A. Paul Heidenheim

Plasma Exchange When Myeloma Presents as Acute Renal Failure: A Randomized, Controlled Trial

Context Does plasma exchange benefit patients with multiple myeloma and renal failure? Contribution This 6-month randomized trial involved 104 patients with acute renal failure at the onset of myeloma. A composite outcome of death, dialysis dependence, or severely reduced kidney function occurred in 57.9% of patients given 5 to 7 plasma exchanges and in 69.2% of patients given conventional therapy (difference, 11.3% [95% CI, 8.3% to 29.1%]). Cautions Although these findings suggest no substantial benefits of plasma exchange, the wide 95% CI around the difference between groups means that large benefit or some harm is possible. The Editors Of patients with newly diagnosed myeloma, 12% to 20% present with acute renal failure (1-3). After correction of hypovolemia and hypercalcemia, 77% to 100% of patients with renal insufficiency may have biopsy-proven cast nephropathy or interstitial inflammation (4-8). Renal inflammation results from excessive filtered monoclonal light chains, which are transported to the interstitium of the kidney via specific receptors in the proximal tubule. These receptors are overloaded by excess light chains, resulting in an overflow to the distal tubule where combination with TammHorsfall protein produces obstructive casts (9-13). Plasma exchange transiently removes light chains and, thus, may be beneficial in treating some patients with acute renal failure (14-19). Two small, randomized trials involving 29 and 21 participants, respectively, provide conflicting results (4, 19). Despite a lack of convincing evidence, recent reviews and management guidelines endorse plasma exchange as useful for preventing acute renal failure associated with myeloma kidney (15, 20-23). The uncertainty about the role of plasma exchange prompted us to conduct a multicenter randomized, controlled trial in patients with myeloma-associated acute kidney failure. The primary research question was whether 5 to 7 plasma exchanges, in addition to conventional therapy, at the onset of myeloma with acute renal failure reduced the composite outcome of death, dialysis dependence, or a glomerular filtration rate (GFR) less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) at 6 months. Methods Study Participants Study participants included patients with newly diagnosed multiple myeloma and progressive acute kidney failure. All had a bone marrow aspirate with more than 10% plasma cells and a monoclonal light chain in their urine, plasma, or renal tissue. We defined progressive acute kidney failure as a serum creatinine level greater than 200 mol/L (>2.3 mg/dL) with an increase greater than 50 mol/L (>0.6 mg/dL) in the preceding 2 weeks despite correction of hypercalcemia, hypovolemia, and metabolic acidosis in patients with normal-sized kidneys on renal ultrasonography. Exclusion criteria were age less than 18 years or greater than 81 years, obstruction on renal ultrasonography (required examination), use of intravenous contrast or nonsteroidal anti-inflammatory drugs during the previous 2 weeks, previous treatment for myeloma, pregnancy, or inability to provide informed consent. Research Design and Intervention Fourteen Canadian medical centers participated in the trial: 3 centers recruited more than 10 patients each, 5 centers recruited 5 to 9 patients each, and 6 centers recruited fewer than 5 patients each. Patients who fulfilled entry criteria were referred by their oncologist or nephrologist to the apheresis physician at their center. The apheresis physician explained the nature of the study by using a human ethicsapproved letter of information. We requested informed consent, and if we obtained it, we randomly assigned the participants centrally by telephone, by using a computer random-number generator (24, 25), to either receive or not to receive plasma exchange. We stratified randomization by 4 strata according to whether patients were receiving vincristineadriamycindexamethasone (VAD) and whether patients were receiving short-term hemodialysis. Recruiting physicians were unaware of the treatment allocation before study entry. Of note, randomization used 104 of the 1568 concealed random-numbergenerated allocations, and the imbalanced assignment of 61 patients to plasma exchange and 43 patients to control was solely due to random chance. After random blinded allocation, participants were treated in an unblinded manner. We enrolled participants from September 1998 to October 2003. The institutional ethics review boards of the 14 Canadian sites approved the protocol. Patients who were randomly assigned to receive plasma exchange underwent 5 to 7 plasma exchange procedures within the first 10 days of study entry, concurrent with the initiation of chemotherapy. They received a routine plasma exchange of 50 mL per kg of body weight with acid citrate dextrose as the anticoagulant through a Spectra cell separator (Gambro