppressive therapy has been advocated in selected patients with quiescent lupus [6]. However, we report here four patients with diffuse lupus nephritis who had relapses more than 10 years after complete remission.



   Cases
 Top
 Introduction
 Cases
 Discussion
 References
 
Patient 1
A 23-year-old woman was admitted to our hospital in 1993 because of proteinuria and abnormal urinary sediment. Starting 3 months earlier, she had noted skin lesions in sun-exposed areas and mild arthralgias. Her blood pressure was 124/80 mmHg, serum creatinine (Scr) 0.9 mg/dl, creatinine clearance (Ccr) 116 ml/min and proteinuria 3.5 g/24 h, and her urinary sediment showed 15–20 erythrocytes and 5–10 leukocytes per high power field. Serum C3 was 43 mg/dl and C4 6 mg/dl. ANA were positive (1/1260) as was anti-DNA antibody titre (1/320). A renal biopsy was performed, showing diffuse and global endocapillary glomerular proliferation, together with wire-loop deposits and occasional hyaline thrombi. Immunofluorescence revealed deposits of IgG, IgA, IgM, C3 and C1q. Electronmicroscopy showed abundant mesangial and subendothelial electron-dense deposits.

With the diagnosis of diffuse lupus nephritis, Class IV-G (A), the patient was treated with prednisone (1 mg/kg/day) and monthly boluses of intravenous cyclophosphamide. During the following months she recovered completely, with the disappearance of skin lesions. After 6 months of treatment, blood pressure was 114/65 mmHg, renal function was normal as was the urinary sediment, and her 24 h urine for protein was negative. C3 was 107 mg/dl, C4 20 mg/dl and ANA 1/320 and anti-DNA was negative. After six intravenous boluses, cyclophosphamide was withdrawn due to severe side effects (nausea and vomiting). Throughout the following years the patient was treated with 5 mg/day of oral prednisone.

On her visit of March 2004, we noted an increase in ANA titre from 1/40 to 1/320 and a decrease of serum C3 to 55 mg/dl. Anti-DNA remained negative as did proteinuria and urinary sediment. In the following visit 2 months later, she had proteinuria (1.5 g/24 h) and abnormal urinary sediment (microhaematuria and leukocyturia). She complained of arthralgia and mild asthenia. Scr was 0.8 mg/dl, Ccr 97 ml/min, ANA 1/1250, anti-DNA 1/80, C3 50 mg/dl and C4 12 mg/dl. A second renal biopsy showed proliferation of mesangial and endothelial cells, not involving all the glomerular surface, in less than one-half of the glomeruli. Mild fibrosis in isolated interstitial areas was also observed. Mesangial and subendothelial deposits were detected by electron microscopy. Renal tissue was not available for immunofluorescence studies.

A diagnosis of focal lupus nephritis (Class III-A) was established and treatment with prednisone (1 mg/kg/day) and mycophenolate mofetil (MMF; 1500 mg/day) was started. Three months later the patient was asymptomatic; 24 h urine for protein was negative and the urinary sediment search normal. ANA titre had decreased to 1/320 and anti-DNA was negative.

Patient 2
A 15-year-old boy was admitted to our hospital in February 1989 because of dark urine, pedal oedema and hypertension (136/94 mmHg). For the preceding month, he had complained of arthralgias, low grade fever and a malar rash. Scr was 2.4 mg/dl and Ccr 48 ml/min. He had proteinuria, 4.5 g/24 h, and his urine was grossly bloody, and the urinary sediment showed numerous red cell and granular casts. ANA and anti-DNA were positive (1/1204 and 1/320, respectively) and hypocomplementaemia was observed (C3 30 mg/dl, C4 8 mg/dl). A renal biopsy showed severe diffuse lupus nephritis, Class IV-G (A), with endocapillary glomerular proliferation, infiltration by polymorphonuclear leukocytes and ‘wire-loop’ thickening of the glomerular capillary walls; 50% of the glomeruli showed circumferential crescents, lesions of fibrinoid necrosis and karyorrhexis. Immunofluorescence showed deposits of IgG, IgA, IgM, C3 and C1q and electronmicroscopy demonstrated numerous subendothelial and mesangial deposits.

