I recently evaluated a young patient for kidney transplant who had been diagnosed at age 13 with MPGN III. He had a slow reacting C3NeF, low C3, normal C4, low terminal complement levels, and by biopsy had paramesangial and subendothelial but no subepithelial deposits. I was confused by the diagnosis of MPGN III, which I understood to be a controversial and exceedingly rare diagnosis. Without subepithelial deposits the histologic pattern was not consistent with my understanding of MPGN III, and my knowledge of the complement abnormalities associated with the subtypes of idiopathic MPGN was vague at best. I decided to read more about the specifics of MPGN III, but instead of instant enlightenment I developed a deeper confusion. This was going to take a while. So I grabbed a glass of wine and kept reading.
MPGN is a progressive form of renal failure defined by histologic features. All forms have diffuse mesangial proliferation and subendothelial extension of the mesangium. MPGN I is characterized by activation of the classical complement cascade by immune complexes. On IF, MPGN I is distinguished by subendothelial deposits of IgG and C3 or isolated C3, with frequent presence of C1q, properdin, and C4. MPGN type I is far and away more commonly a secondary disorder- if MPGN type I morphology is found on biopsy, you should probably not rest until all possible underlying causes have been ruled out. Idiopathic forms do exist, most commonly appearing in childhood and adolescence. With activation of the classical pathway, serum C3 levels are low or normal, C4 levels are low, and CH50 levels are low.
MPGN II (dense deposit disease) is defined by intramembranous, elongated, brightly eosinphilic, variably refractile electron dense deposits that stain positive for C3 and much less commonly IgM or IgG. This is not thought to be an immune complex disease. It is associated with dysregulation of the alternative complement pathway through C3NeF (C3 nephritic factor), which stabilizes and inhibits the inactivation of the alternative C3 convertase C3bBb, resulting in perpetual breakdown of C3 and continuously activated alternative complement pathway. Factor H deficiency or mutation has also been identified as a cause of MPGN II. MPGN II is also associated with acquired partial lipodystrophy and macular drusen, both of which are also caused by activation of the alternative complement pathway. With activation of the alternative pathway, C3 levels are low, C4 levels are normal, and CH50 levels are low.
MPGN type III is thought to be an extremely rare, and possibly not existent (depending on the expert) disease associated with abnormalities of the complement cascade. It appears identical on light microscopy to MPGN I, with somewhat less hypercellularity. On EM there is the additional finding of subepithelial deposits as well as subendothelial deposits and intramembranous interposition of mesangium. It is associated with a slow acting nephritic factor of the terminal pathway(NeFt), which stabilizes a properdin dependent C5 convertase ((Cb3)2BbP)- resulting in persistent activation of the terminal pathway. With activation of the alternative and terminal pathways, C3 levels are low, C4 levels are normal, and levels of C5 through C9 are low. The lack of literature on this disease highlights its rarity.
Here is an excellent review of the pathophysiology, clinical manifestations, and treatment of idiopathic MPGN.
What I’ve just reviewed makes the differences between MPGN I, II, and III sound very clear-cut, but this is not actually the case. Some cases of C3NeF positive and hereditary MPGN I have been identified, which implies a completely different pathophysiology of disease than classical MPGN I despite the presence of classical MPGN I histology. As a result, there is a movement to reclassify MPGN based on pathogenesis as opposed to histologic criteria. This makes the literature more than a little confusing. In my patient, despite the lack of subepithelial deposits, he fit the diagnosis for MPGN III based on his serum complement profile, with slow reacting C3NeF, low C3, normal C4, and low terminal complement components.
I am also wondering about the risk of recurrence of MPGN in my patient’s pending allograft. Idiopathic MPGN I recurs with a frequency of 20-40% and II recurs in about 80-90% of allografts. In pediatric patients, recurrence of MPGN II results in a 15% rate of graft failure at 5 years post transplant. What about MPGN III? I couldn’t find anything in the literature. Does anyone out there have any MPGN III transplant patients?
Of side note, HUS and TTP also result from dysregulation of this very same complement cascade at some of the very same locations, and it is worthwhile to review and compare to the pathogenesis of MPGN.
Thank you for the correction. For those interested in further reading on Dense Deposit Disease throw "Richard Smith Dense Deposit Disease" into pubmed.
The statement: "In pediatric patients, recurrence of MPGN II results in a 15% rate of graft failure at 5 years post transplant…" is wrong. The 5 year post transplant failure rate is closer to 50% (see Lu et al. Pediatr Nephol (in press, 2011) where the authors point out: Of the 28 total kidney transplant events (including 6 who had 2 transplants) among 22 recipients, 10 grafts were lost and all these were the first transplant. All losses occurred during the first five years following transplantation (X2 =7.368, p=0.007). Thank you. Richard Smith