BCT, Lakewood, Colorado), using 5% human serum albumin and normal saline as the replacement solutions. Chemotherapy was either melphalan and prednisone taken daily for 4 days every 28 days for up to 12 cycles or 4 days of slow intravenous infusion of VAD given on days 1 to 4, 9 to 12, and 17 to 20 for 28-day cycles up to 6 cycles. For participants allocated to plasma exchange, we stopped VAD treatment 1.5 hours before the plasma exchange and did not give VAD treatment during the plasma exchange. After the plasma exchange, patients received a bolus volume of VAD that would have been the amount infused during this time. Measurements We assessed the following blood and urine test results at study entry and at 1 and 6 months: serum creatinine, serum calcium, serum albumin, and 24-hour urine for protein levels. We used DurieSalmon staging to classify the severity of multiple myeloma at presentation, and we estimated GFR by using the Modified Diet in Renal Disease (MDRD) equation (26, 27). Our primary outcome, assessed at 6 months, was a composite measure that included death, dialysis dependence, and an estimated GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) calculated from the 6-month serum creatinine level. We included this GFR as a component of the outcome because this degree of kidney impairment is associated with increased risk for death, cardiovascular events, and hospitalization (28). Statistical Analysis On the basis of historical data, which suggested a probable event rate greater than 50%, we calculated a sample size that would detect an effect of plasma exchange on dialysis dependence, without informative censoring from death, at 6 months (4, 17, 19). To detect a difference of 50% in that outcome with a type 1 error of 0.05 (2-sided) and a type 2 error probability of 0.20, we required a sample size of 46 participants per group. We used this historical-based power analysis to provide a conservative estimate of sample size to detect a statistically significant difference in the composite outcome of death, dialysis dependence, or a GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) in our future study. The safety subcommittee conducted an interim analysis when the fiftieth participant had completed the 6-month follow-up to prevent some patients from unnecessarily receiving a less effective treatment. The committee evaluated differences between the plasma exchange and control groups, with respect to the primary composite and secondary outcomes at 6 months by using Pearson chi-square. The committee evaluated the time to death by treatment groups by using KaplanMeier survival analysis with a log-rank test for differences between groups. It conducted univariate and multivariate modeling of death and composite outcomes by using logistic regression to determine the unadjusted and adjusted odd ratios for the selected baseline determinants of chemotherapy, dialysis, age, urine protein level, serum albumin level, and DurieSalmon stage for plasma exchange (29). The committee performed these secondary analyses to determine which factors, if any, influenced outcomes. No variables were missing for analyses, except for age of 1 patient, which reduced our GFR determination to 57 of 58 patients in the plasma exchange group. We conducted all statistical analyses by using the Statistical Package for the Social Sciences (SPSS), version 12.0 for Windows (SPSS, Inc., Chicago, Illinois). All significance testing used 2-tailed tests, reflecting the open-ended research hypothesis. Role of the Funding Source The Canadian Institute of Health Research, Gambro BCT, and The Kidney Foundation of Canada funded the trial. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication. Gambro BCT has a direct financial interest in the study outcome since they are the purveyor of the Gambro Spectra, which was the cell separator used in the trial. Results Of 104 patients who were initially enrolled in the study, 7 were withdrawn. Of these 7 patients, 3 were ineligible and 4 were lost to follow-up (Figure 1). Among the 4 patients lost to follow-up, 1 was a homeless person and the other 3 withdrew from all medical care and follow-up after diagnosis. Thus, intention-to-treat analyses included 58 patients in the plasma exchange group and 39 patients in the conventional therapy control group. No patient crossed over from his or her treatment assignment group during the trial, and all 58 patients randomly assigned to receive plasma exchange received 5 to 7 treatments. Figure 1. Flow of patients through the study to death or dialysis dependence. Baseline characteristics were similar between groups (Table 1). Forty-three participants had a monoclonal , 36 participants had a monoclonal , and the remainder had a monoclonal BenceJones protein in excess. The monoclonal protein occurred in both the plasma and urine in 59 participants, in the plasma in 76 participants, in the urine in 79 participants, and in the casts of the renal biopsy in 1 participant. Table 1. Baseline Charact

