Case 5 -

Nodular Diabetic Glomerulosclerosis Samih Nasr Columbia Presbyterian Medical Center New York, NY

Case History: A 67 year old White male presented with a 1 week history of productive cough and shortness of breath. He was found to have a left lower lobe pneumonia and was admitted to the hospital and started on antibiotics. He developed acute renal failure shortly after admission (creatinine rising from 1.4 mg/dl on admission to 2.0 mg/dl on hospital day 4). His past medical history was significant for diabetes for 7 years with neuropathy (no retinopathy), coronary artery disease (status-post CABG), mitral valve regurgitation (status-post replacement), atrial fibrillation, longstanding hypertension (well-controlled on medications), and chronic renal insufficiency (creatinine 1.4 mg/dl on admission). He denied alcohol or IV drug use. He had no family history of renal disease. His medications on admission included furosemide, low dose aspirin, coumadin, glyburide, and metoprolol. He had 1+ lower extremity edema bilaterally. There were no cutaneous findings. Laboratory results during hospitalization were: Hct 38 %, hemoglobin 12.2 g/dL, WBC 14,600/mm3 (left shift, no eosinophilia), platelets 243,000/ mm3, serum creatinine 2.0 mg/dl on hospital day 47.0 mg/dl on hospital day 20, normal serum electrolytes, urine protein 150 mg/day, serum albumin 3.6 g/dl, cholesterol 172 mg/dl, depressed C3, and normal C4. All other serologies were negative or normal including ANA, Anti-DNA antibody, hepatitis B antigen, hepatitis C antibody, ASLO, serum cryoglobulin, ANCA, and anti-GBM antibody. There was no paraprotein on SPEP. Urinalysis showed trace protein, 2+ blood, numerous RBCs/hpf, 5-10 WBCs/hpf, and several RBC casts. Sputum and blood cultures were positive for methicillin-resistant Staphylococcus aureus. Urine culture was negative. Chest X-ray showed consolidation of the left lower lobe. Kidneys were normal in size on ultrasound. Hemodialysis was initiated and a renal biopsy was performed on hospital day 20. Renal Biopsy: Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Light Microscopy: Diffuse global endocapillary hypercellularity with neutrophils, and nodular sclerosis. Immunofluorescence Microscopy: IgA-dominant immune complex deposits. Electron Microscopy: Mesangial, subendothelial and subepithelial (hump) electron dense deposits. Diagnosis: Diffuse endocapillary proliferative and exudative glomerulonephritis, consistent with IgA-dominant acute post-staphylococcal glomerulonephritis. Nodular diabetic glomerulosclerosis FOLLOW-UP: Treated with antibiotics and hemodialysis Continued to have HTN, proteinuria, and hematuria Remained on hemodialysis Died 3 months later of sepsis Discussion: Acute post-infectious glomerulonephritis (APIGN) is mainly a disease of children. It usually follows streptococcal upper respiratory tract or skin infections. Among adults, APIGN is most common in alcoholic, diabetic, and intravenous drug-abusing patients. [1] In developed countries, the epidemiology of adult APIGN has evolved such that the responsible bacteria are more commonly Staphylococcus or Gram-negative bacteria than Streptococcus. [1] In a large Italian study of 393 type 2 diabetic patients who underwent renal biopsy, Mazzucco et al. [2] found that membranous glomerulopathy, APIGN, and IgA nephropathy were the three most common nondiabetic glomerular diseases encountered. In their series, 70.3% of cases of APIGN in diabetic patients occurred superimposed on diabetic nephropathy. Thus, in diabetics, APIGN is most frequently seen with preexisting diabetic nephropathy. Compared to diabetic patients without renal involvement, patients with diabetic nephropathy are more likely to have neuropathy and peripheral vascular disease, and hence are at higher risk for the development of skin ulcers with superimposed bacterial infection. In the setting of underlying diabetic nephropathy, APIGN usually displays atypical ultrastructural and immunofluorescence features. There is a predominance of mesangial and subendothelial electron dense deposits with only sparse and small subepithelial deposits, even during the active phase of the disease where diffuse endocapillary hypercellularity and neutrophil infiltration are present on light microscopy. It is likely that the underlying mesangial sclerosis and glomerular basement membrane thickening of diabetic glomerulosclerosis modify the morphological expression of the disease such that the immune deposits preferentially localize to the mesangium, perhaps because of defective mesangial clearing. The glomerular basement membrane thickening may hinder the development of typical subepithelial "humps". APIGN superimposed on diabetic nephropathy is frequently IgA-dominant on immunofluorescence, typically in patients with staphylococcal infection. We previously reported 5 cases of IgA-dominant acute post-staphylococcus glomerulonephritis complicating diabetic nephropathy [3]. The clinical presentation was typically acute renal failure in the context of preexisting chronic renal insufficiency. Hypocomplementemia was present in all patients. Light