Immunoglobulin-mediated membranoproliferative glomerulonephritis (ORPHA:329903)
A primary form of membranoproliferative glomerulonephritis (MPGN) characterized by deposition in the renal glomeruli of immunoglobulin with complement fractions, especially C3. Clinical presentation may range from nephrotic syndrome and acute kidney injury to asymptomatic proteinuria and hematuria.
Epidemiology
It is amongst the rarest forms of glomerular disease; the annual incidence is unknown. Distribution between males and females tends to be equal, and presents at all ages, starting from early childhood.
Clinical description
Clinical features and severity are heterogenous, ranging from asymptomatic proteinuria which is noticed on routine urinalysis, to typical nephritic syndrome with mild proteinuria and hematuria, to a more acute presentation with nephrotic syndrome (edema, oligoanuria), hypertension and possibly acute renal failure. An infectious trigger, typically but not exclusively an upper respiratory tract infection, is frequently described, particularly in children presenting with macroscopic hematuria. Circulating complement evaluation shows frequently reduced C3, while C4 is usually normal.
Etiology
When a clear underlying etiology cannot be identified despite a thorough evaluation, Ig-mediated MPGN is considered primary or idiopathic. Variants in genes encoding for complement alternative pathway proteins and C3 nephritic factor are detected in 10%-25% and in 40%-54% of patients respectively.
Diagnostic methods
Diagnosis relies on renal biopsy, which shows features of MPGN with deposition of both immunoglobulins (IgG, IgA, IgM) and of complement (mainly C3, but also C1q, C4d). Upon histological diagnosis, secondary forms need to be excluded by screening for infection (mainly hepatitis B and C), autoimmune conditions (mainly systemic lupus erythematosus) and monoclonal gammopathies (especially in adults > 50 years of age). In primary forms, especially if circulating C3 is persistently reduced, screening for alternative pathway of complement dysregulation, both genetic and serological, should be performed in expert centers.
Differential diagnosis
At onset, this glomerular disease may resemble acute post-infectious glomerulonephritis, especially in children, which is a more frequent and self-limiting form of glomerulonephritis. Forms presenting with intra or post-infectious macrohematuria and proteinuria may resemble IgA nephropathy clinically, but the renal biopsy will give a different picture. The histological picture can also be found in secondary forms of MPGN, mostly due to infections, autoimmune conditions or monoclonal gammopathies.
Genetic counseling
The forms of immunoglobulin-mediated MPGN with genetic mutations identified in genes encoding for alternative pathway regulator proteins are very rarely familial and disease pathogenesis is multifactorial. Therefore, genetic counseling may be useful but is not essential.
Management and treatment
Management is based on the severity of the presenting features. Due to the rarity of these conditions, expert advice should be sought both for appropriate treatment and for genetic and serological work-up. All patients with proteinuria should receive optimal conservative treatment with low-salt diet, renin-angiotensin system inhibitors and, when appropriate, lipid lowering agents. Although evidence is limited, immunosuppressive treatment is usually used when proteinuria and glomerular inflammation are present, using oral glucocorticoids and mycophenolate mofetil. Response is not always optimal. In the presence of intense inflammation with extracapillary proliferation or acute renal failure, more intense immunosuppression is attempted with anti-proliferative agents such as cyclophosphamide and intravenous boli of methylprednisolone. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.
Prognosis
Though this disease is very heterogenous and can be extremely subtle with low-grade relapsing proteinuria, long-term prognosis in forms which do not respond to treatment is poor, leading not only to terminal renal failure but also to a consistent risk of relapse post-renal transplantation.

                            Last update: 
                            July 2021


                            - Expert reviewer(s): 
                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*


                                * European Reference Network