Secondary Membranous Nephropathy—One Center Experience

Abstract

Introduction. Secondary membranous nephropathy (MN) is most commonly seen in the setting of autoimmune disease, infection, and neoplasia, and with certain therapeutic agents. The aim of our study was to analyze the presenting features and outcome of the patients with secondary MN. Patients and Methods. We retrospectively studied patients with secondary MN diagnosed between the years 1991–2002. In this period, we performed a total of 1874 renal biopsies. MN was diagnosed in 129 cases. Results. In 40 patients (31%), an underlying primary cause was verified (70% women, 30% men, median age 49.5 years). In 18 patients (45%), the disease was drug induced, 11 patients (27.5%) had autoimmune disease, seven patients (17.5%) solid tumors, three patients (7.5%) hepatitis B, and one patient was diagnosed with both hepatitis B and prostate carcinoma. At presentation, median proteinuria was 4.09 g/24 h; 60% were nephrotic. Most of the patients had normal renal function with a median serum creatinine 79 µmol/L and a median GFR 1.285 ml/s. The patients were treated according to the underlying disease. At the end of the follow-up, the patients with drug-induced MN were in complete remission after the discontinuation of the drug. The patients with autoimmune disease were treated with immunosuppression, most of them with very good results. The outcome of the patients with neoplasia was much worse. Conclusion. A thorough and repeated exclusion of secondary forms of MN has significant prognostic and therapeutic implications, especially in drug-induced and autoimmune MN.

• membranous nephropathy (MN)
• autoimmune disease

Introduction

Membranous nephropathy (MN) is a glomerular disease in which immune deposits of immunoglobulin G (IgG) and complement components develop predominantly or exclusively on the subepithelial surface of the glomerular capillary wall. Deposition is associated with a marked increase in glomerular permeability to protein, which is manifested clinically as nephrotic syndrome (NS). The incidence and prevalence of MN are impossible to quantify, as many patients are asymptomatic with subclinical proteinuria that never prompts renal biopsy. The disease is uncommon in children. In adults, about 30% of all biopsies for NS reveal MN, and the disease accounts for about 50% of biopsied cases of NS in older Caucasian adults, a population in which MN remains the leading cause of NS.[1] MN is more common in men than women by about a 2–3:1 ratio, and individual peaks occur between ages 30 and 40 and again between ages 50 and 60 years.[2]

MN most commonly is idiopathic (primary), but secondary causes are common in children and older adults. A secondary cause may be detected in 20–30% of adult cases. Whereas the infectious causes (hepatitis B, quartan malaria, schistosomiasis) predominate in endemic areas, the most common secondary causes of MN in industrialized countries include malignancy and systemic lupus erythematosus (SLE).[3-9] In the majority of cases, secondary MN can be readily detected by a combination of clinical, serological, and morphological analyses. The immunopathologic appearance is similar to that of idiopathic MN. However, the presence of certain features may suggest a secondary cause. These include the absence of total injury of the glomeruli, mesangial cell proliferation, mesangial or subendothelial deposits by electron microscopy, and immunoglobulin A or C1q deposition by immunofluorescence.[6], [10&11]

Patients and Methods

We retrospectively studied patients with MN diagnosed between the years 1991–2002 in our center. In this period, we performed a total of 1874 renal biopsies (RB). Our catchment area is approximately 4 million inhabitants. MN was diagnosed in 129 cases, which represents almost 7% of all biopsies. The available data from the Czech Registry of RB from 1994–2000 show that 39.3% of indications for RB represents nephrotic syndrome.[12] We can thus roughly estimate that MN is diagnosed in about 18% of patients with nephrotic syndrome.

All the patients with biopsy proven MN were routinely tested for the presence of potential underlying disease. Apart from a history including risk factors and family history, the study included hepatitis B and C and syphilis serology, complement levels and autoantibodies, chest radiography, ultrasound of the abdomen, stool guaiacs, mammography in women over 50 years of age, gynecologic examination, and tumor markers (AFP, CEA, PSA, CA 15-3, CA 19-9). Where symptoms were present or in the case of positive results of screening tests, the study was much more thorough.

