34 Hong Kong J Nephrol • April 2005 • Vol 7 • No 1
Department of Nephrology and 1Histopathology Laboratory, Ibn Rochd Hospital, Casablanca, Morocco.
Address correspondence and reprint requests to: Dr. Faissal Tarrass, Salama 3, Gr 6, B, N$ 21, Casablanca 20450, Morocco.
Idiopathic Membranous Glomerulonephritis in Patients with Type 2 Diabetes Mellitus
Faissal Tarrass, Abbelkabir Anabi, Mohamed Zamd, Beyounes Ramdani, Mohamed Gharbi Benghanem, Driss Zaid, Saida Sqalli1
The occurrence of membranous glomerulonephritis (MGN) in patients with type 2 diabetes mellitus (DM) is a rare event and of pathogenetic interest. We report two males (52 and 64 years old) with type 2 DM and nephrotic syndrome of recent onset. Renal biopsy was performed because of the unusual clinical pictures: microscopic hematuria; heavy proteinuria without evidence of diabetic retinopathy; and, in one case, a sudden onset of renal failure. Renal biopsy disclosed pure MGN without glomerulosclerosis. In both cases, clinical history, physical examination and biologic assessment failed to reveal the cause; MGN was thus considered idiopathic.
Treatment, including glycemic control and angiotensin-II receptor blockers, led to resolution of proteinuria in one case. We suggest that renal biopsies should be performed in diabetic patients with a sudden onset of renal failure, proteinuria without retinopathy, or other evidence of microvascular disease. [Hong Kong J Nephrol 2005;7(1):34–7]
Key words: membranous glomerulonephritis, renal biopsy, type 2 diabetes mellitus
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Diabetic nephropathy (DN) is the most frequent cause of renal disease in patients with diabetes mellitus (DM).
The most common histologic lesions are either diffuse or nodular glomerulosclerosis and hyalinosis of small arterioles . Although less frequent, other types of primary glomerular diseases may affect the kidney and cause proteinuria or renal insufficiency in these patients . Precise diagnosis of these various diseases has obvious prognostic and therapeutic implications [1,2].
We report two patients with type 2 DM who had clinical and laboratory features of nephrotic syndrome. In both cases, histologic examination of renal biopsies disclosed idiopathic membranous glomerulonephritis (MGN).
A 52-year-old male was admitted for evaluation of rapidly deteriorating renal function. Five years pre-
Hong Kong J Nephrol • April 2005 • Vol 7 • No 1 35 Idiopathic MGN in type 2 diabetes
viously, he had been diagnosed with type 2 DM and hypertension. There was no known history of diabetic ketoacidosis, retinopathy, or polyneuropathy. On phy- sical examination, the patient’s blood pressure was 160/85 mmHg, heart rate was 76 beats/min, and tem- perature was 36.8ºC. Peripheral edema was present.
The lung fields were clear, and the heart and abdomen were normal. Urinalysis showed 4+ protein and 3+
blood; microscopic analysis disclosed 8–10 red blood cells and 3–5 granular casts per high-power field.
Laboratory assessments showed normal hematology, electrolytes, and liver function tests. The serum creat- inine level was 221.2 +mol/L, creatinine clearance was 30 mL/min, albumin was 27 g/L, fasting blood glucose was 8.85 mmol/L and proteinuria was 8 g/day.
Ultrasound examination showed normal renal size without abnormal features. A percutaneous renal biop- sy was performed because of the magnitude of protein- uria and the rapidity with which renal function had deteriorated. Microscopic examination of sections from the biopsy material showed diffuse thickening of the glomerular capillary wall with the presence of spikes along the capillary basement membrane (Figure 1).
There was no cellular proliferation, mesangial matrix expansion, or arteriolar hyalinosis. Tubules and inter- stitium were unremarkable.
Immunofluorescence microscopy revealed finely granular deposits positive for immunoglobulin G (IgG) and the complement factors C3 and C1q along the glomerular basement membrane (GBM) of all glomeruli. All laboratory screening for secondary causes was negative or normal, including tests for complement profile, antinuclear antibodies, anti- neutrophilic cytoplasmic antibodies, hepatitis B virus (HBV) and hepatitis C virus (HCV) serology, human immunodeficiency virus (HIV) serology, and serum
immunoglobulins. A chest X-ray and abdominal echo- graphy were normal. There was no evidence of oc- cult gastrointestinal bleeding. It was concluded that the patient had idiopathic MGN, and he was given angiotensin-II (AT)-receptor blockers. After a follow- up duration of 4 months, the AT-receptor blockers continued to provide good blood pressure control, and, at his most recent visit 1 month ago, the patient had a serum creatinine level of 265.5 +mol/L, creatinine clearance of 24.5 mL/min, and urinary protein excretion of 2.70 g/day.
