Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.

BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Biased estimation with shared parameter models in the presence of competing dropout mechanisms.

Recently, Thomadakis et al. quantified potential sources of bias that can occur when shared parameter (SP) models are used to jointly model longitudinal trends of a biomarker over time (e.g., a slope) and time-to-dropout in an effort to address concerns over possible informative censoring. Although SP models induce no bias under a missingness completely at random dropout mechanism, the authors demonstrate that bias can occur under a missingness at random (MAR) dropout mechanism wherein dropout depends on the observed biomarker data. To address this, the authors propose including the most recent observed marker value within the hazard function for the time-to-dropout portion of an SP model. They demonstrate via a limited simulation that the proposed model minimizes bias under a specific MAR dropout mechanism and a specific missingness not-at-random dropout mechanism. In the present article, we compare and contrast their work with that of previous authors by illustrating via simulation and an example the degree of bias or lack thereof that can occur when applying SP models, particularly, in the presence of competing dropout mechanisms. We propose the use of a competing risk SP model as a means to minimize bias whenever competing dropout mechanisms are suspected assuming the competing mechanisms result from distinct observable causes of dropout.

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.

BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point. RESULTS: Across all studies, the treatment effect on 3-year total GFR slope (median R2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. CONCLUSIONS: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. RESULTS: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. CONCLUSIONS: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.

Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease.

In March of 2018, the National Kidney Foundation, in collaboration with the US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented.

Calculating Standard Kt/V during Hemodialysis Based on Urea Mass Removed.

BACKGROUND/AIMS: We derived a novel equation for calculating weekly urea standard Kt/V (stdKt/V) during hemodialysis (HD) based on urea mass removed, comparable to the approach during peritoneal dialysis. METHODS: Theoretical consideration of urea mass balance during HD led to the following equation for stdKt/V, namely, stdKt/V = N × (URR + UFV/V), where N is the number of treatments per week, URR is urea reduction ratio per treatment, UFV is ultrafiltration volume per treatment, and V is postdialysis urea distribution volume. URR required corrections for postdialysis rebound and intradialytic urea generation. We compared the accuracy of this approach with previous equations for stdKt/V by numerical simulations using a 2-compartment model of urea kinetics for thrice-weekly and more frequent HD prescriptions. RESULTS: The proposed equation based on urea mass removed predicted values of stdKt/V that are equivalent to those calculated by previous equations for stdKt/V. CONCLUSION: This work provides a novel approach for calculating stdKt/V during HD and strengthens the theoretical understanding of stdKt/V.

Survival of propensity matched incident peritoneal and hemodialysis patients in a United States health care system.

We sought to compare survival among incident peritoneal dialysis (PD) patients to matched hemodialysis (HD) patients who received pre-dialysis care, including permanent dialysis access placement. Patients starting PD were propensity matched to those starting HD. HD patients who used a central venous catheter during the first 90 days of dialysis were excluded. Stratified Cox proportional hazards models were used to compare patient survival using both intent-to-treat and as-treated analyses. In the intent-to-treat analysis, patients were followed from the date of first dialysis until death and censored at the earliest of the following: renal transplantation, death, renal recovery, loss to follow-up or study end. In the as-treated analysis, patients were also censored at the time of modality change. A total of 1003 matched pairs were obtained from 11,301 incident patients (10,298 HD and 1003 PD). The cumulative hazard ratio for death at one year was 2.38 (95% CI 1.68-3.40) and 2.10 (1.50-2.94) for HD relative to PD patients in the as-treated and intent-to-treat analyses, respectively. The cumulative risk of death, as estimated by the cumulative hazard ratio, favored PD for almost up to 3 years of follow-up in the as-treated analysis and nearly 2 years of follow-up in the intent-to-treat analysis with no differences thereafter. The higher adjusted rate of death observed for HD patients cannot be attributed to initial use of central venous catheters or lack of pre-dialysis care.

PSA enzymatic activity: a new biomarker for assessing prostate cancer aggressiveness.