Nocturnal but not Short Hours Quotidian Hemodialysis Requires an Elevated Dialysate Calcium Concentration

Interest in quotidian (daily) hemodialysis (HD) is growing. Some advocate short-hours high-efficiency daily HD (SDH) and others long-hours slow-flow nocturnal HD (NH) while the patient is asleep, both being used 5 to 7 d/week. The London Daily/Nocturnal Hemodialysis Study was the first attempt to obtain data of SDH and NH that may be compared with conventional thrice weekly HD (CH). This was a 4-yr observational study designed to enter and follow 40 patients: 10 receiving SDH, 10 receiving NH, and 20 receiving CH. The CH patients were cohort control subjects matched for each SDH and NH patient by age, gender, comorbidity, and original dialysis modality (in-center, home, self-care, or satellite HD). All SDH and NH treatments were at home. Data collection to December 2001 was analyzed. Then enrollment had been completed and all patients had been followed for 15 mo, eight SDH plus six NH for 18 mo, seven SDH plus six NH for 21 mo, and seven SDH and five NH for 24 mo. This report gives data on calcium and phosphorus metabolism in these patients. All patients were initially dialyzed against a 1.25-mmol/L calcium bath. Predialysis serum calcium levels became lower in NH versus SDH patients by the first month and at 9 mo were 2.67 +/- 0.25 mmol/L (M +/- SD) in SDH, 2.40 +/- 0.16 mmol/L in NH, and 2.52 +/- 0.21 mmol/L in CH (SDH versus NH, P = 0.038; SDH versus CH versus NH, NS). Predialysis phosphorus levels were better controlled by NH than by SDH or CH, and with NH, all phosphate binders were discontinued. By 12 mo, a rise in bone alkaline phosphatase was seen in NH patients (but not in SDH or CH patients), which peaked at 15 to 18 mo (NH 191 IU/L +/- 70; SDH 82 +/- 34; CH 80 +/- 36; P < 0.002) and similarly with intact parathyroid hormone (iPTH) levels (NH 159 pmol/L +/- 75; SDH 13.1 +/- 10; CH 18 +/- 18; P < 0.00001). Because of these changes, the dialysate calcium concentration was increased to 1.75 mmol/L for the NH patients. Postdialysis calcium then rose to 2.57 +/- 0.21, and alkaline phosphatase and iPTH normalized completely by 21 mo. These observations prompted mass balance studies that showed that a 1.25-mmol/L calcium dialysate was associated with a mean net calcium loss of 2.1 mmol/h of dialysis time, whereas 1.75-mmol/L calcium dialysate provides a net gain of 3.7 mmol/h. In addition, the mass balance studies showed that phosphate removal by NH (43.5 +/- 20.7 mmol) was significantly (P < 0.05) higher than by SHD (24.2 +/- 13.9 mmol) but not by CH (34.0 +/- 8.7 mmol) on a per-treatment basis. With the increased frequency of treatments provided by quotidian dialysis, the weekly phosphorus removal (261.2 +/- 124.2 mmol) by NH was significantly higher than by SDH (P = 0.014) and CH (P = 0.03). This allowed the discontinuation of P binders in the NH group, which in turn eliminated approximately 8 g elemental Ca/wk oral intake. This, together with a 4 g elemental Ca/wk dialysate loss induced by a 1.25-mmol/L Ca bath, explains the changes in Ca, alkaline phosphatase, and iPTH seen in the NH patients. The SDH patients have weekly dialysis times similar to CH and still require P binders and do not become Ca deficient using 1.25-mmol/L Ca dialysate. With NH but not SDH, an elevated dialysate Ca concentration is required.

