Membranoproliferative glomerulonephritis

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Membranoproliferative glomerulonephritis
ICD-10	N00-N08 with .2 suffix
ICD-9	581.2, 582.2, 583.2
MeSH	D015432

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• Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2]; Associate Editor-In-Chief: Olufunmilola Olubukola M.D.[3]Cafer Zorkun, M.D., Ph.D. [4]

Overview

Membranoproliferative Glomerulonephritis (MPGN) is a relatively uncommon inflammatory glomerulopathy that can cause chronic nephritis. Based on the histological pattern of glomerular injury it has been described as a chronic kidney disease found mostly in children and young adults. Like many forms of glomerulopathies, membranoproliferative glomerulonephritis (glomerulopathy) has been a diagnosis of tissue pathology rather the diagnosis of a specific disease entity. Therefore, the term membranoploriferative glomerulonephritis (MPGN) relates to a pattern of glomerular injury characterized by mesangial proliferation and expansion, lobularization of the glomerular tufts and double contours which can be caused by many disease states . Glomerular injury occurs due to deposition of immune complexes on the glomerular mesangium or on the glomerular basement membrane. MPGN has been categorized into 3 types based on the histological pattern of glomerular damage. Clinically, MPGN often present with hematuria, varying degrees of proteinuria, with or without Glomerular filtration rate impairment depending on the severity of glomerular injury, and the underlying etiology.

Historical Perspective

• The term membranous glomerulonephritis was used first by Bell in 1946 to describe a category of glomerular renal disease classified within the spectrum of Ellis type II glomerulonephritis. This category also included lipoid nephrosis, lobular glomerulonephritis, and chronic glomerulonephritis .

• In 1957, David Jones, a renal pathologist from Syracuse University in New York, separated membranous glomerulonephritis as a distinct morphologic entity using the special stain periodic acid–silver methenamine (now known as Jones stain). Jones fully illustrated the special features of this lesion such as lobular glomerulonephritis (now known as membranoproliferative glomerulonephritis), lipoid nephrosis (now known as minimal change disease), and chronic glomerulonephritis (now known as focal and segmental glomerulosclerosis). The thickening of the capillary wall and alteration in basement membrane structure, so characteristic of the membranous lesion, were convincingly shown . 

• The electron-dense subepithelial location of the were also subsequently identified by Movat and McGregor in 1959 using electron microscopic methods applied to renal biopsy specimens in 1957. Mellors  in 1957 had identified the third component of the unique lesion of membranous glomerulonephritis; namely, the presence of immunoglobulin in the deposits, using the immunofluorescence technique. Thus, over the span of just 2 years, the triad of essential features of membranous glomerulonephritis were delineated. These are still the fundamental features used today to identify membranous glomerulonephritis, now called Membranoproliferative glomerulonephritis.

Classification

Classification of MPGN based on immunofluorescence microscopy is a result of all advances in the understanding of the pathogenesis of the disease. Based on this advanced techniques, there are three types of MPGN ;

• Immune-complex-mediated MPGN (Type I)
• Complement-mediated MPGN (Type II)
• Non-Ig/complement-mediated MPGN (Type III)

