Association 6f Type I (Insulin-dependent) Diabetes ... - Diabetes Care

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ssociation 6f Type I (Insulin-dependent) Diabetes Nlellitus, Autoimmunity, Antinuclear Antibody, and Membranoproliferative Glomerulonephritis S. SRIKANTA, A. N. MALAVIYA, P. RAJAGOPALAN, U. N. BHUYAN, AND M. M. S. AHUJA

In a large series of patients with insulin-dependent diabetes mellitus who were screened for autoantibodies, two patients were positive fot antinuclear antibodies. Both of these patients developed severe renal disease with the renal biopsy findings of membranoproliferative glomerulonephritis. Multiple autoantibodies and circulating immune complexes were demonstrated in their sera. There was evidence suggesting complement consumption. This article illustrates that immune complex glomerulonephritis can occur in some patients with IDDM, particularly in those with antinuclear antibody and polyendocrine involvement, and that renal biopsy in such cases may have prognostic and therapeutic importance. DIABETES CARE 6: 71-74, JANUARY-FEBRUARY 1983.

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utoimmune mechanisms, both humoral and cellular, play an important role in the etiopathogenesis of insulin-dependent diabetes mellitus (IDDM, type I). 1 On the other hand, the significance of the immune mechanisms in the pathogenesis of the late diabetic complications like nephropathy is not well understood.2 Out of the 110 North Indian IDDM patients who were being screened for various autoantibodies,3 we came across two patients who were strongly positive for antinuclear antibody (ANA). Subsequently, they developed evidence of renal involvement, and the renal biopsy showed a picture of membranoproliferative glomerulonephritis (MPGN) without the usual changes of diabetic glomerulosderosis. Both patients were positive for thyroid microsomal antibody (TMA) and thyroglobulin antibody (TGA), and one of them had in addition gastric parietal cell antibody (PCA) and persistent islet cell antibody (ICA). Circulating immune complexes (CIC) were detected in both patients, and in one patient we could demonstrate glomerular deposition of immunoglobulins and complement in a granular pattern. The unusual type of renal involvement and the associated immunologic findings suggest that immune complex glomerulonephritis (ICGN) can occur in certain patients with IDDM, particularly the subset demonstrating "autoimmune diathesis." MATERIALS AND METHODS

Case Reports Case 1. Mr. S. C , a 38-yr-old man with IDDM of 16-yr duration, was admitted for the evaluation of a febrile illness

that lasted 2 wk. The exact cause of the fever could not be ascertained despite all investigations. There was no family history of diabetes mellitus. On admission he was found to have diabetic peripheral and autonomic neuropathy and background diabetic retinopathy (only microaneurysms). He was normotensive, had mild albuminuria (24-h urinary protein 0.52 g), but the microscopic examination of the urine was normal. His hemoglobin was 12.8 g/dl; his white cell count was 8300 with a normal differential count. His erythrocyte sedimentation rate was 47 mm/h. His blood urea was 24 mg/dl and serum creatinine was 2.4 mg/dl; serum cholesterol was 200 mg/dl and uric acid, 4 mg/dl. Plain x-ray films of the abdomen revealed kidneys with normal size and outlines. Twelve days after admission he developed progressive oliguria, puffiness of the face, abdominal distension, and anorexia. On examination he was afebrile, delirious, and pale with a pulse rate of 100 and blood pressure 160/95 mm Hg. He had developed pedal and facial edema and minimal ascites. Investigations at this time revealed hemoglobin of 10.1 g/dl, a white cell count of 5800 with a normal differential count, and an erythrocyte sedimentation rate of 41 mm/h. Urine had a specific gravity of 1020 with albuminuria (24h urine protein 1.1-1.4 g), 30-40 RBCs, and 4-8 WBCs per high power field; there were no casts. Serum protein was 4-7 g/dl, albumin 1.9 g/dl, serum cholesterol 264 mg/dl, and uric acid 7 mg/dl. His blood urea rose progressively to 300 mg/dl and serum creatinine to 9.3 mg/dl. Hemoglobin fell to 5.7 g/dl. He was put on alternate-day hemodialysis for the management of rapidly progressive renal failure. A retrograde

