Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy:results from 8 years follow-up of NID-2 study

The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics. A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan-Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91-1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy. © 2014 Springer-Verlag Italia.

Dabigatran-Related Nephropathy in a Patient with Undiagnosed IgA Nephropathy

Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long term anticoagulation. Warfarin-related nephropathy is an increasingly recognized entity, but recent evidence suggests that dabigatran can cause a WRN-like syndrome. We describe a case of a biopsy-proven anticoagulant nephropathy related to dabigatran in a patient with IgA nephropathy and propose that, despite the base glomerular disease, acute kidney injury was due to tubular obstruction by red blood cells and heme-associated tubular injury, and through a mechanism involving inhibition of anticoagulation cascade and barrier abnormalities caused by molecular mechanisms.

Cast nephropathy: an extremely rare renal presentation of Waldenström's macroglobulinaemia

Renal involvement in Waldenström's macroglobulinaemia (WM) is very unusual when compared to multiple myeloma. We report a case of a patient who developed anuric acute kidney injury secondary to cast nephropathy, dependent on high-flux haemodialysis. Complementary study revealed the presence of blood IgM monoclonal gammopathy and a massive bone marrow lymphoplasmacytic infiltration. There were no osteolytic lesions and no clinical signs/symptoms of hyperviscosity syndrome. The diagnosis of WM was established and a dexamethasone plus cyclophosphamide regime was started, in addition to plasmapheresis. The patient partially recovered renal function allowing haemodialysis and plasmapheresis withdrawal. He remained asymptomatic with a good response to chemotherapy and 12 months after his renal function remained stable. This is a rare clinical case in which WM presented as an IgM cast nephropathy, which in turn is an extremely rare renal presentation of this equally rare haematological disorder.

Molecular markers for diabetic nephropathy

Type 2 diabetes is one of the most common metabolic disorders in the world. Globally, the prevalence of this disorder is predicted to increase, along with the risk of developing diabetic related complications. One of those complications is diabetic nephropathy, defined by a progressive increase in proteinuria and a gradual decline in renal function. Approximately 25% to 30% of type 2 diabetic individuals develop this complication. However, its underlying genetic mechanisms remain unclear. Thus, the aim of this study is to contribute to the discovery of the genetic mechanisms involved in the development and progression of diabetic nephropathy, through the identification of relevant genetic variants in Portuguese type 2 diabetic individuals. The exomes of 36 Portuguese type 2 diabetic individuals were sequenced on the Ion ProtonTM Sequencer. From those individuals, 19 did not present diabetic nephropathy, being included in the control group, while the 17 individuals that presented the diabetic complication formed the case group. A statistical analysis was then performed to identify candidate common genetic variants, as well as genes accumulating rare variants that could be associated with diabetic nephropathy. From the search for common variants in the study population, the statistically significant (p-value ≤ 0.05) variants rs1051303 and rs1131620 in the LTBP4 gene, rs660339 in UCP2, rs2589156 in RPTOR, rs2304483 in the SLC12A3 gene and rs10169718 present in ARPC2, were considered as the most biologically relevant to the pathogenesis of diabetic nephropathy. The variants rs1051303 and rs1131620, as well as the variants rs660339 and rs2589156 were associated with protective effects in the development of the complication, while rs2304483 and rs10169718 were considered risk variants, being present in individuals with diagnosed diabetic nephropathy. In the rare variants approach, the genes with statistical significance (p-value ≤ 0.05) found, the STAB1 gene, accumulating 9 rare variants, and the CUX1 gene, accumulating 2 rare variants, were identified as the most relevant. Both genes were considered protective, with the accumulated rare variants mainly present in the group without the renal complication. The present study provides an initial analysis of the genetic evidence associated with the development and progression of diabetic nephropathy, and the results obtained may contribute to a deeper understanding of the genetic mechanisms associated with this diabetic complication.

Chronic Active Hepatitis B with HBV-Associated Nephropathy: Close Resemblance to Lupus Nephritis

We present a rare case of a 23-year-old male incidentally detected with hepatitis B virus (HBV) infection presenting with features suggestive of HBV-associated nephropathy. A renal biopsy specimen suggested a mesangioproliferative glomerulonephritis with a full-house pattern on immunoflourescence consistent with a diagnosis of diffuse lupus nephritis. Glomerular HbeAg and HbsAg antigens were not detectable by immunofluorescence. Antiviral therapy was instituted to suppress viral replication, thereby leading to clinical and virological remission, including that of the glomerulonephritis, without the need for additional immunosuppressant therapy. This case depicts the uniqueness of the presentation of the two conditions mimicking each other, the strategy adopted to prevent the activation of viral replication and the achievement of clinical remission.

Is renal medullary carcinoma the seventh nephropathy in sickle cell disease? A multi-center Nigerian survey.

