Steven J. Rosansky

The Calcimimetic AMG 073 as a Potential Treatment for Secondary Hyperparathyroidism of End-Stage Renal Disease

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.

Background: Most cases of hyponatremia – serum sodium concentration ([Na+]) <135 mEq/l (<135 mM) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V1A/V2-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na+] 115 to <130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na+], measured by the baseline-adjusted area under the [Na+]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na+] increase, total time patients had serum [Na+] ≧4 mEq/l higher than baseline, change in serum [Na+] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na+] or normal [Na+] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na+]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na+] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. Conclusion: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na+] and was well tolerated.

Association between estimated glomerular filtration rate at initiation of dialysis and mortality

Background Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate) and an association between early initiation and increased risk of death. We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis. Methods The analytic cohort consisted of 25 910 patients at least 18 years of age who initiated hemodialysis, as identified from the Canadian Organ Replacement Register (2001–2007). We defined the initiation of dialysis as early if the estimated glomerular filtration rate was greater than 10.5 mL/min per 1.73 m2. We fitted time-dependent proportional-hazards Cox models to compare the risk of death between patients with early and late initiation of dialysis. Results Between 2001 and 2007, mean estimated glomerular filtration rate at initiation of dialysis increased from 9.3 (standard deviation [SD] 5.2) to 10.2 (SD 7.1) (p < 0.001), and the proportion of early starts rose from 28% (95% confidence interval [CI] 27%–30%) to 36% (95% CI 34%–37%). Mean glomerular filtration rate was 15.5 (SD 7.7) mL/min per 1.73 m2 among those with early initiation and 7.1 (SD 2.0) mL/min per 1.73 m2 among those with late initiation. The unadjusted hazard ratio (HR) for mortality with early relative to late initiation was 1.48 (95% CI 1.43–1.54). The HR decreased to 1.18 (95% CI 1.13–1.23) after adjustment for demographic characteristics, serum albumin, primary cause of end-stage renal disease, vascular access type, comorbidities, late referral and transplant status. The mortality differential between early and late initiation per 1000 patient-years narrowed after one year of follow-up, but never crossed and began widening again after 24 months of follow-up. The differences were significant at 6, 12, 30 and 36 months. Interpretation In Canada, dialysis is being initiated at increasingly higher levels of glomerular filtration rate. A higher glomerular filtration rate at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics.

Renal function trajectory is more important than chronic kidney disease stage for managing patients with chronic kidney disease.

Management of patients with chronic kidney disease (CKD) emphasizes a current level of function as calculated from the modification of diet in renal disease glomerulofiltration rate equations (eGFR) and proteinuria for staging of CKD. Change in a patient’s eGFR over time (renal function trajectory) is an additional and potentially more important consideration in deciding which patients will progress to the point where they will require renal replacement therapy (RRT). Many patients with CKD 3–5 have stable renal function for years. Proteinuria/albuminuria is a primary determinant of renal trajectory which may be slowed by medications that decrease proteinuria and/or aggressively lower blood pressure. A renal trajectory of >3 ml/min/1.73 m2/year may relate to a need for closer renal follow-up and increased morbidity and mortality. Additional CKD population-based studies need to examine the relationship of renal trajectory to: baseline renal function; acute kidney injury episodes; age, race, sex and primary etiologies of renal disease; blood pressure control and therapies; dietary protein intake; blood glucose control in diabetics and the competitive risk of death versus the requirement for renal replacement therapy. In the elderly CKD 4 population with significant comorbidities and slow decline in renal function, the likelihood of death prior to the need for RRT should be considered before placing AV access for dialysis. Prediction models of renal progression must account for the competitive risk of death as well as stable or improved renal function to be clinically useful.

Multiple cholesterol emboli syndrome after angiography.

Multiple cholesterol emboli syndrome (MCES) after angiography has been reported infrequently. Seven patients (from five reports) who developed MCES after angiography are reviewed. An eighth case is described. All patients had evidence of extensive atherosclerosis. Following angiography of the eight patients, six demonstrated livedo reticularis below the umbilicus; technical difficulties were reported in four; four became febrile and/or hypertensive; and only one survived. Since therapy has been unsuccessful, careful angiographic technique is essential to prevent this syndrome.

Dialysis Initiation: What's the Rush?

