Nodular Glomerulosclerosis in the Nondiabetic Smoker
Samih H. Nasr and
Vivette D. D'Agati
Department of Pathology, Columbia University, College of Physicians & Surgeons, New York, New York
Correspondence: Dr. Vivette D. D'Agati, Department of Pathology, Columbia University, College of Physicians & Surgeons, 630 West 168th Street, VC14-224, New York, NY 10032. Phone: 212-305-7460; Fax: 212-342-5380; E-mail: vdd1{at}columbia.edu
Emerging evidence supports that the entity known as idiopathicnodular glomerulosclerosis is not idiopathic. A strong causativeassociation with longstanding cigarette smoking and hypertensionhas been identified. Morphologically, smoking-associated nodularglomerulosclerosis closely resembles diabetic nephropathy. Thepotential roles of advanced glycation end products, oxidativestress, angiogenesis, and hemodynamic perturbations are explored.
Admitted to the hospital was a 70-yr-old white woman with cellulitisof the right foot. She had a history of longstanding hypertensionand bilateral severe peripheral artery disease with a chronicnonhealing right foot ulcer. She did not have diabetes but hadsevere chronic obstructive pulmonary disease (COPD) and a historyof heavy cigarette smoking (2 packs per day for 30 yr), whichwas discontinued 20 yr ago. She was found to have acute on chronicrenal insufficiency with an increase in serum creatinine frombaseline of 1.9 mg/dl 5 mo before to 3.2 mg/dl on admissionin the setting of recent diarrhea and ibuprofen use.
Physical examination revealed a BP of 153/60 mmHg and no peripheraledema. Medications included metoprolol, furosemide, amlodipinebesylate, and home oxygen (4 L/min). Pertinent laboratory resultsincluded white blood count 17,700/mm3 (normal range 4000 to11,000/mm3), glucose 62 mg/dl (normal range 70 to 110 mg/dl),serum albumin 3.2 g/dl (normal range 3.5 to 4.9 g/dl), and serumcholesterol 113 mg/dl (normal range 130 to 200 mg/dl). The 24-hurine protein was 2.1 g. All serologies were negative, and noM spike was detected on serum protein electrophoresis. Urinalysisshowed 3+ protein and inactive sediment. Kidney size was normalby ultrasound.
On renal biopsy, nine of 32 glomeruli were globally sclerotic.Glomeruli were hypertrophied with diffuse and global, moderateto marked mesangial sclerosis forming large nodules that narrowedthe capillary lumina. Some nodules were densely sclerotic andstained periodic acid Schiff positive, argyrophilic and trichromeblue, consistent with matrix material (Figure 1A). Other nodulesappeared more cellular owing to internal neovascularizationby small endothelial-lined channels (Figure 1B) that were highlightedwith CD34 immunostain (data not shown). There was diffuse thickeningof glomerular basement membranes (GBM), some of which appearedduplicated. Moderate tubular atrophy and interstitial fibrosisoccupied approximately 30 to 40% of the cortex. There was thickeningof the tubular basement membranes (TBM) of both atrophic andnonatrophic tubules. Proximal tubular cells displayed focalepithelial simplification, suggesting acute ischemic tubularinjury. There was moderately severe arteriosclerosis and arteriolarhyalinosis. Congo red stain for amyloid was negative.
Figure 1. Renal biopsy findings. (A) A representative glomerulus contains large acellular periodic acid-Schiff (PAS)-positive nodules composed of lamellated matrix material. (B) In some glomeruli, the mesangial nodules appeared more cellular as a result of the presence of numerous minute endothelial-lined channels. (C) By electron microscopy, the nodules are composed of dense matrix material with reduction in capillary luminal diameter. There is also regular thickening of the glomerular basement membranes, without evidence of electron-dense deposits. Foot processes appear focally effaced. Magnifications: x400 in A and B; x2000 in C.
Immunofluorescence showed 1+ linear staining for IgG and albumininvolving GBM and TBM. Staining for IgA, IgM, C3, C1q, fibrin,and and was negative. On ultrastructural examination, themesangial areas were segmentally expanded by marked increasein mesangial matrix (Figure 1C). GBM were moderately and diffuselythickened by matrix material. No immune-type electron-densedeposits were seen. There was moderate (50%) effacement of footprocesses.
