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Below is a summary of the salient features of the patient history on a 71 yo male who was referred to me at the end of 2016 to determine if an elevated IgE level is in any way responsible for renal failure or merely a marker of the disease process.  

•    Pt had ostensibly been in very good health, on no medications, when diagnosed with stage 4 renal disease in 2010. His medical hx is remarkable for a GSW to the chest X 30 yrs ago (pneumothorax) leaving multiple bullet fragments; recovered uneventfully with no residual pulmonary sxs or need for medications; exercises regularly.
•    He had no h/o any type of allergic disorders at any anytime during his life, including food/resp allergies, AD, AE, hives, med allergies.
•    Current BUN/Crt = 54/3.4.  
•    The pt has been to 3 nephrologists locally: kidney bx's failed to elucidate a cause (according to the patient).
•    He was recently seen by a nephrologist at UCLA who felt that the renal failure may be linked to his abuse of Fleet's Enemas over the yrs (phosphate). I tried to get in touch with this physician who had suddenly left the practice with no forwarding number. He is scheduled to be seen by one of the leading nephrologists on the UCLA team in the near future.  
•    As part of his w/u in 2010, labs were done by his PCP including an IgE 2991. This prompted referral to another allergist in the area.
•    sIgE levels in 2010: Olive tree = 6kU/L; mites = 2; cat = 1; other misc trees and weeds = 1-2.  He owned an indoor cat beginning in 2006. Once he learned of the potential cat allergy, he kept the cat outside of the house with limited contact (again -- no allergy sxs at all).  
•    Allergy skin testing was done by the same allergist in 2012: Prick tests: Neg to multiple foods; 1-2 + to several trees.  ID's: 4+ to DM; mold = 2/3
•    Allergy shots were recommended. Pt declined since he was 100% asymptomatic re allergy sxs. And note: No h/o AI disorders either. There were no further visits to that allergist.
•    I was asked to consult in Dec 2016. Worsening renal failure. Pt was told that he is in stage 4 renal failure; biopsies are inconclusive; no consultants are able to determine the etiology of the renal disease. He is currently waiting to see one of the head nephrologists at UCLA.  
•    Only potentially relevant allergy hx I uncovered: He raises monarch butterflies on his property; they lay their eggs on milkweed plants (many on property). No skin test or sIgE test is available to milkweed as per my research into the matter. No sxs.  
•    Additional labs done by me: ESR = 9; SPEP = WNL; QIGs = WNL; CH50 = >60; IgE = 1454 (lower); TP = 5.9
•    I read an elevated IgE is a prognostic indicator of progressively worsening renal disease in pts with IgA glomerulonephritis (which he apparently does not have since bx's were inconclusive) but does not point to an elevated IgE as the cause of disease.  
•    My questions: Do I need to do any further w/u as an allergy consultant? Is the elevated IgE just a prognositc indicator of worsening renal failure or is it potentially linked to the etiology of the disease?
•    The pt is an otherwise healthy and bright individual who finds himself with unexplained renal failure?  I would like to be able to reassure him about the role of the elvated IgE - the only abnormal test (other than renal function) according to him. Suggestions?


I doubt there is any value in additional laboratory testing in your patient with progressive renal disease and an IgE of 1454 IU/ml. Any decision would be dependent on the findings of the renal biopsy. There is an association of an increase in IgE with lymphoid malignancy, so perhaps the renal disease could be associated with monoclonal gammopathy with tubular disease, renal amyloidosis, or renal heavy or light chain disease. None of these possibilities are considerations if appropriate renal biopsy stains did not reveal immunoglobulin fragments or amyloid. IgE myeloma would be associated with increases of 100-1000 times higher serum IgE than your patient. Immunofixation or immunoelectrophoresis of urine and serum along with analysis of ratio of kappa and lambda light chains would be relatively inexpensive tests to exclude monoclonal gammopathy or heavy or light chain disease.

Another consideration would be IgG4 disease which can cause both a tubulointerstitial renal disease, more common, as well as a membranous glomerulopathy. Typically there would be a distinctive fibrotic whorl pattern on histology with eosinophil and plasma cell infiltration (Stone et al). Isolated involvement of the kidney with IgG4 disease is very unusual and would expect sialadenitis, pancreatitis, lymphadenopathy, lung lesions or dacryoadenitis. IgG4 staining of renal biopsy would show a majority of mast cells to be IgG4 positive. Peripheral blood usually, but not always, shows an increase in IgG4 and eosinophilia in addition to an increase in IgE. There is a report that the prognosis for progressive renal disease is more likely when the IgE is greater than 436 IU/ml in patients with IgG4 renal disease.