He was treated with four intravenous boluses of methylprednisolone, 0.5 g each, followed by oral steroids (1 mg/kg/day), oral cyclophosphamide (2 mg/kg/day) and five sessions of plasmapheresis. One month later, Scr had decreased to 1.7 mg/dl and proteinuria to 2 g/24 h; however, macroscopic haematuria reappeared 2 weeks later. Because of the suspicion of haemorrhagic cystitis, cyclophosphamide was changed to azathioprine (100 mg/day). His lupus symptoms disappeared and he recovered normal renal function (Scr 0.7 mg/dl, Ccr 104 ml/min) in the following months, with normal blood pressure, negative proteinuria and a normal urinary sediment. Azathioprine and prednisone, the latter reduced step-wise, were maintained for 18 months, after which he received 5 mg daily of prednisone. He remained clinically normal and without laboratory abnormalities, with the exception of a positive ANA (1/40 to 1/120) during the following years. He was examined every 6 months in follow-up.

In July 2002, more than 13 years after the first bout of lupus, he noted arthralgias and progressive asthenia. His physical examination was normal—blood pressure was 120/75 mmHg. His renal function was normal (Scr 1.1 mg/dl, Ccr 90 ml/min), but other tests showed proteinuria (3 g/24 h), abnormal urinary sediment (microscopic haematuria, leukocyturia, isolated red cell casts), hypocomplementaemia (C3 48 mg/dl, C4 2.7 mg/dl) and positive ANA (1/2560) and anti-DNA (1/320). A second renal biopsy demonstrated endocapillary proliferation in one-half of the glomeruli, one of which showed segmental necrosis. The interstitium showed isolated cellular infiltrates and the vessels were normal. Immunofluorescence microscopy was not available; electron microscopy revealed focal and segmental subendothelial and mesangial deposits. With a diagnosis made of focal lupus nephritis, Class III-A, his prednisone was increased to 40 mg/day and MMF (750–1000 mg/day) was started. Lupus symptoms resolved, and 3 months later his Scr was 0.9 mg/dl, proteinuria 0.6 g/24 h and urine sediment normal. Six months later, MMF was changed to azathioprine, because of digestive complaints. On the last follow-up visit in October 2004, his renal function was normal, urinary protein 0.2 g/24 h, ANA 1/320, anti-DNA negative and serum complement normal. The patient was then on prednisone (5 mg/day) and azathioprine (50 mg/day).

Patient 3
A 17-year-old boy was admitted to our hospital in September 1984 because of dark urine, oedema, hypertension and fever. Laboratory data were as follows: Scr 3.5 mg/dl, Ccr 35 ml/min, serum total proteins 4.5 g/dl, serum albumin 2 g/dl, urinary protein 6.8 g/24 h, ANA 1/320, anti-DNA 1/128, C3 56 mg/dl, C4 22 mg/dl. The urinary sediment showed uncountable erythrocytes, leukocyturia, granular and cellular casts together with isolated red cell casts. A renal biopsy showed lesions consistent with diffuse lupus nephritis, Class IV-G (A)—with mesangial and endothelial cell proliferation, mesangial matrix expansion with subendothelial mesangial interposition, wire-loop images, and cellular crescents in 25% of the glomeruli. There were cellular infiltrates in the interstitium, and IgG, IgA and C3 deposits were detected on immunofluorescence. Electron microscopy was not done. Treatment with steroids (three intravenous boluses of methylprednisolone, 1 g each, followed by oral prednisone, 60 mg/day) and oral cyclophosphamide (100 mg/day) was started. Two month later, renal function was normal (Scr 1 mg/dl, Ccr 84 ml/min) and proteinuria had decreased to 1.2 g/24 h. Cyclophosphamide was withdrawn after 1 year of treatment, when Scr was 0.9 mg/dl and urinary protein 0.1 g/24 h. Throughout the following years, the patient remained asymptomatic, and had normal blood pressure and renal function, proteinuria, normal urinary sediment and normal levels of serum complement. Anti-DNA antibody was absent, with occasional positive ANA (1/40–1/320). Prednisone was maintained at a dose of 5 mg daily during the first few years and 5 mg every other day since 1995.