A 64-year-old male presented for evaluation of mi- croscopic hematuria and proteinuria. There was no known history of type 2 DM, diabetic ketoacidosis or hypertension. Funduscopy was normal. On admission, the patient’s blood pressure was 130/70 mmHg, heart rate was 74 beats/min, and temperature was 37ºC.
The patient appeared “puffy” and had pretibial ede- ma. Urinalysis showed 3+ protein, and microscopic hematuria with occasional granular and hyaline casts.
Laboratory investigations revealed proteinuria (6.5 g/day), with a serum albumin level of 22 g/L, and fasting blood glucose level of 11.8 mmol/L. Serum creatinine was 70.8 +mol/L, and creatinine clearance was 78 mL/min. Hematologic parameters and liver function tests were normal. Renal ultrasound showed normal kidney size without abnormal features. Immunology showed no changes in immunoglobulin levels, and there was no monoclonal band in serum. Complement factors (C3, C4), anti-DNA antibodies and antinuclear antibodies were normal.
As there was an absence of retinopathy and other evidence of microvascular disease, and in light of heavy proteinuria, a needle biopsy of the kidney was performed to delineate the histologic lesion. Eighteen glomeruli and two glomerular scars were examined.
All glomeruli showed uniform changes. The GBMs were slightly thickened and, on silver stain, showed discrete spike formation on their outer aspects. There was no mesangial matrix increase or mesangial hy- percellularity. Extraglomerular blood vessels showed no pathologic changes. The interstitium was, focally, slightly fibrotic with a few atrophic tubular cross sections in areas of fibrosis. Immunofluorescence microscopy revealed diffuse staining for both IgG and C3 in a granular pattern along the GBM (Figure 2).
Serologic tests for HBV, HCV and HIV were negative.
Chest X-ray and abdominal echography were un- remarkable. There was no evidence of occult gastro- intestinal bleeding. No possible causative agents (drugs or toxins) could be identified. The patient re- ceived furosemide and AT-receptor blockers. With this regimen, proteinuria decreased continuously, achieving levels of less than 1 g/day after 2 months. At 3 years
Figure 1. Case 1: a glomerulus showing distinct spikes on the outer aspect of the capillary basement membrane (periodic acid- Schiff stain; original magnification = 100).
F. Tarrass, et al
36 Hong Kong J Nephrol • April 2005 • Vol 7 • No 1
after admission, the patient’s serum creatinine level was 101.7 +mol/L, creatinine clearance was 56 mL/min, and urinary protein excretion was 0.35 g/day.
About 10–35% of patients with type 2 DM eventually develop DN over the course of several years; DN then progresses towards end-stage renal disease . Recently, there have been several reports of non- diabetes-related, sometimes treatable, renal diseases in patients with type 2 DM [1–3]. Biopsy studies sug- gest that up to one-third of patients with type 2 DM have glomerular lesions unrelated to or in addition to DN . Reported types of superimposed glomeru- lar diseases include IgA nephropathy, endocapilla- ry proliferative glomerulonephritis, minimal change disease, membranoproliferative glomerulonephritis, rapidly progressive glomerulonephritis, and cryo- globulinemic glomerulonephritis [1–3]. To our know- ledge, MGN has been reported in patients with DM.
In reviewing the medical literature, we found 68 cases of DM and MGN documented by immunofluo- rescent examination of biopsy specimens (Table).
The finding of MGN in diabetic patients could be coincidental [3,8]. However, it is known that various immunologic abnormalities and infections predisposing to immune complex nephritis are common in diabetic patients, and immune complex deposition could be involved in the pathogenesis of MGN [1,2]. Furuta et al reported three cases of MGN in patients with diabetes managed by porcine insulin, and in whom immune complex nephritis developed through the formation of anti-insulin antibodies . However, insulin was not
given to any of our patients before histologic diagnosis.
Therefore, a potential pathogenetic role for insulin in superimposed glomerulonephritis may be excluded.
The course of idiopathic MGN is often benign, and progression to chronic renal failure occurs at a much slower pace over a period of several years . In con- trast, the presence of pure MGN in diabetic patients may have a better prognosis, but the combination of MGN and diabetic glomerulosclerosis perhaps wors- ens the nephrotic syndrome and may lead to rapidly deteriorating renal function and the need for early dialysis or transplantation .
