Quantitation of dialysis: historical perspective.

This article is an attempt to provide a historical perspective to the ongoing attempts to quantify dialysis therapy. It is immediately apparent that motivated chemists, physicists, engineers, mathematicians, and other scientists from all over the world have greatly aided this effort. Dialysis, described by Graham in 1861, was furthered by Abel et al. and Hass before World War I. Willem Kolff attempted to evaluate mass removed and Alwall used a solute extraction ratio. However, the concept of "clearance" and "dialysance" awaited the studies of Wolf et al. in 1951. This classic work describes most of the information concerning actual dialyzer performance known today. A. S. Michaels provided the equations leading to the KoA/Ro/A concept in 1966 which only very recently required updating. The interaction of diffusion and convection is complex and was studied by Villarroel in 1977 and recently by Jaffrin. L. W. Henderson studied and described hemofiltration and hemodiafiltration from 1967-1975. Efforts to relate the patient's outcome to the dialyzer's performance have been difficult and ongoing since 1971; the Babb-Scribner Square meter-hour (which included the expression "Kt/V"); the Kopp et al. Liter-Kilogram concept; 1972 Kjellstrand clearance * time/kg or Liter. A NIH sponsored conference on the Adequacy of Dialysis in Monterey, California in March of 1974 was focused somewhat on the "middle molecule" theory of uremic toxicity, but contained a presentation by Sargent and Gotch on the possibilities of urea kinetic modeling. They developed iterative computer programs to obtain the best estimates of the required variables. At about this same time, Teschan, Ginn et al. published a series of neurofunctional tests and EEG power spectra analyses which most convincingly showed that dialysis two times a week was inadequate, and that dialysis delivered three times a week at urea clearance equal to body water volume was required to normalize these abnormalities: a major contribution! The National Cooperative Dialysis Study reported in Kidney International, 1983, was either misunderstood or ignored by most practitioners. The mechanistic analysis of the study by Gotch and Sargent appeared in 1985 and indicated that at adequate protein intake a Kt/V >0.8 yielded better patient survival. In 1982 Malchesky reported the Direct Dialysis Quantification (DDQ) based on calculations from the total mass removed in the dialysate. Although cumbersome, it avoids many errors including the effect of hematocrit and other factors on dialyzer clearance and many consider it to be "the gold standard." The 1990s were characterized by the development of many simple logarithmic equations to estimate Kt/V and eKt/V suitable for spreadsheets which could be used for CQI by individual units. These are primarily by J. T. Daugirdas and coworkers, Smye and Tattersall. In 1991 the Urea Reduction Ratio (URR) was introduced by Lowrie, who in 1999 suggested that Kt and V (as indicator of lean body mass) were independent predictors of survival. Peritoneal dialysis: Although performed before and immediately after World War II, almost all of the basic quantification mechanistics and data are found in the publications of S. T. Boen (1964). New quantifiers, the Mass Transport Area Coefficient (MTAC) or Pyle-Popovich model, the Henderson-Nolph, and Garred models, were compared by Waniewski. Gotch announced a PD modeling program which suggested that a weekly PKt/V at 2.1 was needed to supply the same urea removal as a Kt/V of 3.6, but warned that both were sensitive to decreased time.

HEMO equilibrated Kt/V goals are difficult to achieve in large male patients.

The long-term outcome of chronic hemodialysis patients is influenced by the adequacy of dialysis treatment. A major objective of the ongoing US HEMO Study is to determine if a higher target value of treatment as measured by the equilibrated Kt/V (eKt/V), a calculation of dialysis adequacy developed for the study, of 1.45 results in a better outcome than the presently accepted target value for eKt/V of 1.05 (approximately equal to spKt/V of 1.2). eKt/V corrects for urea rebound and gives a better estimate of actual treatment received. To examine the feasibility of achieving the higher eKt/V in large hemodialysis patients, a retrospective analysis of 389 monthly eKt/V values from 65 men on chronic hemodialysis of larger than average size dialyzed at high blood and dialysate flows (QB 400, QD 800 ml/min) with large dialyzers (1.8-2.2 m2) for longer than 4 hours three times weekly was performed. A total of 278 treatments considered optimal by a blood water urea clearance estimate were included in the final analyses. The mean body weight and Chertow water volume were 84.3+/-16.5 kgm and 50.0+/-6.7 L, respectively. The mean sp Kt/V was 1.29+/-0.17. The mean eKt/V was 1.16+/-0.14 and was inversely correlated with weight and water volume (p < 0.0001). Despite the large dialyzers and high blood and dialysate flow rates, no patient weighing more than 80 kgm or with body water volume exceeding 46 liters achieved an eKt/V of 1.45. This study suggests that creative dialyses will be required to achieve the HEMO "high arm" target in large patients.

Clinical evaluation of a new high efficiency hemodialyzer: polysynthane.

