|Year : 2019 | Volume
| Issue : 2 | Page : 531-536
|Primary membranous nephropathy with concomitant IgA nephropathy
Reza Khorsan, Ramy M Hanna, Khalid Ameen, Farid Arman, Niloofar Nobakht, Huma Hasnain, Ashley Hyunh, Anjay Rastogi
Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, California, USA
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|Date of Submission||06-Apr-2018|
|Date of Acceptance||09-May-2019|
|Date of Web Publication||23-Apr-2019|
| Abstract|| |
Membranous nephropathy (MN), an autoimmune glomerulonephritis which can occur in primary and secondary forms, is one of the most common inflammatory glomerulopathies in elderly patients. The pathophysiology of the primary form is generally due to circulating immunoglobulin (IgG4) antibodies which often target phospholipase A2 receptors (anti-PLA2R) and Thrombospondin Type 1 Domain containing 7A (anti THSD7A). IgA nephropathy is one of the most common autoimmune glomerular diseases in the world and presents with a spectrum of disease ranging from asymptomatic mild hematuria and proteinuria to rapidly progressive crescentic glomerulonephritis. We present a rare case of concomitant IgA and primary MN in a single patient treated successfully with renin–angiotensin–aldosterone blockade, corticosteroids, and calcineurin inhibitors. The peak proteinuria was near 7.5–8 g protein/g creatinine by various measures. Serum creatinine remained normal, and anti-PLA2R was detectable and decreased with successful treatment. Clinicians should be aware of the possibility of two glomerular disorders in patients with glomerulonephritis and atypical presentations for any single disorder.
|How to cite this article:|
Khorsan R, Hanna RM, Ameen K, Arman F, Nobakht N, Hasnain H, Hyunh A, Rastogi A. Primary membranous nephropathy with concomitant IgA nephropathy. Saudi J Kidney Dis Transpl 2019;30:531-6
|How to cite this URL:|
Khorsan R, Hanna RM, Ameen K, Arman F, Nobakht N, Hasnain H, Hyunh A, Rastogi A. Primary membranous nephropathy with concomitant IgA nephropathy. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 21];30:531-6. Available from: http://www.sjkdt.org/text.asp?2019/30/2/531/256863
| Introduction|| |
Membranous nephropathy (MN), an autoimmune glomerular disease, is one of the most common causes for nephrotic syndrome in older and is characterized by the formation of sub-epithelial immune deposits in the glomerular basement membrane. The disease is characterized by immunoglobulin G4 (IgG4) subtype and anti-phospholipase A2 receptor (PLA2R) antibodies in the majority (70%–80%) of cases of primary disease. The secondary form of the disease is associated with IgG1 and 2 and mesangial IgG deposits.,, Of note, hypercoagulability is a notable feature of MN and the secondary form is associated with malignancy among diverse causes.,,
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in Caucasians, Asians,, and pediatric populations, which is characterized by the presence of prominent IgA1 deposits in the glomerular mesangium. It is the most common glomerulopathy world-wide and has a high prevalence in the populations of Asian nations.,
There are other cases reported of concomitant IgAN and MN.,, Here, we report a case of a 50-year-old female presented with proteinuria who was diagnosed with coexisting MN and IgAN on renal biopsy.
| Case Report|| |
We present a 50-year-old female who presented with heavy proteinuria with no gross hematuria. She was hospitalized for deep venous thrombosis of her right lower extremity, multiple pulmonary emboli, and bilateral renal vein thrombosis (RVT) four months before her initial visit to our medical center. At presentation, she had a history of taking longterm oral contraceptive pills with no other significant past medical history. She is a lifetime nonsmoker with occasional alcohol use and no illicit drug use. When she was examined, only peripheral edema was found. She described no shortness of breath without any paroxysmal nocturnal dyspnea or orthopnea.
Initially, her proteinuria was thought to be due to her bilateral RVT. Renal biopsy was deferred until completion of anticoagulation therapy. Her renal function was normal; however, urine protein-to-creatinine ratio UPC was elevated at 7.5 mg/g. Repeat Doppler ultrasound study of her renal veins was performed to rule out continuous RVT, and the study revealed no evidence of RVT. Renal biopsy was performed and revealed the presence of primary MN with superimposed IgA nephropathy. The specific findings confirming concomitant IgAN and primary MN on renal biopsy is shown in [Figure 1].
|Figure 1: Renal biopsy findings suggestive of IgAN and MN.|
(a) Light microscopy showing glomerular basement membrane thickening and mesangial deposits consistent with MN and IgAN. (b) Immunofluorescence showing IgG in granular pattern consistent with MN. (c) Immunofluorescence showing IgA deposition in mesangium consistent with IgAN. (d) Electron micrograph showing subepithelial spike and ball deposits consistent with MN. (e) Positive anti-PLA2R stain. IgAN: Immunoglobulin A nephropathy, MN: Membranous nephropathy, PLA2R: Phospholipase A2 receptor.
