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.

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.

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.

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.

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.

Renal function and mortality following cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) improves outcomes in heart failure, yet selection of patients likely to have survival benefit is problematic. Chronic kidney disease (CKD) is an important determinant of mortality in patients with congestive heart failure therefore we sought to determine the impact of CKD on mortality benefit after CRT. METHODS AND RESULTS: All CRT device implantations in patients not on dialysis at Mayo Clinic between January 1999 and December 2005 were included. Of 482 patients, 342 (71%) had CKD (defined as a glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m(2)) at the time of device implantation. Patients with CKD were older (71 ± 10 vs. 63 ± 14 years, P < 0.01) than patients without CKD, and more often anaemic (12.70 ± 1.73 vs. 13.24 mg/L, P < 0.01), with similar ejection fraction (22 ± 8 vs. 23 ± 8%, P = 0.32). Survival was superior in patients with normal or mild renal dysfunction compared with patients with CKD (72 vs. 57% at 3 years, P < 0.01). After multivariate analysis, CKD remained a significant predictor of poor survival following CRT. CONCLUSION: Chronic kidney disease is common in patients undergoing CRT and associated with a higher mortality and should be considered when evaluating patients for CRT.

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.

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.

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.

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.

Exploratory study of relationship between hospitalized heart failure patients and chronic renal replacement therapy.

BACKGROUND: Chronic kidney disease (CKD) is common in heart failure (HF) and is associated with poor outcomes. Renal replacement therapy (RRT) may be deferred over concerns regarding tolerability and outcomes in HF. Our objectives were to ascertain the incidence of RRT, changes in RRT incidence over time and the association between RRT and survival in hospitalized HF patients. METHODS: A retrospective cohort study of consecutive hospitalized HF patients was performed at a single centre from 1987 to 2002 with RRT data from the United States Renal Data System. RESULTS: Of 6276 HF patients without RRT on admission, 304 commenced chronic (>or=3 months) RRT (280 dialysis only; 24 transplant) at a median of 475 days after dismissal. Overall incidence was 1.6% per year. Risk-adjusted incidence increased over time and was similar in those with preserved or reduced (<50%) ejection fraction. RRT patients were younger but had worse renal function and anaemia, and more diabetes, hypertension and coronary disease. Unadjusted survival was worse in the RRT group. However, risk-adjusted survival was similar in RRT and non-RRT groups (HR = 1.11, 95% CI 0.94-1.29, P > 0.05). CONCLUSIONS: Our data show that although RRT is increasingly used in HF patients, the impact on risk-adjusted mortality remains to be established. Further studies should focus on defining the appropriate clinical settings in which RRT should be used in HF, the timing and type of RRT and whether RRT can improve specific outcomes.

Cardiorenal metabolic syndrome in the African diaspora: rationale for including chronic kidney disease in the metabolic syndrome definition.

Chronic kidney disease (CKD) is more likely to progress to end-stage renal disease (ESRD) in African Americans while the reasons for this are unclear. The metabolic syndrome is a risk factor for the development of diabetes, cardiovascular disease, and has been recently linked to incident CKD. Historically, fewer African Americans meet criteria for the definition of metabolic syndrome, despite having higher rates of cardiovascular mortality than Caucasians. The presence of microalbuminuria portends increased cardiovascular risks and has been shown to cluster with the metabolic syndrome. We recently reported that proteinuria is a predictor of CKD progression in African American hypertensives with metabolic syndrome. In this review we explore the potential value of including CKD markers--microalbuminuria/proteinuria or low glomerular filtration rate (GFR)-in refining the cluster of factors defined as metabolic syndrome, ie, "cardiorenal metabolic syndrome."

Acute decompensated heart failure and the cardiorenal syndrome.

Heart failure is one of the leading causes of hospitalizations in the United States. Concomitant and significant renal dysfunction is common in patients with heart failure. Increasingly, the syndrome of heart failure is one of cardiorenal failure, in which concomitant cardiac and renal dysfunctions exist, with each accelerating the progression of the other. One fourth of patients hospitalized for the treatment of acute decompensated heart failure will experience significant worsening of renal function, which is associated with worse outcomes. It remains unclear whether worsening renal function specifically contributes to poor outcomes or whether it is merely a marker of advanced cardiac and renal dysfunction. Diuretic resistance, with or without worsening renal function, is also common in acute decompensated heart failure, although the definition of diuretic resistance, its prevalence, and prognostic implications are less well defined. The term cardiorenal syndrome has been variably associated with cardiorenal failure, worsening renal function, and diuretic resistance but is more comprehensively defined as a state of advanced cardiorenal dysregulation manifest by one or all of these specific features. The pathophysiology of the cardiorenal syndrome is poorly understood and likely involves interrelated hemodynamic and neurohormonal mechanisms. When conventional therapy for acute decompensated heart failure fails, mechanical fluid removal via ultrafiltration, hemofiltration, or hemodialysis may be needed for refractory volume overload. While ultrafiltration can address diuretic resistance, whether ultrafiltration prevents worsening renal function or improves outcomes in patients with cardiorenal syndrome remains unclear. Evidence regarding the potential renal-preserving effects of nesiritide is mixed, and further studies on the efficacy and safety of different doses of nesiritide in heart failure therapy are warranted. Newer therapeutic agents, including vasopressin antagonists and adenosine antagonists, hold promise for the future, and clinical trials of these agents are underway.

