MO646PATHOLOGICAL PROGNOSTIC FACTORS IN DIABETIC NEPHROPATHY: A RETROSPECTIVE STUDY

Background and Aims Kidney Biopsies (KB) performed in patients with Type-2 diabetes (T2D) usually aim at differentiating diabetic nephropathy (DN) from other kidney diseases. However, KB could also help refining patients’ prognosis, both in terms of renal survival, and in terms of patient survival. In 2010, the Renal Pathology Society developed a pathological classification of DN, but the prognostic value of the described items , is still imperfectly documented. We aimed to assess the prognostic performances of these items to predict renal and patient survival. Method Native KBs with diabetic and/or hypertensive nephropathy (DN/HN) performed in patients with T2D in four French centers were analyzed and scored according to the classification developed by the Renal Pathology Society. Clinical and biological data was collected from the patients’ records. Survival analyses were performed for renal survival (time to first dialysis or preemptive transplantation) and death after dichotomization of continuous data). For each of the analyses, we first established a model comprising clinical data only. We then assessed the benefit of adding each of the pathological item to the clinical model. Finally, we performed a backward stepwise analysis to identify items predictive of renal and/or patient survival. Results We analyzed 165 biopsies with DN/HN from patients with T2D and with at least 12 months of follow-up (unless they reached an endpoint during the first year). Among them, 73 (44%) were male, 155 (94%) had hypertension, 53 (34%) hematuria, 22 (15%) had proliferative diabetic retinopathy (DR), 33 (23%) had non-proliferative DR, 90 (62%) had no DR (20 had missing data). Mean (SD) age was 63 (11), median [IQR] eGFRCKD-EPI was 29 [18;45] ml/min/1.73m², urinary protein-to-creatinine ratio was 0.38 [0.14;0.83] g/mmol, HbA1c was 7 [6.2;8.2] % and diabetes duration before KB was 10 [5;19] years. The median [IQR] follow-up was 33 months[18;57]. During the follow-up, 43 (26%) patients died and 69 (42%) required renal replacement therapy (RRT). The percentage of ischemic glomeruli, and presence of more than one area of arteriolar hyalinosis (ah=2), were predictive of renal survival and improved the predictive value of the model when added to clinical parameters. Presence of at least one convincing Kimmelstiel–Wilson lesion (nodular glomerulosclerosis or Class III DN) was predictive of death and similarly improved the predictive model (See figure). Conclusion Pathological findings on KB, as classified by the Renal Pathology Society, carry significant prognostic value in patients with T2D and DN/HN. Vascular lesions (presence of arteriolar hyalinosis and less than 7% of ischemic glomeruli) predicted the need for RRT, while nodular glomerulosclerosis was predictive of death.

MO158CLINICOPATHOLOGICAL FEATURES OF COEXISTENT LIGHT CHAIN CASE NEPHROPATHY AND LIGHT CHAIN DEPOSITION DISEASE IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA

Background and Aims Several patients with multiple myeloma suffered from more than one type of kidney disease simultaneously, of which the most common pattern is coexistent light chain cast nephropathy and light chain deposition disease (LCCN+LCDD). We investigated clinicopathological characteristics of LCCN+LCDD in comparison with pure LCCN and pure LCDD. Method Forty-seven percent of the renal biopsies revealed a monoclonal κ light chain restriction, ranging from 31% in the pure LCCN group to 90% in the pure LCDD group. Of note, more than half of the patients with LCCN+LCDD showed λ light chain isotype, which was significantly different from patients with pure LCDD (56% vs. 10%, p = 0.033). Compared with patients with pure LCDD, patients with LCCN+LCDD usually presented atypical features of LCDD with less nodular glomerulosclerosis (p = 0.003) and less diffuse deposit distribution (p = 0.027). Compared to patients with pure LCDD, patients with LCCN+LCDD had lower hemoglobin (126.5 g/L vs. 82.0 g/L, p = 0.008), higher incidence of AKI (20% vs. 89%, p = 0.003), lower percentage of urinary albumin excretion (%UAE) (68.9% vs. 5.1%, p = 0.003). There was no significant clinical difference between patients with LCCN+LCDD and patients with pure LCCN. Compared to patients with pure LCDD, patients with pure LCCN had lower hemoglobin (126.5 g/L vs. 87.0 g/L, p = 0.001), higher incidence of AKI (20% vs. 85%, p < 0.001), higher incidence of hemodialysis at diagnosis (10% vs. 65%, p = 0.003), higher serum creatinine (165.8 μmol/L vs. 627.0 μmol/L, p = 0.02) and lower incidence of hematuria (6/10 vs. 4/26, p = 0.035). Results Forty-seven percent of the renal biopsies revealed a monoclonal κ light chain restriction, ranging from 31% in the pure LCCN group to 90% in the pure LCDD group. Of note, more than half of the patients with LCCN+LCDD showed λ light chain isotype, which was significantly different from patients with pure LCDD (56% vs. 10%, p = 0.033). Compared with patients with pure LCDD, patients with LCCN+LCDD usually presented atypical features of LCDD with less nodular glomerulosclerosis (p = 0.003) and less diffuse deposit distribution (p = 0.027). Compared to patients with pure LCDD, patients with LCCN+LCDD had lower hemoglobin (126.5 g/L vs. 82.0 g/L, p = 0.008), higher incidence of AKI (20% vs. 89%, p = 0.003), lower percentage of urinary albumin excretion (%UAE) (68.9% vs. 5.1%, p = 0.003). There was no significant clinical difference between patients with LCCN+LCDD and patients with pure LCCN. Compared to patients with pure LCDD, patients with pure LCCN had lower hemoglobin (126.5 g/L vs. 87.0 g/L, p = 0.001), higher incidence of AKI (20% vs. 85%, p < 0.001), higher incidence of hemodialysis at diagnosis (10% vs. 65%, p = 0.003), higher serum creatinine (165.8 μmol/L vs. 627.0 μmol/L, p = 0.02) and lower incidence of hematuria (6/10 vs. 4/26, p = 0.035). Conclusion Pathologically, patients with LCCN+LCDD were more likely to have λ light chain isotype and presented atypical features of LCDD including less nodular glomerulosclerosis and less deposit distribution than patients with pure LCDD. In clinical characteristics, patients with LCCN+LCDD and patients with pure LCCN shared similar features. For patients with LCCD, especially those with λ restriction, nephrologists should carefully evaluate the kidney specimens to exclude the possibility of combined LCCN.

DNA damage in human glomerular endothelial cells induces nodular glomerulosclerosis via an ATR and ANXA2 pathway

Collagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (β: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.

Idiopathic nodular glomerulosclerosis and differential diagnosis

ABSTRACT 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.

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

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.