Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Risk of left atrial appendage thrombus and stroke in patients with atrial fibrillation and mitral regurgitation.

OBJECTIVE: To investigate the association of mitral regurgitation (MR) on thromboembolic risk of patients with non-valvular atrial fibrillation (NVAF) undergoing transoesophageal echocardiography (TEE)-guided cardioversion. METHODS: Data for consecutive patients who underwent TEE-guided cardioversion for NVAF between 2000 and 2012 were analysed. MR severity was assessed by Doppler echocardiography and classified as ≤mild, moderate or severe. Left atrial appendage emptying velocities were averaged for five consecutive cycles. Multivariable regression models were used to identify independent predictors of left atrial appendage thrombus (LAAT) and stroke. RESULTS: 2950 patients (age, 69.3±12.2 years, 67% men) were analysed. 2173 (73.7%) had ≤mild MR; 631 (21.4%), moderate MR; and 146 (4.9%), severe MR. Patients with moderate (age, 72.4±10.7 years) and severe (age, 72.8±12.1 years) MR were older than those with ≤mild MR (age, 68.2±12.5 years). The prevalence of LAAT was 1.5% (n=43). CHA2DS2-VASc scores (≤mild MR, 3.0±1.6; moderate MR, 3.5±1.5; severe MR, 3.9±1.5; p<0.001) and heart failure frequency (≤mild MR, 38.4%; moderate MR, 48.0%; severe MR, 69.2%; p<0.001) were increasingly higher with greater MR severity. Multivariable logistic regression analysis showed no association of moderate MR (OR 0.77, 95% CI 0.38 to 1.56) or severe MR (OR 0.55, 95% CI 0.21 to 1.49) with LAAT. During a mean follow-up of 7.3±5.1 years (median 7.5, IQR, 2.7-10.9), 216 patients had an ischaemic stroke. Adjusted Cox regression analysis showed no significant association of moderate MR (HR 1.22, 95% CI 0.88 to 1.68) or severe MR (HR 0.73, 95% CI 0.31 to 1.46) with stroke. CONCLUSIONS: Among patients with NVAF, the presence or severity of MR was not associated with a decreased risk of LAAT or stroke.

Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection.

OBJECTIVE: To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. PATIENTS AND METHODS: Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. RESULTS: The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21). CONCLUSION: In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Renal Dysfunction following Direct Current Cardioversion of Atrial Fibrillation: Incidence and Risk Factors.

INTRODUCTION: Emerging data suggest that cardioversion for atrial fibrillation (AF) may be associated with acute kidney injury (AKI). However, limited data are available regarding the incidence and risk factors for AKI after direct current cardioversion (DCCV) of AF. METHODS: All patients undergoing DCCV at Mayo Clinic between 2001 and 2012 for AF were prospectively enrolled in a database. All patients with serum creatinine (SCR) values pre- and post-cardioversion were reviewed for AKI, defined as a ≥25% decline in eGFR (estimated glomerular filtration rate) from baseline value within 7 days of the DCCV. RESULTS: Of the 6,427 eligible patients, 1,256 (19.5%) patients had pre- and post-DCCV SCR available and formed the cohort under study. The mean age was 70.4 (SD 11.7) years, and 67.3% were male. During the study period, 131 (10.4%) patients suffered from AKI following DCCV. AKI was independently associated with inpatient status (OR 26.79; 95% CI 3.69-194.52), CHA2DS2-VASc score (OR 1.25; 95% CI 1.11-1.41), prior use of diuretics (OR 1.59; 95% CI 1.03-2.46), and absence of CKD (OR 1.61; 95% CI 1.04-2.49), and was independent of the success of the DCCV. None of the patients required acute dialysis during the study outcome period. CONCLUSION: AKI following DCCV of AF is common, self-limited, and without the need for replacement therapies.

Impact of Diabetes Mellitus on Stroke and Survival in Patients With Atrial Fibrillation.

