No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
?Diabetic nephropathy? in a non-diabetic patient
Abstract
Kimmelstiel and Wilson originally described nodular glomerulosclerosis as the pathognomonic lesion of diabetic nephropathy. Nevertheless, nodular glomerulosclerosis pattern can rarely occur in non-diabetic patients. In such cases, the differential diagnosis includes membranoproliferative glomerulonephritis, light or heavy chain deposition disease, amyloidosis, fibrillary and immunotactoid glomerulonephritis and chronic hypoxic or ischemic conditions. In cases that the above entities cannot be proven, the term idiopathic nodular glomerulosclerosis is given.
... The finding of a TMA and a thrombomodulin mutation in this report may be a fortuitous discovery that sheds light on a possible connection between the alternative pathway of complement and ING. [1][2][3][4][5][6][7][8][9][10][15][16][17][18][19][20][21][22][23][24][25][26][27] The connections of ING to hyperlipidemia, obesity, and atherosclerosis are also interesting since they all represent inflammatory states, and this could be suggestive of a role for complement as well. 2 Studies of the coagulation cascade may be useful in ING and TMA presentations given that the coagulation cascade and the complement system interact. Ultimately many more elegant translational and basic science studies are needed to unravel the etiology of ING. ...
Idiopathic nodular glomerulosclerosis is an unusual histopathological finding that has commonly been observed in male smokers with hypertension. It has remained an enigmatic condition and is best described as a diabetic pattern of glomerular injury seen in non-diabetic patients. It is also one of the few nicotine (smoking)-associated/smoking-associated patterns of renal injury. We present an even more unusual manifestation of this pathological finding in a 59-year-old Hispanic female who presented with chronic kidney disease approaching need for renal replacement therapy. The patient had idiopathic nodular glomerulosclerosis on kidney biopsy, despite no prior history of diabetes, nor smoking history, including no secondhand smoking exposure. The patient did have hypertension. The renal biopsy also showed evidence of chronic thrombotic-microangiopathic changes within arteries and arterioles. Genetic testing of the alternative pathway revealed an unusual and likely pathological variant of thrombomodulin supporting complement dysfunction as having a role in the presentation.
Introduction:
Idiopathic nodular glomerulosclerosis (ING) is a condition that has a vasculopathic glomerular histological pattern.
Case presentation:
The authors present the case of a 44-year-old Hispanic smoker female with hypertension and peripheral arterial disease who presented nephrotic syndrome for 2 weeks. The patient was diagnosed with ING by percutaneous renal biopsy results, which showed global nodular mesangial matrix expansion, with linear staining accentuation of glomerular and tubular basement membrane for Immunoglobulin G (IgG) and albumin on immunofluorescence.
Conclusions:
ING is a rare disease with a poor renal prognosis and wide diagnostic approach; we highlight the importance of analyzing every piece of detail together to reach a definitive diagnosis.
Diabetic nephropathy without diabetes (DNND), previously known as idiopathic nodular glomerulosclerosis, is an uncommon entity and thus rarely suspected; diagnosis is histological once diabetes is discarded. In this study we describe two new cases of DNND and review the literature. We analyzed all the individualized data of previous publications except one series of attached data. DNND appears to be favored by recognized cardiovascular risk factors. However, in contrast with diabetes, apparently no factor alone has been demonstrated to be sufficient to develop DNND. Other factors not considered as genetic and environmental factors could play a role or interact. The most plausible hypothesis for the occurrence of DNND would be a special form of atherosclerotic or metabolic glomerulopathy than can occur with or without diabetes. The clinical spectrum of cardiovascular risk factors and histological findings support this theory, with hypertension as one of the characteristic clinical features.
Nodular glomerulosclerosis, although once identified as a histopathological diagnosis identical with diabetes mellitus (DM), can be seen in many diseases like membranoproliferative glomerulonephritis, amyloidosis, fibrillary and immunotactoid glomerulopathy. Idiopathic nodular glomerulosclerosis (ING) can be diagnosed by exclusion of these diseases. Medical history, serology and immunohistochemical and electron microscopical examination of renal biopsy are helpful also. ING has been related with smoking and hypertension in recent studies. Herein, we present a case of ING who is smoker and had hypertension for seven years. A 43 year-old man with swollen ankles had laboratory examinations showing creatinine:2.1mg/dl, albumin:2.9g/l and daily proteinuria:4380mg. Hepatitis B surface antigen was positive. DM was excluded. Renal size was normal by ultrasound. Renal biopsy contained 30 glomeruli, 18 of which were globally sclerotic. Mesangial nodular lesions were striking in the others. With these findings we diagnosed ING. As a result, relation of ING with smoking and hypertension has been highlighted by recent studies. ING should be considered if nodular glomerulosclerosis is identified in renal biopsy of a smoker nondiabetic with hypertension. Although hepatitis B infection is among the classical secondary reasons of nodular glomerulosclerosis; co-existing serum hepatitis B surface antigen positivity has been reported in a few case reports.