Results

Demographic Data

In 40 patients (31%), an underlying primary cause was verified. There were 28 women (70%) and 12 men (30%). Their median age was 49.5 (21–74) years. The median follow-up was 48 (2–127) months.

Laboratory and Clinical Data

At presentation, the median proteinuria (PU) was 4.09 (0.45–22) g/24 h; 60% of the patients were nephrotic. The median serum albumin was 27.8 (12–46.4) g/L; the median serum cholesterol was 7.45 (3.8–15) mmol/L. Most of the patients had normal renal function with the median serum creatinine level 79 (54–333) µmol/L and the median GFR 1.285 (0.23–2.4) ml/s. Sixty-five percent of the patients were hypertensive. Microscopic hematuria was observed in 50% of them. The histologic stages were relatively equally distributed (14 × stage I, 15 × stage II, 9 × stage III, 2 × stage not determined).

Drug-Induced Disease

In 18 patients (45% of secondary MN, 14% of MN), the disease was drug induced. In the majority of them (12 patients), the responsible drug was gold, in three penicillamine, in two sulfasalazine, and in one patient a mercury ointment. Their median age was 47 (21–72) years; there were 12 women (median age 47 years) and six men (median age 54 years). The median PU was 4.31 (0.6–22) g/24 h, in women 2.65 g/24 h, in men 6.7 g/24 h.

Autoimmune Disease

Eleven patients (27.5% of secondary MN, 8.5% of MN), all of them women (median age 42 years), had autoimmune disease. Eight patients had SLE, one had rheumatoid arthritis (RA), one mixed connective tissue disease (MCTD), and in one patient the MN was associated with thrombotic thrombocytopenic purpura (TTP). Their median PU was 3 (0.45–6.38) g/24 h.

Malignancy

Seven patients (17.5% of secondary MN, 5.4% of MN) were diagnosed with solid tumors. One patient had both hepatitis B and prostatic cancer. Their data are summarized in Table 1.

Table 1. Paraneoplastic membranous nephropathy

Number	Sex	Age	Cancer	PU	Diagnosis
1.	F	70	Lung	3.82	0
2.	F	68	Lung	8.05	0
3.	M	71	Lung	4.92	Relapse
4.	F	64	Endometrium	4.67	0
5.	F	74	Hepatocellular	4.38	60
6.	M	56	Colon	2.25	48
7.	M	48	Cholangio	2	9
8.	M	52	Prostate	1.4	0

F, female; M, male; age in years, PU in g/24 h, the number in the last column stands for how many months after the renal biopsy the cancer was diagnosed. The third patient was diagnosed with a relapse of lung carcinoma at the time of renal biopsy.

Hepatitis B

In the subgroup of patients with MN secondary to HBV infection (three patients, 7.5% of secondary MN, 2.3% of MN), there were two men aged 73 and 51 years, respectively, and one 59-year-old woman. They all had nephrotic range proteinuria. The underlying cause was determined serologically at the time of RB.

Treatment and Outcome

The patients were treated according to the underlying disease.

In drug-induced MN, the responsible drug was discontinued, which retrospectively confirmed its role in the nephropathy. Thirteen out of the 18 patients achieved complete remission after discontinuation of the drug. At the end of the follow-up, they had nondetectable proteinuria and perfectly preserved renal function. Four were lost from the follow-up, and one patient died of cardiovascular disease, and no data on her renal function and urinary findings were obtainable.

The patients with autoimmune disease were treated with immunosuppression, mostly with cyclophosphamide and steroids. At the end of the follow-up, nine of the 11 patients were in complete remission without any therapy. One patient with SLE currently has active disease, which is being treated, and one patient with RA died 4 months after the diagnosis of MN of infectious complications following treatment with methotrexate.