In July 2002, 17 years after the first episode, the patient noted asthenia, arthralgias and low-grade fever. His blood pressure was 145/85 mmHg—the rest of his physical examination was normal. Laboratory tests showed the following: Scr 1 mg/dl, Ccr 79 ml/min, urinary protein 2.8 g/24 h, normal levels of total serum proteins and albumin, ANA 1/2560, anti-DNA 1/320, C3 58 mg/dl, C4 12 mg/dl. The urinary sediment showed 30–40 red cells and 25 leukocytes per high power field, with hyaline and granular casts. In a renal biopsy, 50% of the glomeruli showed mesangial proliferation accompanied, in most of them, by a severe cellular proliferation involving mesangial and endothelial cells. Homogeneous thickening of capillary walls and isolated areas of interstitial fibrosis were also observed. On immunofluorescence microscopy, mesangial and capillary deposits of IgG, IgA, C3 and C1q were detected. Electron microscopy showed numerous electron-dense deposits located in the mesangium and in the subendothelial and subepithelial sides of the glomerular basement membrane. A diagnosis of Class III (A) plus Class V (membranous) lupus nephritis was established. Treatment with oral prednisone (1 mg/kg/day) and MMF (1000–1500 mg/day) was started. Over the course of his follow-up visits, lupus symptoms disappeared, renal function remained normal, proteinuria decreased to 0.2–0.5 g/day with a normal urinary sediment, and he had normal values of serum complement and negative anti-DNA. On his last visit (November 2004) his treatment consisted of prednisone 5 mg daily, MMF (1000 mg/daily) and losartan (50 mg/day).

Patient 4
A 10-year-old girl was diagnosed as having systemic lupus erythematosus in November 1978. For the preceding 2 months she had complained of arthralgias, malar rash, fever and asthenia. Her ANA and anti-DNA were positive (1/640 and 1/120, respectively). Laboratory tests showed haemoglobin at 11.6 g/dl, white cell count 2000/mm3, with a normal differentiation, total serum protein 5 g/dl, serum albumin 2.5 g/dl and Scr 1.1 mg/dl. Ccr was 55 ml/min. Urine examination revealed protein, 3.2 g/24 h, and 8–10 red cells and 10–15 leukocytes per high power. A renal biopsy showed lesions consistent with diffuse lupus nephritis, Class IV-G (A): diffuse proliferation of endothelial and mesangial cells, infiltration by polymorphonuclear leukocytes and thickening of glomerular capillary walls by subendothelial deposits. Hyaline thrombi and lesions of fibrinoid necrosis were also detected. On immunofluorescence microscopy, deposits of IgG, IgM, C3 and C1q were observed. Treatment with prednisone (1 mg/kg/day) and oral cyclophosphamide (50 mg/day) was started. Lupus symptoms, proteinuria and other laboratory abnormalities resolved in the following months, and his urinary sediment became normal. Cyclophosphamide was maintained for 18 months and steroids were gradually tapered. A maintenance dose of prednisone, 5 mg/daily initially and, since 1990, 2.5 mg/daily was prescribed and regular check-ups were performed every 6 months. The patient remained asymptomatic, with an occasionally positive ANA as the only laboratory abnormality.

In March 2004, more than 25 years after the first bout of lupus, she noted asthenia, fever, erythematous and desquamative skin lesions, hair loss and oral ulcers. Laboratory data at that time were as follows: haemoglobin 10.6 g/dl, white blood cell count 1800/mm3, Scr 0.7 mg/dl, Ccr 90 ml/min, total serum proteins 6.3 g/dl, serum albumin 2.5 g/dl, bilirubin 0.4 mg/dl, GOT 557 UI/l, GPT 472 IU/l, GGT 441 IU/l, C3 22 mg/dl, C4 3 mg/dl, ANA 1/2560, anti-DNA 1/320, and urinary protein was 4.5 g/24 h; and the urinary sediment showed too many red cells to count, 10–15 leukocytes and numerous granular casts per high power field.