To describe an unusual case of development of diabetes mellitus (DM) several years after manifestation of diabetic nephropathy and to review the related literature.
We present a case report, including detailed laboratory and pathologic findings in a 51-year-old man who was diagnosed as having DM several years after presenting with diabetic nephropathy. The pertinent literature is also reviewed.
A 51-year-old African American man presented with proteinuria of 4 g/24 h. Past medical history was significant for impaired glucose tolerance diagnosed 2 years previously. Subsequent follow-up demonstrated fasting blood glucose levels ranging from 108 to 123 mg/dL and glycated hemoglobin levels ranging from 5.3 to 5.8%. The patient also had chronic hepatitis C, hypertension, a history of intravenous drug abuse, and a family history of DM and hypertension. On examination of the patient, his blood pressure was 180/90 mm Hg. Funduscopy revealed mild diabetic retinopathy. Work-up was negative for glomerulonephritis, connective tissue disease, vasculitis, or multiple myeloma. Kidney biopsy revealed thickened glomerular basement membranes and diffuse glomeru-losclerosis, consistent with diabetic nephropathy. During follow-up, 9 years after presenting with proteinuria and 4 years after diagnosis of biopsy-proven diabetic nephropathy, the patient had a blood glucose level of 890 mg/dL and diabetic ketoacidosis.
This case provides one explanation for the natural course of patients who present with "diabetic complications" but have no diabetes. Some of those patients may have "prediabetes" and may manifest with DM during follow-up. We also conclude that hyperglycemia is not the only important factor in the pathogenesis of diabetic nephropathy.
Diabetic nephropathy is a common cause of end-stage renal disease worldwide. It is characterised by diffuse or nodular glomerulosclerosis, afferent and efferent hyaline arteriolosclerosis, and tubulointerstitial fibrosis and atrophy. Diffuse and nodular diabetic glomerulosclerosis share similar histological features with other clinical conditions. Immunofluorescence and electron microscopy studies, and clinicopathological correlation are essential to differentiate diabetic nephropathy from other conditions that result in diffuse and nodular glomerulosclerosis.
Lobular glomerulonephritis is an entity first thought to have represented a primary disease of uncertain histogenesis, but more recently has generally been considered to represent a morphologic variant of membranoproliferative glomerulonephritis. We have encountered five patients who were found to have a lobular glomerulonephritis by renal biopsy, but in whom features of membranoproliferative glomerulonephritis types I, II, or III, could not be demonstrated and in whom alternate known diagnostic categories could be excluded. We suggest that lobular glomerulonephritis, or alternately, idiopathic nodular mesangial sclerosis, is an uncommon but persistent disease entity with a distinctive pathologic appearance and unknown pathogenesis.
Seventeen kidney specimens (6 biopsies and 11 autopsies) of Takayasu's arteritis disclosed two types of glomerular lesions. One was a mild axial mesangial proliferation associated with intramembranous and mesangial electron dense deposits consisting of IgG, IgM and C3 (axial type). The other was a centrolobular mesangial thickening associated with a hyaline deposition showing a mosaic pattern ("centrolobular mesangiopathy": centrolobular type). Mesangiolytic lesions, nodulous lesions, microaneurysms in glomeruli and extensive deposition of hyaline materials both in afferent and efferent arterioles were also observed. The former lesion was found in 4 patients with an active arteritis; and the latter was mainly observed in autopsy cases having a long-term clinical course. In the genesis of the axial type, immune complex deposition caused by the active aortitis may be involved, while the glomerular ischemia caused by the vascular lesions may be implicated in the development of the centrolobular type.
