Roger A. Rodby

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

Comparison of Drug Dosing Recommendations Based on Measured GFR and Kidney Function Estimating Equations

BACKGROUND Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation. STUDY DESIGN Diagnostic test study. SETTINGS & PARTICIPANTS Pooled data set for 5,504 participants from 6 research studies and 4 clinical populations with measured glomerular filtration rate (GFR). INDEX TEST Estimated kidney function using the MDRD Study and CG equations incorporating actual (CG) or ideal body weight (CG(IBW)) and standardized serum creatinine concentrations. REFERENCE TEST Measured GFR assessed by using iodine-125-iothalamate urinary clearance. OUTCOME Concordance of assigned kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies and recommended dosages of 15 medications cleared by the kidneys. RESULTS Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P < 0.001) and 66% for the CG(IBW) equation (P < 0.001). Concordance between the MDRD Study equation and CG and CG(IBW) equations was 78% and 75%, respectively (P < 0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P < 0.001) and 82% for the CG(IBW) equation (P < 0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CG(IBW) equations and MDRD Study equation were 89% and 88%, respectively (P < 0.05). LIMITATIONS Results based on simulation rather than pharmacokinetic studies. Outcome was drug dosage recommendations, rather than observed drug efficacy and safety. CONCLUSIONS The MDRD Study equation can also be used for pharmacokinetic studies and drug dosage adjustments. As more accurate GFR-estimating equations are developed, they should be used for these purposes.

Equations to Estimate Creatinine Excretion Rate: The CKD Epidemiology Collaboration

BACKGROUND AND OBJECTIVES Creatinine excretion rate (CER) indicates timed urine collection accuracy. Although equations to estimate CER exist, their bias and precision are untested and none simultaneously include age, sex, race, and weight. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Participants (n = 2466) from three kidney disease trials were randomly allocated into equation development (2/3) and internal validation (1/3) data sets. CER served as the dependent variable in linear regression to develop new equations. Their stability was assessed within the internal validation data set. Among 987 individuals from three additional studies the equations were externally validated and compared with existing equations. RESULTS Mean age was 46 years, 42% were women, and 9% were black. Age, sex, race, weight, and serum phosphorus improved model fit. Two equations were developed, with or without serum phosphorus. In external validation, the new equations showed little bias (mean difference [measured - estimated CER] -0.7% [95% confidence interval -2.5% to 1.0%] and 0.3% [95% confidence interval -2.6% to 3.1%], respectively) and moderate precision (estimated CER within 30% of measured CER among 79% [76% to 81%] and 81% [77% to 85%], respectively). Corresponding numbers within 15% were 51% [48% to 54%] and 54% [50% to 59%]). Compared with existing equations, the new equations had similar accuracy but showed less bias in individuals with high measured CER. CONCLUSIONS CER can be estimated with commonly available variables with little bias and moderate precision, which may facilitate assessment of accuracy of timed urine collections.

A health economic analysis of screening and optimal treatment of nephropathy in patients with type 2 diabetes and hypertension in the USA

BACKGROUND Nephropathy is an indicator of end-organ damage and is a strong predictor of an increased risk of cardiovascular disease and death in patients with diabetes. Screening can lead to early identification and treatment, both of which incur costs. However, identification and treatment may slow or prevent progression to a more expensive stage of the disease and thus may save money. We assessed the health economic impact of screening for nephropathy (microalbuminuria and overt nephropathy) followed by optimal renoprotective-based antihypertensive therapy in a US setting. METHODS A Markov model simulated the lifetime impact of screening with semi-quantitative urine dipsticks in a primary care setting of hypertensive patients with type 2 diabetes and subsequent treatment with irbesartan 300 mg in patients identified as having nephropathy. Progression from no nephropathy to end-stage renal disease (ESRD) was simulated. Probabilities, utilities, medication and ESRD treatment costs came from published sources. Clinical outcomes and direct medical costs were projected. Second order Monte Carlo simulation was used to account for uncertainty in multiple parameters. Annual discount rates of 3% were used where appropriate. RESULTS Screening, followed by optimized treatment, led to a 44% reduction in the cumulative incidence of ESRD and improvements in non-discounted life expectancy of 0.25 +/- 0.22 years/patient (mean +/- SD). Quality-adjusted life expectancy was improved by 0.18 +/- 0.15 quality-adjusted life years (QALYs)/patient and direct costs increased by

