LaTonya J. Hickson

Rituximab therapy in idiopathic membranous nephropathy: a 2-year study.

BACKGROUND AND OBJECTIVES It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) × 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations. RESULTS Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow-up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX. CONCLUSIONS Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy.

Patient Survival and Cardiovascular Risk After Kidney Transplantation: The Challenge of Diabetes

An increasing proportion of kidney recipients have diabetes mellitus (DM). Herein, we assessed the impact of DM on morbidity and mortality. The study included 933 recipients of first transplants. DM was present in 212 (23%). Compared to non‐diabetics (NoDM), DM were older, heavier and had more pretransplant cardiovascular (CV) disease (16% vs. 48%, p < 0.0001). DM had reduced survival (5 years, 93% vs. 70%, p < 0.0001) and higher incidence of CV events (9% vs. 37%, p < 0.0001). CV disease was the most common cause of death in DM (61%) but not in NoDM (26%). Mortality from infections was also higher in DM (p = 0.001). In NoDM, survival related to recipient age (hazard ratio (HR) = 1.07, p < 0.0001) and dialysis pretransplant HR = 2.21, p = 0.01, while in DM, survival related to dialysis (HR = 2.89, p = 0.01) and pretransplant CV disease (HR = 2.79, p = 0.007). In NoDM, the incidence of posttransplant CV events was related to traditional CV risk factors, while in DM only the pretransplant CV history related to this outcome. In conclusion, survival differs between NoDM and DM recipients quantitatively, by cause of death and by risk factors. In NoDM, survival is excellent, and the main threat to survival relates to immunosuppression. In DM, survival is inferior primarily due to CV disease generally present prior to transplantation.

Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.

Introduction. Pulmonary hypertension (PH) is common in patients on dialysis where it is associated with reduced survival. The possible association between PH and kidney transplant recipient survival has not been previously evaluated. Methods. In this retrospective study, we screened for PH pretransplant in 215 transplant candidates using cardiac echocardiography and measurements of right ventricular systolic pressure (RVSP). Results. Sixty-eight percent of patients had normal RVSP (<35 mm Hg), 47 (22%) had mild to moderately elevated RVSP (36-50), and 22 (10%) had markedly elevated RVSP more than 50 suggestive of severe PH. Time on dialysis was the strongest correlate of an elevated RVSP (r=0.253, P<0.001) and this relationship was independent of other variables. Elevated RVSP was observed in 25%, 25%, 38%, and 58% of patients not on dialysis, on dialysis for less than 1 year, more than 1 to 2 years, or more than 2 years, respectively. An RVSP more than 50 was associated with significantly reduced posttransplant survival (hazard ratio =3.75 [1.17-11.97], P=0.016). This relationship seemed to be independent of other variables including older age, reduced left ventricular ejection fraction, low serum albumin, and delayed graft function. Conclusion. These analyses suggest for the first time that pretransplant PH correlates with patient survival after kidney transplantation.

Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T.

Patients waiting for a kidney transplant have high mortality despite careful preselection. Herein, we assessed whether cardiac troponin T (cTnT) can help stratify risk in patients selected for kidney transplantation. cTnT levels were measured in all kidney transplant candidates but the results were not used for patient selection. Among 644 patients placed on the kidney waiting list from 9/2004 to 12/2006, 61% had elevated cTnT levels (>0.01 ng/mL). Higher levels related to diabetes, longer time on dialysis, history of cardiovascular disease and low serum albumin. High cTnT also related to cardiac anomalies, including left ventricular hypertrophy (LVH), wall motion abnormalities and stress‐inducible ischemia by dobutamine echo (DSE). However, 54% of patients without these cardiac findings had elevated cTnT. Increasing cTnT levels were associated with reduced survival (HR = 1.729, CI (1.25–2.39), p = 0.01) independently of low serum albumin (0.449 (0.24–0.83), p = 0.011) and history of stroke (3.368 (1.47–7.73), p = 0.0004). The results of the DSE and/or coronary angiography did not relate significantly to survival. However, high cTnT identified patients with abnormal echo findings and poor survival. Wait listed patients with normal cTnT have excellent survival irrespective of other factors. In contrast, high cTnT levels are strongly predictive of poor survival in the kidney transplant waiting list.

