FINAL DIAGNOSIS Early Dense Deposit Disease (Membranoproliferative Glomerulonephritis type II)
Membranoproliferative glomerulonephritis (MPGN), also called mesangiocapillary glomerulonephritis, is characterized histologically by thickening of the glomerular capillary walls (membrano) and hypercellularity of the glomerular capillary tufts (proliferative). Three types of membranoproliferative glomerulonephritides are recognized based on the immunopathology and ultrastructural abnormalities. Membranoproliferative glomerulonephritis types I and III are immune-complex mediated diseases. Type I MPGN is frequently associated with chronic hepatitis C viral infection and mixed cryoglobulinemia (type II (monoclonal IgM-Kappa, polyclonal IgG), type III (polyclonal IgG, polyclonal IgM)); both serum C3 and C4 are decreased, but usually C4 is disproportionately depressed relative to C3. Light microscopy reveals a lobular proliferative glomerulonephritis with characteristic double glomerular basement contours (tram tracking) on silver stain secondary to mesangial interposition in the glomerular capillary loops. Immunofluorescence of MPGN type I reveals intense staining with C3 in a granular pattern in the periphery of the glomerular capillary loops and the mesangium and also frequently stains with IgG, IgM and variably with C1q. Ultrasctructurally, MPGN type I shows variable interposition of mesangial and inflammatory cells in the glomerular basement membrane (GBM) and electron dense deposits in the subendothelial and mesangial regions; in patients with cryglobulinemia the electron dense deposits typically have substructure. MPGN type III has two types (Strife-Anders and Burkholder) which both show coarse granular staining in the glomerular capillary loops and mesangium with C3 in about half of the cases and combined C3 and IgG staining in the other half. The ultrastructural findings of the Strife-Anders variant are similar to MPGN type I plus subepithelial deposits with basement membrane material in between causing "spikes" which can be appreciated by light microscopy. MPGN type II seems to be a distinct pathologic entity and is more commonly referred to as dense deposit disease (DDD).1
Clinical Presentation of DDD
DDD is a rare entity that affects approximately 2-3 people per million. It is more common in children (ages 5-15) and is associated with an upper respiratory tract infection in half of the cases. The clinical presentation is usually a mixture of nephritic and nephrotic features characterized by hematuria, mild to moderate proteinuria, hypertension and progression to renal insufficiency with an elevated serum creatinine. Red blood cell casts may be present in the urine. Nephrotic syndrome may occur as well. Patients may develop whitish-yellow deposits within the ocular Bruch's membrane, drusen, which may over time interfere with retinal function. It may also be associated with acquired partial lipodystrophy (APL) with the loss of subcutaneous adipose tissue of the upper half of the body preceding the onset of renal disease. DDD is chronic, causing deterioration of renal function resulting in end-stage renal disease usually within 10 years of the diagnosis.1,2
DDD is characterized by electron dense deposits within the lamina densa of the GBM. The deposits are usually discontinuous and segmental within the lamina densa and can also be found in the mesangium, Bowmen's capsule and around small vessels. By light microscopy, the deposits stain brightly with periodic acid-Schiff (PAS). As the disease progresses, mesangial hypercellularity and matrix interposition occur as well as podocyte damage and death. Immunofluorescence demonstrates C3 deposition along the glomerular capillary walls and coarse granular staining of the mesangial regions. IgG deposition is usually absent within the glomerulus, supporting the idea that the deposits are not immune-complex deposits.
Complement in DDD: Autoantibodies and Genetics
DDD is caused by the dysregulation and activation of the alternative complement pathway. A low level of C3 activity is present via spontaneous hydrolysis of C3. This conformational change allows binding of Factor B to form the initial C3 convertase of the alternative pathway which cleaves C3 to C3b. C3b then binds with Factor B to form C3Bb, i.e. the alternative complement pathway C3 convertase. C3 convertase cleaves C3 to C3b thereby forming more C3 convertase and the amplification loop continues. C3b by itself has a short half-life, but when bound to IgG or basement membranes, it evades inactivation. Because this system is always activated by spontaneous hydrolysis, several mechanisms to control this self-propagation are constituitively activated. Complement factor H (CFH) binds to C3b and inhibits the binding of Factor B, thereby decreasing C3 convertase levels.3 Conversely, stabilizing proteins are also present, such as properdin. In DDD, the alternative pathway is overactive leading to deposition of activated C3. C3 nephritic factor (C3NeF), an autoantibody, stabilizes the binding of Factor B to C3, thereby stabilizing C3 convertase and increasing the half-life to minutes or hours. It may also prevent the action of decay accelerators, including CFH. C3NeFs have been detected in approximately 80% of patients with DDD and are also found in patients with APL, but have been seen in normal individuals.3,4 The antibody may be against any part of the C3 convertase or native protein and some appear to be dependent on properdin. Autoantibodies to CFH have also been detected. These antibodies bind to short consensus repeats necessary for the interaction of CFH and C3b and prevent inhibition of C3 convertase production. Homozygous deficiency of CFH has been shown to lead to DDD as well as mutations in C3 causing mutant C3 convertase which is not regulated by CFH.3
Table 2: Serum levels of components of the complement system and antibodies in MPGN I, DDD and MPGN III.
Another recently described form of GN has been termed glomerulonephritis with C3 deposits (GN-C3). Similar to DDD, it is characterized by mesangial C3 deposits with no immune-complex deposition. However, ultrastructural findings are similar to MPGN type I with the electron dense deposits in the mesangium, along the capillary walls and in the subendothelium. The lack of immune-complex deposition and positive C3 staining in the mesangium on immunofluorescence have led to the idea that this is also caused by dysregulation of the alternative pathway.5
Approximately half of patients with DDD require a renal transplant. DDD recurs in almost all allografts with progression to ESRD in half of all allografts. As the pathogenesis of DDD is better understood, targeting the etiology of the disease may prove to be the best treatment strategy. The use corticosteroids and immunosuppressants has proven useful in MPGN I and III, however randomized controlled studies in children with DDD showed no better response than to lactose.2 Removal of antibodies through plasmapheresis has been evaluated and showed improvement in renal function in most cases.2 B-cell depletion with anti-CD20 drugs such as Rituximab has been proposed as a method of treatment in those with antibodies, however conclusive studies have not been published.3 The use of exogenous CFH has been proposed in those with genetic deficiency of CFH but has not been tested. Ultimately, the majority of patients are placed on angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors to reduce proteinuria and glomerular leukocyte infiltration.
Contributed by Anna Woodard, MD and Sheldon Bastacky, MD