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The patient was started on cyclosporine 25 mg twice daily and prednisone 10 mg daily. She was also put on simvastatin for hyperlipidemia and lisinopril for the high blood pressure. In subsequent follow-up, cyclosporine was uptitrated up to 125 mg BID to control proteinuria. Renin angiotensin aldosterone blockade was accomplished with lisinopril, which was titrated up to 20 mg BD.
Four months after starting treatment, the patient was hospitalized for an episode of hypertensive emergency with systolic blood pressure >200 mm Hg. Cyclosporine was withheld, and she was started on metoprolol 25 mg twice daily, amlodipine 10 mg daily, and lisinopril 40 mg daily. A month later, when her blood pressure was stabilized, a retrial of cyclosporine 100 mg twice daily was started as the 24 h protein was 7.8 g/day at that time.
Seven months after starting treatment, the level of anti-PLA2R decreased, and her blood pressure improved, necessitating a decrease of diuretics and antihypertensive agents. Eight months later, on cyclosporine 100 mg twice daily, she felt well, proteinuria improved to nearly 1 g protein/24 h, and edema resolved. Her antihypertensive needs decreased, diuretics were not needed, and anti-PLA2R level decreased from 213.5 reference unit (RU)/mL to 1.9 RU/mL and became undetectable two months later at 10 months after presentation. Although proteinuria had greatly improved, some residual levels may persist due to segmental sclerosis from superimposed IgAN. The patient has developed a left-sided hearing loss possibly as a side effect due to cyclosporine. Laboratory findings of urine protein/ creatinine ratio, anti-PLA2R antibody levels, and serum creatinine versus date are shown in [Figure 2].
|Figure 2: Plot of serum creatinine μmol/L, 24 h urine protein (g protein/24 h), and anti-PLA2R antibodies (RU/mL) versus date. Green arrows show start and restart of calcineurin therapy; red line shows the date of stopping calcineurin therapy due to hypertensive urgency.|
PLA2R: Phospholipase A2 receptor.
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| Discussion|| |
MN and IgAN are common primary glomerular diseases, which are mediated by immune complex deposition. The concomitant presence of idiopathic MN (IMN) and IgAN is rare in adults and children, and limited cases of coexisting MN and IgAN have been previously reported.,,,,, The etiology of overlapping MN and IgAN remains unclear. Genetic factors may contribute to the development of overlapping IgAN and MN, and familial overlapping of IgAN and MN has been reported.,, There have been six reports of overlapping IgAN and MN reported in literature.,,,,, All published reports of concomitant IgAN and MN in literature are show in [Table 1].
|Table 1: Publications featuring cases of combined IgA and MGN nephropathies.|
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MN is characterized by the formation of subepithelial immune deposits that predominantly consist of IgG and C3 in the glomerular basement membrane. The majority of cases of primary MN are associated with autoantibodies against the podocyte antigen M-type PLA2R., In IgAN, the distribution of IgA may include a presence in the mesangium, with or without capillary loop staining. IgG, IgM, and C3 may be present, but not in greater intensity than IgA, except that IgM may be prominent in sclerotic areas.
IMN combined with IgAN comprises the clinical and pathological features of both diseases. Histopathologic reports of previous studies in patients with overlapping MN and IgAN have shown that IgG deposits are mainly in the capillary walls, while IgA deposits are predominantly in the mesangial area in the renal pathology.,,
A recent retrospective study, which included large patient cohort of overlapping MN and IgAN (73 cases) and MN alone (425 cases), has compared the renal pathological features of overlapping IMN and IgAN versus IMN only. Result analysis showed that the renal histopathology of the overlapping MN and IgAN groups not only exhibited significantly increased mesangial cell proliferation and matrix expansion characteristic of the renal histopathology of IgAN but also showed an increase in the inflammatory cell infiltration and higher proportions of arteriolar hyalinosis.
However, there was a lower proportion of segmental sclerosis in the overlapping IMN and IgAN group compared with the MN alone group. The results of previous case series studies proposed that overlapping MN and IgAN appears to correlate with an increased incidence of disease remission and thus may not lead to a poorer prognosis compared with MN only.,,
The primary means for diagnosing IgAN is renal biopsy. Recently, progress has been made in using M-type PLA2R for diagnosing idiopathic MN.,,,, It has been found the majority of patients with IMN to have anti-PLA2R autoantibodies in peripheral circulation, which is rarely detected in secondary MN., Another study has proposed that IFI27 may serve a useful noninvasive biomarker for diagnosing chronic GN using peripheral blood; nevertheless, more data are needed in this regard.
The cases of coexisting MN and IgAN are rare, and they comprise the clinical and pathological features found in both diseases. Serum anti-PLA2R is considered an increasingly important biomarker that can support in the diagnosis of IMN associated with IgAN. We report this rare presentation of IgAN and MN as a rare presentation of concomitant glomerulopathies and to illustrate the usefulness of anti-PLA2R as a disease marker for MN, and the successful strategy of treating both underlying pathological findings that lead to successful clinical remission.
| Acknowledgments|| |
We would like to acknowledge Dr. Mark Haas, MD, PhD, for his assistance in providing the biopsy slides for this report.
Conflict of interest: None declared.
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Ramy M Hanna
Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, California
[Figure 1], [Figure 2]
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