Associations of pretransplant serum albumin with post-transplant outcomes in kidney transplant recipients.

The association between pretransplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes. Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all-cause mortality (HR = 0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89-0.97]) and 4% lower DGF risk (OR = 0.96[0.93-0.99]). Hence, lower pretransplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-waitlisted hemodialysis patients and their impacts on post-transplant outcomes are indicated.

Associations of body mass index and weight loss with mortality in transplant-waitlisted maintenance hemodialysis patients.

A body mass index (BMI) below morbid obesity range is often a requirement for kidney transplant wait-listing, but data linking BMI changes to mortality during the waitlist period are lacking. By linking the 6-year (7/2001-6/2007) national databases of a large dialysis organization and the Scientific Registry of Transplant Recipients, we identified 14 632 waitlisted hemodialysis patients without kidney transplantation. Time-dependent survival models examined the mortality predictability of 13-week-averaged BMI, pretransplant serum creatinine as a muscle mass surrogate and their changes over time. The patients were on average 52 ± 13 years old, 40% women and had a BMI of 26.9 ± 6.3 kg/m². Each kg/m² increase of BMI was associated with a death hazard ratio (HR) of 0.96 (95%CI: 0.95-0.97). Compared to the lowest creatinine quintile, the 4th and 5th quintiles had death HRs of 0.75 (0.66-0.86) and 0.57 (0.49-0.66), respectively. Compared to minimal (< ± 1 kg) weight change over 6 months, those with 3 kg- < 5 kg and ≥ 5 kg weight loss had death HRs of 1.31 (1.14-1.52) and 1.51 (1.30-1.75), respectively. Similar associations were observed with creatinine changes over time. Transplant-waitlisted hemodialysis patients with lower BMI or muscle mass and/or unintentional weight or muscle loss have higher mortality in this observational study. Impact of intentional weight change remains unclear.

Accidental salicylate intoxication in a hemodialysis patient.

A 61-year-old woman receiving long-term hemodialysis presented with symptoms of tinnitus, insomnia, malaise, and disequilibrium. On close questioning, it was discovered that she had received a prescription for salsalate (Disalcid) from a consulting physician who had evaluated her for joint pain. This tablet was similar in appearance to a dried aluminum hydroxide gel preparation (Alu-tab) that the patient was taking as a phosphate binder. She had mistakenly been taking six Disalcid tablets with each meal. Her salicylate level was 5.86 mmol/L, but she had no change in her serum electrolyte levels or acid-base status. When the salsalate treatment was stopped and regular dialysis treatments were continued, the symptoms of salicylism resolved. This case illustrates one of the potential dangers of polypharmacy in patients with chronic disease. The midl course was probably due to ongoing hemodialysis, which prevented the appearance of the usual acid-base abnormalities of salicylate intoxication.

Military antishock trousers. Effect on hemodialysis-induced hypotension.

To evaluate the effect of military antishock trousers (MAST) on hemodialysis-induced hypotension, we observed seven patients undergoing maintenance hemodialysis treatment. We saw each patient on two separate occasions during four-hour hemodialysis treatments. On one occasion , we inflated the MAST to a pressure of 45 mm Hg over the lower extremities and 15 mm Hg over the abdomen; on the second occasion, the MAST were not inflated. Blood pressure was recorded at 15-minute intervals. We found no significant difference between the mean arterial pressure with MAST inflation and that in the control studies. The weight losses during the two studies were also similar. We suggest that, despite their reported efficacy in post-trauma hypotension, MAST are not effective in managing dialysis-induced hypotension.

Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry.

We evaluated the bone metabolic activity in patients with renal osteodystrophy using positron emission tomography and [18F]fluoride ion. Eight patients had secondary hyperparathyroidism (HPT), and three had low-turnover bone disease. Eleven normal subjects were also studied, and three of the eight HPT patients were reevaluated after therapy. A rate constant (K) describing the net transport of [18F] fluoride ion into a bound compartment in bone was calculated using both a three-compartment model and Patlak graphical analysis. Values of K were compared with biochemical data and with histomorphometric indices. The results indicate that K is significantly higher (P < 0.01) in HPT patients than in normal subjects and patients with low-turnover bone disease. Values of K correlated with serum alkaline phosphatase (r = 0.81) and PTH (r = 0.93) levels and with histomorphometric indices of bone formation rate (r = 0.84, P < 0.01) and eroded perimeter (r = 0.77, P < 0.05). Values of K decreased by 40 and 30%, respectively, in two patients who underwent parathyroidectomy and medical therapy. Positron emission tomography studies of bone using [18F]fluoride ion can differentiate low turnover from high turnover lesions of renal osteodystrophy and provide quantitative estimates of bone cell activity that correlate with histomorphometric data.

Moxalactam kinetics in hemodialysis.