Patient Survival After Kidney Transplantation: Relationship to Pretransplant Cardiac Troponin T Levels

Assessing cardiovascular (CV) risk pretransplant is imprecise. We sought to determine whether cardiac troponin T (cTnT) relates to patient survival posttransplant. The study includes 603 adults, recipients of kidney transplants. In addition to cTnT dobutamine stress echography and coronary angiography were done in 45% and 19% of the candidates respectively. During 28.4 ± 12.9 months 5.6% of patients died or had a major cardiac event. cTnT levels were elevated (>0.01 ng/ml) in 56.2% of patients. Elevated cTnT related to reduced event‐free survival (hazard ratio (HR) = 1.81, CI 1.33–2.45, p < 0.0001) whether those events occurred during the first year or beyond. This relationship was statistically independent of all other variables tested, including older age, reduced left ventricular ejection fraction (EF) and delayed graft function. cTnT levels allowed better definition of risk in patients with other CV risk factors. Thus, event‐free survival was excellent in older individuals, patients with diabetes, low EF and those with preexisting heart disease if their cTnT levels were normal. However, elevated cTnT together with another CV risk factor(s) identified patient with very poor survival posttransplant. Pretransplant cTnT levels are strong and independent predictors of posttransplant survival. These results suggest that cTnT is quite helpful in CV risk stratification of kidney transplant recipients.

Development of reduced kidney function in rheumatoid arthritis.

BACKGROUND Rheumatoid arthritis (RA) is associated with a variety of kidney disorders. However, it is unclear whether the development of reduced kidney function is higher in patients with RA compared to the general population. STUDY DESIGN Retrospective review. SETTING & PARTICIPANTS Incident adult-onset RA cases (813) and a comparison cohort of non-RA individuals (813) in Olmsted County, MN, in 1980-2007. PREDICTOR Baseline demographic and clinical variables. OUTCOMES Reduced kidney function: (1) estimated glomerular filtration rate (eGFR)<60mL/min/1.73m(2) and (2) eGFR<45mL/min/1.73m(2) on 2 consecutive occasions at least 90 days apart; cardiovascular disease (CVD); and death. MEASUREMENTS The cumulative incidence of reduced kidney function was estimated adjusting for the competing risk of death. RESULTS Of 813 patients with RA and 813 non-RA individuals, mean age was 56±16 (SD) years, 68% were women, and 9% had reduced kidney function at baseline. The 20-year cumulative incidence of reduced kidney function was higher in patients with RA compared with non-RA participants for eGFR < 60mL/min/1.73m(2) (25% vs 20%; P=0.03), but not eGFR<45mL/min/1.73m(2) (9% vs 10%; P=0.8). The presence of CVD at baseline (HR, 1.77; 95% CI, 1.14-2.73; P=0.01) and elevated erythrocyte sedimentation rate in patients with RA (HR per 10-mm/h increase, 1.08; 95% CI, 1.00-1.16; P=0.04) was associated with increased risk of eGFR<60mL/min/1.73m(2). eGFR<60mL/min/1.73m(2) was not associated with increased risk of CVD development in patients with RA (HR, 0.99; 95% CI, 0.63-1.57; P=0.9), however, a greater reduction in GFR (eGFR<45mL/min/1.73m(2)) was associated with increased risk of CVD (HR, 1.93; CI, 1.04-3.58; P=0.04). LIMITATIONS Reduced kidney function was defined by estimating equations for kidney function. We are limited to deriving associations from our findings. CONCLUSIONS Patients with RA were more likely to develop reduced kidney function over time. CVD and associated factors appear to play a role. The presence of RA in individuals with reduced kidney function may lead to an increase in morbidity from CVD development, for which awareness may provide a means for optimizing care.