A second renal biopsy showed proliferation of mesangial cells in all the glomeruli; in some glomeruli (<50%), segmental proliferation of endothelial cells was also detected, together with occasional hyaline thrombi and subendothelial deposits. Neither immunofluorescence nor electron microscopy were available. With the diagnosis of focal lupus nephritis, Class III (A), therapy with prednisone (1 mg/kg/day) and MMF (1500 mg/day) was started. The patient's general clinical condition improved, with the disappearance of skin lesions and oral ulcers, and she recovered normal leukocyte blood count and normal liver transaminases. Two months later, her renal function continued to be normal, proteinuria had decreased to 1 g/day, and urinary sediment had normalized. One year later she was on prednisone (15 mg/day) and MMF (1500 mg/day). She was asymptomatic, and had the following laboratory parameters: Scr 0.7 mg/dl, Ccr 107 ml/min, urinary protein 0.2 g/24 h, C3 68 mg/dl, C4 12 mg/dl, ANA 1/640 and negative anti-DNA.



   Discussion
 Top
 Introduction
 Cases
 Discussion
 References
 
As several studies have shown, relapses of lupus nephritis are common: 37–45% of patients successfully treated at their first episode show a later relapse of nephritis [3–5]. The median time to relapse is between 18 and 40 months after the first episode, generally coinciding with a reduction in the number or the doses of immunosuppressive drugs.

Although some patients show recurrent renal flare-ups, it is generally considered that renal relapses in patients with prolonged clinical quiescence are uncommon. This assumption has led some authors to propose discontinuation of immunosuppressive therapy in selected patients [6]. In fact, only one case of late recurrence after a long-term clinical remission of lupus nephritis has been reported [7], of a 33-year-old woman with diffuse lupus nephritis successfully treated with prednisone and oral cyclophosphamide, who had renal activity after 23 years of clinical quiescence. Her second renal biopsy showed, again, a diffuse nephritis, which resolved after treatment with steroids, cyclophosphamide and cyclosporine.

Nevertheless, our four cases would indicate that very late relapses of lupus nephritis may be more common than believed. Each of them initially had presented with diffuse lupus nephritis, three of them also with acute derangement of renal function (patients 2, 3 and 4); in two of their renal biopsies, cellular crescents involving 50% (patient 2) and 25% (patient 3) of the glomeruli were observed. In spite of these aggressive clinical and histological presentations, they responded well to immunosuppressive therapy; all of them recovered normal renal function, negative proteinuria and normal urinary sediments after a few months of treatment with high doses of steroids plus cyclophosphamide taken orally or monthly intravenously.

After the successful therapy of their initial episodes of lupus, they remained clinically asymptomatic, without any indication of renal damage (negative proteinuria, normal urinary sediment) and showing low titres of ANA as the only sign of serologic activity. Each of them continued to be treated with low doses of prednisone (5 mg daily or every other day) and were regularly checked at our outpatient clinic. However, after >10 years (11, 13, 17 and 25 years) of complete remission and clinical quiescence, each had a relapse of lupus nephritis without any identifiable cause.

The types of renal lesions observed in the second biopsies also deserve mention: a focal lupus nephritis Class III (A) was observed in each case, accompanied in one (patient 3) by a membranous (Class V) nephritis. Renal function did not deteriorate in any of the patients, and all showed complete clinical and biochemical responses to prednisone and MMF treatment (MMF was changed to azathioprine in one case because of digestive intolerance). Therefore, the severity of renal involvement was milder in the relapses than in the initial episodes. It could be speculated that the regular check-ups of our patients (allowing early detection of the recurrence) and their maintenance on low doses of steroids helped avoid more severe relapses of lupus nephritis. By comparison, in the patient reported by Moroni et al. [7] prednisone had been discontinued 6 years after the initial episode of lupus nephritis, due to her excellent clinical course; and 18 years later she developed a fulminant flare-up, with deterioration of renal function and severe lesions of diffuse lupus nephritis. However, it must be kept it mind that the effectiveness of low doses of corticosteroids for the prevention of renal flare-ups of lupus has not been investigated in long-term prospective studies. The need for regular follow-up of patients who have had lupus nephritis is easier to acknowledge intuitively, although no prospective studies have been conducted to confirm this theory. Based on our experience with the cases we report here, we think that regular check-ups should be performed every 4–6 months in stable lupus nephritis patients.

