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NDT Advance Access originally published online on September 5, 2006
Nephrology Dialysis Transplantation 2006 21(12):3571-3575; doi:10.1093/ndt/gfl422
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Idiopathic nodular glomerulosclerosis in a non-diabetic hypertensive smoker—case report and review of literature

Sarat Kuppachi1, Naqi Idris1, Praveen N. Chander2 and Jinil Yoo1

1Department of Nephrology, Our Lady of Mercy Medical Center, Bronx and 2Department of Pathology, Westchester Medical Center, Westchester, NY, USA

Correspondence and offprint requests to: Sarat Kuppachi MD, Department of Nephrology, Our Lady of Mercy Medical Center, 4141 Carpenter Avenue, Bronx, NY 10466, USA. Email: saratalka{at}gmail.com

Keywords: hypertension; nephrotic syndrome; nodular glomerulosclerosis; non-diabetic renal disease; smoking

Nodular glomerulosclerosis in diabetes mellitus (DM) has been a well-recognized occurrence since first described by Kimmelsteil and Wilson [1]. Other disease conditions in which nodular glomerulosclerosis has been observed include lobular variant of membranoproliferative glomerulonephritis [2,3], Takayasu's arteritis [4], light chain glomerulopathy [5], immunotactoid glomerulopathy [6], amyloidosis and fibrillary glomerulopathy [7,8] and collagen type III disease [9]. But when nodular glomerulosclerosis occurs in the absence of any of these conditions, it is called idiopathic nodular glomerulosclerosis (ING) [10], a diagnosis of exclusion. We report a case of this rare condition in a patient who had a long history of hypertension, hypercholesterolaemia and smoking with persistent hyperamylasaemia. This review aims to analyse all reported cases of ING to try and delineate the nature of this entity in order that ING be included in the long list of causes of nephrotic syndrome.



   Case report
Top
 Case report
Renal biopsy
 Discussion and review of...
 Conclusion
 References
 
A 77-year-old Caucasian lady was referred to our hospital in February 2003 after being diagnosed with acute renal failure (serum creatinine (Cr) 5.9 mg/dl) following an episode of urinary sepsis. Her past medical history included hypertension for 25 years, for which she was on atenolol, diltiazem, losartan and hydrochlorothiazide, hyperlipidaemia for which she was taking atorvastatin, and a 60-pack year smoking history. In October 2002, her serum Cr level was 1.4 mg/dl with blood urea nitrogen of 37 mg/dl. Evaluation during this admission noted persistent hyperamylasaemia (serum amylase 330–562 U/l), and increased levels of lipase (142–554 U/dl). Renal sonography revealed symmetrical, normal sized, mildly echogenic kidneys. A magnetic resonance imaging (MRI) revealed a 3.5 cm lobulated lesion in the head of the pancreas suspicious for a cystic neoplasm, possibly a duct ectatic mucinous tumour. Her renal function improved to a Cr of 2.5 mg/dl at discharge. Between June 2003 and October 2004, her Cr fluctuated between 2.0 and 2.2 mg/dl. From October 2004 her Cr started rising, reaching 2.5 mg/dl in February 2005, with evidence of protein in her urine. Urine protein measured 1.4 gm/day in April 2005. Further workup showed a serum albumin of 3.0 g/dl; haemoglobin 10.4 g/dl; serum triglycerides 150 mg/dl and total low-density lipoprotein (LDL) cholesterol 77 mg/dl; anti-nuclear antibody titre 1:40; serum protein electrophoresis was normal; immunofixation of immunoglobulins in serum revealed no monoclonal protein; CH50 57 mg/dl (normal 26–58 mg/dl); C3 103 mg/dl (normal 90–180 mg/dl); C4 58 mg/dl (normal 16–47 mg/dl); erythrocyte sedimentation rate (ESR) of 98; Hepatitis B s Ag and Hepatitis C Ab negative. At the end of June 2005, her Cr further increased to 2.8 mg/dl with her albumin decreasing to 2.8 g/dl and a repeat 24 h urine protein identified 3.82 gm/day. A percutaneous kidney biopsy was performed.