Idiopathic nodular glomerulosclerosis is an unusual entity with light microscopic and ultrastructural features similar to those of nodular diabetic glomerulosclerosis but without evidence of abnormal glucose metabolism. We report 2 patients whose renal biopsies showed nodular glomerulosclerosis with afferent and efferent arteriolosclerosis, glomerular basement membrane thickening, focal mesangiolysis and capillary microaneurysm formation, and who had no evidence of abnormal glucose metabolism or other features of diabetes mellitus. Review of the literature shows that, of the 27 reported cases of idiopathic nodular glomerulosclerosis (not including the 2 cases reported herein), 11 showed evidence of abnormal glucose metabolism or were frankly diabetic. Of the remaining 16 cases with normal serum blood glucose measurements, 3 had diabetic retinopathy and 1 had a delayed insulin response curve. The cause and pathogenesis of the glomerular nodules are discussed, and it is suggested that arteriolar stenosis and glomerular ischemia may be involved in the development these lesions.
Idiopathic nodular glomerulosclerosis (ING) is an enigmatic condition that resembles nodular diabetic glomerulosclerosis but occurs in nondiabetic patients. We reviewed clinicopathologic features, immunohistochemical profiles, and outcomes in 23 patients with ING diagnosed from among 5,073 native renal biopsy samples (0.45%) at Columbia University from January 1996 to March 2001. This cohort, in which diabetes mellitus was excluded, consisted predominantly of older (mean age, 68.2 years) white (73.9%) men (78.3%). Clinical findings at presentation included renal insufficiency in 82.6% (mean serum creatinine = 2.4 mg/dL), proteinuria (> 3 g/d in 69.6%; mean 24-hour urine protein = 4.7 g/d), and-less frequently-full nephrotic syndrome (21.7%). There was a high prevalence of hypertension (95.7%; mean = 15.1 +/- 3.4 years), smoking (91.3%; mean = 52.9 +/- 6.9 pack-years), hypercholesterolemia (90%), and extrarenal vascular disease (43.5%). All 23 patients had prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis, and arteriolosclerosis. Immunohistochemical staining for CD34, a marker of endothelial cells, showed an increased number of vascular channels within ING glomeruli compared with normal controls. Follow-up data were available for 17 patients, 6 of whom reached end-stage renal disease (ESRD) (35.3%). By Kaplan-Meier estimates, the median time after biopsy to ESRD was 26 months. Predictors of progression to ESRD included continuation of smoking (P =.0165), lack of angiotensin II blockade (P =.0007), degree of tubular atrophy and interstitial fibrosis (P =.0517), and degree of arteriosclerosis (P =.0096). In conclusion, ING is a progressive vasculopathic lesion linked to hypertension and cigarette smoking.
Despite the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator, being widely expressed throughout the kidney, there is no clearly defined renal phenotype in patients with cystic fibrosis. As patients with cystic fibrosis survive longer progressive pancreatic destruction may lead to abnormal glucose tolerance and diabetes mellitus, which in the kidney may be associated with the characteristic changes of nodular glomerulosclerosis.
The adult cystic fibrosis service at the Alfred hospital consists of a cohort of 200 patients. We describe 3 cystic fibrosis patients with impaired renal function who had renal biopsies performed as part of their diagnostic work-up. All patients had fasting plasma glucose levels, oral glucose tolerance tests and measurements of HbA1c performed to assess for the presence of cystic fibrosis-related diabetes mellitus.
The renal biopsies of all 3 patients showed histological changes characteristic of diabetic nephropathy. In all cases described characteristic Kimmelstiel-Wilson nodules were present. However, in all 3 patients the presence of impaired glucose tolerance and diabetes mellitus was excluded using standard biochemical diagnostic criteria.
We describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. We speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis, predisposes to the lesions described.
Emerging evidence supports that the entity known as idiopathic nodular glomerulosclerosis is not idiopathic. A strong causative association with longstanding cigarette smoking and hypertension has been identified. Morphologically, smoking-associated nodular glomerulosclerosis closely resembles diabetic nephropathy. The potential roles of advanced glycation end products, oxidative stress, angiogenesis, and hemodynamic perturbations are explored.
- K López-Revuelta
- A A Abreu
- C Gerrero-Márquez
- R I Stanescu
- M I Marín
- E P Fernández
K. López-Revuelta, A.A. Abreu, C. Gerrero-Márquez, R.I. Stanescu, M.I. Marín,
E.P. Fernández, Diabetic nephropathy without diabetes, J. Clin. Med. 4 (7)
(2015) 1403–1427.