Disease-Specific Patient Reported Outcome Tools for Systemic Lupus Erythematosus

244 +/- 3499/patient. The incremental cost-effectiveness ratio was

Editorial: Gadolinium Use in Patients with Kidney Disease: A Cause for Concern

20 011 per QALY gained for screening and optimized treatment versus no screening. There was a 77% probability that screening and optimized therapy would be considered cost effective with a willingness to pay a threshold of

The cost-effectiveness of irbesartan in the treatment of hypertensive patients with type 2 diabetic nephropathy

50 000. CONCLUSION In patients with type 2 diabetes and hypertension, screening for nephropathy and treatment with a renoprotective-based antihypertensive agent was projected to improve patient outcomes and represent excellent value in a US setting.

Reversal of cardiac dysfunction secondary to type 1 primary hyperoxaluria after combined liver-kidney transplantation

PURPOSE Systemic lupus erythematosus (SLE) can significantly affect both health and non-health-related quality of life (HRQOL and non-HRQOL). However, of the existent published patient-reported outcome (PRO) tools, none were developed from US patients, an ethnically diverse population. Furthermore, these tools do not address men with SLE or assess non-HRQOL issues. Herein, we present the development and validation of the Lupus Patient-Reported Outcome tool (LupusPRO) and discuss its clinical utility and research value compared with other PRO tools currently available for SLE. METHODS Beginning with a conceptual framework, items for LupusPRO were generated using feedback from women and men with SLE. The tool underwent iterations based on patient feedback and clinimetric and psychometric analyses. Validity (content, construct, and criterion) and reliability (internal consistency and test-retest) for the 44-item LupusPRO tool are presented. RESULTS Consistent with the conceptual framework, items were identified that were related to HRQOL and non-HRQOL constructs. HRQOL domains included (1) lupus symptoms; (2) physical health (physical function, role physical); (3) pain-vitality; (4) emotional health (emotional function and role emotional); (5) body image; (6) cognition; (7) procreation; and (8) lupus medications. Non-HRQOL domains were (1) available social support and coping; (2) desires-goals; and (3) satisfaction with medical care. Internal consistency reliability (0.68-0.94), test-retest reliability (0.55-0.92), content, construct (r > 0.50 with SF-36), and criterion (r > -0.35 with disease activity) validity were fair to good. CONCLUSIONS LupusPRO is a valid and reliable disease-targeted patient-reported health outcome tool that is generalizable to SLE patients in the United States of varied ethnic backgrounds and either gender.

Abnormal acyltransferase activities and accelerated cholesteryl ester transfer in patients with nephrotic syndrome

Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra‐renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium‐related contrast‐induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF‐gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium‐chelate binding may expose tissues to toxic free Gd3+ and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced CKD or ESRD.

LupusQoL-US Benchmarks for US Patients with Systemic Lupus Erythematosus

BACKGROUND End-stage renal disease (ESRD)-related health care costs are substantial. Improving clinical outcomes in patients at risk of progression to ESRD could lead to considerable health care savings. OBJECTIVE We estimated the cost-effectiveness of irbesartan compared with placebo or amlodipine in the treatment of patients with type 2 diabetes mellitus, hypertension, and overt nephropathy. METHODS Three treatments for hypertension patients with type 2 diabetes mellitus and nephropathy were assessed: (1) irbesartan, (2) amlodipine, and (3) placebo. A Markov model was developed based on primary data from the Irbesartan in Diabetic Nephropathy Trial and the United States Renal Data System. Projected survival and costs were compared for each treatment at 3-, 10-, and 25-year time horizons. Different assumptions of treatment benefits and costs were tested with use of sensitivity analyses. RESULTS At 10 and 25 years, the model projected irbesartan to be both the least costly and most effective (ie, demonstrating a survival advantage) strategy. At 25