The outcome of the patients with neoplasia was less favorable. Two lung cancer patients died despite oncologic treatment (4 and 7 months after RB, respectively), as did the patient with multinodular hepatocellular carcinoma (a few months after the diagnosis of the tumor) and cholangiocarcinoma (9 months after RB). The third patient with lung cancer and the woman with endometrial carcinoma were lost from the follow-up. The other two patients were cured. The man with colon cancer underwent a successful colectomy with complete remission of the neoplasia. Nevertheless, his proteinuria of about 2 g/24 h remained basically unchanged. The patient with prostate carcinoma and hepatitis B was treated with interferon and subsequently with lamivudine, and a seroconversion in HBe system was achieved. He also underwent a successful operation of his prostate gland. Fourteen months after RB, he had to be started on peritoneal dialysis (initial creatinine level 340 µmol/L), and he died 2 years later of myocardial infarction.

As regards the three patients with hepatitis B, one patient was lost from the follow-up and one died of myocardial infarction 27 months after the RB. The third patient achieved remission of the nephrotic syndrome under interferon treatment. He died of cirrhosis 6 years later.

Discussion

The reported incidence of secondary MN and different etiological factors vary according to socioeconomic, geographic, and racial conditions. Correa-Rotter et al.[13] reported almost 50% of their MN as secondary, the vast majority of them secondary to SLE. This unusually high number can probably be explained by an inclusion of WHO class V lupus nephritis in the assessment and a higher incidence of SLE in the Mexican population. Cahen et al.[14] had 21% of secondary forms in the French population with a relatively equal distribution of autoimmune, neoplastic, and drug-induced disease. Mohacsi et al.[15] from Hungary reported a similar incidence (23.5%). The incidence of secondary forms of MN in our study is relatively high (31%), mainly due to close cooperation with rheumatologists, meaning that the majority of the patients had either autoimmune or drug-related disease. The proportion of drug-related cases decreases with time as the respective drugs are no longer used.

The renal glomeruli are vulnerable to immunologically mediated injury by a number of drugs. Most drug-mediated glomerulopathies take the form of an MN. Drugs involved in our cases of MN included mainly gold, penicillamine, and sulfasalazine, in all but two patients used for the treatment of RA. The two exceptions were one patient with lung fibrosis and one with systemic scleroderma, both treated with penicillamine. The association of MN with all these drugs has been repeatedly described.[4&5], [7], [16] In patients with rheumatoid arthritis, the incidence of MN may be as high as 7% in patients treated with penicillamine and 1–3% in those treated with gold.[4&5], [7] The proteinuria generally develops within the first 6–12 months of drug therapy, but may take as long as 3–4 years.[7] Other drugs have also been associated with MN: tiopronin, diuretics, captopril, diclofenac, and other nonsteroidal antiinflammatory drugs,[8] bucillamine (its structure and pharmacologic action resembles d-penicillamine), and mercury.[9&10] Our patient with a mercury ointment intoxication with neuropsychological and renal symptoms, described previously in detail, was cured after cessation of the treatment.[17] The discontinuation of the drug leads to resolution of the proteinuria in virtually all cases[5], [7], as it did in all our patients.

MN may occur in patients with RA even in the absence of, and therefore unrelated to, the previous use of the drugs described above,[18-20] which suggests that RA may be the responsible cause of MN. Autoimmunity is now regarded as the predominant pathogenetic process underlying most forms of primary and secondary glomerulonephritis. MN has been described with many autoimmune diseases (Table 1). Although it was originally believed that nephropathy was a rare complication of MCTD, it is now reported in up to 50% of these patients, MN being the most common.[21] The association of TTP with MN was previously described.[22] Our patient had repeated relapses of both conditions at the same time during the course of her disease. With every remission of TTP achieved after plasmapheresis, proteinuria disappeared. We therefore strongly believe that the relationship was not incidental. Nevertheless, by far the most common autoimmune disease associated with MN is SLE, as in our observation. Approximately 10–20% of cases of lupus nephritis have an MN picture.[10] We have, however, included only patients with MN secondary to not yet developed SLE, not the WHO class V lupus nephritis patients (five patients in this period). The importance of the diagnosis lies in the detection of early cases of SLE, often when the disease is not yet developed, and the possibility of closer monitoring of these patients. In one of our cases, the diagnosis of MN preceded the diagnosis of SLE by up to 5 years. The treatment of autoimmune MN is focused on the underlying disease. In almost all our patients, we managed to induce remission of the autoimmune disease and the related nephropathy.