   Renal biopsy
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 Case report
 Renal biopsy
Discussion and review of...
 Conclusion
 References
 
The renal biopsy specimen contained 37 glomeruli of which 27 were undergoing obsolescence. Most of the glomeruli were moderately enlarged with minimal basement membrane thickening, and focal and diffuse mesangial nodules (Figure 1). Capsular drop involving the Bowman's capsules was seen in two glomeruli (Figure 1). Efferent and afferent arteriolar hyalinosis was observed (Figure 2). Immunoflourescence did not show deposits of immune or dysproteinemic type including lambda and kappa light chains. Congo red and immunoflourescent stains for amyloid were negative. Electron microscopy identified the presence of wrinkled thickened basement membranes and expanded mesangium with prominent hyalinosis. No deposits of any other type were seen in any location. The glomerular basement membranes were mildly diffusely thickened. The disease was quite advanced and approaching end stage. Though she had previously tested negative for diabetes, the tests were repeated and showed fasting serum glucose 91 mg/dl, serum insulin level 19 µ IU/ml (normal <17 µ IU/ml) and glycosalated haemoglobin 5.2% (normal <6%). An ophthalmological evaluation with fluorescein angiography also failed to show any evidence of diabetic retinopathy. A serum amylase and lipase level measured continued to be elevated. An MRI of her abdomen revealed no interval changes in the pancreatic mass. She progressed to end-stage disease by August 2005 and required haemodialysis.


Figure 1
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  		Fig. 1. Nodular glomerulosclerosis with evidence of capsular drop.

 

Figure 2
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  		Fig. 2. Afferent and efferent arteriolar hyalinosis.

 


   Discussion and review of literature
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 Case report
 Renal biopsy
 Discussion and review of...
Conclusion
 References
 
Our patient had progressively worsening renal function with proteinuria resulting in nephrotic syndrome, and significant medical history for an episode of acute renal failure, long-term hypertension and smoking, hypercholesterolaemia. On her kidney biopsy histological findings of nodular mesangial sclerosis, basement membrane thickening and arteriolar hyalinosis favoured a diagnosis of diabetic glomerulosclerosis, but she had no evidence of diabetes on biochemical testing, no immune deposits on immunoflourescence and no fibrillar or microtubular structures on electron microscopy, leading to the diagnosis of ING [10].

Kimmelsteil and Wilson [1] originally described nodular glomerulosclerosis in 1936 and these lesions were considered pathognomonic of diabetic nephropathy. But, it is now known that nodular glomerulosclerosis can occur in other disease entities, which include a lobular variant of membranoproliferative glomerulonephritis [2,3], Takayasu's arteritis [4], light chain glomerulopathy [5], amyloidosis and fibrillary glomerulopathy [6,7], immunotactoid glomerulopathy [8] and collagen type III disease [9]. These diseases are usually distinguished or excluded with help of clinical history, serologies and renal biopsy with histochemistry, immunohistochemistry, direct immunoflourescence and electron microscopy.

We have reviewed all reported cases of idiopathic glomerulosclerosis in English literature, reported after 1971 [11–27]. Cases reported prior to 1971 were not reviewed, as it is unclear if some of the causes of nodular glomerulosclerosis, such as fibrillary glomerulonephritis, immunotactoid glomerulonephritis could be adequately excluded. We have compiled a table (Table 1) of all the cases thus far reported looking at age, sex, ethnicity (where available), clinical history, hypertension, proteinuria and serum creatinine. Proteinuria was considered to be present if urine protein measured >0.2 gm/day. Proteinuria >3 gm/day has been considered to be of nephrotic range. Blood pressure >140 systolic and 90 diastolic has been considered hypertension. All cases with evidence of an impaired fasting glucose or an impaired glucose tolerance have been excluded [13,15,17,20,27,28]. Three of the reported cases had evidence of proliferative retinopathy on fundoscopy and these too have been excluded [16,19]. Excluding our case report there are 45 cases of ING in the literature. The youngest patient was a 13-year-old African American girl and the eldest an 80-year-old patient. Of all the patients, 36 (80%) were males and nine females indicating a M:F ratio of 4:1. Among 37 of the reported 45, 26 were Caucasian (70.3%), 10 African American (27%) and one Philipino. All cases had proteinuria (≥0.2 gm/day), 32 (68.9%) had nephrotic range proteinuria. Thirty-eight (82.2%) patients had a history of hypertension. Among those who did not have hypertension, four were under the age of 35 years. Average serum Cr measured 2.94 mg/dl (not included are two cases, reported only with Cr clearance). A history of smoking was available in 24 cases and 21 (87.5%) were current or ex-smokers.