Flaxseed in Lupus Nephritis: A Two-Year Nonplacebo-Controlled Crossover Study

Objective: The objective of this study was to determine the renoprotective effects of ground flaxseed in patients with lupus nephritis. Methods: Forty patients with lupus nephritis were asked to participate in a randomized crossover trial of flaxseed. Twenty-three agreed and were randomized to receive 30 grams of ground flaxseed daily or control (no placebo) for one year, followed by a twelve-week washout period and the reverse treatment for one year. At baseline and six month intervals, serum phospholipids, flaxseed sachet counts, serum creatinine, 12-hour urine albumin excretion and urine albumin to creatinine ratios, serum viscosity and plasma lipids were measured. Results: There were eight drop-outs and of the 15 remaining subjects flaxseed sachet count and serum phospholipid levels indicated only nine were adherent to the flaxseed diet. Plasma lipids and serum viscosity were unaltered by the flaxseed supplementation whereas serum creatinine in the compliant patients during flaxseed administration declined from a mean of 0.97±0.31 mg/dL to a mean of 0.94±0.30 mg/dL and rose in the control phase to a mean of 1.03±0.28 mg/dL [p value <0.08]. Of the fifteen patients who completed the study, similar changes were noted [p value <0.1]. The nine compliant patients had lower serum creatinines at the end of the two-year study than the 17 patients who refused to participate [p<0.05]. Microalbumin at baseline declined in both control and flaxseed time periods, but there was a trend for a greater decline during flaxseed administration [p<0.2]. Conclusions: Flaxseed appears to be renoprotective in lupus nephritis, but this interpretation is affected by under powering due to poor adherence and potential Hawthorne effects.

Central, peripheral, and other blood volume changes during hemodialysis.

Volume overload is a factor in development of hypertension in hemodialysis patients. Fluid removal by hemodialysis (HD), however, may cause intradialytic hypotension and associated symptoms. A better understanding of the relationships between blood pressure volume status and the pathophysiology of fluid removal during HD are, therefore, necessary to control blood pressure and to eliminate intradialytic hypotension. The objectives of the study were to determine the amount and direction of change of body fluid compartments after ultrafiltration (UF) and to determine whether any correlations exist between mean arterial pressure (MAP), change in circulating blood volume (&Dgr;BV), total body water (TBW), central blood volume (which constitutes the volume of blood in the lungs, heart, and great vessels [CBV]), and intracellular and extracellular fluid volumes (ICF, ECF). The study population included 20 patients on regular HD. Each individual had their CBV, cardiac output, and peripheral vascular resistance (PVR) measured by means of saline dilution technique and &Dgr;BV monitored by an online hematocrit sensor (Crit Line). MAP was calculated from measured blood pressure and ICF and ECF were measured using bioelectric impedance analysis techniques. Measurements were obtained before and after maximum UF measured by &Dgr;BV (reduction of 6–10% by Crit Line). Ten healthy controls also had ECF and ICF values measured by bioelectric impedance analysis. Before HD, MAP correlated with TBW (r = 0.473, p = 0.035) and CBV (r = 0.419, p = 0.066), suggesting that hypertension here may be due to volume overload. Patients were ECF expanded before HD with an ECF:ICF ratio of 0.96, which was significantly higher than the control ratio of 0.74 (p < 0.0001). During UF, fluid was removed from both ECF and ICF, but more from the ECF volume ratio 0.92 post UF, a significant reduction (p < 0.0001). After UF, MAP no longer correlated with TBW or CBV but correlated with peripheral vascular resistance (r = 0.4575, p = 0.043). After UF, &Dgr;BV correlated inversely with PVR (r = −0.50, p = 0.024). Despite the fall in &Dgr;BV (7.11 ± 2.49%) with UF, CBV was maintained. CBV were 0.899 L and 0.967 L pre and post UF, respectively. These data suggest that in hemodialysis patients, predialysis volume status influences predialysis blood pressure. UF causes BV to fall, but CBV is preferentially conserved by increasing PVR, which also maintains blood pressure. Failure of a PVR response likely leads to intradialytic hypotension.