A paraneoplastic MN is a condition that has not always been generally accepted. Nevertheless, several observations considerably support this association, especially with observed remissions of the proteinuria after the removal of the tumor and its reappearance with tumor recurrence. Furthermore, tumor antigens in immune complexes in RB samples have repeatedly been detected.[23&24] It is now believed that an underlying malignancy is responsible for up to 5–10% of cases of MN in adults (5.4% in our study), with the risk being highest in patients over 60. In this age group, MN is associated with malignancy in 20–30% of patients.[3] The malignancy rate appears to be up to five times higher in the patients with MN than in the baseline population.[23] In the majority of cases, a solid tumor is involved, but MN has also been detected in patients with hematologic malignancies.[3], [24] The malignancy in presumed tumor-induced MN has usually been diagnosed or is clinically apparent at the time when proteinuria is noted. The incidence of MN caused by occult tumor is under 1–2%.[3] Therefore, a tumor work-up should probably be initiated only if some suggestive findings such as unexplained anemia, guaiac positive stools, or weight loss are present. In our study, there were eight patients with a diagnosis of a solid tumor. In five of them, the diagnosis of the malignancy was made at the time of renal biopsy. We were able to obtain follow-up data on three of them: two patients died of the tumor (lung carcinoma in both), one underwent a successful treatment of his prostate carcinoma, but nevertheless progressed to end-stage renal failure, probably due to nonimmunologic reasons, because his renal insufficiency was already advanced at the time of RB. The remaining three patients developed malignancy in the course of several months to years. In the case of the patient with cholangiocarcinoma (diagnosis 9 months after RB), it was probably due to a late diagnosis of a previously existing condition. The relationship between the neoplasia and MN in the remaining two cases (hepatocellular and colon carcinoma) is probably not causal. A possibility of secondary malignancy cannot be excluded in these two patients, as they were treated with immunosuppressive drugs (cyclophosphamide and chlorambucil, respectively). Nevertheless, they were diagnosed with a malignant condition thanks to the previously performed renal biopsy, because they were repeatedly checked.

An infection (e.g., hepatitis B, C, quartan malaria, schistosomiasis, syphilis, and others) is the main cause of MN worldwide. MN due to hepatitis B virus infection primarily occurs in children in endemic areas, many of whom are asymptomatic carriers with no history of active hepatitis. The serum transaminases tend to be normal or only mildly elevated, and the serology is positive for surface antigen, anti-core antibody, and usually e antigen. It appears that it is the e antigen and cationic anti-e antibody that are primarily deposited in the glomeruli.[25&26] Spontaneous resolution of the proteinuria is common in children but not in adults, many of whom will have progressive disease. Therapy with corticosteroids is contraindicated, as these agents can enhance viral replication and lead to chronic active hepatitis.[27] On the other hand, antiviral therapy with interferon and other candidate therapies may lead to seroconversion and improvement of proteinuria.[26], [28] We have treated two of the four patients with HBV with interferon with a documented seroconversion in one. The other died of cirrhosis despite treatment.

The purpose of this study was to analyze the frequency, presenting features, and outcome of the patients with secondary MN. We observed a relatively high percentage of secondary causes, mostly autoimmune or drug induced. In some cases, the finding of MN was the first sign of not yet developed autoimmunity. In other patients, it enabled us to diagnose a malignancy. We would therefore like to enhance the clinical awareness of potential underlying diseases in MN. A thorough and repeated exclusion of secondary forms of MN has significant prognostic and therapeutic implications, especially in drug-induced and autoimmune MN. An early diagnosis of cancer can be life saving.