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  		Table 1. ING cases reported 1971–2005

 
In 1989, Alpers and Biava [10] coined the term ‘idiopathic nodular mesangial sclerosis’ in their report on five patients who had nodular glomerulosclerosis in the absence of immune complex deposition or systemic metabolic or inflammatory disease. This was the first report suggesting that this is actually a distinct clinical entity. They had noticed three of their five cases had evidence of glomerular capillary microaneurysm formation believed to occur due to disruption of anchoring points where peripheral capillary loop basement membranes attach to mesangial stalks [10].

Herzenberg et al. [14] in 1999 first used the term ING. Their careful review of all reported cases in literature of nodular glomerulosclerosis without DM concluded that some of the patients indeed had DM, and still others had impaired glucose tolerance or impaired fasting glucose. Of the 27 cases reported in the literature (between 1971 and 1999) only 16 were truly ING (although three more could be excluded since they had diabetic retinopathy). Suggestions as to the pathogenesis included arteriolar stenosis and glomerular ischaemia that may play a role in producing mesangiolysis and capillary microaneurysm formation with subsequent nodule development similar to that produced in diabetic sclerosis. In addition, the role of obesity and hypertension in contributing to the pathogenetic mechanism was raised. The largest series to date of 23 cases was reported in 2002 by Markowitz et al. [12]. They identified a high prevalence of hypertension (95.7%), smoking (91.3%), hypercholesterolaemia (90%) and extrarenal vascular disease (43.5%) among their patients. Studying the biopsy specimens they noted an increase in vascular channels, commonly at the vascular pole of the glomeruli on light microscopic exam, and increased endothelial lined vascular spaces in the mesangial nodules on staining for endothelial cell marker CD34; which are suggestive of angiogenesis (neovascularization). Considering the recent findings of smoking as a promoter of progression in diabetic nephropathy [29,30] and as a possible reactive glycation product [31], they proposed that the pathogenesis of ING involves the interplay of hypertension, smoking, and an increased glomerular extracellular matrix and angiogenesis.

The pathogenesis remains unclear, but since the features of biopsy specimens of ING patients are strikingly similar to those of diabetic glomerulosclerosis, especially the evidence of neovascularization in the sclerotic nodules, a similar pathogenetic mechanism may play a role in both diseases. ING has been reported in patients within a spectrum of either no DM, or those in whom a subtle evidence of DM as indicated by impaired glucose tolerance tests [13,15,17,20,27] or diabetic retinopathy without DM [16,19], exists. It is possible that these individuals suffer from an increased or reset sensitivity to the non-diabetic range of glucose especially in the presence of hypertension, hypercholesterolaemia or smoking. Follow-up of a patient with features of diabetic nephropathy and retinopathy with an impaired glucose tolerance test showed clinical evidence of DM 9 years later [32]. This evidence calls for regular long-term follow-up of similar patients, as biochemical confirmation of DM may simply occur years later. Male preponderance of the disease points towards a possible hormonal predisposition. The role of hypertension cannot be downplayed, but its absence in four out of five patients under the age of 35 cannot be ignored either. This leads us to believe that hypertension is a contributor to the progression of the disease. Tobacco smoke may be a promoter in the progression of ING, being a possible source of reactive glycation products [31].



   Conclusion
Top
 Case report
 Renal biopsy
 Discussion and review of...
 Conclusion
References
 
ING remains a rare disease entity with an unclear pathogenesis, but there may lie an increased sensitivity to a non-diabetic range of blood glucose levels resulting in an exaggerated glomerulovascular response among those affected especially in the setting of hypertension, hypercholesterolaemia and smoking. Our patient had long standing hypertension, hypercholesterolaemia, and a history of smoking, factors that may be linked to this disease. Further reports would be needed to more conclusively study factors involved in the pathogenesis, yet ING is a rare cause of nephrotic syndrome and is to be included in the long list of its causes. Long-term screening for later onset of diabetes is essential.

Conflict of interest statement. None declared.



   References
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 Case report
 Renal biopsy
 Discussion and review of...
 Conclusion
 References
 

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Received for publication: 6. 6.06
Accepted in revised form: 20. 6.06


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