Pathophysiology

Causes

Differentiating Membranoproliferative glomerulonephritis from other Diseases

Epidemiology and Demographics

• Membranoproliferative glomerulonephritis (MPGN) is observed in 6-12% of US patients receiving renal biopsies to evaluate glomerular diseases. This entity accounts for 7% of children and 12% of adults with idiopathic nephrotic syndrome.
• MPGN causes a significant proportion of the cases of nephritis among patients in nonindustrialized countries. For example, in Mexico, MPGN accounts for 40% of all patients with nephritis. Most of these patients have type I disease; MPGN type II is uncommon. However, the incidence of MPGN type I is decreasing progressively in developed countries, which may be explained by a change in environmental factors, especially a decline in infections.
• In an investigation of the changing patterns of adult primary glomerular disease occurrence in a single region of the United Kingdom, Hanko analyzed the results of 1844 native renal biopsies taken between 1976 and 2005 (inclusive) and found the presence of primary glomerulonephritis was revealed in 49% of the biopsies, with the most common forms being immunoglobulin A (IgA) nephropathy (38.8%).
• Other common forms were membranous nephropathy (29.4%), minimal-change disease (MCD) (9.8%), MPGN type 1 (9.6%), and focal segmental glomerulosclerosis (FSGS) (5.7%). The incidence of IgA nephropathy increased significantly over the study period, whereas the occurrence of membranous nephropathy decreased.
• In the United States, MPGN predominantly affects the white population. Type I disease affects women more often than men, whereas a nearly equal sex distribution is seen in MPGN type II.
• The idiopathic forms of MPGN are more common in children and young adults (range, 6-30 y). Isolated reports of involvement in patients as young as 2 years and as old as 80 years are noted in the literature. Secondary types of MPGN predominate among adults.

Risk Factors

Risk Factor
Immune complex–mediated disease	Autoimmune Systemic lupus erythematosus (SLE), Sjögren syndrome Rheumatoid arthritis Inherited complement deficiencies (in particular, C2 deficiency) Scleroderma Celiac disease  Chronic infections Viral – Hepatitis B, hepatitis C, cryoglobulinemia type II Bacterial – Endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy Protozoal – Malaria, schistosomiasis
thrombotic microangiopathies	Healing phase of hemolytic uremic syndrome (HUS) and/or thrombotic thrombocytopenic purpura (TTP) Syndromes of circulating antiphospholipid (anticardiolipin) antibodies Radiation nephritis Nephropathy associated with bone marrow transplantation Sickle cell anemia and polycythemia Transplant glomerulopathy
Paraprotein deposition diseases	Glomerulonephropathies associated with cryoglobulinemia type I Waldenström macroglobulinemia Immunotactoid glomerulopathy Immunoglobulin light-chain or heavy-chain deposition diseases Fibrillary glomerulonephritis Monoclonal gammopathy of unknown significance
Malignant neoplasms	Lymphoma Leukemia, and carcinoma are associated with a membranoproliferative pattern of renal injury.

Natural History, Complications and Prognosis

Complications

• Recurrent disease after transplantation : Recurrent disease is a risk among those patients who receive a renal transplant. [2] Of patients with type I disease, 30-70% develop recurrent MPGN, and 30-40% of the recurrences lead to graft failure. The rate of recurrence of MPGN type II ranges from 50% to 100%; although recurrences may be mild, eventually 50% of the grafts fail. Recurrence rates of MPGN type III are not known.
• Secondary hypertension, edema, and infections: Hypertension is present in 80% of patients at presentation; patients generally develop worsening of hypertension with the progression of renal insufficiency. Periorbital or dependent edema may occur in patients with a nephritic or nephrotic presentation, and anasarca is present in a few patients. The propensity for infections with encapsulated bacteria, including Streptococcus, Haemophilus, and Klebsiella species, is increased. Prophylactic antibiotics and hyperimmune globulins may be useful in some patients. Administer the pneumococcal vaccine and yearly influenza vaccination to all patients.
• Thromboembolism tendency : Loss of anticoagulant antithrombin III, proteins C and S, increased procoagulants, defective fibrinolysis, increased platelet aggregability, hyperlipidemia, endothelial cell injury, and steroids may lead to thrombosis. The renal vein is a common site of thrombosis because of hemoconcentration and loss of the anticoagulants through glomerular filtration.
• Hyperlipidemia : Hyperlipidemia is a significant adverse event in patients with nephrotic syndrome. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and intermediate density lipoprotein (IDL) levels are increased early in the disease. High-density lipoprotein (HDL) levels may be variable, but levels of the cardioprotective fraction HDL2 usually are decreased. Lipoprotein-a levels are increased. Hyperlipidemia in patients with nephrotic syndrome may cause accelerated atherosclerosis and increased coronary events. Also, hyperlipidemia may accelerate the progression of renal disease.
• Anemia : is often multifactorial; urinary losses of transferrin cause iron deficiency, decreased production of erythropoietin, and complement-mediated red blood cell lysis
• Hypocalcemia : and secondary hyperparathyroidism may result from vitamin D deficiency due to urinary losses of cholecalciferol-binding globulin and failure to form activated vitamin D
• Protein calorie malnutrition
• Growth retardation

