John J. Dillon

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.

Outcomes of Arteriovenous Fistula Creation after the Fistula First Initiative

BACKGROUND AND OBJECTIVES The arteriovenous fistula (AVF) is the preferred hemodialysis access, but AVF-failure rate is high, and complications from AVF placement are rarely reported. There is no clear consensus on predictors of AVF patency. This study determined AVF outcomes and patency predictors at Mayo Clinic Rochester following the Fistula First Initiative. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A retrospective cohort study of AVFs placed at Mayo Clinic from January 2006 through December 2008 was performed. The AVF placement-associated primary and secondary failure rates, complications, interventions, and hospitalizations were examined. Kaplan-Meier survival curves and Cox proportional hazard models were used to determine primary and secondary patency and associated predictors. RESULTS During this time frame, 317 AVFs were placed in 293 individual patients. The primary failure rate was 37.1% after excluding patients not initiated on hemodialysis during follow-up (n = 38) or those with indeterminate outcome (37 lost to follow-up; six died; two transplanted). Of usable AVFs, 11.4% later failed. AVF creation incurred complications and hospitalization in 21.2% and 12.3% of patients, respectively. The risk for reduced primary patency was increased by diabetes (HR, 1.54; 95% CI, 1.14 to 2.07); the risk for reduced primary and secondary patency was decreased with larger arteries (HR, 0.83; 95% CI, 0.73 to 0.94; and HR, 0.69; 95% CI, 0.56 to 0.84, respectively). CONCLUSIONS Primary failure remains a major issue in the post-Fistula First era. Complications from AVF placement must be considered when planning AVF placement. Our data demonstrate that artery size is the main predictor of AVF patency.

Prevalence of Renal Artery and Kidney Abnormalities by Computed Tomography among Healthy Adults

BACKGROUND AND OBJECTIVES Management of incidental renal artery and kidney abnormalities in patients undergoing computed tomography scans is a clinical challenge because their frequency in healthy subjects has not been precisely estimated. Therefore, the prevalence and management of these abnormalities were determined among a large cohort of potential kidney donors undergoing protocol evaluations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients at the Mayo Clinic who underwent computed tomographic angiography and urography as part of their kidney donor evaluation between 2000 and 2008 were identified. Radiographic reports were abstracted for abnormalities of the renal arteries and kidneys. The prevalence of radiographic abnormalities was stratified by age and gender, and the effect on approval for kidney donation was determined. RESULTS Among 1957 potential kidney donors, the mean +/- SD age was 43 +/- 12 years, and 58% were women. The most common abnormalities were kidney stones (11%), focal scarring (3.6%), fibromuscular dysplasia (2.8%), and other renal artery narrowing or atherosclerosis (5.3%). Fibromuscular dysplasia, focal scarring, parenchymal atrophy, and upper tract dilation were more common in women. Renal artery narrowing, focal scarring, and indeterminate masses increased with age. Overall, 25% of potential donors had at least one abnormality. However, these incidental radiographic abnormalities contributed to exclusion from donation in only 6.7% of potential donors. CONCLUSIONS Incidental radiographic abnormalities of the renal arteries and kidneys are common. The majority of imaging findings are not perceived to be harmful enough to prevent kidney donation, but future studies are needed to determine their clinical relevance.

Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus

The purpose of the study was to determine the extent to which urinary sediment findings (changes in red blood cells [RBCs], white blood cells [WBCs], and the appearance of RBC and WBC casts) predict the onset of renal relapse (defined as a specific increase in proteinuria and/or serum creatinine level) in patients with systemic lupus erythematosus (SLE). Seventeen SLE patients with biopsy-proven diffuse proliferative glomerulonephritis at initial presentation were followed prospectively for 1,129 patient-months under a study protocol. Semiquantitative urinalyses were performed at 2-month intervals during periods with little or no SLE activity and, more frequently, during periods with increased SLE activity. Each urinalysis was accompanied by a clinical evaluation and a panel of screening tests relevant to the evaluation of SLE activity. During this study, 877 semiquantitative urinalyses were performed and 43 renal relapses were observed in 14 patients. No relapse occurred in three patients. Of the renal relapses, 30 were defined as proteinuria relapses (mean baseline proteinuria increased from 0.8 +/- 0.1 g/24 hr to 2.7 +/- 0.3 g/24 hr; P < 0.001) and 13 were defined as serum creatinine relapses (mean baseline serum creatinine increased from 2.7 +/- 0.4 mg/dL to 3.8 +/- 0.5 mg/dL; P < 0.001). Red blood cell and/or WBC casts (cellular casts) were observed before or at the onset of 35 of the 43 renal relapses (sensitivity, 81%). The mean and median intervals between the appearance of cellular casts and the onset of renal relapse was 10 +/- 2 weeks and 8 weeks, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The quantitative relationship between treated blood pressure and progression of diabetic renal disease