Nodular glomerulosclerosis denotes a histologic pattern of nodularmesangial sclerosis with accentuated glomerular lobularity.Differential diagnosis includes the entities listed in Table 1.1–3In our case, the absence of immune deposits by immunofluorescenceexcluded chronic membranoproliferative glomerulosclerosis–anddysproteinemia-related glomerulopathies. By electron microscopy,no organized deposits were seen. Although the mesangial sclerosisand GBM and TBM thickening were typical of diabetic glomerulosclerosis,the patient had no history of diabetes. In the past, the occurrenceof diabetic-like nephropathy in a patient without diabetes wastermed "idiopathic nodular mesangial sclerosis" or "idiopathicnodular glomerulosclerosis" (ING).4,5 This previously enigmaticcondition recently has been linked to cigarette smoking andchronic hypertension, supporting its emergence as a distinctclinicopathologic entity.6 In the case reported here, the historyof longstanding hypertension, smoking, COPD, and severe peripheralvascular disease strongly favored smoking-associated nodularglomerulosclerosis.
Table 1. Differential diagnosis of nodular glomerulosclerosis
Fewer than 50 cases of ING have been published in the Englishliterature (reviewed by Kuppachi et al.7). Our group reportedthe largest series of ING (23 patients) and was the first toidentify a causative association with smoking.6 ING composed0.45% of native kidney biopsies that were accessioned over a5-yr period (1996 to 2001) at Columbia University. The 23 patientswere predominantly elderly (mean age 68.2 yr), white (73.9%),and male (78.3%). There was a high prevalence of longstandinghypertension (95.7%; mean duration 15.1 yr) and heavy smoking(91.3%; mean cumulative intake 52.9 pack-years). Among smokers,57% were actively smoking and 43% were reformed smokers, underscoringthe importance of careful history taking. Hypercholesterolemia(90%) and atherosclerotic peripheral vascular disease (43.5%)were common. The majority of patients presented with renal failure(82.6%; mean serum creatinine 2.4 mg/dl) and proteinuria (>3g/d in 69.6%; mean 24-h urine protein 4.7 g). Nephrotic syndromewas present in 21.7% of patients. All renal biopsies discloseddiffuse and nodular mesangial sclerosis, thickening of GBM,arteriosclerosis, and arteriolosclerosis. Some had additionalfeatures of diabetic nephropathy, such as Bowman's capsularhyalinosis, glomerular microaneurysms, TBM thickening, and afferentand efferent arteriolar hyalinosis. Since the time of our publication,we also have observed examples with diffuse mesangial sclerosislacking nodules. Median time from biopsy to ESRD was only 26mo. Pathologic predictors of progression to ESRD included severityof interstitial fibrosis/tubular atrophy and arteriosclerosis.Continuation of smoking and lack of angiotensin II blockadehad a negative impact on renal survival.
Smoking is associated with microalbuminuria in healthy individualsand is an independent risk factor for renal functional deteriorationin diverse renal diseases.8 Potential pathophysiologic mechanismsby which smoking promotes ING include the formation of advancedglycation end products (AGE), induction of oxidative stress,angiogenesis, and altered intrarenal hemodynamics (Figure 2).In diabetes, AGE alter extracellular matrix (ECM) architectureand function through the formation of protein cross-links andmodulate cellular functions through interactions with cell surfacereceptors, the best characterized of which is receptor to AGE(RAGE).9 In the kidney, RAGE is predominantly expressed in podocytes.10Ligand binding to RAGE activates multiple signaling cascadesthrough NF-B, mitogen-activating protein kinases, JAK/STAT pathways,and the Smad pathway, thereby promoting mesangial cell synthesisof fibrogenic cytokines, PDGF and TGF-.11,12 Exposure of mesangialcells to AGE in vitro stimulates production of ECM componentsincluding type IV collagen, laminin, heparan sulfate, and fibronectin.13,14Reactive glycation products are present in aqueous extractsof tobacco and in tobacco smoke and can react rapidly with proteinsto form AGE.15 Increased levels of AGE are found in the lensesand blood vessels of cigarette smokers,16 and RAGE is upregulatedin human gingival fibroblasts incubated with nornicotine, ametabolite of nicotine.17 A potential pathogenetic role of AGEis supported by our immunohistochemical demonstration of similaraccumulations of the AGE species, pentosidine, in the mesangialnodules and zones of interstitial fibrosis in both ING and diabeticnephropathy.6,10
Figure 2. Flow chart illustrating the hypothetical pathophysiologic mechanisms in smoking-associated nodular glomerulosclerosis.