In eight patients with end-stage renal disease undergoing chronic hemodialysis moxalactam kinetics were examined. Volume of distribution (Vd), dialysance (Cd), and serum half-life (t1/2) were determined during dialysis with a 1.3 or 1.6 m2 dialyzer. The t1/2 was also determined during the interdialytic period. Vd was 0.25 +/- 0.04 l/kg and Cd was 32.6 +/- 11.7 ml/min and 67 +/- 25.5 ml/min with the 1.3 and 1.6 m2 dialyzers. The t1/2 was 4.8 +/- 0.9 hr using the 1.3 m2 dialyzer and 2.8 +/- 0.6 hr using the 1.6 m2 dialyzer. Moxalactam t1/2 during the interdialytic period was 23.4 +/- 9.6 hr.

Cognitive function, mood and P3 latency: effects of the amelioration of anemia in dialysis patients.

Attention difficulties and psychomotor slowing associated with depressed mood affect the ability of individuals to perform on most neuropsychological tests. It has been suggested that latency of the P3 (P300) component of the event-related EEG potential is an index of neurocognitive status which is not affected by mood. Dialysis patients, who experience diminished dysphoric mood with the reversal of anemia when treated with recombinant human erythropoietin (rHuEPO), were tested for neurocognitive performance, mood and latency of P3. Prior to rHuEPO treatment mood was dysphoric, and neurocognitive testing showed mild deficits, but P3 latency was normal. After treatment, mood improved and neurocognitive test performance was normal. P3 amplitude increased over frontal areas, while P3 latency remained unchanged. Thus, in the case of dysphoric mood, P3 latency may provide a more accurate index of cognitive capacity (as opposed to level of functioning) than neurocognitive test measures.

Novel erythropoiesis stimulating protein for managing the anemia of chronic kidney disease.

Since its introduction, recombinant human erythropoietin (rHuEPO) has become the standard of care for renal anemia. Because of its relatively short half-life, however, it generally is administered two to three times per week. Darbepoetin alfa (novel erythropoiesis stimulating protein [NESP]) is a longer acting erythropoietic agent that allows less frequent dosing to treat anemia. Decreased dosing frequency should result in enhanced patient compliance and convenience and minimize the burden of frequent administration on staff. NESP is biochemically distinct from rHuEPO, having five N-linked carbohydrate chains (two more than rHuEPO). In animal studies, NESP had a half-life approximately three times longer than rHuEPO and raised hemoglobin effectively when administered less frequently than rHuEPO. NESP has been evaluated in clinical trials of dialysis and chronic kidney disease patients. Pharmacokinetic data confirmed that patients with anemia required less frequent dosing with NESP than rHuEPO. After intravenous administration, the mean elimination half-life of NESP was 25.3 hours versus 8.5 hours for rHuEPO. In patients who are rHuEPO-naive and in patients previously managed with rHuEPO, NESP is as effective as rHuEPO for maintaining hemoglobin concentration when administered intravenously or subcutaneously at a reduced frequency of once weekly or once every other week. NESP is well tolerated and has a safety profile comparable to that of rHuEPO. There have been no reports of antibody formation associated with NESP. NESP is an important new tool for physicians to use in the treatment of anemia of chronic kidney disease.

Complications of chronic renal insufficiency: beyond cardiovascular disease.

The less rigorous attention to the management of the complications of chronic renal insufficiency (CRI) and its comorbid conditions has potentially tragic consequences. In fact, with early recognition and intervention, many of the complications of CRI and its comorbid conditions can be ameliorated or prevented. We review here the most prevalent, troublesome, and potentially preventable complications and comorbidities of CRI with a view toward developing high-quality, cost-effective strategies for delivering early interventional care. Complications of CRI include malnutrition, anemia, disorders of divalent ion metabolism and osteodystrophy, metabolic acidosis, and dyslipidemia. Important comorbid conditions of CRI are hypertension, diabetes mellitus, and cardiovascular disease. Clinical intuition suggests that early intervention will avert morbidity related to the hypoalbuminemia and other nutritional disorders of CRI, the metabolic acidosis, and the dyslipidemias, but prospective data are lacking at present. Correction of anemia, usually with recombinant human erythropoietin, may be key to the prevention of cardiac disease and other comorbidities of CRI. Incipient disorders of bone and mineral metabolism are managed prospectively using such measures as protein restriction to reduce phosphorus intake, phosphate binders, calcium supplementation, and vitamin D analogues. Hypertension, whatever its original etiology, is clearly an important risk factor for the progression of kidney failure and for the development of diffuse vascular disease; appropriate and aggressive treatment is essential. In patients with diabetic nephropathy, the principles of both primary and secondary prevention have been validated in several large trials of glycemic and blood pressure control. The seeds of these insidious, challenging, and costly comorbid conditions are sown very early in CRI, at a time when they are-in theory-most amenable to intervention. We therefore must be as proactive as possible in the timely implementation of relatively simple therapies that have the potential to prevent some of these adverse outcomes of CRI.

