60 year old Caucasian man with progressive renal insufficiency, hematuria, proteinuria and new-onset HTN

CLINICAL SUMMARY

60 year old Caucasian man presents with progressive renal insufficiency, microscopic hematuria, proteinuria and new-onset hypertension. Over the last year, creatinine has increased from baseline of 0.9 mg/dL to 2.9 mg/dL. The patient has no history of diabetes and has only recently been noted to develop hypertension (BP 140/90 at time of biopsy). Urinalysis shows 2+ protein, 3+ blood, 10 RBCs and 6-10 WBCs per hpf. No cellular casts or urine eosinophils are seen. 24 hour urine collection shows 813 mg of protein. Serologic workup shows positive ANA (1:320) but negative or normal anti-DNA, ANCA, anti-GBM, hepatitis B surface antigen, hepatitis C antibody and HIV. Serum C3 is noted to be 65 mg/dL (normal 75-135 mg/dL) with normal C4. Past medical history is notable for a partial pancreatectomy 5 years prior which was performed for a mass lesion and recurrent pancreatitis.  No malignancy was found within the pancreas and the diagnosis of “lymphoplasmacytic sclerosing pancreatitis” was rendered. The patient remains non-diabetic. His only medications are aspirin 81 mg/day, simvastatin and pantoprazole.

A biopsy was performed.

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FINAL PATHOLOGIC DIAGNOSIS:

IgG4-related tublointerstitial nephritis (answer c)

DISCUSSION

IgG4-related sclerosing disease is a recently described multisystem disease that is thought to be autoimmune in origin. It most frequently involves the pancreas, often manifesting as obstructive jaundice, with or without a mass. Patients usually have involvement of more than one site, and hepatobiliary, lymph node, salivary gland and/or orbital involvement are relatively common. Almost any organ can be affected, including the kidney, as in this case. The previous history of partial pancreatectomy showing “lymphoplasmacytic sclerosing pancreatitis” is highly suggestive of pancreatic involvement by an IgG4-related process; however at the time of the pancreatectomy, this entity was not well described.

IgG4-related sclerosing disease predominantly affects older Caucasian males.  Renal manifestations include azotemia of varying degrees, microscopic hematuria and mild (usually <1g/day) proteinuria. Importantly, a significant portion of patients will have mass lesions at the involved site, and cancer is frequently at the top of the clinical differential diagnosis.  It is unusual for the only site of involvement to be the kidney, therefore prior history of pancreatic, hepatobiliary or salivary gland disorders should be specifically sought. Aside from the non-specific laboratory abnormalities described above, almost all patients with IgG4 related sclerosing disease show hypergammaglobulinemia with markedly elevated serum IgG4 levels. Hypocomplementemia is also a frequent finding affecting approximately 70% of patients. To the extent possible, Sjogren’s syndrome should be clinically excluded, however due to the overlap in clinical symptoms and some pathologic features, definitive differentiation is often difficult.

Histologically, in the kidney IgG4-related sclerosing disease manifests as a tubulointerstitial nephritis with abundant plasma cells.  Immunohistochemistry should reveal a prominent IgG4 plasma cell population.  Typically, IgG4 plasma cells compose <5% of the total plasma cell population, however in IgG4-related sclerosing disease >30 IgG4 positive plasma cells may be seen in a single high power field and IgG4 cells account for upwards of 40% of the total plasma cell infiltrate.  The inflammation is often obliterative, causing mass-like fibrosis.  IgG immune deposits are present in tubular basement membranes or the interstitium in a substantial minority of cases.

The diagnosis of this entity is of significant importance for two main reasons.  First, because many patients develop inflammatory mass-like lesions that are often mistaken for cancer, potentially unnecessary morbid operations (like pancreatoduodenectomy) are performed. Secondly, this entity is remarkably responsive to steroid therapy, and if properly diagnosed, can often be successfully treated. Definitive diagnostic criteria for this multisystem disorder are yet to be developed.  Several sets of diagnostic criteria have been proposed, most of them aimed specifically at pancreatic involvement.  The Mayo Clinic Criteria, also referred to as the HISORt criteria address histologic abnormalities, findings on radiographic imaging, serologic testing, multisystem involvement and response to steroid therapy (for details see Chari et.al. in Clin Gastroenterol Hepatol, 2006; 4:1010-1016). Relating these criteria to the kidney, histologic findings (namely an IgG4-rich lymphoplasmacytic infiltrate) are similar to what is seen in the pancreas, renal imaging sometimes reveals mass lesions, serologic testing typically shows elevated IgG and IgG4 levels, other organ systems are frequently involved and response to steroid therapy is typically good.

The pathogenesis of IgG4-related sclerosing disease is not yet understood.  Many experts in the field believe that the finding of IgG4 plasma cells is a surrogate marker of disease activity, rather than the driving pathologic factor.  IgG4 is the least prevalent IgG subtype and elevated IgG4 levels are often seen in the setting of chronic antigen exposure (beekeepers, parasite infection etc). It is thought to play a role in dampening allergic responses. IgG4 does not efficiently fix complement and its primary role may turn out to be serving as a “blocking” antibody that helps to quench more damaging chronic inflammation. Patients with pancreatic involvement have been found to have multiple IgG4 auto antibodies directed against antigens in the pancreatobilliary system.  Some targets, such as lactoferrin and carbonic anhydrase II are also found in renal tubules and may help explain the propensity for multisystem involvement.

REFERENCES

Cheuk W, Chan J. IgG4-related sclerosing disease: A critical appraisal of an evolving cliniocopathologic entity. Adv Anat Pathol 17(5):303-332, 2010.

Saeki T, Nishi S, Imai N et.al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int, epub ahead of print 2010.

Cornell et.al. “Pseudotumors due to IgG4 Immune-Complex TIN Associated with Autoimmune Pancreatocentric Disease. Am J Surg Pathol 31(10): 1586-97 Oct 2007

Chari ST, Smyrk TC, Levy MJ et.al. Diagnosis of autoimmune pancreatitis: the Mayo Clnic experience. Clin Gastroenterol Hepatol 4:1010-1016, 2006.

Raissan Y, Nasr SH, Larsen CP, et.al. Diagnosis of IgG4-Related Tubulointerstitial Nephritis. J Am Soc Nephrol 22:1343-52, 2011

CORRESPONDANCE

Leal C. Herlitz M.D.
Columbia University Medical Center, New York, NY