Idiopathic Nodular Glomerulosclerosis in a Long-term Passive Smoker With Recently Diagnosed Hypertension: A Case Report

Abstract

Idiopathic nodular glomerulosclerosis (ING) is mostly associated with long-standing active smoking and hypertension (HTN). Herein, we present a rare case of ING in a passive smoker with recently diagnosed uncontrolled HTN. A 60-year-old white female with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes (POEMS) syndrome and newly diagnosed HTN was referred because of an elevated creatinine level. She denied being an active smoker but reported long-term exposure to cigarette smoke due to living with a heavy smoking family and working as a bartender. Further investigations revealed microscopic hematuria and nephritic range proteinuria. Kidney biopsy revealed diffuse and focal nodular mesangial expansion without hypercellularity, with negative staining for amyloid, fibrillary glomerulonephritis, and immunoglobulins, leading to a diagnosis of ING. This case highlights a rare case of ING secondary to heavy passive smoking and uncontrolled HTN.

Introduction

Nodular glomerulosclerosis is defined as mesangial expansion associated with increased glomerular nodularity on kidney biopsies. ¹ Kimmelstiel and Wilson ² first described this lesion as a pathognomonic sign for diabetic nephropathy. However, it was later described in other nondiabetic-related diseases such as amyloidosis, collagen type III disease, Takayasu’s arteritis, light chain deposition disease, and nodular membranoproliferative glomerulonephritis.^2-5 Alpers et al ⁶ first reported this lesion as a separate pathological entity and coined the term “idiopathic nodular glomerulosclerosis” (ING). Herzenberg and colleagues ⁷ used the same term when describing nodular glomerulosclerosis in patients without evidence of diabetes mellitus or other pathology that could cause these lesions. Although, historically, ING has been recognized as a disease of exclusion, several comorbidities including long-standing hypertension (HTN), active smoking, and obesity have been reported to play roles. ⁸ However, ING’s occurrence in the context of passive smoking has not been previously reported in the literature. Herein, we present a rare case of ING in a passive smoker with new-onset uncontrolled HTN.

Case Presentation

A 60-year-old white female was referred to the nephrology clinic for further evaluation for unexplained rise in the creatinine (Cr) level to 1.4 mg/dL during her routine hematology visit from the baseline of 0.9 mg/dL. She was diagnosed with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes (POEMS) syndrome approximately 1 year prior due to the presence of sciatica, hypothyroidism, monoclonal gammopathy of undetermined significance (MGUS), and onychomycosis, with regular hematology visits afterwards. Her serum protein electrophoresis around 2 years prior showed m-spike of 1.0 g/dL with immunofixation electrophoresis demonstrated the presence of monoclonal IgG having kappa light chain restriction (kappa free light chain: 2.12 mg/dL, lambda free light chain: 2.01 mg/dL, kappa/lambda free light chain ratio: 1.05). Complementary bone marrow biopsy indicated mildly increased plasma cell (5%-7%) with kappa light chain predominance, in favor of MGUS.

She was diagnosed with HTN approximately 3 years before her referral. Despite having few episodes of high blood pressure, her HTN status was well controlled. Patient has been receiving allopurinol, aspirin, losartan, hydrochlorothiazide, levothyroxine, metoprolol, and prednisone (20 mg daily). The latter was prescribed by the patient’s hematologist due to suspected vasculitis approximately 1 year after the nephrology visit, and the patient continues to take it. She did not report long-standing use of nonsteroidal anti-inflammatory drugs; however, she mentioned intermittent consumption (approximately 500 mg weekly) over the past couple of years, with normal Cr levels. She had no family or personal history of kidney diseases. The patient denied any active smoking. However, she reported long-standing exposure to passive cigarette smoking because of living with a heavy smoking family member and working as a bartender for more than 30 years. At her first nephrology visit, her blood pressure, pulse rate, and body mass index were 97/64 mm Hg, 59 beats/minute, and 19.32 kg/m², respectively, and there was no rash on physical examination. She was not diabetic (hemoglobin A_1c [HbA_1c]: 5.4%). At the time of the nephrology consultation request, her Cr level was 1.4 mg/dL (blood pressure: 101/65 mm Hg), a value that had also been observed 2 months earlier. Therefore, the patient was diagnosed with chronic kidney disease stage 3B at the nephrology visit (estimated glomerular filtration rate [eGFR]: 43 mL/min/1.73 m²), with the increase in serum Cr to 1.8 mg/dL 1 week after her first nephrology visit. One month later, complementary tests showed a similar Cr value (1.8 mg/dL), and urinalysis results were in favor of nephritic range proteinuria, hematuria, and pyuria with moderate bacteriuria and negative nitrite without any urinary symptoms. Autoimmune and infectious markers (antinuclear Ab, anti-ds DNA Ab, anti-smith Ab, anti-SSA and SSB Abs, anti-SCL70 Ab, anti-Jo1 Ab, anti-centromere Ab, cytoplasmic antineutrophil cytoplasmic Ab [C-ANCA], perinuclear ANCA [P-ANCA], hepatitis B virus [HBV]) were negative. Other laboratory data are shown in Table 1. Kidney ultrasound was unremarkable.