Prognosis

• The main predictors of an adverse outcome in membranoproliferative glomerulonephritis (MPGN) are nephrotic syndrome and hypertension at presentation, low glomerular filtration rate (GFR) at 1 year, and older age.
• Histologic characteristics of crescent formation, interstitial fibrosis, tubular atrophy, and multiple sclerotic glomeruli indicate a poor prognosis. However, hypocomplementemia is not a predictor of disease severity or prognosis.
• MPGN type I with nephrotic syndrome is a progressive disease, with 50% of patients developing end-stage renal disease (ESRD) after 10 years and 90% of patients developing ESRD after 20 years. MPGN type I without nephrotic proteinuria has a 10-year renal survival rate of 85%.
• MPGN type II is generally more aggressive than type I disease and has a median renal survival rate of 5-12 years. ESRD develops in 50% of the patients within 10 years of diagnosis. C3 glomerulonephritis, on the other hand, has been associated with preserved renal function in about 50% of patients, whereas approximately 15% of patients progress to ESRD.
• Data on outcomes with MPGN type III are very limited. Iitaka found that 7 patients who were followed for 9-17 years maintained their renal function over this period, whereas Anders reported that 4 of 8 patients in their series developed ESRD. In a study comparing therapy with alternate-day corticosteroids in 21 patients with type I disease and 25 patients with type III disease (followed for a minimum of 5 y), the investigators found that patients with MPGN type III had a greater decline in GFR, but there was no difference in the number of patients reaching ESRD in the 2 groups.
• Kawasaki reported worse prognosis in pediatric patients with MPGN related to complement component C3 than in those with immune complex–mediated MPGN. In their study of 37 patients, those with C3-related MPGN were more likely to be nonresponsive to therapy or progress to ESRD.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case presentation

A 54-year-old white man was referred with a 1-week history of bilateral pedal edema, worsening hypertension, and a rise in serum creatinine from 111 μmol/L to 213 μmol/L over 2 weeks. He had microscopic hematuria and proteinuria quantified at 24 grams/day (see Additional file 1). His serum albumin was 24 g/L compared with 35 g/L 2 weeks earlier. Other relevant investigations included negative hepatitis B and C serology, weakly positive speckled antinuclear antibody (ANA) titer of 160 (normal <40) with double-stranded deoxyribonucleic acid (DNA) of 0 IU/mL (normal <7), normal ratio of serum free light chains, negative cryoglobulin screen, negative serum protein electrophoresis, and a normal C3 of 1.77 g/L and C4 of 0.38 g/L.

He had a background history of hypertension, obstructive sleep apnea, and a 3-year history of colorectal carcinoma with hepatic metastasis. His initial treatment included neoadjuvant chemotherapy with capecitabine and bevacizumab, and 26 fractions of radiotherapy. He then underwent a right hemicolectomy and a partial right hemihepatectomy, followed by 6 months of capecitabine and bevacizumab. One year later, a new 74 mm metastatic lesion developed in his residual right liver lobe, and a 16 mm mucin-secreting adenocarcinoma occurred at the left vesicoureteric junction, which was managed by distal ureterectomy. He was recommenced on capecitabine, bevacizumab, and cetuximab, and continued on this treatment until presentation with nephrotic syndrome.

A renal biopsy was diagnostic of MPGN type I. Functioning glomeruli showed mesangial hypercellularity, endocapillary proliferation, and double contours in capillary loops. No hyaline deposits were noted in the capillary loops and no segmental sclerosis was seen (Fig. 1a). There was interstitial fibrosis and tubular atrophy together with lymphocytes, plasma cells, and eosinophils in the scarred interstitium (Fig. 1b). Immunofluorescence showed moderate granular deposition of IgG and C3 in the mesangial areas and around the capillary loops. Electron microscopy showed deposits in the mesangial, paramesangial, and subendothelial regions. Focal duplication of the glomerular basement membrane was seen and there was mild expansion of mesangial matrix.

