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Autoimmune blistering diseases associated with renal disease: With some hesitancy, reports are beginning to flow

DII small banner By Warren R. Heymann, MD
Sept. 12, 2018

Cryoglobulinemic glomerulonephritis. Patient 3: kidney biopsy found membranoproliferative glomerulonephritis with cryoglobin plugs/hyaline thrombi (arrows), suggestive of cryoglobulinemic glomerulonephritis. (Hematoxylin-eosin stain; original magnification: ×60.) 
Credit: JAAD

Admittedly, other than monitoring blistering disease patients treated with systemic immunosuppressants, I have not thought much about kidney disease as part of the disease process.

I am changing my tune.

It is no surprise that acute renal insufficiency (ARI) may be a byproduct of inadequate fluid intake due to painful oral erosions. This was depicted by the case of a 64 year-old woman with pemphigus vulgaris with ARI that resolved quickly with intravenous fluid administration (in addition to systemic steroids). (1)

What caught my attention was the article by Abreu-Velez et al, reporting a statistically significant association of renal autoantibodies in patients with a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia (termed El Bagre-EPF, or pemphigus Abreu-Manu). In their discussion, the authors note that reports of kidney disease in pemphigus patients predate the PubMed era. They assert:

In the pre‐steroid era, kidney involvement was described in patients with FS [Fogo Selvagem]. Indeed in countless publications, autopsies of patients with pemphigus vulgaris (PV), bullous pemphigoid (BP) and other autoimmune diseases demonstrated renal compromise. In some cases acute disease was noted, but in most cases, renal function steadily declined during the course of these diseases.

The authors had previously reported that about 30% of El Bagre EPF had systemic compromise. In their study of 57 live patients, 19 had renal autoantibodies, with polyclonal reactivity (P < 0.01). Most cases were positive along the basement membrane of the proximal tubules, but in some cases there was also positivity against the glomeruli and/or mixed patterns. Fifteen patients had increases in serum urea and creatinine compared with controls (P < 0.01). The autoantibodies colocalized with commercial antibodies to desmoplakins I and II, p0071, armadillo repeat gene deleted in velo–cardio–facial syndrome (ARCVF) and myocardium‐enriched zonula occludens‐1‐associated protein (MYZAP) (P < 0.01). They also performed autopsies on 7 patients who died of the disease. All of the kidney disease autopsies showed alterations, mostly in the vessels The authors concluded that one‐third of patients with El Bagre‐EPF have polyclonal autoantibodies to kidney, demonstrating a mixed histological pattern resembling lupus nephritis. (2)

Their findings lead to the obvious question: Is there lupus nephritis in pemphigus erythematosus (Senear-Usher syndrome)? I did not check the pre-PubMed literature. Patients with pemphigus erythematosus produce both antiepithelial antibodies specific for desmoglein 1 and 3 and antinuclear antibodies specific for Ro, La, Sm, and double-stranded DNA antigens. The autoantibodies in pemphigus erythematosus are directed against different antigens. These autoantibodies are produced by independent clones, suggesting that pemphigus erythematosus behaves as a multiple autoimmune disease. (3) Given the fact that renal disease may be observed in 16% of patients with subacute cutaneous lupus (4), I suspect that a similar number of patients with pemphigus erythematosus have renal disease.
The association of pemphigus with other autoimmune disorders such as myasthenia gravis and thymomas is well known. Thymoma-associated nephropathy is a rare, but recognized entity. In a review of 21 cases, 2 were associated with pemphigus vulgaris. (5)

Bullous pemphigoid (BP) has been reported in association with glomerular disease, including anti–glomerular basement membrane (anti-GBM) disease and membranous nephropathy. Hoorn et al presented a 75 year-old non-diabetic man with bullous pemphigoid and nephrotic syndrome in whom the glomerular disease had characteristics of both anti-GBM disease and membranous nephropathy. What role his anti-BP 180 KD antibodies played in the pathogenesis of his nephropathy remains speculative. His skin and kidneys responded well to prednisone and azathioprine. (6) BP has also been linked to allograft rejection, as well as membranous nephropathy in renal transplant recipients. Although there is a possibility of multiple distinct autoimmune processes, immune stimulation induced by allograft rejection or anti-basement membrane antibody interactions are possible mechanisms for simultaneous skin and renal involvement. (7)

In conclusion, we dermatologists must treat autoimmune blistering disease patients with all our heart, using our brains, and thinking about the kidneys.
Point to remember: Autoimmune blistering disease may be associated with clinically significant renal disease.

1. Tran C, et al. Stomatitis, cutaneous bullae and renal failure. JAMA 2015; 314: 2296-2297.
2. Abreu-Velez AM, et al. Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2, and ARVCF, causing renal damage. Clin Exp Dermatol 2018; 43: 692-702.
3. Pérez- Pérez M, et al. Autoantibodies in Senear-Usher syndrome: Cross-reactivity or multiple autoimmunity. Autoimmune Dis 2012;2012:296214.
4. Black DR, et al. Frequency and severity of systemic disease in patients with subacute cutaneous lupus erythematosus. Arch Dermatol 2002; 138: 1175-8.
5. Karras A, et al. Renal and thymic pathology in thymoma-associated nephropathy: Report of 21 cases and review of the literature. Nephrol Dial Transplant 2005; 20: 1075-82.
6. Hoorn EJ, et al. Bullous pemphigoid with a dual pattern of glomerular immune complex disease. Am J Kidney Dis 2016; 67: 302-6.
7. Koratala A, et al. The skin-kidney connection: Bullous pemphigoid associated with acute allograft rejection and membranous nephropathy. Clin Case Rep 2017; 6: 432-3.

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