BACKGROUND: With the advent of widespread prostate-specific antigen (PSA) testing in recent decades, prostate cancer (PCa) has emerged as the most frequently diagnosed non-skin cancer among men in the U.S. and Europe. Greater screening rates coupled with improved detection methods have caused a controversial upsurge in the number of men undergoing prostate biopsy and subsequent treatment. However, current diagnostic techniques generally suffer from limited ability to identify which seemingly indolent cancers are biologically aggressive. METHODS: We collected prostatic fluid from 778 post-radical prostatectomy specimens and randomly selected samples from both the clinically confirmed aggressive (n = 50) and non-aggressive (n = 50) prostate cancer populations. We measured the level of proteolytic enzyme activity of PSA (aPSA) in each sample and used receiver operating characteristic (ROC) analysis to correlate aPSA levels with prostate cancer aggressiveness. RESULTS: We found aPSA in prostatic fluid to be inversely proportional to disease stage, such that patients with the most aggressive PCa have on average significantly reduced aPSA compared to those with less aggressive disease. Significantly, our results suggest that many (22% in our study population) of the diagnosed patients with non-aggressive PCa could have averted or delayed radical prostatectomy. CONCLUSIONS: Given the high level of debate surrounding PSA screening effectiveness [3-5] and the recent U.S. Preventative Services Task Force recommendation to discontinue PSA screening [6], our results provide renewed hope that a clinical monitoring tool may emerge that truly refines PCa treatment decision-making.

Hemodialysis and peritoneal dialysis are associated with similar outcomes for end-stage renal disease treatment in Canada.

BACKGROUND: There were 35 265 patients receiving renal replacement therapy in Canada at the end of 2007 with 11.0% of patients on peritoneal dialysis (PD) and 48.9% on hemodialysis (HD) and a remaining 40.1% living with a functioning kidney transplant. There are no contemporary studies examining PD survival relative to HD in Canada. The objective was to compare survival outcomes for incident patients starting on PD as compared to HD in Canada. METHODS: Using data from the Canadian Organ Replacement Register, the Cox proportional hazards (PH) model was employed to study survival outcomes for patients initiating PD as compared to HD in Canada from 1991 to 2004 with follow-up to 31 December 2007. Comparisons of outcomes were made between three successive calendar periods: 1991-95, 1996-2000 and 2001-04 with the relative risk of death of incident patients calculated using an intent-to-treat (ITT) analysis with proportional and non-PH models using a piecewise exponential survival model to compare adjusted mortality rates. RESULTS: In the ITT analysis, overall survival for the entire study period favored PD in the first 18 months and HD after 36 months. However, for the 2001-04 cohort, survival favored PD for the first 2 years and thereafter PD and HD were similar. Among female patients > 65 years with diabetes, PD had a 27% higher mortality rate. CONCLUSIONS: Overall, HD and PD are associated with similar outcomes for end-stage renal disease treatment in Canada.

Hemodialysis vascular access modifies the association between dialysis modality and survival.

Several comparisons of peritoneal dialysis (PD) and hemodialysis (HD) in incident patients with ESRD demonstrate superior survival in PD-treated patients within the first 1 to 2 years. These survival differences may be due to higher HD-related mortality as a result of high rates of incident central venous catheter (CVC) use or due to an initial survival advantage conferred by PD. We compared the survival of incident PD patients with those who initiated HD with a CVC (HD-CVC) or with a functional arteriovenous fistula or arteriovenous graft (HD-AVF/AVG). We used multivariable piece-wise exponential nonproportional and proportional hazards models to evaluate early (1 year) mortality as well as overall mortality during the period of observation using an intention-to-treat approach. We identified 40,526 incident adult dialysis patients from the Canadian Organ Replacement Register (2001 to 2008). Compared with the 7412 PD patients, 1-year mortality was similar for the 6663 HD-AVF/AVG patients but was 80% higher for the 24,437 HD-CVC patients (adjusted HR, 1.8; 95% confidence intervals [CI], 1.6 to 1.9). During the entire period of follow-up, HD-AVF/AVG patients had a lower risk for death, and HD-CVC patients had a higher risk for death compared with patients on PD. In conclusion, the use of CVCs in incident HD patients largely accounts for the early survival benefit seen with PD.