microscopy showed a diffuse endocapillary proliferative and exudative glomerulonephritis arising on a background of diabetic mesangial sclerosis. On immunofluorescence, IgA was the sole or dominant immunoglobulin deposited in glomeruli. On ultrastructural examination, the glomerular deposits were predominantly mesangial in distribution with sparse subepithelial humps. In a consecutive series of 18 diabetic patients with APIGN seen in the Renal Pathology Laboratory of Columbia University, 16 (90%) occurred superimposed on diabetic nephropathy. Among the ones superimposed on diabetic nephropathy, 12 (75%) were associated with staphylococcus infection, 2 (12.5%) with streptococcus infection, and 2 with unknown pathogens. Of the 12 cases associated with staphylococcus, 8 (67%) were IgA-dominant on immunofluorescence (including the 5 published cases). The other 4 cases (33%) showed diffuse endocapillary hypercellularity and neutrophil infiltration on light microscopy, glomerular immune deposits that stained for either IgG and C3 or C3 alone on immunofluorescence and abundant mesangial and some subendothelial electron dense deposits with only rare subepithelial deposits on electron microscopy. Hence, at least from this cohort, it appears that IgA-dominant APIGN is the most common histological pattern in patients with staphylococcal infection and underlying diabetic nephropathy. We did not encounter any case of IgA-dominant APIGN association with staphylococcal infection in nondiabetics, nor in associated with other bacteria in diabetic or nondiabetic patients. Of note, few cases of acute post-staphylococcal glomerulonephritis with IgA dominant or co-dominant deposits in patients without diabetic nephropathy have been reported by others [4, 5, 6, 7]. The pathomechanism of the selective IgA deposition in patients with post-staphylococcal glomerulonephritis superimposed on diabetic nephropathy is unknown. The role of host factors in mounting an IgA-dominant immune response to staphylococcal infection might be important. Multiple studies have shown that serum levels of IgA and IgA-containing circulating immune complexes are higher in diabetics compared with nondiabetics [8, 9], possibly as a result of subclinical mucosal infection or decreased IgA clearance caused by serum IgA1 hypersialylation. IgA glycosylation in the diabetic milieu may also predispose to mesangial immune deposition. IgA-dominant post-staphylococcal glomerulonephritis must be distinguished from IgA nephropathy, another disease commonly complicating diabetic nephropathy. Features that favor APIGN over IgA nephropathy or Henoch Schönlein purpura include the presence of hypocomplementemia, intercurrent culture-documented bacterial infection, diffuse endocapillary hypercellularity with prominent neutrophil infiltration on light microscopy, and subepithelial "humps" on electron microscopy. This pathological distinction has important clinical implications because of the different treatment and prognosis of the two diseases. It appears that IgA-dominant APIGN superimposed on diabetic nephropathy has a poor prognosis. Six of our seven cases of acute post-staphylococcal glomerulonephritis superimposed on diabetic nephropathy with available follow-up remained dialysis-dependent, whereas IgA nephropathy in the setting of diabetic nephropathy may have a small effect on outcome. [10]. References: J.J. Montseny, A. Meyrier, D. Kleinknecht et al.: The current spectrum of infectious glomerulonephritis. Experience with 76 patients and review of the literature. Medicine 74 (1995), pp. 63–73. G. Mazzucco, T. Bertani, M. Fortunato et al., Different patterns of renal damage in type 2 diabetes mellitus: A multicentric study on 393 biopsies. Am J Kidney Dis 39 (2002), pp. 713–720. SH Nasr, GS Markowitz, LD Whelan et al.: IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Hum Pathol 34 (2003), pp. 1235-41.. D.A Spector, J. Millan, N. Zauber et al.: Glomerulonephritis and staphylococcal aureus infections. Clin Nephrol 14 (1980), pp. 256–261. M. Sato, H. Nakazoro and T. Ofuji: The pathogenetic role of Staphylococcus aureus in primary human glomerulonephritis. Clin Nephrol 11 (1979), pp. 190–195 A. Koyama, M. Kobayashi, N. Yamaguchi et al.: Glomerulonephritis associated with MRSA infection: A possible role of bacterial superantigen. Kidney Int 47 (1995), pp. 207–216. K. Yoh, M. Kobayashi, A. Hirayama et al.: A case of superantigen-related glomerulonephritis after methicillin-resistant Staphylococcus aureus (MRSA) infection. Clin Nephrol 48 (1997), pp. 311–316. . K. Eguchi, M. Yagame, D. Suzuki et al., Significance of high levels of serum IgA and IgA-class circulating immune complexes (IgA-CIC) in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 9 (1995), pp. 42–48. S. Rodréguez-Segade, M.F. Camina, A. Carnero et al., High serum IgA concentrations in patients with diabetes mellitus: Agewise distribution and relation to chronic complications. Clin Chem 42 (1996), pp. 1064–1067. S.K. Mak, P.N. Wong, K.Y. Lo et al., Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients. Nephrol Dial Transplant 16 (2001), pp. 1183–1188.