Table 1.

Laboratory Data of the Patient During the Initial Nephrology Visit and the Most Recent Follow-up.

Laboratory data	Prior to nephrology visit	First nephrology visit	Most recent follow-up (12 months later)	Reference range (unit)
White blood cell	4.81	4.60	5.58	4.80-11.80 (*109/L)
Red blood cell	2.84	2.97	3.0	3.80-5.30 (*1012/L)
Hemoglobin	8.6	8.9	8.1	11-16 (g/dL)
Platelets	179	192	46	140-340 (*109/L)
Sodium	140	138	135	134-147 (mmol/L)
Potassium	4.3	4.6	4.2	3.5-5 (mmol/L)
Blood urea nitrogen	56	53	123	7-20 (mg/dL)
Creatinine	1.4	1.8	2.9	0.7-1.3 (mg/dL)
Calcium	2.3	2.3	1.9	2.1-2.6 (mmol/L)
Glucose, random	97	92	112	70-140 (mg/dL)
Total protein	7.4	7.5	6.1	6.3-8.2 (g/dL)
Albumin	3.7	3.6	2.8	3.2-4.6 (g/dL)
Aspartate aminotransferase	16	17	54	0-35 (U/L)
Alanine aminotransferase	10	11	106	7-45 (U/L)
Alkaline phosphatase	72	72	95	37-132 (U/L)
Urine analysis
	Around 1 month after the initial nephrology visit		Twelve months after initial the nephrology visit
Blood	Positive		Positive	Negative
Red blood cell	50		615	0-3 (/high power field)
White blood cell	15		13	0-2 (/high power field)
Protein	100		300	Negative (mg/dL)
UPCR	2.4		5.3	g/g creatinine
Bacteria	Moderate		Rare	/high power field
Nitrite	Negative		Negative	Negative

Abbreviations: UPCR, urine-protein-creatinine ratio.

The patient underwent kidney biopsy, and the results of hematoxylin and eosin, periodic acid-Schiff, Jones silver, and Masson trichrome staining revealed diffuse and focal nodular mesangial expansion without hypercellularity and moderate arteriosclerosis (Figure 1A-C). Out of 49 glomeruli, 18 (37%) showed signs of diffuse glomerulosclerosis and 3 (10%) showed segmental sclerosis. DNAJB9 immunohistochemical staining and immunofluorescent studies (IgA, IgG, IgM, C1q, kappa, and lambda light chains) as well as Congo red staining were negative. On electron microscopy, mesangial matrix expansion was confirmed with the additional finding of scattered embedded distinct curved fibrils ranging from 7 to 12 nm in diameter (Figure 1D and E). The patient was finally diagnosed with ING in the context of HTN and passive smoking. During follow-up and after kidney biopsy, the patient’s blood pressure became uncontrolled, reaching a peak of 183/93 mm Hg. Several first-line antihypertensive regimens failed to control her blood pressure, and she was subsequently prescribed carvedilol, clonidine, and hydralazine. A duplex kidney ultrasound revealed left renal artery stenosis, and she was referred for appropriate management. Regarding her hematological condition, her most recent serum protein electrophoresis showed an M-spike of 0.8 g/dL, with immunofixation electrophoresis confirming the presence of monoclonal IgG with kappa light chain restriction (kappa free light chain: 4.51 mg/dL, lambda free light chain: 2.86 mg/dL, kappa/lambda free light chain ratio: 1.58). The patient remains under regular follow-up with a stable condition. At her most recent nephrology visit, 12 months later, the patient reported no symptoms, and her blood pressure reduced to 144/78 mm Hg. Table 1 shows the most recent patient’s laboratory data approximately 12 months after her first nephrology visit.

Figure 1.

Periodic acid-Schiff (PAS) (A and B) and silver staining (C) showing diffuse and focal nodular mesangial expansion without hypercellularity, electron microscopy demonstrating mesangial matrix expansion with irregular densities and cellular debris (D), and distinct curved fibrils ranged 7 to 12 nm (E).

Discussion

Previous studies have shown an association between ING, long-standing smoking, and HTN.^1,9 This has led to the introduction of a new term, smoking-modified HTN-associated nodular glomerulosclerosis (SHaNGS), a form of hypertensive glomerulosclerosis in the context of alteration by smoking products.^8,9 It has been reported that among 127 ING patients, more than 90% and 70% had HTN and smoking history, respectively. ¹⁰ Despite our patient denied history of active smoking, she reported long-term heavy passive smoking exposure for more than 30 years.