Although diabetes mellitus (DM) has been established as a risk factor for developing atrial fibrillation (AF) and is a known risk factor for stroke, it is unclear whether the presence or duration of DM is the primary adverse influence on the clinical course of AF. We retrospectively analyzed patients diagnosed with incident AF to examine the impact of DM on ischemic stroke and all-cause mortality. The diagnosis of DM was established by ICD-9 codes and review of medical records. To account for the significant differences in baseline characteristics of patients with and without diabetes, we matched 909 AF patients with DM with 909 AF patients without DM using propensity score matching based on 26 baseline variables. Cox regression analysis was used to identify independent factors associated with ischemic stroke and mortality. The mean age of the propensity matched cohort was 74 ± 11.5 years and 55.4% were male. Over a median follow-up period of 5.4 years (maximum 23.9 years), cumulative survival was significantly lower for patients with DM than those without DM; Log-rank p <0.001. In the propensity-matched comparison, the risk of mortality was significantly higher in the DM group compared with the non-DM group (hazard ratio 1.25; 95% confidence interval 1.12 to 1.69; p <0.001). Likewise, patients with DM had a higher risk of stroke (hazard ratio 1.32; 95% confidence interval 1.02 to 1.69; p = 0.03). Duration of DM was not associated with increased risk for stroke or mortality. In conclusion, the co-morbidity of DM represents an independent predictor of reduced survival and further highlights the excess risk of thromboembolism in patients with AF.

Prognostic significance of patent foramen ovale in anticoagulated patients with atrial fibrillation.

Objective: Previous studies have postulated a causal role of patent foramen ovale (PFO) in the aetiology of embolic stroke in the general population. We hypothesised that the presence of concomitant PFO and atrial fibrillation (AF) will add incremental risk of ischaemic stroke to that linked to AF alone. Methods: We analysed data on 3069 consecutive patients (mean age 69.4±12.2 years; 67.1% men) undergoing transoesophageal echocardiography-guided electrical cardioversion (ECV) for AF between May 2000 and March 2012. PFO was identified by colour Doppler and agitated saline contrast study. All patients were followed up after ECV for first documentation of ischaemic stroke. Outcomes were compared using Cox regression models. Results: The prevalence of PFO was 20.0% and the shunt direction was left-to-right in the majority of patients (71.4%). Patients with PFO had a higher frequency of obstructive sleep apnoea (21.7% vs 17.1%, p=0.01) and higher mean peak left atrial appendage emptying velocity (38.3±21.8 vs 36.1±20.4 cm/s; p=0.04) compared with those without PFO. Otherwise, baseline characteristics were similar between groups. During a mean follow-up period of 7.3±4.6 years, 214 patients (7.0%) had ischaemic stroke. Multivariable analysis showed no significant association between PFO and ischaemic stroke (HR, 0.82 (95% CI 0.57 to 1.18)). PFO shunt direction was strongly associated with stroke: HR, 1.91 (95% CI 1.16 to 3.16) for right-to-left shunt and HR, 0.58 (95% CI 0.36 to 0.93) for left-to-right shunt. Conclusions: The presence of concurrent PFO in this largely anticoagulated group of patients with AF was not associated with increased risk of ischaemic stroke.

Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Disparities in Hypertension Among African-Americans: Implications of Insufficient Sleep.

PURPOSE OF REVIEW: Sleep deficiency has been proposed as a potential contributor to racial disparities in cardiovascular health. We present contemporary evidence on the unequal burden of insufficient sleep in Blacks/African-Americans and the repercussions for disparate risk of hypertension. RECENT FINDINGS: The prevalence of insufficient sleep is high and rising and has been recognized as an important cardiovascular risk factor. Presumably due to a constellation of environmental, psychosocial, and individual determinants, these risks appear exacerbated in Blacks/African-Americans, who are more likely to experience short sleep than other ethnic/racial groups. Population-based data suggest that the risk of hypertension associated with sleep deficiency is greater in those of African ancestry. However, there is a paucity of experimental evidence linking short sleep duration to blood pressure levels in African-Americans. Blacks/African-Americans may be more vulnerable to sleep deficiency and to its hypertensive effects. Future research is needed to unequivocally establish causality and determine the mechanism underlying the postulated racial inequalities in sleep adequacy and consequent cardiovascular risk.

A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR).

BACKGROUND: Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. METHODS AND DESIGN: Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with i.v. rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. DISCUSSION: This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.

Urinary podocyte excretion and proteinuria in patients treated with antivascular endothelial growth factor therapy for solid tumor malignancies.