Prevalence and characteristics of individuals with chronic kidney disease in a large health maintenance organization.

This study is designed to estimate the prevalence of and gain further insight into the characteristics of the chronic kidney disease (CKD) population in a large US health maintenance organization (HMO) to better understand the CKD population in the United States overall. Analyses were performed using data from a staff and network model HMO in the southwestern United States with more than 150,000 members per year during 1994 to 1997. The estimated prevalence of CKD in the HMO population varied from 0.4% to 7.1%, depending on the definition of CKD used. Regardless of the definition, CKD was more common in men compared with women and in patients with diabetes mellitus and/or hypertension. Applying the age- and sex-specific prevalence rates in the HMO to the US population in 1990, we estimate there were approximately 9.1 million Americans with at least one elevated sex-specific creatinine (Cr) value and approximately 4.2 million Americans with at least two elevated Cr values separated by 90 days or greater, a more rigorous definition of CKD. From these results, it is apparent that there are a large number of patients in the United States with CKD. Most have not been identified because screening for CKD generally is not performed. Considering the high prevalence of CKD and the high cost and clinical morbidity associated with end-stage renal disease (ESRD), it is clear that CKD is an important public health problem. Early identification of patients with CKD would allow treatment that could slow the progression to ESRD, improve clinical outcomes, and constrain the growth of costs in the ESRD program. The time has come for a structured public and professional educational program to address this serious condition.

Normalizing hematocrit in dialysis patients improves brain function.

Recombinant human erythropoietin (rHuEPO) treatment has been shown to improve brain and cognitive function in anemic dialysis patients. Significant debate continues, however, regarding the appropriate target hematocrit (Hct) that will lead to the greatest benefits while considering possible side effects and costs of rHuEPO. Current practice results in an Hct averaging only 31% to 32% in dialysis patients, a level less than that achieved in the initial clinical trials and well less than normal. This study was designed to evaluate dialysis patients at the current practice Hct levels versus normal Hct levels (40% to 45%) to see if improvement in brain function resulted. Twenty patients with end-stage renal disease (ESRD) currently being treated with rHuEPO (mean Hct, 31.6%) were administered additional rHuEPO to reach normal Hct levels (mean, 42. 8%). Electroencephalogram (EEG) frequency analysis showed a significant decrease in EEG slowing at greater Hct values, and the auditory oddball and Continuous Performance Task tasks yielded significant electrode and time-by-electrode effects for P300 amplitude. Changes in P300 latency significantly correlated with increased Hct in the auditory oddball task. These findings suggest that further correction of anemia to normal Hct levels may result in continued improvement in neurocognitive function by improving the ability to sustain attention in easier tasks and by enhancing the ability to recognize, discriminate, and hold stimuli in memory for more difficult tasks.

Evaluation of disease-state management of dialysis patients.

Dialysis patients are the only Medicare beneficiaries prohibited from joining managed care plans. Concerns have been raised about the ability of such plans to provide the comprehensive care required by patients with this complex condition. However, more than 20,000 dialysis patients belong to such plans because they were enrolled before developing end-stage renal disease (ESRD). Disease-state management, successfully applied to patients with diabetes mellitus and congestive heart failure, is now being used in patients with ESRD. Standardized mortality ratios (SMRs) and standardized hospitalization ratios (SHRs) were calculated for 1998 and 1999 in 1,541 patients enrolled in the RMS Disease Management program of renal disease-state management using US Renal Data System methods. SMRs were 0.643 and 0.806 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). SHRs were 0.620 and 0.503 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). Although additional studies are needed to define the aspects of care that are most important for the outcomes seen, this study shows that favorable outcomes are achievable for this vulnerable patient population within a managed care setting that applies coordinated approaches to care.

Recombinant human erythropoietin: impact on brain and cognitive function, exercise tolerance, sexual potency, and quality of life.

The clinical manifestations of uremia are only incompletely reversed by chronic hemodialysis. Signs and symptoms can include abnormalities in electrophysiologic indices, clinical mental status, and neuropsychological test performance, as well as decreases in exercise tolerance, sexual potency, and general quality of life. Though retention of uremic toxins is responsible for many of these symptom complexes, some may be caused, or substantially aggravated, by the anemia that almost invariably accompanies chronic renal failure. Treatment with recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) increases hematocrit values and thus reduces the anemia, in turn improving brain and cognitive function, exercise tolerance, sexual potency, and quality of life.

Erythropoietin and anemia.

Recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of anemia of chronic renal failure. RHuEPO has been shown to increase survival, decrease hospitalizations, improve brain and cognitive function, and improve quality of life for renal patients. Much has been learned about the normal and pathologic physiology of anemia because rHuEPO has become available to investigators, and this has been widely applied. Additional work is needed in better defining the sites of production of endogenous EPO as well as the nature and control of the oxygen sensor(s) in the kidney. Remaining clinical issues related to this remarkable compound include predicting and overcoming resistance; avoiding iron deficiency; determining the appropriate target hemoglobin; increasing the use strategies such as subcutaneous administration to increase efficiency; and devising a more rational payment scheme.

The current and future state of the ESRD program: a provider roundtable.

The decade of the 1990s have seen substantial consolidation of services in the dialysis industry in the United States. A small number of horizontally and/or vertically integrated companies oversee the care of over two-thirds of dialysis patients. There are many questions regarding this trends as well as the vision of these large organizations regarding the future of the ESRD program. The senior physicians in the four largest such organizations agreed to participate in a provider roundtable to share their thoughts on the following issues: What are the advantages and disadvantages of industry consolidation?; What steps has your organization taken to succeed?; What are the key issues facing this industry in the next decade?; What policy changes by the Federal Government do you anticipate?; What policy changes would you like to see? Although significant differences in specifics are clear in the responses, a recurrent theme relates to how value will be maintained in the program-the balance between high-quality outcomes and the costs of achieving these outcomes. This is clearly the challenge in the years ahead.

Dialysis therapy in the elderly patient.

It is clear that an increasing number of elderly patients will require ESRD care as the decade proceeds. Currently available data suggest that outcomes on HD and CPD are similar in this patient group, although the data in elderly diabetics are not all in. A number of questions remain to be answered, however: (1) Can severity indices be developed so that patients can be properly matched for co-morbid conditions? This is essential if firm conclusions about the outcome of one modality compared to another can be drawn. (2) Is survival of elderly diabetics worse on CPD compared to HD? If so, is this because of differences in patient selection or co-morbidity or in the effects of the modality? (3) Can a simple, easy to use modality selection algorithm be developed for the elderly ESRD patient? (4) What factors add to the risk of morbidity and mortality in elderly ESRD patients, and how they can be modified? (5) What is the incidence of malnutrition in elderly ESRD patients? How does it relate to morbidity and mortality? Does it differ from those on HD compared to CPD? (6) Are there elderly patients who should not be started on dialysis? How can they be identified?

Acute renal failure: definition and pathogenesis.

Acute renal failure (ARF) in the critical care setting is defined as the abrupt decline in glomerular filtration rate (GFR) resulting from ischemic or toxic injury to the kidney. ARF is often only one of several organ-system failures that are present in this patient population. Recent evidence suggests that there are four major factors that are the most important in the initiation and maintenance of ARF. These include a decrease of glomerular capillary permeability, back-leak of glomerular filtrate, tubular obstruction, and intrarenal vasoconstriction. Both sub-lethal and lethal cell injury have been found in ARF, with the latter related either to necrosis or apoptosis. Intrarenal vasoconstriction, related to a shift in the balance between endothelin and endothelium-derived nitric oxide, is receiving considerable attention as a major contributor to the pathogenesis of ARF, with therapeutic maneuvers targeted at restoring the usual balance, and relieving intrarenal vasoconstriction. If such approaches prove to be of value, the outcome of patients with this serious condition might be substantially improved.

Iron deficiency in patients with renal failure.

The anemia of renal failure is caused by the lack of sufficient quantities of endogenous erythropoietin. With the availability of recombinant human erythropoietin (rHuEPO), however, it has become apparent that to achieve a given target, hematocrit requires proper management of iron replacement, as well as the administration of rHuEPO. Iron deficiency, either absolute or functional, will occur in most, if not all, patients on hemodialysis receiving rHuEPO because of the increased demand for iron driven by the accelerated erythropoiesis that occurs with exogenous rHuEPO administration, coupled with ongoing blood losses from dialyzer and tubing, blood sampling, gastrointestinal blood loss, and blood losses at the time of dialysis needle placement and removal. Blood loss is less of a problem in patients on peritoneal dialysis, but poor iron intake and increased demand for iron are also seen, the latter in patients receiving rHuEPO. It is essential, therefore, for renal health professionals to understand iron metabolism in dialysis patients in order to properly balance the therapy of renal anemia with rHuEPO and supplemental iron.

Medicare's end-stage renal disease program: current status and future prospects.

The twenty-five years of the end-stage renal disease (ESRD) program have been characterized by remarkable clinical achievements, which have prolonged and improved the quality of life for thousands of patients. As the program enters the next millennium, it faces considerable challenges: As the number and acuity of patients increase, the availability of trained nephrologists will decrease, and total costs will continue to rise. Policymakers will need to work closely with the renal professional and patient communities to develop creative approaches to delivering and financing ESRD care that is of the highest quality, yet is affordable.