Changes in free water fraction and aquaporin function with dwell time during continuous ambulatory peritoneal dialysis.

Diffusive (K(BD), A0/Δx(t)) transport parameters and sieving coefficients (S) for small solutes and free water fraction (FWF), that is, the fraction of total water flow that is transported through aquaporins, were assessed as functions of dwell time t for 35 continuous ambulatory peritoneal dialysis patients using glucose 3.86% dialysis fluid.The individual values of the unrestricted pore area over diffusion distance, A0/Δx(t), were estimated using the mixed effects nonlinear regression and applied for evaluation of S(t) for sodium and FWF(t). FWF decreased on average from the initial 51% of the total transcapillary water flow to 36% at 120 min, whereas the small pore water fraction and sodium sieving coefficient increased. Our results were consistent with the three-pore model if the contribution of the transcellular pores (α(TP)) at the beginning of dwell study was doubled and later decreased to the standard value of 0.02.We conclude that transport characteristics of fluid and small solutes should be considered as time-dependent variables during the peritoneal dialysis.

The outcomes of continuous ambulatory and automated peritoneal dialysis are similar.

Recent reports indicate a decreased mortality risk for patients on chronic peritoneal dialysis in the United States. We sought to determine whether a higher use of automated versus continuous ambulatory peritoneal dialysis was associated with this improvement. Analyses were carried out using data from the United States Renal Data System on 66,381 incident patients on chronic peritoneal dialysis in the years 1996-2004 that were adjusted for demographic, clinical, laboratory and dialysis facility characteristics. Patients were followed until the time of transfer to other modes of dialysis, transplant, or death, whichever occurred first, or until their last follow-up through September 2006. Over time, the risks were substantially reduced such that the adjusted hazard ratios for death or technique failure of these patients in the 2002-2004 period were 0.55 (0.53, 0.57) and 0.62 (0.59, 0.64), respectively, compared with those of incident patients during the years 1996-1998. The risk improvements for both modes of dialysis were, however, found to be similar. Under intent-to-treat, time-dependent, and as-treated analysis, there was little or no difference in risk for death or in technique failure. Thus, the improved chronic peritoneal dialysis outcomes cannot be attributed to a greater use of automated peritoneal dialysis.

Association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder: US-based retrospective cohort study.

OBJECTIVE: To estimate the association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder (OAB). DESIGN: A retrospective claims-based study (2007-2015) of patients with OAB; outcomes from a subset were contrasted to a non-OAB comparison. SETTING: United States, commercially and Medicare-insured population. PARTICIPANTS: 154 432 adults with OAB and 86 966 adults without OAB, mean age of 56 years, and 67.9% women. MAIN OUTCOME MEASURES: Cumulative anticholinergic burden, a unitless value representing exposure over time, was estimated over the 12 months pre-index ('at baseline') and every 6 months post index. Burden was categorised as no burden (0), low burden (1-89), medium burden (90-499) or high burden (500+). Unadjusted rates of falls or fractures were estimated, and the increased risk associated with anticholinergic burden (measured at the closest 6-month interval prior to a fall or fracture) was assessed using a Cox proportional hazards model and a marginal structural model. RESULTS: Median (IQR) baseline anticholinergic burden was 30 (0.0-314.0) and higher among older (≥65 years, 183 [3.0-713.0]) versus younger (<65 years, 13 [0.0-200.0]) adults. The unadjusted rate of falls or fractures over the period was 5.0 per 100 patient-years, ranging from 3.1 (95% CI 3.0-3.2) for those with no burden, to 7.4 (95% CI 7.1-7.6) for those with high burden at baseline. The adjusted risk of falls and fractures was greater with higher anticholinergic burden in the previous 6 months, with an HR of 1.2 (95% CI 1.2 to 1.3) for low burden versus no burden, to 1.4 (95% CI 1.3 to 1.4) for high versus no burden. Estimates from marginal structural models adjusting for time-varying covariates were lower but remained significantly higher with a higher anticholinergic burden. Rates of falls and fractures were approximately 40% higher among those with OAB (vs those without). CONCLUSION: Higher levels of anticholinergic burden are associated with higher rates of falls and fractures, highlighting the importance of considering anticholinergic burden when treating patients with OAB.