Clinical characteristics and long-term follow-up of patients with renal vein thrombosis.

BACKGROUND: To determine whether treatment guidelines for patients with lower-extremity venous thrombosis (DVT) could be applied to patients with renal vein thrombosis (RVT). The rates of recurrent venous thrombosis and survival for patients with these 2 diseases were compared. STUDY DESIGN: Inception cohort of individuals was identified with their first lifetime incident of RVT. Recurrent thrombosis and survival were compared with those for patients with DVT in a case-control fashion. SETTING & PARTICIPANTS: All patients with a diagnosis of RVT at Mayo Clinic from 1980 to 2000. OUTCOMES & MEASURES: Survival and recurrent venous thrombosis rates were compared with those for patients with DVT. Survival rates were also compared with those for US white residents. RESULTS: 218 patients (mean age, 55 +/- 19 years) were included (35% women). Malignancy (66%) and nephrotic syndrome (20%) were the most common underlying causes. Warfarin was prescribed for 74 patients (46% with lifelong therapy). During a mean follow-up of 42 +/- 57 months (768 patient-years), there were 8 recurrent venous thrombotic events (1.0/100 patient-years). This recurrence rate was less than that for patients with DVT (P < 0.001). Survival was lower compared with patients with DVT or age- and sex-matched US white residents (P < 0.001). Active malignancy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7) and infection (HR, 2.4; 95% CI, 1.4 to 4.0) were associated with poor survival. Survival was influenced positively by warfarin therapy (HR, 0.53; 95% CI, 0.31 to 0.90). LIMITATIONS: Retrospective nonrandomized study. CONCLUSIONS: RVT represents a distinct clinical entity with unique recurrence and survival rates. The finding of RVT should prompt a thorough evaluation for an underlying renal malignancy. Oral anticoagulation therapy may be associated with a survival advantage.

Nodular glomerulosclerosis: renal lesions in chronic smokers mimic chronic thrombotic microangiopathy and hypertensive lesions.

Cigarette smoking is associated with vascular lesions and chronic renal failure. In this report, we describe clinical and kidney biopsy findings for a 66-year-old woman with a history of long-term heavy cigarette smoking who developed proteinuria and decreasing renal function. This study also describes clinical and kidney biopsy findings for 9 patients with a history of smoking. None of these patients had hypertension, diabetes mellitus, or other risk factors that might result in vascular injury. Renal biopsy specimens showed a range of long-term changes with varying degrees of focal segmental or focal global glomerulosclerosis, nodular glomerulosclerosis, ischemic glomeruli, interstitial fibrosis and tubular atrophy, and mild to moderate arterial sclerosis and arteriolar hyalinosis. Electron microscopy often showed glomerular capillary wall thickening caused by subendothelial expansion by cellular elements and new basement formation resulting in segments of double contours. These changes indicate endothelial injury and glomerular capillary wall remodeling; the lesions mimic those seen in patients with chronic hypertension and chronic or healed thrombotic microangiopathies.

Use of a novel ultrafiltration device as a treatment strategy for diuretic resistant, refractory heart failure: initial clinical experience in a single center.

BACKGROUND: The System 100 UF device allows ultrafiltration (UF) via peripheral access and is approved for use in heart failure (HF), although clinical trials defining optimal target population and clinical utility are lacking. We report our initial experience with clinical use of this system in very advanced, diuretic resistant HF patients. METHODS AND RESULTS: Eleven HF patients (mean age 70 years) underwent 1 to 5 UF treatments each (total 32 UF). The goal was to remove 4 liters of fluid per 8-hour UF. Baseline creatinine averaged 2.2 mg/dL (range .9-3.2) while estimated glomerular filtration rates (GFRs) averaged 38 mL/min (range 20-87). Nine patients (82%) had moderate (GFR 30-59; n = 3) or severe (GFR <30; n = 6) renal dysfunction. Nine patients (82%) had documented right ventricular dysfunction, 6 with severe tricuspid regurgitation. Average daily intravenous furosemide dose prior to UF was 258 mg (range 80-480). Patients had received nesiritide (n = 4), dopamine (n = 4), and zaroxylyn (n = 7) prior to UF. Of the 32 UF treatments, 13 (41%) removed >3500 mL, 11 (34%) removed 2500-3500 mL, and 8 (25%) removed <2500 mL. Only one UF treatment (3%) was aborted due to hypotension. There were no significant complications related to UF. Five patients (45%) experienced an increase in creatinine of >.3 mg/dl. Five patients required dialysis for persistent diuretic resistant volume overload or uremic symptoms. Six-month mortality was 55%. CONCLUSIONS: Peripheral UF safely but variably removed fluid. In this very high-risk, advanced HF population, 45% of patients developed worsening renal function during UF therapy. Controlled studies are needed to determine the impact of UF on renal function and outcomes in high-risk populations such as this.

HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma.

Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenicity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenicity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenicity.

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.