Renal Pathology Case Studies
Moderators: J. Charles Jennette
Case 5 -
Nodular Diabetic Glomerulosclerosis
Columbia Presbyterian Medical Center
New York, NY
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.
Case 5 - Slide 1
Case 5 - Slide 2
Diffuse global endocapillary hypercellularity with neutrophils, and nodular sclerosis.
IgA-dominant immune complex deposits.
Mesangial, subendothelial and subepithelial (hump) electron dense deposits.
Diffuse endocapillary proliferative and exudative glomerulonephritis, consistent with IgA-dominant
acute post-staphylococcal glomerulonephritis.
Nodular diabetic glomerulosclerosis
Treated with antibiotics and hemodialysis
Continued to have HTN, proteinuria, and hematuria
Remained on hemodialysis
Died 3 months later of sepsis
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.  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. 
In a large Italian study of 393 type 2 diabetic patients who underwent renal biopsy, Mazzucco et al.
 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
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 . 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
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
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. .
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- 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.
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