DIABETES CARE, VOL. 6 NO. 1, JANUARY-FEBRUARY 1983

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ASSOCIATION OF IDDM, AUTOIMMUNITY, ANTINUCLEAR ANTIBODY, AND GLOMERULONEPHR1TIS/S. SRIKANTA AND ASSOCIATES

pyelogram done to rule out acute papillary necrosis and obstructive uropathy was normal. The patient's condition progressively deteriorated; the control of his brittle diabetic state was difficult, with frequent hypoglycemic reactions. A kidney biopsy done 32 days after admission was reported to show MPGN. The patient died 60 days after admission; the immediate cause of his death probably was hypoglycemic encephalopathy. An autopsy could not be obtained. Case 2. Mrs. S.K. was a 24-yr-old woman with IDDM of 3-yr duration, and had a strong family history of diabetes mellitus; her father, maternal grandmother, and two maternal uncles were diabetic. On evaluation at that time, she was normotensive and had background diabetic retinopathy (only microaneurysms). Her urine examination was normal. Blood urea was 22 mg/dl, serum creatinine was 0.9 mg/dl, and serum cholesterol was 172 mg/dl. Renal outlines and size were normal on a plain skiagram of the abdomen. Six months later she developed pedal edema and painful diabetic peripheral neuropathy, and at that time was detected to be hypertensive (BP 160/110 mm Hg). Her hemoglobin was 13.2 g/dl; her white cell count was 6800 with normal differential count and an erythrocyte sedimentation rate of 61 mm/h. Urine examination showed albuminuria (24-h urinary protein 1.0-2.8 g), but the microscopic examination was normal. Serum protein was 5.2 g/dl, albumin 2.6 g/dl,

blood urea 38 mg/dl, serum creatinine 1.3 mg/dl, and cholesterol 240 mg/dl. An intravenous pyelogram was normal. She was started on diuretics and antihypertensive medications. Six months later her hemoglobin was 9.0 g/dl; her white cell count was 6000 and her erythrocyte sedimentation rate was 110 mm/h (very high persistently). Her blood urea was 44 mg/dl, serum creatinine 2.3 mg/dl, uric acid 5.5 mg/dl, and cholesterol 280 mg/dl. A kidney biopsy was done and showed MPGN. Renal Pathology Renal biopsies were fixed in neutral buffered formalin and processed for 3-4-|xm paraffin sections, which were stained with hematoxylin-eosin (HE), periodic acid-schiff (PAS), and silver methenamine (SM). A duplicate piece from case 2 was frozen fresh and cut in the cryostat at 6-^m thickness. The sections were stained with fluorescent monospecific antisera (Wellcome Reagents, London, England) to demonstrate immunoglobulin (IgG, IgM, IgA) and complement (C3) deposits. Light microscopic examination in both cases revealed established features of mesangiocapillary (membranoproliferative) glomerulonephritis, characterized by proliferation of mesangial cells and matrix and thickening and splitting of

FIG. I. Renal biopsies showing features of mesangiocapillary (membranoproliferative) gbmerulonephritis. Photomicrographs I and 2 belong to case I, and 3 and 4 belong to case 2 (I and 3 hematoxyUn and eosin; 2 and 4 silver methenamine; original magnification, X 400). 72


ASSOCIATION OF IDDM, AUTOIMMUNITY, ANTINUCLEAR ANTIBODY, AND GLOMERULONEPHRITIS/S. SR1KANTA AND ASSOCIATES

TABLE 1 Immunologic data

Autoantibodies Islet cell antibody Thyroid microsomal antibody Thyroglobulin antibody Parietal cell antibody Adrenal antibody Antinuclear antibody Serum immunoglobulins IgG IgM IgA Complement (C3) consumption

C3 Alpha-1 -antitrypsin Alpha- 1-AT/C3 ratio Circulating immune complexes Polyethylene glycol Latex agglutination inhibition Anticomplementary activity Rheumatoid factor HLA typing

Case 1

Case 2

(S.C.)

(S.K.)

+ ++ (1:3200) -

Normal values

++ (1:3200)

+

++ ++

(1:100) ++

(membranous)

(diffuse)

330 168 50

28 104 230

166(155-178) lU/ml 190 (170-214) lU/ml 174 (148-204) IU/ml

32 220

84 269 3.2

128 (115-145) mg/dl 102 (83-126) mg/dl 1.15 (0.72-1.23)

0.06

0.04 (0.01-0.07) OD* 12 + out of 94 1.30(Logc)(l:4-l:10) titer

6.87 0.02 Neg 1:1024 (10th well) Neg —

Pos 1:4096 (12th well) Neg A9, A19, B13, B17

*OD = optical density.

the capillary wall (Figure 1). There was no evidence of diabetic glomerulosclerosis. Immunofluorescence showed moderately bright granular deposits of IgG, IgM, IgA, and C3 in the capillary wall in case 2. Immunologic Studies The results of the various immunologic studies have been summarized in Table 1. The autoantibodies,3 immunoglobulins, complement (C3), alpha-1-antitrypsin (alpha-1-AT), rheumatoid factor,4 and circulating immune complexes (polyethylene glycol, latex agglutination inhibition, and anticomplementary activity techniques),5 were determined by using methods described earlier. DISCUSSION

