Nodular Glomerulosclerosis – beyond diabetic nephropathy

A glomerular nodule, i.e. an acellular hyaline structure, can have varied etiologies. Most commonly we see it in the setting of diabetic nephropathy (DN). In these cases, it posesses all the associated features of DN on light microscopy (LM) with glomerular basement membrane (GBM) thickening, mesangial matrix expansion and arteriolar hyalinosis.  These nodules stain well with PAS & silver stains. Immunofluorescence (IF) shows linear IgG deposits along the GBM & tubular basement membrane (TBM) and occasional IgM & C3 trapped in the sclerotic areas. Electron microscopy (EM) shows similar features.
A differential diagnosis is amyloidosis, associated with enlarged glomeruli but poor staining with PAS and silver stain. The striking feature of this condition is red appearance of nodules on Congo staining with characteristic apple green birefringence under the fluorescent microscopy. In the most common form of amyloidosis, the AL type, IF shows light chain restriction with lambda > kappa predominating. EM has the characteristic amyloid fibrils, 7-12 nm in diameter with indefinite length and random orientation.

Among immune mediated glomerulonephritis (GN), MPGN also presents with nodules on biopsy. LM is highlighted by a proliferative morphology with splitting and duplication of the GBM. Cryoglobulinemic GN is associated with pseudo-thrombi in capillaries, which in fact represent large sub-endothelial deposits. IF shows IgG and C3 deposits in GBM. Cryoglobulinemia is associated with IgM and predominance of kappa deposits (Type 1). EM reveals electron dense deposits in sub endothelial, mesangial and sometimes in sub-epithelial locations.

Monoclonal immunoglobulin deposition disease (MIDD) can shows nodules. They stain with PAS and silver stains (see image) and have refractile, PAS-positive deposits in the TBM too. IF is characterized by linear deposits along GBM & TBM with kappa>lambda deposits in LCDD (light chain variant) and IgG in HCDD (heavy chain). EM shows powdery deposits in inner GBM, outer TBM and in the nodules.

Fibrillary and Immunotactoid GN have diffuse a proliferative GN/MPGN pattern, sometimes with crescents. They stain with PAS & silver as well, a feature they share with DN. IF is positive for polyclonal IgG and C3 in Fibrillary GN. The immunotactoid variant has monoclonal IgG with kappa/lambda chains. EM shows large, randomly arranged fibrils (16-20 nm in diameter) in the former, and parallel arrayed microtubules (20-50 nm diameter) in the latter.

Fibronectin glomerulopathy is characterized by nodules positive with PAS and negative with silver. EM shows sub-endothelial electron dense deposits. Immunohistochemistry staining for fibronectin is diagnostic.

The last differential is Idiopathic Nodular Glomerulosclerosis. This entity resembles DN in all aspects except that patient is non diabetic. It is associated with long standing hypertension and smoking. Smoke contains glycation adducts which form AGEs and through oxidative stress is thought to create pathology similar to diabetes.

Thus, a nodule in the glomerulus has a wide differential with definite need for various stains, IF and EM to establish the final diagnosis. The other key feature here is most of the above mentioned diseases can have a similar clinical presentation in the same age group.

Post by Sriram Sriperumbuduri (Images from Paul Phelan)

Pathology Case of the Month

An elderly woman presented for evaluation to the rheumatology service with arthritis and neuropathy. She was hypertensive and had microscopic hematuria with dysmorphic red cells on microscopy. Her creatinine was 1.6 which had not changed in the previous year. She had no history of diabetes. Her serology was notable for a positive ANCA, elevated CRP and ANA 1:640. The sense was that despite the presence of the ANCA, the likelihood of a vasculitis was low due to the indolent course but she went on to have a renal biopsy.

A low power view of the renal cortex revealed an obvious nodular appearance of the glomeruli. The tubules were relatively well-preserved.

High-power view of the glomerulus was characteristic of nodular glomerulosclerosis. Notably, there was no evidence of any crescents and no thickening of the capillary loops.

 IF was completely negative

There were no medullary or BM inclusions on EM

Nodular glomerulosclerosis is classically associated with diabetes and this is the first diagnosis that came to the mind of the pathologist when the slides were processed. However, the patient had no history of diabetes. Alternative diagnoses include chronic MPGN and dysproteinemias. There was no evidence of either in this case. The final diagnosis was "Idiopathic Nodular Glomerulosclerosis". This is somewhat of a misnomer as these days, it is thought that IGN is directly related to smoking. The mechanism is uncertain but is suggested in the flow-chart below from an a review in JASN on the topic.

This is not a benign condition. In the largest case series to date of 23 patients with biopsy-proven IGN, 6 patients reached ESRD in a median of 26 months. Predictors of progression included not quitting smoking, lack of ACEi use and the degree of atrophy, fibrosis and arteriosclerosis on renal biopsy.

(Click on any image to enlarge)

“Idiopathic” or “smoking-related” nodular glomerulosclerosis

Nodular glomerulosclerosis refers to a histologic pattern of nodular mesangial sclerosis with accentuated, lobular-appearing glomeruli on renal biopsy. Although classically described in association with diabetes (the so-called “Kimmelstiel-Wilson lesion”), the lesion is NOT pathognomonic for diabetic nephropathy. In fact, a number of renal conditions have been seen in association with this distinctive, histologic pattern. The differential diagnosis of non-diabetic, nodular glomerulosclerosis includes, but is not limited to:

• Immunotactoid GN
• Fibrillary GN
• Fibronectin GN
• Cryoglobulinemic GN
• Amyloidosis
• Light Chain Deposition Disease (LCDD)
• Heavy Chain Deposition Disease (HCDD)
• Idiopathic Nodular Glomerulosclerosis

In order to determine the specific disease responsible for nodular glomerulosclerosis, a deliberate inspection of the renal biopsy (particularly, Congo red staining and IF) are requisite. The diagnosis of “idiopathic” nodular glomerulosclerosis remains one of exclusion. The following algorithm provides a systematic approach to the diagnosis of non-diabetic, nodular glomerulosclerosis:

A strong, causative association between long-standing cigarette smoking and hypertension has recently been identified in individuals previously categorized as having “idiopathic” nodular glomerulosclerosis. In the largest case series available of “idiopathic” nodular glomerulosclerosis (n=23), Markowitz et al found a high prevalence of hypertension (95.7%), smoking (91.3%), hypercholesterolemia (90%), and extrarenal vascular disease (44%). The mean pack-years for smoking were 53 +/- 7 years. This cohort, in which diabetes was excluded, was comprised mainly of older, Caucasian male patients. The clinical presentation of this condition included renal failure (mean sCr 2.4 mg/dL) and proteinuria (mean 24 urine protein 4.7 g/d). The median time from biopsy to ESRD was 26 months.

Although the pathogenesis of “idiopathic” nodular glomerulosclerosis remains enigmatic, some have proposed that smoking alone is the putative agent. Potential mechanisms of renal damage induced by smoking include: oxidative stress from free radical formation, increased formation of advanced glycation end products (AGE), angiogenesis, and altered intrarenal hemodynamics. Given the plausible role of smoking in the pathogenesis, some have argued the nomenclature be changed to “smoking-associated nodular glomerulosclerosis”.

In summary, if the renal boards present a non-diabetic, elderly man with an extensive history of smoking, who insidiously develops renal failure and proteinuria, in conjunction with a renal biopsy that shows nodular glomerulosclerosis and negative IF and Congo red staining, the diagnosis is assuredly “idiopathic” or “smoking-related” nodular glomerulosclerosis.

Michael Lattanzio, DO