Cigarette smoke contains free radicals that are capable of directlyinducing oxidative stress. Smoking-induced oxidative injuryincreases glomerular ECM production via activation of the TGF-and IGF receptor prosclerotic signaling pathways.18,19 Engagementof RAGE by AGE also can induce oxidative stress indirectly throughcellular upregulation of oxidative enzymes.20
Hypothetically, angiogenic factors could underlie the peculiarneovascularization that is observed in glomerular nodules andabout the glomerular hilus in ING and diabetes.6,21 Vascularendothelial growth factor is expressed in podocytes and is upregulatedin diabetes.22 Vascular endothelial growth factor may promotealbuminuria and GBM thickening in diabetic nephropathy by inductionof endothelium-dependent vasodilation and dysregulation of typeIV collagen production.23,24 Nicotine also induces angiogenesisvia binding to nicotine acetylcholine receptors on endothelialcells.25
Smoking exerts effects on intrarenal hemodynamics, mainly throughsympathetic activation, which induces renal vasoconstrictionand consequent reductions in renal blood flow and GFR.26 Odoniet al.27 studied the effects of cigarette smoking on renal injuryin rats with subtotal nephrectomy. Exposure to cigarette smokecondensate increased glomerulosclerosis and interstitial fibrosisin rats that underwent subtotal nephrectomy but not sham-operatedrats. Importantly, this increase could be prevented by renaldenervation. They concluded that the smoking-induced renal damageoccurred preferentially in the setting of a preexisting scleroticinsult and was mediated primarily by sympathetic activation.27In ING, the major preexisting sclerotic insult is likely tobe hypertensive nephrosclerosis. Chronic hypoxia as a resultof COPD also may activate the sympathetic nervous system, whichin turn stimulates the renin-angiotensin system, suggestinga potential amplification mechanism promoting ECM productionand hypertension.
Most patients with ING are elderly and give a history of longstandinghypertension, in addition to smoking. Of note, ING occasionallyhas been reported in hypertensive patients without documentedhistory of smoking.6 Conversely, smoking is a major risk factorfor hypertension. These complex interrelationships support thathypertension may be an independent risk factor for ING, as wellas a major co-factor. A potential link between these processesis AGE, which have been implicated in the development of aging,vascular stiffness, atherosclerosis, and hypertension.28 Becausearteriosclerosis and mild mesangial sclerosis are also featuresof hypertensive renal injury, it is tempting to speculate thatING represents a special form of hypertensive arterionephrosclerosisthat is modified by smoking.
In short, "idiopathic nodular glomerulosclerosis" is becomingan obsolete term. Patients with a strong link to cigarette smokingand hypertension are emerging as a distinct clinicopathologicgroup. In the appropriate clinical setting, we propose thatthe designation ING should be supplanted by "smoking-associatednodular glomerulosclerosis." Greater study is needed to unravelthe complex and potentially synergistic interplay of AGE formation,oxidative stress, angiogenesis, and altered renal hemodynamics.
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Abstract
Introduction
and 
was negative. On ultrastructural examination, the mesangial areas were segmentally expanded by marked increase in mesangial matrix (Figure 1C). GBM were moderately and diffusely thickened by matrix material. No immune-type electron-dense deposits were seen. There was moderate (50%) effacement of foot processes. 
.11,12 Exposure of mesangial cells to AGE in vitro stimulates production of ECM components including type IV collagen, laminin, heparan sulfate, and fibronectin.13,14 Reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke and can react rapidly with proteins to form AGE.15 Increased levels of AGE are found in the lenses and blood vessels of cigarette smokers,16 and RAGE is upregulated in human gingival fibroblasts incubated with nornicotine, a metabolite of nicotine.17 A potential pathogenetic role of AGE is supported by our immunohistochemical demonstration of similar accumulations of the AGE species, pentosidine, in the mesangial nodules and zones of interstitial fibrosis in both ING and diabetic nephropathy.6,10 