Short daily versus long nocturnal hemodialysis

Interest in quotidian (daily) hemodialysis (HD) seems to be growing. A number of groups have advocated short, high efficiency daily HD, e.g., Buoncristiani and the group at Perugia, Italy,1,2 and a few have advocated long slow HD while the patient is asleep, so-called nocturnal HD. The leader in this area is the Toronto group that was headed by the late Dr. Uldall and now by Dr. A. Pierratos.3, 4 Several presentations have been made at major nephrologic meetings and there are a number of publications that purport improvement in the outcomes of HD patients who are treated with these methods.5 Unfortunately, there are as yet, no randomized prospective studies comparing outcomes in patients who are dialyzing with conventional three times per week HD and either the short daily or long slow nocturnal HD methods. This is the first daily/nocturnal HD study to obtain comparative data in this field. This study commenced in November of 1998 and will be complete by the end of 2001. This article gives, for the first time, preliminary results from the study.

Reduced requirement for erythropoietin with quotidian hemodialysis therapy.

Quotidian (daily) hemodialysis has many potential advantages over conventional three times weekly hemodialysis, including improved control of anemia. However, previous reports do not consistently describe beneficial effects regarding anemia and erythropoietin requirements. We sought to determine whether erythropoietin dose is altered in this form of therapy, and elucidate the potential contributing factors. An analysis of an ongoing, nonrandomized, prospective trial of daily nocturnal, daily short, and their cohort of conventional hemodialysis controls was performed. Those patients who had completed 15 months of the trial were analyzed, which include nine patients in the quotidian dialysis group and nine cohort controls receiving conventional three times weekly dialysis.At 15 months, the weekly Kt/V in the quotidian group was 6.8 (±0.6) and 4.5 (±0.4) in the conventional group (p = 0.001). Mean erythropoietin dose fell in the quotidian group from 87 (±66) to 53 (±50) U/week per kg (p = 0.020). The mean hemoglobin rose from 115 (±18) to 129 (±14) g/L (p = 0.008). There was no significant change in erythropoietin dose or hemoglobin in the conventional hemodialysis group. Serum ferritin and the transferrin saturation did not change significantly and remained above 100 &mgr;g/L and 20%, respectively, throughout. Serum albumin and C-reactive protein were similar between the quotidian and conventional dialysis groups and did not change over time. In patients who were receiving conventional thrice weekly hemodialysis, initiation of quotidian hemodialysis led to a 39% reduction in erythropoietin dose at 15 months, most likely due to the increased dose of delivered dialysis.

The advanced practice nurse–nephrologist care model: Effect on patient outcomes and hemodialysis unit team satisfaction