Curative therapy for the malignancy was not possible, so treatment was commenced with prednisolone for the renal disease. Four months later, his proteinuria had reduced to 1.4 grams/day, creatinine had improved to 155 μmol/L, and albumin returned to baseline of 31 g/L.

Discussion

This case highlights that MPGN can be associated with malignancy, although the mechanism underpinning this association has not been completely elucidated.

Little is known about the association between MPGN and malignancy, although there is a wealth of published information regarding nephrotic syndrome and malignancy. As early as the 1960s, there were suggestions that nephrotic syndrome may be related to thyroid cancers, Hodgkin’s lymphoma, or chronic lymphocytic leukemia [1]. Further, a more recent study analyzed approximately 8 million people in the Danish National Registry of Patients, estimating that that 4.7 % of patients who had nephrotic syndrome (from a total of 4293 patients) had underlying malignancy with lung cancer, multiple myeloma, and prostate cancer being most likely [10].

There are two main hypotheses which have been proposed to explain the pathogenesis of the association between MPGN and malignancy. First, an undiagnosed malignancy associated with immune complex deposition may cause a glomerular disease-like paraneoplastic syndrome. While data are limited in MPGN, studies have shown that paraneoplastic membranous nephropathy is characterized by an increased number of inflammatory cells in the glomeruli compared with that of idiopathic membranous nephropathy [4, 11]. There is a greater prominence of the subtypes of IgG1 and IgG2 in the renal biopsy samples of patients with paraneoplastic membranous nephropathy compared with idiopathic membranous nephropathy [12]. Second, viral infection may have induced both glomerulopathy and cancer by intrinsic viral oncogenic activity. It is possible that disrupted renal clearance of biological mediators may be associated with oncogenesis [13]. However, the most likely explanation for the connection between virus latency and tumorigenesis is that replicating viruses may initiate cell death [14]. When latent viruses produce virions, virus replication generates pathogen-associated molecular patterns from partially synthesized viral chromosomes, double-stranded ribonucleic acid (RNAs) and empty capsids that trigger cellular DNA damage responses and innate immune signaling. Toll-like receptor and interferon signaling by virus infection is subsequently activated, amplifying the innate response [14].

Remission of cancer has led to subsequent remission of nephrotic syndrome. Reports have shown that patients who have paraneoplastic glomerulopathy secondary to renal cell carcinoma have undergone remission or a reduction of proteinuria through either radical nephrectomy, nephron-sparing, partial nephrectomy, or laparoscopic nephrectomy [15]. There are, however, no reports that have specifically looked at the remission of cancer in patients with MPGN. There is some evidence for the use of prednisolone when cure of the cancer is not an option. One case of MPGN developed after surgical removal of a bronchial carcinoid tumor, but responded to prednisolone therapy [16]. Furthermore, there has been a case showing use of prednisolone for paraneoplastic MPGN without ablation in a patient with metastatic prostate cancer [7]. Moreover, paraneoplastic glomerulopathy developed in a patient with minimal change disease, who had retroperitoneal sarcoma, probably secondary to a T-cell-mediated response to malignancy, which went into remission with corticosteroid therapy [17]. Administration of corticosteroids was considered in this setting primarily because of the patient’s high performance status.

The prognosis of MPGN in the setting of malignancy is uncertain [18]. The presence of hypertension at presentation, severe nephrotic syndrome, and renal insufficiency are known poor prognostic factors among non-malignancy-associated nephrotic syndrome [18].

Conclusions

In summary, we report a case of an association between MPGN and metastatic colorectal cancer. Clinicians need to be vigilant about the possible paraneoplastic nature of MPGN. Initial treatment of the underlying malignancy should be the primary management in patients presenting with kidney disease which is suspected to be paraneoplastic in etiology, although prednisolone is an appropriate therapy if cure of the cancer is not feasible.

Case #1

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