Introduction: Previous studies had enlisted renal medullary carcinoma (RMC) as the seventh nephropathy in sickle cell disease (SCD). Clinical experience has contradicted this claim and this study is targeted at refuting or supporting this assumption. Objective: To estimate the prevalence of RMC and describe other renal complications in SCD. Materials and methods: 14 physicians (haematologists and urologists) in 11 tertiary institutions across the country were collated from patients’ case notes and hospital SCD registers. Results: Of the 3,596 registered sickle patients, 2 (0.056%) had been diagnosed with RMC over a ten year period, thereby giving an estimated prevalence rate of 5.6 per 100,000. The most common renal complication reported by the attending physicians was chronic kidney disease (CKD). The frequency of routine renal screening for SCD patients varied widely between centres – most were done at diagnosis, annually or bi-annually. Conclusion: The ten year prevalence of RMC in Nigerian SCD patients was determined to be 5.6 (estimated incidence of 0.56). RMC is not more common in SCD patients and therefore cannot be regarded as a “Seventh Sickle nephropathy”. Most of the managing physicians reported that the commonest nephropathy observed in their SCD patients was chronic kidney disease.

Expression and Role of CD166 in the Chronic Kidney Disease

Background: CD166, an adhesion molecule of the immunoglobulin superfamily, is one of the crucial effectors that traffic lymphocytes into tissues. Till now, the expression and role of CD166 in the chronic kidney disease remains unknown. Objectives: In the present study, we are to examine the expression of CD166 in the chronic kidney disease, and to explore its function with CD4+ T cells. Materials and Methods: CD166 expression was tested by Flow Cytometry (FACS) in the primary macrophages stimulated with LPS. In vivo, the expression of CD166 and CD4 were examined in the kidney tissues of adriamycin-induced nephropathy (AN) mice by immnohistochemistry. Macrophages and lymphocytes were co-cultured, the interaction between CD166 and CD4 was tested by immunofluorescent staining. Furthermore, the effects of CD166 on the activation and proliferation of T cells were explored. Results: In this study, CD166 expression was found to be upregulated on activated macrophages and glomerular endothelia in the adriamycin-induced nephropathy (AN) mice and CD4+ T cells were increased with CD166 expression in the AN mice. The interaction between macrophages and CD4+ T cells indicated that CD166 played a key role in the recruitment of lymphocytes in the chronic kidney disease, and neither proliferation nor activation of T cells was affected by CD166. Conclusions: CD166 expressed on macrophages and endothelia in AN kidney, and the function was related to the recruitment of CD4+ T cells into inflamed kidney, indicating that CD166 may be a potential target for reducing the inflammatory infiltrates in the chronic kidney disease.

Sodium bicarbonate versus isotonic saline solution to prevent contrast-induced nephropathy: a systematic review and meta-analysis

Introduction: Contrast-induced nephropathy is one of the main causes of acute kidney injury and increased hospital-acquired morbidity and mortality. The use of sodium bicarbonate for nephroprotection has emerged as a preventative strategy; however, its efficacy is controversial compared to other strategies, such as hydration using 0.9% saline solution. Objective: To compare the effectiveness of sodium bicarbonate vs. hydration using 0.9% saline solution to prevent contrast-induced acute kidney injury. Methods: A systematic review of studies registered in the COCHRANE, PUBMED, MEDLINE, LILACS, SCIELO and EMBASE databases was conducted. Randomized controlled studies that evaluated the use of 0.9% saline solution vs. sodium bicarbonate to prevent contrast-induced nephropathy were included. Results: A total of 22 studies (5,686 patients) were included. Sodium bicarbonate did not decrease the risk of contrast-induced nephropathy (RD= 0.00; 95% CI= -0.02 to 0.03; p= 0.83; I2= 0%). No significant differences were found in the demand for renal replacement therapy (RD= 0.00; 95% CI= -0.01 to 0-01; I2= 0%; p= 0.99) or in mortality (RD= -0.00; 95% CI= -0.001 to 0.001; I2= 0%; p= 0.51). Conclusions: Sodium bicarbonate administration is not superior to the use of 0.9% saline solution for preventing contrast-induced nephropathy in patients with risk factors, nor is it better at reducing mortality or the need for renal replacement therapy.