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

Chronic kidney disease (CKD) is a global health care burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including proangiogenic, anti-inflammatory, and antifibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This Review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation.

Echocardiography Criteria for Structural Heart Disease in Patients With End-Stage Renal Disease Initiating Hemodialysis.

BACKGROUND Cardiovascular disease among hemodialysis (HD) patients is linked to poor outcomes. The Acute Dialysis Quality Initiative Workgroup proposed echocardiographic (ECHO) criteria for structural heart disease (SHD) in dialysis patients. The association of SHD with important patient outcomes is not well defined. OBJECTIVES This study sought to determine prevalence of ECHO-determined SHD and its association with survival among incident HD patients. METHODS We analyzed patients who began chronic HD from 2001 to 2013 who underwent ECHO ≤1 month prior to or ≤3 months following initiation of HD (n = 654). RESULTS Mean patient age was 66 ± 16 years, and 60% of patients were male. ECHO findings that met 1 or more and ≥3 of the new criteria were discovered in 87% and 54% of patients, respectively. Over a median of 2.4 years, 415 patients died: 108 (26%) died within 6 months. Five-year mortality was 62%. Age- and sex-adjusted structural heart disease variables associated with death were left ventricular ejection fraction (LVEF) ≤45% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.20 to 1.83) and right ventricular (RV) systolic dysfunction (HR: 1.68; CI: 1.35 to 2.07). An additive of higher death risk included LVEF ≤45% and RV systolic dysfunction rather than neither (HR: 2.04; CI: 1.57 to 2.67; p = 0.53 for test for interaction). Following adjustment for age, sex, race, diabetic kidney disease, and dialysis access, RV dysfunction was independently associated with death (HR: 1.66; CI 1.34 to 2.06; p < 0.001). CONCLUSIONS SHD was common in our HD study population, and RV systolic dysfunction independently predicted mortality.

Risk factors for hospitalization among older, incident haemodialysis patients

The number of elderly persons with end‐stage renal disease is increasing with many requiring hospitalizations. This study examines the causes and predictors of hospitalization in older haemodialysis patients.

Functional Plasticity of Adipose-Derived Stromal Cells During Development of Obesity

Obesity is a major risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Expansion of the adipose mass requires adipocyte precursor cells that originate from multipotent adipose‐derived stromal cells (ASCs), which in turn also participate in repair activities. ASC function might decline in a disease milieu, but it remains unclear whether ASC function varies during the development of obesity. We tested the hypothesis that microenvironmental inflammatory changes during development of metabolic disorders in obesity affect ASC function. Domestic pigs were fed with an atherogenic (n = 7) or normal (n = 7) diet for 16 weeks. Abdominal adipose tissue biopsies were collected after 8, 12, and 16 weeks of diet for ASC isolation and immunohistochemistry of in situ ASCs and tumor necrosis factor‐α (TNF‐α). Longitudinal changes in proliferation, differentiation, and anti‐inflammatory functions of ASCs were assessed. At 16 weeks, upregulated TNF‐α expression in adipose tissue from obese pigs was accompanied by increased numbers of adipocyte progenitors (CD24+/CD34+) in adipose tissue and enlarged adipocyte size. In vitro, ASCs from obese pigs showed enhanced adipogenic and osteogenic propensity, which was abolished by anti‐TNF‐α treatment, whereas lean ASCs treated with TNF‐α showed enhanced adipogenesis. Furthermore, obese ASCs showed increased senescence compared with lean ASCs, whereas their immunomodulatory capacity was preserved. Adipose tissue inflammation promotes an increase in resident adipocyte progenitors and upregulated TNF‐α enhances ASC adipogenesis. Thus, adipose tissue anti‐inflammatory strategies might be a novel target to attenuate obesity and its complications.