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enal involvement in diabetes mellitus is often part of the generalized microangiopathy of this disease, though the exact nature and causation of the microangiopathy (basement membrane changes) has been debated for many years. Altered carbohydrate metabolism in diabetes mellitus leading to alterations in basement membrane synthesis and thickening, and mesangial cell function and proliferation, may be the basic pathogenetic mechanism in diabetic nephropathy. Yet other factors like platelet and fibrin deposition, vascular and ischemic changes, and immune complex deposition may have some role. Immu-

nohistopathologic studies have demonstrated that immunoglobulins, complement components, and albumin are deposited in a thin linear fashion along the basement membrane frequently in diabetic glomerulosclerosis. Formation of insulin—anti-insulin complexes has been suggested but not convincingly demonstrated. Although these findings may suggest an immune pathogenesis for diabetic glomerulosclerosis, it is generally felt that such tissue localization represents nonspecific trappings of plasma proteins. Immune complex glomerulonephritis mediated by human thyroglobulin has been clearly demonstrated in Graves' disease8 and it is possible that a similar type of renal involvement can occur in other autoimmune endocrinopathies including diabetes mellitus. But the exact nature of the antigen and antibody involved in glomerular deposition and damage can only be speculative, and has to be investigated in the future by indirect immunofluorescence and elution techniques in renal biopsy tissue. Irvine et al. have demonstrated soluble immune complexes in the sera of diabetic subjects and they have discussed their possible role in the pathogenesis of IDDM and of complications of that form of diabetes.9 It was the strongly positive ANA detected in the two cases during a large screening of IDDM patients for islet cell antibodies that focused our attention on the new association that has been reported in this communication. None of the two cases had any of the other features of systemic connective


ASSOCIATION OF IDDM, AUTOIMMUNITY, ANTINUCLEAR ANTIBODY, AND GLOMERULONEPHRITIS/S. SRIKANTA AND ASSOCIATES

tissue disorders. There have been very few reports in the past of an association between systemic lupus erythematosus and diabetes mellitus. 10~13 Also, few previous studies report the occurrence of ANA (without other features of systemic connective tissue disorders) in cases of diabetes mellitus, particularly those with polyendocrine involvement or other associated autoimmune disorders.14"16 It is possible that the two cases we have reported represent examples of overlap between the organ-specific and non-organ-specific clusters in the spectrum of autoimmune disorders.17 This may have a genetic basis, considering the fact that both IDDM and SLE have been associated with common histocompatibility antigen HLADRW3. 1819 The presence of ANA might be just one of the several manifestations of the impaired suppressor T-cell function that has been proposed to exist in many patients with autoimmune diseases;20 it may be yet another manifestation of a defective immunoregulation. Also of interest is the recent detection of anti-islet antibodies of some patients with lupus erythematosus and other diseases characterized by polyclonal B-lymphocyte activation.21 Apart from the usual lesions of diabetic nephropathy, other types of primary glomerular diseases rarely affect the kidney in diabetic patients, though its exact incidence is unknown, as renal biopsies are not performed routinely in these patients. Venkateshwara-Rao and Crosson have recently reviewed the literature22 and rightly advocate performance of renal biopsies in diabetic patients with unusual clinical features such as persistent hematuria, sudden onset of renal failure, and massive proteinuria without azotemia, retinopathy, or other evidence of microvascular disease. To this can be added the presence of ANA and multiple endocrine or nonendocrine autoimmune phenomena. Such an approach would have obvious prognostic and therapeutic importance, like the use of steroids and immunosuppressive drugs, which might have a favorable influence on the natural history of the renal disorder. ACKNOWLEDGMENTS: The authors thank Dr. George S. Eisenbarth of Duke University Medical Center for his valuable advice in the preparation of the manuscript.

From the Department of Medicine, Divisions of Endocrinology and Metabolism, and the Division of Clinical Immunology, Department of Pathology, All-India Institute of Medical Sciences, New Delhi-110029, India. REFERENCES 1

Bottazzo, G. F., and Doniach, D.: Autoimmunity in diabetes mellitus. In Secondary Diabetes: The Spectrum of the Diabetic Syndromes. Podolsky, S., and Viswanathan, M., Eds. New York, Raven Press, 1980:391-408. 2 Parsons, V., and Watkins, P. J.: Diabetes and the kidney. In Renal Disease, 4th edit. Black, D., Ed. London, Blackwell Scientific Publications, 1981:687-712. 3 Srikanta, S., Malaviya, A. N., Mehra, N. K., Vaidya, M. C , Geevarghese, P. J., and Ahuja, M. M. S.: Autoimmunity in Type

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