Clinical outcomes of kidney transplants on patients with end-stage renal disease secondary to lupus nephritis, polycystic kidney disease and diabetic nephropathy

Background: Patients with lupus nephritis could progress to endstage renal disease (10-22%); hence, kidney transplants should be considered as the treatment of choice for these patients. Objective: To evaluate the clinical outcomes after kidney transplants in patients with chronic kidney diseases secondary to lupus nephritis, polycystic kidney disease and diabetes nephropathy at Pablo Tobon Uribe Hospital. Methods: A descriptive and retrospective study performed at one kidney transplant center between 2005 and 2013. Results: A total of 136 patients, 27 with lupus nephritis (19.9%), 31 with polycystic kidney disease (22.8%) and 78 with diabetes nephropathy (57.4%), were included in the study. The graft survivals after one, three and five years were 96.3%, 82.5% and 82.5% for lupus nephritis; 90%, 86% and 76.5% for polycystic kidney disease and 91.7%, 80.3% and 67.9% for diabetes nephropathy, respectively, with no significant differences (p= 0.488); the rate of lupus nephritis recurrence was 0.94%/person-year. The etiology of lupus vs diabetes vs polycystic disease was not a risk factor for a decreased time of graft survival (Hazard ratio: 1.43; 95% CI: 0.52-3.93). Conclusion: Kidney transplant patients with end stage renal disease secondary to lupus nephritis has similar graft and patient survival success rates to patients with other kidney diseases. The complication rate and risk of recurrence for lupus nephritis are low. Kidney transplants should be considered as the treatment of choice for patients with end stage renal disease secondary to lupus nephritis.

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy:a multicenter prospective 8 years follow up study

Background: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. Methods: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). Results: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). Conclusions: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy.

Reduced Lrp6 Expression And Increase In The Interaction Of Gsk3β With P53 Contribute To Podocyte Apoptosis In Diabetes Mellitus And Are Prevented By Green Tea.

In diabetes mellitus (DM), podocyte apoptosis leads to albuminuria and nephropathy progression. Low-density lipoprotein receptor-related protein 6 (LRP6) is WNT pathway receptor that is involved in podocyte death, adhesion and motility. Glycogen synthase kinase 3 (GSK3) interaction with p53 (GSK3-p53) promotes apoptosis in carcinoma cells. It is unknown if GSK3-p53 contributes to podocyte apoptosis in DM. In experimental DM, green tea (GT) reduces albuminuria by an unknown mechanism. In the present study, we assessed the role of the GSK3β-p53 in podocyte apoptosis and the effects of GT on these abnormalities. In diabetic spontaneously hypertensive rats (SHRs), GT prevents podocyte's p-LRP6 expression reduction, increased GSK3β-p53 and high p53 levels. In diabetic SHR rats, GT reduces podocyte apoptosis, foot process effacement and albuminuria. In immortalized mouse podocytes (iMPs), high glucose (HG), silencing RNA (siRNA) or blocking LRP6 (DKK-1) reduced p-LRP6 expression, leading to high GSK3β-p53, p53 expression, apoptosis and increased albumin influx. GSK3β blockade by BIO reduced GSK3β-p53 and podocyte apoptosis. In iMPs under HG, GT reduced apoptosis and the albumin influx by blocking GSK3β-p53 following the rise in p-LRP6 expression. These effects of GT were prevented by LRP6 siRNA or DKK-1. In conclusion, in DM, WNT inhibition, via LRP6, increases GSK3β-p53 and podocyte apoptosis. Maneuvers that inactivate GSK3β-p53, such as GT, may be renoprotective in DM.

Theobromine Increases Nad⁺/sirt-1 Activity And Protects The Kidney Under Diabetic Conditions.

Reduction in sirtuin 1 (Sirt-1) is associated with extracellular matrix (ECM) accumulation in the diabetic kidney. Theobromine may reduce kidney ECM accumulation in diabetic rats. In the current study, we aimed to unravel, under diabetic conditions, the mechanism of kidney ECM accumulation induced by a reduction in Sirt-1 and the effect of theobromine in these events. In vitro, we used immortalized human mesangial cells (iHMCs) exposed to high glucose (HG; 30 mM), with or without small interfering RNA for NOX4 and Sirt-1. In vivo, spontaneously hypertensive rats (SHR) were rendered diabetic by means of streptozotocin and studied after 12 wk. The effects of treatment with theobromine were investigated under both conditions. HG leads to a decrease in Sirt-1 activity and NAD(+) levels in iHMCs. Sirt-1 activity could be reestablished by treatment with NAD(+), silencing NOX4, and poly (ADP-ribose) polymerase-1 (PARP-1) blockade, or with theobromine. HG also leads to a low AMP/ATP ratio, acetylation of SMAD3, and increased collagen IV, which is prevented by theobromine. Sirt-1 or AMPK blockade abolished these effects of theobromine. In diabetic SHR, theobromine prevented increases in albuminuria and kidney collagen IV, reduced AMPK, elevated NADPH oxidase activity and PARP-1, and reduced NAD(+) levels and Sirt-1 activity. These results suggest that in diabetes mellitus, Sirt-1 activity is reduced by PARP-1 activation and NAD(+) depletion due to low AMPK, which increases NOX4 expression, leading to ECM accumulation mediated by transforming growth factor (TGF)-β1 signaling. It is suggested that Sirt-1 activation by theobromine may have therapeutic potential for diabetic nephropathy.