The tertiary care nurse practitioner/clinical nurse specialist (NP/CNS) is an advanced practice nurse with a relatively new role within the health‐care system. It is stated that care provided by the NP/CNS is cost‐effective and of high quality but little research exists to document these outcomes in an acute‐care setting. The clinical coverage pattern by nephrologists and NP/CNS of a hemodialysis unit in a large academic center allowed such a study. Two NP/CNS plus a nephrologist followed two of three hemodialysis treatment shifts per day; only a nephrologist followed the third shift. The influence of this care pattern of patients was examined using a cross‐sectional review of outcomes such as adequacy of delivered dialysis, anemia management, phosphate control, hospitalizations, etc. In addition, the level of satisfaction of the dialysis team and perceptions of care delivered with the care models was assessed. The care model staff‐to‐patient‐number ratio was similar in both groups (1:27 for NP/CNS plus nephrologist; 1:29 for nephrologist alone). Patient demographics were similar in both groups but the NP/CNS–nephrologist group had patients with more comorbidities. No statistically significant (p < 0.05) differences existed between the groups in patient laboratory data, adherence to standards, medications, inter‐ and intradialytic blood pressure, achievement of target postdialysis weights, and hospitalizations or emergency room visits. Significantly more adjustments were made to target weights and medications and more investigations were ordered by the NP/CNS–nephrologist team. Team satisfaction and perceptions of care delivery were higher with the NP/CNS–nephrologist model. It is concluded that the NP/CNS–nephrologist care model may increase the efficiency of the care provided by nephrologists to chronic hemodialysis patients. The model may also be a solution to the problem of providing nephrologic care to an ever‐growing hemodialysis population.

Determining lung water volume in stable hemodialysis patients

Lung water (LW) reflects the water content of the lung interstitium. Because hemodialysis patients have expanded total body water (TBW) they may also have increased LW. Hypertonic saline promotes a flux of water from lung to blood, which is measured by ultrasound flow probes on hemodialysis tubing. The volume of flux is an indirect measure of LW. Our purpose was to determine the feasibility and reproducibility of LW derived with ultrasound velocity dilution, to determine the effect of ultrafiltration on LW in stable hemodialysis patients, and to compare changes in LW with fluid compartment shifts using bioimpedance. Lung water, cardiac output, total body water, and extracellular and intracellular fluid volumes were measured in 24 stable hemodialysis patients at the beginning of hemodialysis and after ultrafiltration. The LW values at the beginning of hemodialysis (298.8 ± 90.2 ml or 3.67 ± 1.47 ml/kg) fell during hemodialysis (250.8 ± 55.8 ml or 3.12 ± 0.96 ml/kg; p < 0.05), as did TBW and extracellular fluid volumes (p < 0.001). Cardiac output, cardiac index, and central blood volume also decreased significantly with ultrafiltration (p < 0.005, p < 0.005, and p < 0.01, respectively). Results showed that stable hemodialysis patients have higher specific LW values (3.67 ml/kg) than the normal population (2 ml/kg) and ultrafiltration produces a significant decline in LW values.

Extravascular lung water and peripheral volume status in hemodialysis patients with and without a history of heart failure.

Determining volume status in hemodialysis patients with a history of congestive heart failure (CHF) is difficult. Extravascular lung water (EVLW) may be derived from blood ultrasound velocity changes following injections of 0.9% and 5% saline. Bioimpedance spectroscopy can measure total body water (TBW) and its intracellular fluid (ICF) and extracellular fluid (ECF) compartments. We studied 29 clinically euvolemic hemodialysis patients, 12 of whom had a history of CHF. The ECF and ICF were measured before dialysis, and EVLW was measured during dialysis. Values of EVLW were similar between patients without CHF and those with CHF (3.55 ml/kg ± 0.94 SD versus 3.88 ml/kg ± 0.82 SD, respectively; p = NS). The ECF/ICF ratio was higher among patients with a history of CHF (1.27 ± 0.29) than among those without such a history (1.04 ± 0.04; p < 0.05), indicating that ECF volume overload was present in both groups, but was higher in those with a CHF history. There was a positive correlation between EVLW and ECF/ICF ratios (r = 0.54, p < 0.01). Measurements of EVLW were higher in two pulmonary edema patients ((7.95 ml/kg and 5.95 ml/kg; p < 0.05). The results of this study suggest that 1) hemodialysis patients with a history of CHF have more ECF volume overloaded than those without such a history; 2) the degree of ECF expansion is associated with increasing EVLW volume, even in patients without pulmonary edema; and 3) ECF volume expansion eventually exceeds limits and pulmonary edema occurs. These developing technologies of volume measurement may be of value in this challenging clinical area.