In summary, I would not do any additional tests. I would consider asking that stains were performed on the renal biopsy to exclude immunoglobulins, amyloid and IgG4 disease. I would not perform immunoelectrophoresis/immunofixation of urine and blood unless there were other features suggestive of lymphoid or plasma cell malignancy. A protein electrophoresis (SPEP) may miss a monoclonal gammopathy and likely would miss heavy chain disease explaining the value of immunoelectrophoresis/immunofixation. IgG subclasses are a consideration if there are any suspicious findings for IgG4 disease on the renal biopsy. I do not think the IgE is of any predictive value with regards to the renal insufficiency since the cause has not been ascertained; and even if it were predictive of progression, this would not modify therapy. Therapy would be dictated by the cause of the renal insufficiency.

Stone , J. H., et al. (2012). "IgG4-Related Disease." New England Journal of Medicine 366(6): 539-551.
Mizushima I, Yamamoto M, Onoue D et al. Factors related to renal cortical atrophy development after glucocorticoid therapy in IgG4-related kidney disease: a retrospective multicenter study. Athritis Res Ther 2016;18:273

Autoimmune pancreatitis associated with renal lesions mimicking metastatic tumours.
Rudmik L, Trpkov K, Nash C, Kinnear S, Falck V, Dushinski J, Dixon E CMAJ. 2006;175(4):367.

Autoimmune pancreatitis is a chronic inflammatory disorder that is often misdiagnosed as pancreatic cancer. Since autoimmune pancreatitis is benign and responds to steroid management, it is important to diagnose it to avoid unnecessary surgical intervention. We describe a novel case of IgG4-associated autoimmune pancreatitis presenting with tubulointerstitial nephritis as renal lesions mimicking metastatic tumours but with no change in renal function.
Department of Surgery, University of Calgary, Calgary, Alta.

Chronic tubulointerstitial nephritis presenting as multiple renal nodules and pancreatic insufficiency. Murashima M, Tomaszewski J, Glickman JD. Am J Kidney Dis. 2007;49(1):e7.

We report a case of chronic tubulointerstitial nephritis associated with multiple nodular lesions of the kidneys in a patient with autoimmune pancreatitis. Serum immunoglobulin G4 (IgG4) level was increased, and immunohistochemical staining for IgG4 on the renal biopsy specimen showed positive staining of plasma cells and tubular basement membrane within areas of chronic tubulointerstitial nephritis. There are a few reports of nodular lesions of kidneys or interstitial nephritis associated with autoimmune pancreatitis. Our case is unique in that all 3 conditions presented together and suggests that interstitial nephritis can present as nodular lesions.
Renal Electrolyte and Hypertension Division and Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, USA.

Nephropathy in IgG4-related systemic disease. Watson SJ, Jenkins DA, Bellamy CO
Am J Surg Pathol. 2006;30(11):1472.

Lymphoplasmacytic sclerosing pancreatitis ("autoimmune" pancreatitis) is the best-known manifestation of an unusual corticosteroid-sensitive systemic fibrosclerotic disease that is associated with high plasma immunoglobulin G4 (IgG4) and tissue infiltration with IgG4-secreting plasma cells. Pancreatic and biliary manifestations of this condition are well-reported, but reports of other systemic involvement are few. We report here a case of initially unrecognized autoimmune pancreatitis followed 5 years later by a focal sclerosing lymphoplasmacytic tubulointerstitial nephritis and concurrent membranous nephropathy. The patient presented with hypertension, a raised serum creatinine, proteinuria, elevated serum IgG4, and eosinophilia. Immunolabeling of renal tissue showed numerous IgG4 positive plasma cells with peritubular and glomerular subepithelial IgG4 deposition. On steroid therapy serum IgG4 levels normalized, the eosinophilia resolved, and there was improvement in symptomatic wheeze, dry eyes, serum creatinine, and liver function tests. This case highlights a distinctive and potentially treatable form of interstitial nephritis manifesting from a systemic immune disorder, and provides circumstantial evidence to support the notion that dysregulated IgG4 can precipitate the development of a form of membranous nephropathy.
Nephrology, Renal Unit, Queen Margaret Hospital, Whitefield Road, Dunfermline KY12 0SU, UK.

Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.
Saeki T, Nishi S, Imai N, Ito T, Yamazaki H, Kawano M, Yamamoto M, Takahashi H, Matsui S, Nakada S, Origuchi T, Hirabayashi A, Homma N, Tsubata Y, Takata T, Wada Y, Saito A, Fukase S, Ishioka K, Miyazaki K, Masaki Y, Umehara H, Sugai S, Narita I . Kidney Int. 2010;78(10):1016.

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

I hope this information is of some help to you and your patient.

All my best.
Dennis K. Ledford, MD, FAAAA

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