Antihypertensive therapy reduces the rate at which glomerular filtration rate (GFR) declines (delta GFR) in diabetic nephropathy; however, the optimal blood pressure is unknown. The quantitative relationship between treated blood pressure and delta GFR was analyzed retrospectively in 59 patients with established diabetic nephropathy and treated hypertension using weighted univariate and weighted multivariate regression. The GFR was calculated using the Cockcroft and Gault formula. More rapid GFR loss correlated most strongly with higher diastolic blood pressures (r = 0.70; P < 0.0001); for each millimeter of mercury of diastolic blood pressure, the GFR decreased by 0.69 mL/min/yr. This relationship remained present if those individuals with diastolic pressures greater than 90 mm Hg were eliminated from the study (r = 0.50; P < 0.001). The correlation for systolic blood pressure was weaker (r = 0.30; P < 0.05) and explained completely by covariance between systolic and diastolic blood pressures. The correlation for mean blood pressure (r = 0.59; P < 0.0001) fell between the correlations for diastolic and systolic blood pressures. Proteinuria, serum albumin concentration, and serum cholesterol concentration also correlated with delta GFR. In multivariate analysis, neither these indices of disease severity nor the initial GFR explained the correlation between delta GFR and diastolic blood pressure. Age, sex, race, type of diabetes, and percentage of glycosylated hemoglobin did not correlate with delta GFR.

Rituximab therapy for Type I membranoproliferative glomerulonephritis.

AIMS Type I membranoproliferative glomerulonephritis (MPGN) is an immune-complex disease with a relatively poor prognosis. It has no established treatment in adults. Our hypothesis was that this disease would respond to B cell depletion with rituximab, an anti-CD20 monoclonal antibody. METHODS We conducted an openlabel trial, in Canada and the United States, of rituximab in 6 adult patients with Type I MPGN (4 idiopathic, 2 with cryoglobulinemia). The rituximab dose was 1,000 mg intravenously on Day 1 and on Day 15. The patients were followed for 1 year. The primary outcome was the change in proteinuria. RESULTS Peripheral blood B cells were suppressed, after rituximab, in all patients. The mean urinary protein excretion was 3.9 ± 2.0 g/d before treatment. Proteinuria fell in all patients, at all-time points, after rituximab administration. The difference was statistically significant (p < 0.05) at 6, 9 and 12 months, but not at 3 months. The minimum mean urinary protein excretion was 1.4 ± 1.4 g/d at 9 months. There were 2 complete and 3 partial remissions among the 6 patients. The creatinine clearance did not change significantly over the course of the study. There were no adverse effects. CONCLUSIONS Rituximab reduced proteinuria among patients with Type I MPGN. This trial suggests that B cells may play a role in this disease and that additional study of B-cell suppression is warranted.

Effect of Recombinant Erythropoietin Therapy on Autoimmunity in Systemic Lupus Erythematosus

Previous studies of the in vitro effects of recombinant erythropoietin (rEPO) on T and B cells and studies of lymphocyte subsets in dialysis patients receiving rEPO therapy suggest that rEPO might augment immune responses. In the present study indices of autoimmunity (antinuclear antibody, anti-double-stranded DNA, and antiphospholipid antibody [immunoglobulins G and M]) were measured before, during, and after rEPO therapy in five systemic lupus erythematosus patients without renal failure (mean serum creatinine, 1.5 +/- 0.3 mg/dL). The rEPO therapy was self-administered by subcutaneous injection in doses ranging from 4,000 units once weekly to 3,000 units three times weekly for 3 to 7 months. On rEPO therapy, each patient experienced an increase in hematocrit. The mean baseline hematocrit increased from 32 +/- 2.0 to a peak of 42.2 +/- 3 (P < 0.001) at 3 to 7 months and then decreased to baseline values 1 to 2 months after rEPO was discontinued. During this time the indices of autoimmunity were not significantly changed by rEPO therapy. Systemic lupus erythematosus activity, assessed by serum C3, serum creatinine, urinalysis, and 24-hour proteinuria, also was unchanged by rEPO therapy. The rEPO therapy was generally well tolerated. However, one patient, who was also receiving replacement estrogen therapy and had high-titer antiphospholipid antibody, experienced episodes of thrombophlebitis while on rEPO therapy. In conclusion, we found no evidence that rEPO increases autoimmunity in systemic lupus erythematosus. However, we observed a temporal relationship between episodes of thrombophlebitis and rEPO therapy in a single patient with high-titer anticardiolipin antibody who was also receiving replacement estrogen therapy. These associations require further investigation.

Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate

The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.

End of Life, Withdrawal, and Palliative Care Utilization among Patients Receiving Maintenance Hemodialysis Therapy

BACKGROUND AND OBJECTIVES Withdrawal from maintenance hemodialysis before death has become more common because of high disease and treatment burden. The study objective was to identify patient factors and examine the terminal course associated with hemodialysis withdrawal, and assess patterns of palliative care involvement before death among patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We designed an observational cohort study of adult patients on incident hemodialysis in a midwestern United States tertiary center, from January 2001 to November 2013, with death events through to November 2015. Logistic regression models evaluated associations between patient characteristics and withdrawal status and palliative care service utilization. RESULTS Among 1226 patients, 536 died and 262 (49% of 536) withdrew. A random sample (10%; 52 out of 536) review of Death Notification Forms revealed 73% sensitivity for withdrawal. Risk factors for withdrawal before death included older age, white race, palliative care consultation within 6 months, hospitalization within 30 days, cerebrovascular disease, and no coronary artery disease. Most withdrawal decisions were made by patients (60%) or a family member (33%; surrogates). The majority withdrew either because of acute medical complications (51%) or failure to thrive/frailty (22%). After withdrawal, median time to death was 7 days (interquartile range, 4-11). In-hospital deaths were less common in the withdrawal group (34% versus 46% nonwithdrawal, P=0.003). A third (34%; 90 out of 262) of those that withdrew received palliative care services. Palliative care consultation in the withdrawal group was associated with longer hemodialysis duration (odds ratio, 1.19 per year; 95% confidence interval, 1.10 to 1.3; P<0.001), hospitalization within 30 days of death (odds ratio, 5.78; 95% confidence interval, 2.62 to 12.73; P<0.001), and death in hospital (odds ratio, 1.92; 95% confidence interval, 1.13 to 3.27; P=0.02). CONCLUSIONS In this single-center study, the rate of hemodialysis withdrawals were twice the frequency previously described. Acute medical complications and frailty appeared to be driving factors. However, palliative care services were used in only a minority of patients.

Tolerability and Healthcare Utilization in Maintenance Hemodialysis Patients Undergoing Treatment for Tuberculosis-Related Conditions

Background: The incidence of tuberculosis (TB) in end-stage renal disease is significantly higher than that in the general population. Among those with kidney dysfunction, anti-TB treatment is associated with increased side effects, but the effect on healthcare utilization is unknown. Methods/Aim: To assess patient-reported symptoms, adverse effects and describe changes in healthcare utilization patterns during treatment for TB, we conducted a case series (n = 12) of patients receiving maintenance hemodialysis (HD) from Mayo Clinic Dialysis Services and concurrent drug therapy for TB from January 2002 through May 2014. Healthcare utilization (hospitalizations and emergency department (ED) visits independent of hospital admission) was compared before and during treatment. Results: Patients were treated for latent (n = 7) or active (n = 5) TB. The majority of patients with latent disease were treated with isoniazid (n = 5, 71%), while active-disease patients received a 4-drug regimen. Adverse effects were reported in 83% of patients. Compared to measurements prior to drug initiation, serum albumin and dialysis weights were similar at 3 months. Commonly reported anti-TB drug toxicities were described. More than half (58%) of the patients were hospitalized at least once. No ED or hospital admissions occurred in the period prior to drug therapy, but healthcare utilization increased during treatment in the latent disease group (hospitalization rate per person-month: pre 0 vs. post 1). Conclusions: Among HD patients, anti-TB therapy is associated with frequently reported symptoms and increased healthcare utilization. Among this subset, patients receiving treatment for latent disease may be those with greatest increase in healthcare use. Careful monitoring and early complication detection may help optimize medication adherence and minimize hospitalizations.