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-β1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (~260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg·kg-1·day-1 (D0.01, N = 14), 1 mg·kg-1·day-1 (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-β1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40%), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28% (P < 0.0001) and GLUT2 by 76% (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P ≤ 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-β1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.

Endothelial Nitric Oxide Genotypes and Haplotypes Are Not Associated with End-Stage Renal Disease

The identification of genetic markers associated with chronic kidney disease (CKD) may help to predict its development. Because reduced nitric oxide (NO) bioavailability and endothelial dysfunction are involved in CKD, genetic polymorphisms in the gene encoding the enzyme involved in NO synthesis (endothelial NO synthase [eNos]) may affect the susceptibility to CKD and the development of end-stage renal disease (ESRD). We compared genotype and haplotype distributions of three relevant eNOS polymorphisms (T(-786) C in the promoter region, Glu298Asp in exon 7, and 4b/4a in intron 4) in 110 healthy control subjects and 127 ESRD patients. Genotypes for the T(-786) C and Glu298Asp polymorphisms were determined by TaqMan (R) Allele Discrimination assay and real-time polymerase chain reaction. Genotypes for the intron 4 polymorphism were determined by polymerase chain reaction and fragment separation by electrophoresis. The software program PHASE 2.1 was used to estimate the haplotypes frequencies. We considered significant a probability value of p < 0.05/number of haplotypes (p < 0.05/8 = 0.0063). We found no significant differences between groups with respect to age, ethnicity, and gender. CKD patients had higher blood pressure, total cholesterol, and creatinine levels than healthy control subjects (all p < 0.05). Genotype and allele distributions for the three eNOS polymorphisms were similar in both groups (p > 0.05). We found no significant differences in haplotype distribution between groups (p > 0.05). The lack of significant associations between eNOS polymorphisms and ESRD suggests that eNOS polymorphisms may not be relevant to the genetic component of CKD that leads to ESRD.

T cells, adhesion molecules and modulation of apoptosis in visceral leishmaniasis glomerulonephritis

Background: Immune complex deposition is the accepted mechanism of pathogenesis of VL glomerulopathy however other immune elements may participate. Further in the present study, no difference was seen between immunoglobulin and C3b deposit intensity in glomeruli between infected and non-infected dogs thus T cells, adhesion molecules and parameters of proliferation and apoptosis were analysed in dogs with naturally acquired VL from an endemic area. The dog is the most important domestic reservoir of the protozoa Leishmania (L.) chagasi that causes visceral leishmaniasis (VL). The similarity of VL manifestation in humans and dogs renders the study of canine VL nephropathy of interest with regard to human pathology. Methods: From 55 dogs with VL and 8 control non-infected dogs from an endemic area, kidney samples were analyzed by immunohistochemistry for immunoglobulin and C3b deposits, staining for CD4+ and CD8+ T cells, ICAM-1, P-selectin and quantified using morphometry. Besides proliferation marker Ki-67, apoptosis markers M30 and TUNEL staining, and related cytokines TNF-alpha, IL-1 alpha were searched and quantified. Results: We observed similar IgG, IgM and IgA and C3b deposit intensity in dogs with VL and non-infected control dogs. However we detected the Leishmania antigen in cells in glomeruli in 54, CD4+ T cells in the glomeruli of 44, and CD8+ T cells in 17 of a total of 55 dogs with VL. Leishmania antigen was absent and T cells were absent/scarse in eight non-infected control dogs. CD 4+ T cells predominate in proliferative patterns of glomerulonephritis, however the presence of CD4+ and CD8+ T cells were not different in intensity in different patterns of glomerulonephritis. The expression of ICAM-1 and P-selectin was significantly greater in the glomeruli of infected dogs than in control dogs. In all patterns of glomerulonephritis the expression of ICAM-1 ranged from minimum to moderately severe and P-selectin from absent to severe. In the control animals the expression of these molecules ranged from absent to medium intensity. It was not observed any correlation between severity of the disease and these markers. There was a correlation between the number of Leishmania antigen positive cells and CD4+ T cells, and between the number of CD4+ T cells and CD8+ T cells. In dogs presenting different histopathological patterns of glomerulonephritis, parameters of proliferation and apoptosis were studied. Ki-67, a proliferative marker, was not detected locally, but fewer apoptotic cells and lower TNF-alpha expression were seen in infected animals than in non-infected controls. Conclusion: Immunopathogenic mechanisms of VL glomerulonephritis are complex and data in the present study suggest no clear participation of immunoglobulin and C3b deposits in these dogs but the possible migration of CD4+ T cells into the glomeruli, participation of adhesion molecules, and diminished apoptosis of cells contributing to determine the proliferative pattern of glomerulonephritis in VL.