+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Finding of pathological thrombomodulin gene variant in a patient with idiopathic nodular glomerulosclerosis and chronic thrombotic microangiopathy-like changes

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          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.

          Related collections

          Most cited references 25

          • Record: found
          • Abstract: found
          • Article: not found

          Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.

          Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.
            • Record: found
            • Abstract: found
            • Article: not found

            Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking.

            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. Copyright 2002, Elsevier Science (USA). All rights reserved.
              • Record: found
              • Abstract: found
              • Article: not found

              Nodular glomerulosclerosis in the nondiabetic smoker.

              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.

                Author and article information

                SAGE Open Med Case Rep
                SAGE Open Med Case Rep
                SAGE Open Medical Case Reports
                SAGE Publications (Sage UK: London, England )
                10 July 2020
                : 8
                [1 ]Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine, Irvine, CA, USA
                [2 ]Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
                [3 ]Department of Medicine, University of California Irvine, Irvine, CA, USA
                [4 ]School of Pharmaceutical Sciences, Chapman University, Orange, CA, USA
                [5 ]University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
                [6 ]Division of Nephrology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
                Author notes
                Ramy Hanna, Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine, 333 The City Drive, Suite #400, Orange, CA 92868, USA. Email: Rhannamd81@ 123456yahoo.com
                © The Author(s) 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                Funded by: Center for Scientific Review, FundRef https://doi.org/10.13039/100005440;
                Award ID: K24-DK091419
                Case Report
                Custom metadata
                January-December 2020


                Comment on this article