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Nodular glomerulosclerosis is a histopathologic finding on kidney biopsy characterized by nodule formation due to the accumulation of homogenous, eosinophilic hyaline material within the glomerular mesangium and is commonly associated with diabetic nephropathy. This classic finding, also known as the Kimmelstein-Wilson nodules, is a hallmark of diabetic nephropathy and is formed due to non enzymatic glycosylation of the proteins in the mesangial matrix (1). The eosinophilic material in the nodules is mainly composed of collagen and stains positive for Periodic acid-Schiff (PAS) and Jones methenamine silver(JMS) on histochemical staining. However, nodular glomerulosclerosis has been associated with several other conditions, such as amyloidosis, in which the hyaline material is composed of amyloid and not collagen and stains positive for Congo red and negative for PAS or JMS stain. Other conditions that give similar appearance of nodular glomerulosclerosis on H&E staining in light microscopy include light chain deposition disease, primary and secondary MPGN, fibrillary glomerulonephritis, immunotactoid glomerulonephritis, fibronectin glomerulopathy, collagen III glomerulopathy, and chronic hypoxic and ischemic conditions such as cyanotic heart disease, cystic fibrosis and takayasu’s arteritis (2). Distinguishing the cause of nodular glomerulosclerosis between these entities requires a thorough history, serologic testing, kidney biopsy with histochemical staining, immunofluorescence (IF), and electron microscopy (EM) (table 1)
In <1% of reported cases of nodular glomerulosclerosis, the histological findings are indistinguishable from diabetic nodular glomerulosclerosis but with no history of diabetes. These cases, previously described as idiopathic nodular glomerulosclerosis (ING), are more common in elderly white men and are strongly associated with hypertension, smoking, obesity, hyperlipidemia, peripheral vascular disease, and impaired glucose intolerance (3)
This cluster of metabolic risk factors and vasculopathy promoters likely causes nodular glomerulosclerosis by inducing arteriolar stenosis and glomerular ischemia, which causes mesangiolysis, capillary microaneurysm formation, and subsequent nodularity. Therefore, it is appropriate to consider nodular glomerulosclerosis as a form of metabolic vasculopathy.
Like diabetes, these risk factors promote the formation of advanced glycation end (AGE) products that bind to receptors expressed in podocytes, thereby promoting the synthesis of the components of the extracellular matrix in the mesangium, notably collagen. In fact, >40% of patients with nondiabetic nodular glomerulosclerosis have impaired glucose tolerance, suggesting that these patients may have increased sensitivity to pre-diabetic glucose levels due to the complex interplay of several other metabolic and vascular risk factors present in these patients that promote AGE formation leading to a clinical picture that resembles diabetic kidney disease and exhibits similar histologic findings of diabetic nodular glomerulosclerosis on kidney biopsy (4). Additionally, these risk factors accelerate oxygen-free radical formation, causing oxidative stress injury, angiogenesis, and altered renal hemodynamics (5). These promote mesangiolysis and collagen proliferation in the ECM, leading to capillary nodularity, as seen in nodular glomerulosclerosis. Immunohistochemistry staining with CD34, a marker of endothelial cells, is positive in nodular glomerulosclerosis, indicating angiogenesis following ischemic injury to the glomerulus (6).
Given that the culprits implicated in nondiabetic glomerulosclerosis and metabolic syndrome affect more than 1 in 3 adults in the US, it is surprising that nondiabetic nodular glomerulosclerosis is so rare. This rarity underscores the need for increased awareness and vigilance among primary physicians and nephrologists. It is likely that this condition is underreported or underdiagnosed, as most of these patients present with advanced proteinuric chronic kidney disease, which may dissuade nephrologists from seeking kidney biopsy. In fact, most patients progress to ESRD within 2 to 3 years from the time the diagnosis is made, further emphasizing the urgency and importance of early detection and intervention (3).
It is, therefore, imperative that patients with metabolic syndrome, with or without a history of smoking, be screened for albuminuria and chronic kidney disease. The good news is that early intervention with renin-angiotensin blockers, SGLT2 inhibitors, aggressive BP control, and reversal of modifiable risk factors can halt the progression of this otherwise fairly progressive chronic kidney disease (7). This proactive approach offers hope for improved outcomes and underscores the importance of early detection and intervention.
References
P. Kimmelstiel and C. Wilson, “Intercapillary Lesions in the Glomeruli of the Kidney,” Am. J. Pathol., vol. 12, no. 1, pp. 83–98.7, Jan. 1936.
2. S. R. A. Solares, H. R. Ibarra-Sifuentes, M. G. R. Ramírez, G. Y. A. Muller, and J. C. Valdez, “Idiopathic nodular glomerulosclerosis and differential diagnosis,” J. Bras. Nefrol., vol. 42, no. 4, pp. 484–488, Oct-Dec 2020.
3. G. S. Markowitz, J. Lin, A. M. Valeri, C. Avila, S. H. Nasr, and V. D. D’Agati, “Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking,” Hum. Pathol., vol. 33, no. 8, pp. 826–835, Aug. 2002.
4. K. O. Alsaad and A. M. Herzenberg, “Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update,” J. Clin. Pathol., vol. 60, no. 1, pp. 18–26, Jan. 2007.
5. S. H. Nasr and V. D. D’Agati, “Nodular glomerulosclerosis in the nondiabetic smoker,” J. Am. Soc. Nephrol., vol. 18, no. 7, pp. 2032–2036, Jul. 2007
6. T. Uchida et al., “Idiopathic nodular glomerulosclerosis in a never-smoking, normotensive, non-obese, normal-glucose-tolerant middle-aged woman,” Clin. Kidney J., vol. 5, no. 5, pp. 445–448, Oct. 2012
7. H. Yamaguchi et al., “A case of idiopathic nodular glomerulosclerosis successfully treated by intensive blockade of the renin-angiotensin-aldosterone system,” CEN Case Rep, vol.12, no. 3, pp. 311–317, Aug. 2023
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