Treatment decisions for older adults with advanced chronic kidney disease.

Dialysis initiation rates among older adults, aged 75 years or greater, are increasing at a faster rate than for younger age groups. Older adults with advanced CKD (eGFR < 30 ml/min/1.73 m2) typically lose renal function slowly, often suffer from significant comorbidity and thus may die from associated comorbidities before they require dialysis.A patient's pattern of renal function loss over time in relation to their underlying comorbidities can serve as a guide to the probability of a future dialysis requirement. Most who start dialysis, initiate treatment "early", at an estimated glomerulofiltration rate (eGFR) >10 ml/min/1.73 m2 and many initiate dialysis in hospital, often in association with an episode of acute renal failure. In the US older adults start dialysis at a mean e GFR of 12.6 ml/min/1.73 m2 and 20.6% die within six months of dialysis initiation. In both the acute in hospital and outpatient settings, many older adults appear to be initiating dialysis for non-specific, non-life threatening symptoms and clinical contexts. Observational data suggests that dialysis does not provide a survival benefit for older adults with poor mobility and high levels of comorbidity. To optimize the care of this population, early and repeat shared decision making conversations by health care providers, patients, and their families should consider the risks, burdens, and benefits of dialysis versus conservative management, as well as the patient specific symptoms and clinical situations that could justify dialysis initiation. The potential advantages and disadvantages of dialysis therapy should be considered in conjunction with each patient's unique goals and priorities.In conclusion, when considering the morbidity and quality of life impact associated with dialysis, many older adults may prefer to delay dialysis until there is a definitive indication or may opt for conservative management without dialysis. This approach can incorporate all CKD treatments other than dialysis, provide psychosocial and spiritual support and active symptom management and may also incorporate a palliative care approach with less medical monitoring of lab parameters and more focus on the use of drug therapies directed to relief of a patient's symptoms.

Starting dialysis at eGFR >5 ml/min per1.73 m(2): are we barking up the wrong tree?

Although the goal glomerular filtration rate (GFR) for chronic dialysis initiation is currently above 5 ml/min per 1.73 m(2), there is no convincing evidence that patients will benefit from this approach. With close follow-up of advanced chronic kidney disease patients, aiming to start dialysis at an estimated GFR (eGFR) less than 5 ml/min per 1.73 m(2) may result in the avoidance of potentially unnecessary end-of-life dialysis and could result in significant dialysis-free time for a large segment of the world's future dialysis population.

Dialysis initiation: what's the rush?

The recent trend to early initiation of dialysis (at eGFR >10 ml/min/1.73 m(2) ) 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.

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 m(2)/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.

Starting dialysis is dangerous: how do we balance the risk?

Recent studies of timing of dialysis initiation have challenged the recent trend to earlier initiation of therapy. The observed outcomes though are a consequence of the balance between the risks of advanced uremia versus the inherent dangers relating to dialysis therapy itself. Many of these risks are inherent in how dialysis treatment is currently carried out, and may indeed be amenable to mitigation, through refinement of clinical practice (and potentially modality choice). This article aims to lay out a discussion relating to patient outcomes being the composite result of this balance, pivoting on the vulnerability of a particular patient to these attendant risks.

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.

Early start of hemodialysis may be harmful.

BACKGROUND: A dramatic increase in the "early start" of dialysis with an estimated glomerular filtration rate (eGFR) at least 10 mL/min/1.73 m(2) has occurred in the United States since at least 1996. Several recent studies have reported a comorbidity-adjusted survival disadvantage of early start of dialysis. The current study examines a relatively "healthy" dialysis cohort to minimize confounding issues and determine whether early initiation of hemodialysis is associated with a survival benefit or harm. METHODS: We examined demographics, year of dialysis initiation, primary etiology of renal failure, and body mass index, hemoglobin, and serum albumin levels in 81,176 nondiabetic, 20- to 64-year-old, in-center incident hemodialysis patients with no reported comorbidity besides hypertension. We compared survival, using a piecewise proportional hazards model to estimate covariate-adjusted mortality hazard ratios (HRs) for eGFR at the time of initiation of dialysis. We also performed time-dependent adjusted analysis stratified by initial serum albumin levels lower than 2.5 g/dL, 2.5 to 3.49 g/dL, and 3.5 g/dL or higher (the "healthiest" group [HG]). RESULTS: Unadjusted 1-year mortality by eGFR ranged from 6.8% in the reference group (eGFR <5.0 mL/min/1.73 m(2)) to 20.1% in the highest eGFR group (≥15.0 mL/min/1.73 m(2)). Compared with the reference group, the HR for the HG was 1.27 (eGFR, 5.0-9.9 mL/min/1.73 m(2)), 1.53 (eGFR, 10.0-14.9 mL/min/1.73 m(2)), and 2.18 (eGFR ≥15.0 mL/min/1.73 m(2)) and ranged from 1.50 to 3.53 mL/min/1.73 m(2) in the first year of dialysis for the early-start group. CONCLUSION: The increased HR during hemodialysis associated with early start in the healthiest group of patients undergoing dialysis indicates that early start of dialysis may be harmful.

Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.

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.