Estrogen and progesterone levels in nipple aspirate fluid of healthy premenopausal women: relationship to steroid precursors and response proteins.

BACKGROUND: Concentrations of estrogen and progesterone within the breast could provide a better reflection of breast cancer risk than levels in the circulation. We developed highly sensitive immunoassays for multiple steroid hormones and proteins in the nipple aspirate fluid (NAF), which can be obtained noninvasively with a simple suction device. Previous studies showed that NAF hormone levels are strongly correlated between breasts and within a single breast over time and are predictably related to hormone replacement therapy or use of oral contraceptives. This study evaluates the relationship of NAF estrogen and progesterone levels to those in serum and saliva, the relationship of NAF estradiol to androgenic and estrogenic precursors in NAF, and the relationship of NAF hormone levels to those of response proteins such as cathepsin D and epidermal growth factor (EGF). METHODS: Normal premenopausal women collected saliva daily and donated blood and NAF in the midluteal phases of menstrual cycles at intervals of 0, 4, 12, and 15 months. Analytes were measured by immunoassays after solvent fractionation. Log-transformed values were fit to repeated measures analysis of covariance models to ascertain associations between analytes. RESULTS: Small nonsignificant associations were found between NAF and serum or salivary estradiol. However, progesterone in NAF was significantly associated with progesterone in serum and saliva (R=0.18 and 0.32, respectively). Within NAF, the estradiol precursors estrone sulfate, androstenedione, and dehydroepiandrosterone were significantly associated with estradiol concentration (P<0.06), and a multiprecursor model explained the majority of variance in NAF estradiol (model R(2)=0.83). Cathepsin D and EGF in NAF could not be predicted from serum or salivary steroid measurements; however, both could be predicted from estradiol and its precursors in NAF (model R(2)=0.70 and 0.93, respectively). CONCLUSIONS: By showing consistent associations between estradiol and its precursors and response proteins, these data provide support for the biological validity of NAF hormone measurements and for the importance of steroid interconversion by aromatase and sulfatase within the breast. The low correlation between estrogen levels in NAF and those in serum or saliva suggests that the degree of association between estrogen or its androgen precursor levels and risk of breast cancer observed in epidemiologic studies using serum estimates might be highly attenuated.

Modeling of icodextrin in PD Adequest 2.0.

OBJECTIVE: To validate the use of a modified three-pore model for predicting fluid transport during long dwell exchanges that use a 7.5% icodextrin solution. DESIGN: A nonrandomized, single group, repeated measures study. PATIENTS: Ten peritoneal dialysis patients underwent a single 8-hour exchange of a 7.5% icodextrin solution. All patients were naive to icodextrin. MAIN OUTCOME MEASURES: A modified three-pore model was used to model solute and fluid transport during each 8-hour exchange. Concordance correlation coefficients were used to estimate the level of agreement between modeled and measured values of net ultrafiltration (UF) and intraperitoneal volume. METHODS: Each patient underwent a modified 8-hour standard peritoneal permeability analysis using a 2-L 7.5% icodextrin exchange. Dextran 70 was added to the icodextrin solution as volume marker to estimate fluid transport kinetics. Transcapillary UF, fluid absorption, and intraperitoneal volumes were assessed via the volume marker at 0, 5, 15, 30, 60, 120, 240, 300, 360, 420, and 480 minutes. RESULTS: There was strong agreement (concordance correlation = 0.9856) between net UF as measured by the volume marker data and net UF as modeled using the modified three-pore model implemented in PD Adequest (Baxter Healthcare, Deerfield, Illinois, USA). CONCLUSIONS: Net UF and intraperitoneal volumes for long dwell exchanges using a 7.5% icodextrin solution can be accurately modeled with a modified three-pore model. Steady state icodextrin plasma levels are needed to accurately predict net UF for chronic users of icodextrin.