The exact ING pathophysiological mechanism is still unknown, but several theories are suggested. One possible pathogenesis is related to smoking-induced free radicals.^11,12 Free radicals are thought to cause oxidative stress which activate transforming growth factor and insulin-like growth factor, consequently leading to increased extracellular matrix production and mesangial expansion. Free radicals as well as chronic hypoxia in the context of smoking activate the renin-angiotensin-aldosterone system and cause deposition of extracellular matrix. Sympathetic nervous system activation is another theory which can alter the hemodynamics of kidney tissue, leading to glomerulosclerosis. ¹¹ Nicotine has been shown to accelerate neovascularization by activation of growth factors and hypoxia-inducible factors leading to arteriosclerosis. Furthermore, endothelin-1 (ET-1) is also overexpressed by nicotine exposure. These activated angiogenic pathways result in intranodular vascular channels. ¹³

Histopathologic features of ING have been reported to be similar to diabetic nephropathy. For instance, mesangial nodular expansion, glomerulomegaly, and glomerular basement membrane thickening can be observed in both conditions. ¹³ In contrast, this feature was not found in our patient, and the results were in favor of glomerular basement membrane (GBM) thinning. Another case reported similar findings in a patient who also had microscopic hematuria, indicating that GBM thickening might not necessarily preclude ING diagnosis. ¹⁴

Obesity is another potential ING risk factor. Obesity-related glomerulopathy develops in obese individuals due to various cytokine production pathways (including leptin, adiponectin, interleukin-6, and tumor necrosis factor alpha) resulting in different glomerular pathologies including glomerulosclerosis and mesangial matrix expansion. ¹⁵ However, our patient was underweight.

The differential diagnosis of nodular glomerulosclerosis is usually a diagnosis of exclusion and definitive diagnosis is usually made using a combination of clinical history, serologies, and kidney biopsy (Table 2).^12,16 Our patient had normal HbA_1c level, ruling out diabetic glomerulosclerosis. Although scattered fibrillar materials were seen on the kidney biopsy specimen, they were not indicative of amyloid (negative Congo Red staining), collagenous or fibrillary glomerulonephritis (negative DNJB9 staining). Owing to the history of MGUS, light chain deposition disease was the most probable differential diagnosis. However, immunofluorescent studies did not reveal abnormal deposition of immunoglobulin light chains, and electron microscopy failed to demonstrate the characteristic “powdery” electron-dense deposits. Thus, the patient was finally diagnosed as ING.

Table 2.

Characteristics of Differential Diagnosis in Nodular Glomerulosclerosis.

Pathologies	PAS	Congo red	Silver stain	Immunofluorescence	Electron microscopy
Diabetic glomerulosclerosis	+++	−	+	Nonspecific pseudolinear staining of glomerular and tubular basement membranes with anti-IgG and anti-albumin	Thickening of GBM with expansion of the mesangium plus nodules formation
Monoclonal immunoglobulin deposition disease	++	−	−	Staining with heavy chains or light chains (kappa or lambda)	Electron-dense, granular material observed on the endothelial side of the GBM and the outer side of the TBM
Amyloidosis	−	+++	−	Amorphous positive staining with anti-light chains or anti-heavy chains antibodies	Presence of nonbranching fibrils with a crisscross, intersecting distribution
Immunotactoid glomerulonephritis	+++	−	−	Presence of variable glomeruli staining with IgG and complement	Presence of microtubules or fibrils, sometimes in a parallel stack
Fibronectin glomerulopathy	++	−	−	Positive staining with anti-fibronectin	Presence of large electron-dense deposits on mesangial and subendothelial areas
Collagen glomerulopathy	−	−	−	Negative staining	Presence of expanded mesangial matrix and subendothelial space of the GBM with significant accumulation of fibrillar material
Membranoproliferative glomerulonephritis	−	−	Presence of mesangial nodules and double contour of the GBM	Presence of peripheral lobular pattern of C3 and IgG in a fringe pattern	Type 1: presence of immune deposits in subendothelial and mesangial areas Type 2: presence of dense and intramembranous deposits in GBM, TBM, and Bowman capsule
Idiopathic nodular glomerulosclerosis	+++	−	+	Nonspecific	Presence of mesangial sclerosis, GBM thickening, and lack of immune deposits

Abbreviations: GBM, glomerular basement membrane; TBM, tubular basement membrane; PAS, periodic acid-Schiff.

Columbia University conducted a study on ING proven kidney biopsies from 1996 and 2001, which showed an incidence rate of 0.45% (n = 23). ¹⁷ Among these, 35% (n = 6) progressed to a more severe condition. This condition is recognized as a progressive kidney disorder with a 35.3% occurrence rate of end-stage kidney disease (ESKD) over a median follow-up period of 26 months. ¹⁷ Smoking was reported as one of the crucial predicting factors for ING in a way that patients who continued smoking reached ESKD after median of 11 months in comparison to those who never smoked or discontinued smoking (P = .0165). ¹⁷ Although our patient was not an active smoker, she had significant exposure to smoking which might have caused similar effects.

Owing to limited research, treatment of ING treatment still needs to be defined. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are thought to be protective. ¹⁸ Markowitz and colleagues ¹⁷ showed that ING patients on angiotensin II blockade had significantly higher mean time to ESKD incidence compared to nonrecipients.

In conclusion, despite ING is mostly observed in active smokers with long-standing HTN, our case suggests it might also occur in heavy passive smokers with recent onset uncontrolled HTN and a high index of suspicion is warranted in clinical settings.