We suggest that renal biopsy should be performed in diabetic patients with unusual features, such as proteinuria without retinopathy and sudden deterio- ration of renal function. Renal histology under these circumstances may help clinicians to uncover some of the superimposed and treatable disorders, and may thus favorably influence the course of renal disease.
In summary, the appearance of urinary changes or a rapid deterioration of renal function against a natural history of DN increases the possibility of non-diabetic renal disease . The use of renal biopsy to confirm such a diagnosis may be of fundamental importance to both treatment and prognosis.
1. Lee EY, Chung CH, Choi SO. Non-diabetic renal disease in pa- tients with non-insulin dependent diabetes mellitus. Yonsei Med J 1999;40:321–6.
2. Venkateswara K, Crosson JT. Idiopathic membranous glomerulonephritis in diabetic patients: report of three cases and review of the literature. Arch Intern Med 1980;140:624–7.
3. Costero O, Diaz C, de Alvaro F, Torre A, Gil F, Picazo ML, Figure 2. Case 2: a glomerulus showing granular fluorescence
along capillary loops of 3+ intensity after staining with antisera to human immunoglobulin G (original magnification = 150).
Table. Reports in the medical literature of membranous glomerulonephritis and diabetes mellitus
Authors [Ref] Year Number of cases
Warms et al  1973 4
Venkateswara & Crosson  1980 3
Kobayashi et al  1981 3
Ditscherlein & Schneider  1983 10
Amoah et al  1988 3
Yoshikawa et al  1990 15
Kleinknecht et al  1992 5
Furuta et al  1992 3
Richards et al  1992 3
Gambara et al  1993 2
Suzuki et al  1994 7
John et al  1994 6
Lee et al  1999 3
Costero et al  2001 1
All authors – 68
Hong Kong J Nephrol • April 2005 • Vol 7 • No 1 37 Idiopathic MGN in type 2 diabetes
Martinez-Ara J. Idiopathic membranous nephropathy in an elderly patient with type 2 diabetes mellitus. Nefrologia 2001;21:402–5.
4. Warms PC, Rosenbaum BJ, Michelis MF, Haas JE. Idiopathic membranous glomerulonephritis occurring with diabetes mellitus.
Arch Intern Med 1973;132:735–8.
5. Kobayashi K, Harada A, Onoyama K, Shimamatsu K, Maeda T, Fujimi S, et al. Idiopathic membranous glomerulonephritis asso- ciated with diabetes mellitus: light, immunofluorescence and elec- tron microscopic study. Nephron 1981;28:163–8.
6. Ditscherlein G, Schneider W. Membranous glomerulonephritis in 10 diabetics. Zentralbl Allg Pathol 1983;127:245–51.
7. Amoah E, Glickman JL, Malchoff C, Sturgill BC, Kaiser DL, Bolton WK. Clinical identification of nondiabetic renal disease in diabetic patients with type I and type II disease presenting with renal dysfunction. Am J Nephrol 1988;8:204–11.
8. Yoshikawa Y, Truong LD, Mattioli CA, Ordonez NG, Balsaver AM.
Membranous glomerulonephritis in diabetic patients: a study of 15 cases and review of the literature. Mod Pathol 1990;3:36–42.
9. Kleinknecht D, Bennis D, Altman JJ. Increased prevalence of non- diabetic renal pathology in type II diabetes mellitus. Nephrol Dial
10. Furuta T, Seino J, Saito T, Sato H, Agatsuma J, Ootaka T, et al.
Insulin deposits in membranous nephropathy associated with diabetes mellitus. Clin Nephrol 1992;37:65–9.
11. Richards NT, Greaves I, Lee SJ, Howie AJ, Adu D, Michael J.
Increased prevalence of renal biopsy findings other than diabetic glomerulopathy in type II diabetes mellitus. Nephr Dial Transplant 1992;7:397–9.
12. Gambara V, Mecca G, Remuzzi G, Bertani T. Heterogenous nature of renal lesions in type II diabetes. J Am Soc Nephr 1993;3:1458–66.
13. Suzuki Y, Ueno M, Hayashi H, Nishi S, Satou H, Karasawa R, et al. A light microscopic study of glomerulosclerosis in Japanese patients with noninsulin-dependent diabetes mellitus: the relationship between clinical and histological features. Clin Nephrol 1994;42:155–62.
14. John GT, Date A, Korula A, Jeyaseelan L, Shastry JC, Jacob CK.
Nondiabetic renal disease in noninsulin-dependent diabetics in a south Indian Hospital. Nephron 1994;67:441–3.
15. Cattran DC. Idiopathic membranous glomerulonephritis. Kidney Int 2001;59:1983–94.