BACKGROUND: Urinary podocyte excretion (podocyturia) may function as a more specific marker of ongoing glomerular damage. This study sought to analyze the relationship between proteinuria and podocyturia in cancer patients treated with antivascular endothelial growth factor (anti-VEGF) agents. METHODS: Thirty-seven patients treated with anti-VEGF medications were analyzed in a single-institution, cross-sectional study. Podocyte cultures were performed on random urine collections (50-100 ml), and podocytes were identified by positive podocin staining. The corresponding urine samples were analyzed for protein and creatinine (Cr) measurements. RESULTS: Proteinuria ≥0.5 g/g Cr was found in 30% of the patients (median, 0.12; interquartile range, 0.04-0.86), and 62% had podocyturia. There was a significant difference in the amount of podocyturia between patients with proteinuria ≥0.5 g/g Cr and those with a value <0.5 g/g Cr (median podocyturia, 1.08 cells/mg Cr, range, 0-14.55 vs. 0.03 cells/mg Cr, range, 0-1.64, respectively; p < 0.001). A statistically significant correlation was observed between the cumulative dose of bevacizumab and both proteinuria (r = 0.48, p = 0.004) and podocyturia (r = 0.34, p = 0.045) as well as between proteinuria and podocyturia (r = 0.63, p < 0.001), suggesting that these are mechanistically related. DISCUSSION: Ongoing podocyte loss may be mechanistically related to the onset and severity of proteinuria in patients treated with anti-VEGF agents.

Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation.

Venous neointimal hyperplasia (VNH) causes hemodialysis vascular access failure. Here we tested whether VNH formation occurs in part due to local vessel hypoxia caused by surgical trauma to the vasa vasorum of the outflow vein at the time of arteriovenous fistula placement. Selective targeting of the adventitia of the outflow vein at the time of fistula creation was performed using a lentivirus-delivered small-hairpin RNA that inhibits VEGF-A expression. This resulted in significant increase in mean lumen vessel area, decreased media/adventitia area, and decreased constrictive remodeling with a significant increase in apoptosis (increase in caspase 3 activity and TUNEL staining) accompanied with decreased cellular proliferation and hypoxia-inducible factor-1α at the outflow vein. There was significant decrease in cells staining positive for α-smooth muscle actin (a myofibroblast marker) and VEGFR-1 expression with a decrease in MMP-2 and MMP-9. These results were confirmed in animals that were treated with humanized monoclonal antibody to VEGF-A with similar results. Since hypoxia can cause fibroblast to differentiate into myofibroblasts, we silenced VEGF-A gene expression in fibroblasts and subjected them to hypoxia. This decreased myofibroblast production, cellular proliferation, cell invasion, MMP-2 activity, and increased caspase 3. Thus, VEGF-A reduction at the time of arteriovenous fistula placement results in increased positive vascular remodeling.

Acute kidney injury following bariatric surgery.

BACKGROUND: Postoperative acute kidney injury (AKI) following bariatric surgery has not been well studied. The aim of this study is to identify factors associated with risk of AKI. METHODS: The medical records of adult patients who underwent bariatric surgery between March 1, 2005 and March 31, 2011 at the Mayo Clinic were reviewed to identify patients who experienced AKI, defined as postoperative increase in serum creatinine (sCr) by 0.3 mg/dL within 72 h. For each AKI case, two controls were matched for surgical approach (laparotomy vs. laparoscopic). A chart review was conducted and conditional logistic regression analyses were performed to identify risk factors for AKI. RESULTS: There were 1,227 patients who underwent bariatric surgery, and of these, 71 developed AKI (5.8 %). The median sCr increase was 0.4 (interquartile range 0.3-0.6) mg/dL. Independent patient factors associated with increased risk included higher body mass index [odds ratio (OR) 1.24, 95 % CI 1.06-1.46 per 5 unit increase, P = 0.01] and medically treated diabetes mellitus (OR 2.77, 1.36-5.65, P = 0.01). Patients experiencing AKI had higher rates of blood transfusions (P < 0.01), postsurgical complications (P < 0.01), and longer hospital stays (P < 0.01). Another 30 patients developed kidney injury after 72 postoperative hours, usually in the setting of dehydration. CONCLUSIONS: Kidney injury following bariatric surgery is not uncommon and is associated with higher body mass index and diabetes. Further, there should be a high risk of suspicion for kidney injury in postoperative patients developing volume depletion.