The recent trend to early initiation of dialysis (at eGFR >10 ml/min/1.73 m2) appears to have been based on conventional wisdoms that are not supported by evidence. Observational studies using administrative databases report worse comorbidity‐adjusted dialysis survival with early dialysis initiation. Although some have concluded that the IDEAL randomized controlled trial of dialysis start provided evidence that patients become symptomatic with late dialysis start, there is no definitive support for this view. The potential harms of early start of dialysis, including the loss of residual renal function (RRF), have been well documented. The rate of RRF loss (renal function trajectory) is an important consideration for the timing of the dialysis initiation decision. Patients with low glomerular filtration rate (GFR) may have sufficient RRF to be maintained off dialysis for years. Delay of dialysis start until a working arterio‐venous access is in place seems prudent in light of the lack of harm and possible benefit of late dialysis initiation. Prescribing frequent hemodialysis is not recommended when dialysis is initiated early. The benefits of early initiation of chronic dialysis after episodes of congestive heart failure or acute kidney injury require further study. There are no data to show that early start benefits diabetics or other patient groups. Preemptive start of dialysis in noncompliant patients may be necessary to avoid complications. The decision to initiate dialysis requires informed patient consent and a joint decision by the patient and dialysis provider. Possible talking points for obtaining informed consent are provided.

Has the Yearly Increase in the Renal Replacement Therapy Population Ended

The recent decline in the number of new patients undergoing dialysis and transplantation in the United States may be linked to a reduction in the incidence of early-start dialysis, defined as the initiation of renal replacement therapy (RRT) at an estimated GFR ≥10 ml/min per 1.73 m(2). We examined the most recent data from the U.S. Renal Data System to determine how this trend will affect the future incidence of ESRD in the United States. The percentage of early dialysis starts grew from 19% to 54% of all new starts between 1996 and 2009 but remained stable between 2009 and 2011. Similarly, the incident RRT population increased substantially in all age groups between 1996 and 2005, with the largest increase occurring in patients aged ≥75 years. Early dialysis starts accounted for most of the increase in the incident RRT population in all age groups during this time period, and between 2005 and 2010, the increase slowed dramatically. Although the future incident RRT population will be determined in part by population growth, these results suggest that later dialysis starts and greater use of conservative and palliative care, which may improve quality of life for elderly patients with advanced renal failure, will continue to attenuate the increase observed in previous years.

Circadian blood pressure variation versus renal function.

Several published reports describe an abnormal circadian blood pressure profile in chronic renal failure subjects. Factors other than renal failure, including age, diagnosis of diabetes mellitus, autonomic dysfunction, and race, also may affect circadian blood pressure profiles. To further elucidate the relationship between renal function and circadian blood pressure variation, we compared day/night circadian blood pressure changes in three groups of male veteran hypertensive patients: group A, creatinine clearance (CC) > 80 mL/min, n = 20; group B, CC 20 to 80 mL/min, n = 19; and group C, CC < 20 mL/min, n = 14. We use postural changes in catecholamines, renin, and aldosterone as a measure of autonomic function. No significant difference in day/night percent change in systolic, diastolic, mean arterial pressure (MAP), or heart rate was seen by renal function group. Regression analysis using age, diagnosis of diabetes mellitus, postural hormonal changes, and creatinine clearance found race to be the only significant predictor of the day/night percent change in MAP (P < 0.05). Compared with whites, black subjects had higher nocturnal heart rates (P = 0.01); smaller day/night heart rate changes (P = 0.03); significantly higher diastolic blood pressure (P = 0.01); and a trend toward smaller day/night change in diastolic blood pressure (P = 0.06). In conclusion, renal function level does not influence day/night blood pressure changes. The blunting or reversal of the normal circadian blood pressure pattern seen in some chronic renal failure hypertensive subjects may be attributable to the association between chronic renal failure and cofactors associated with abnormal circadian blood pressure, including black race and possibly severity of atherosclerosis.

Use of Peritoneal Dialysis in the Treatment of Patients with Renal Failure and Paraproteinemia

The effect of alterations in dwell time, dialysate dextrose concentration, and nitroprusside on immunoglobulin removal during peritoneal dialysis and a comparison of plasmapheresis versus peritoneal dialysis on immunoglobulin removal was studied. 1 h of plasmapheresis removed approximately 100 times as much IgG and 50 times as much IgM and IgA as 1 h of peritoneal dialysis. Nitroprusside added to peritoneal dialysate doubled the hourly removal rate of IgG using 1- and 8-hour cycles and increased IgA and IgM removal by 25 and 10%, respectively, using 8-hour cycles. It was estimated that peritoneal dialysis with nitroprusside added to peritoneal dialysate augments intact immunoglobulin clearance (above endogenous clearance) by approximately 10%. We hypothesized that peritoneal dialysis could significantly increase light-chain removal and thereby may be efficacious in the treatment of light chain related amyloid formation and light chain induced renal failure.

Is a decline in estimated GFR an appropriate surrogate end point for renoprotection drug trials

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