Some studies have concluded that flare-ups of lupus nephritis may be predicted by measuring anti-double-stranded DNA antibody levels [8], but increases in anti-DNA antibody levels preceded renal flare-ups by 8–10 weeks. Therefore, patients should be checked every 8–10 weeks in order to detect significant changes in anti-DNA antibody levels early, a protocol rather difficult to justify in patients clinically quiescent for decades. Only in one of our patients (patient 1) was the results of some laboratory tests (increased ANA titre and decreased C3) predictive of the onset of renal relapse. In contrast, in the four patients here reported, late relapses were preceded by unspecific symptoms (asthenia, arthralgias, low-grade fever). Patients should be advised about the importance of these initial symptoms, which would indicate the need for earlier laboratory testing.

The importance of lupus nephritis flare-ups is illustrated by several studies that have shown the number of renal flares as one of the most important predictors of the development of end stage renal disease among lupus nephritis patients [1–5,9–10]. Every renal flare-up leaves a number of sclerosed glomeruli and areas of tubulointerstitial fibrosis, which play a fundamental role in the progression of renal failure [1,5]. Most of these studies agree that renal relapses are common (appearing in 37–45% of lupus nephritis patients, depending on the study), but they cannot be readily predicted. Some studies have shown that the cumulative rate of renal flare-up is 25 and 46% at 5 and 10 years, respectively [10]. In our experience (four cases in a total population of 162 lupus nephritis patients followed in our department), the frequency of very late relapses (>10 years after the first episode) could be estimated to be one case in 40 patients with lupus nephritis.

In conclusion, very late relapses of lupus nephritis after decades of clinical quiescence may be more common than believed previously. Our cases illustrate the importance of regular examinations of lupus nephritis patients even after decades of complete remission.



   References
 Top
 Introduction
 Cases
 Discussion
 References
 

  1. Ponticelli C, Moroni G. Flares in lupus nephritis: incidence, impact on renal survival and management. Lupus 1998; 7: 635[CrossRef][ISI][Medline]
  2. Austin HA, Balow JE. Natural history and treatment of lupus nephritis. Semin Nephrol 1999; 19: 2–11[ISI][Medline]
  3. Illei GG, Takada K, Parkin D et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 2002; 46: 995–1002[CrossRef][ISI][Medline]
  4. El Hachmi M, Jadoul M, Lefebvre C, Depresseux G, Houssiau FA. Relapses of lupus nephritis: incidence, risk factors, serology and impact on outcome. Lupus 2003; 12: 692–696[ISI][Medline]
  5. Mok CC, Ying KY, Tang S et al. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum 2004; 50: 2559–2568[CrossRef][ISI][Medline]
  6. Ponticelli C, Moroni G, Banfi G. Discontinuation of therapy in diffuse proliferative lupus nephritis. Am J Med 1988; 85: 275[ISI][Medline]
  7. Moroni G, Greloni GC, Ponticelli C. Late recurrence of lupus nephritis after long-term clinical remission. Nephrol Dial Transplant 2001; 16: 849–852[Free Full Text]
  8. ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum 1990; 33: 634–643[ISI][Medline]
  9. Ioannidis JP, Boki KA, Katsorida ME et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int 2000; 57: 258–264[CrossRef][ISI][Medline]
  10. Ciruelo E, de la Cruz J, Lopez I, Gómez Reino JJ. Cumulative rate of relapse of lupus nephritis alter successful treatment with cyclophosphamide. Arthritis Rheum 1996; 39: 2028–2034[ISI][Medline]
Received for publication: 9. 2.05
Accepted in revised form: 12. 4.05





This Article
Extract
Full Text (PDF)
All Versions of this Article:
20/9/1994    most recent
gfh954v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Carlavilla, A.
Articles by Praga, M.
PubMed
PubMed Citation
Articles by Carlavilla, A.
Articles by Praga, M.