Two increasingly common characteristics of the American chronic hemodialysis (HD) population, high hematocrit and large body size, may render the currently recommended adequacy targets difficult to achieve, even with very efficient dialyzers. In a group of patients with these characteristics, we assessed the ability of a new high efficiency dialyzer (PSN210; Baxter Healthcare Corporation) to achieve the currently recommended adequacy targets. Six patients (mean pre-HD weight and hematocrit, 90.3 +/- 18.0 kg and 0.40 +/- 0.03 kg, respectively) were evaluated. At prescribed blood and dialysate flow rates of 400 and 800 ml/min, respectively, and a mean treatment duration of 4 hrs, mean delivered urea Kt/V and reduction ratio (URR) were 1.38 +/- 0.25 and 0.73 +/- 0.07, respectively. For the same flow rates, whole blood clearances for urea, creatinine, and phosphate were 315 +/- 13, 246 +/- 28, and 260 +/- 27 ml/min, respectively. These data indicate this dialyzer has an efficient mass transfer design allowing adequate dialysis to be delivered even to very large patients under high efficiency conditions.

Severe hypersensitivity reaction during hemodialysis.

BACKGROUND: Hemodialysis-associated hypersensitivity reactions are well documented in the literature. Ethylene oxide sensitization and activation of complement are important factors involved during such reactions. The majority of severe hypersensitivity reactions in dialysis patients, however, is due to sensitization to ethylene oxide. METHODS: We report a patient admitted to the hospital with worsening of his renal function. He subsequently required three hemodialysis treatments, all of which resulted in severe hypersensitivity reactions requiring endotracheal intubation. The initial hypersensitivity episode was thought to be due to complement activation to the cupramonium-rayon membrane dialyzer. Despite changing to a polyacrylonitrile membrane, which does not activate complement, a second hypersensitivity reaction developed. Suspecting ethylene oxide hypersensitivity, the third hemodialysis session incorporated a biocompatible dialyzer that was sterilized with gamma irradiation, not ethylene oxide. Yet again, an anaphylactoid reaction resulted. It was postulated that residual ethylene oxide in the tubing might have triggered this last attack. RESULTS: Despite a negative RAST (radioallergosorbent test) to ethylene oxide, the strong history surrounding each of the hypersensitivity episodes and high index of suspicion pointed to ethylene oxide hypersensitivity as the etiologic factor. To this end, the patient fared much better when peritoneal dialysis was initiated. The patient subsequently died from other complications of his illness. CONCLUSIONS: This case report demonstrates both the complex nature involving a hypersensitivity reaction to hemodialysis and the life-threatening severity of such a reaction. Replacing ethylene oxide with steam or gamma radiation to sterilize dialyzers and thoroughly rinsing new dialyzers and tubing with normal saline may help circumvent this problem.

Erythropoietin alert: risks of high hematocrit hemodialysis.

The impending release of erythropoietin (EPO) is expected to result in a dramatic increase in hematocrit (Hct) for most hemodialysis (HD) patients. Our studies indicate that as Hct rises, dialyzer mass transport for some clinically critical solutes will be adversely affected. When whole blood clearances are corrected for solute-specific blood-water flows (QBH2O), the effect on the surrogate molecule, urea, used in urea kinetic modeling (UKM) is deceptively minimal, because only urea can diffuse almost instantly from red cells into blood water. For the critical solutes, potassium and phosphate, QBH2O is reduced to Q (plasma water). With a KoA of 690 ml/min at QB = 300, clearance of potassium falls at least 19.3% as Hct rises from 20 to 40% so that steady-state predialysis potassium could rise from 6.0 to 6.95 mEq/L. Already inadequate phosphate clearance falls at least 10% and additional loss results from physical interference by RBCs with solute diffusion. Hcts are further increased with rapid weight losses during high-efficiency dialyses (0.15 per 5% weight loss in 3 hours, r = 0.82) resulting in blood-side pressures such that most dialysis machines cannot provide adequate dialysate pressures to maintain low ultrafiltration rates (UFRs) at the high QB levels. The combination of pre-existing diffuse vascular disease, postdialysis hypovolemia, hypotension, decreased cardiac output, and increased blood viscosity has and will produce disastrous syndromes of organ ischemia, thrombosis, and infarction. Predialysis hypertension can worsen. Extreme caution and adjustment of dialysis regimen is necessary as patient Hct rises above 36%.

Reversal of aluminum-related bone disease after substituting calcium carbonate for aluminum hydroxide.

Aluminum-related osteodystrophy, a crippling disease in patients with renal failure, can develop from the long-term ingestion of aluminum hydroxide gels. We present a diabetic patient treated with continuous ambulatory peritoneal dialysis (CAPD) who developed markedly elevated plasma aluminum levels but no musculoskeletal symptoms. Bone biopsy revealed features of the aplastic form of aluminum-related disease with significant aluminum staining, decreased osteoblastic osteoid, and decreased bone formation by double tetracycline labeling, but no excess accumulation of unmineralized osteoid. Aluminum hydroxide gels were discontinued and the patient received calcium carbonate to control hyperphosphatemia; 9 months later, a bone biopsy showed marked improvement of the aluminum-related bone disease, and at 2 to 10 months, plasma aluminum had decreased from 208.7 +/- 10.3 (SE) to 55.7 +/- 3.9 micrograms/L.

The use of intracatheter instillation of streptokinase in the treatment of recurrent bacterial peritonitis in continuous ambulatory peritoneal dialysis.

Recurrent bacterial peritonitis resistant to therapy with antibiotics is seen in a small percentage of patients maintained on continuous ambulatory peritoneal dialysis. In these patients, removal of the Tenckhoff catheter is necessary to achieve a cure. Sequestration of bacteria within fibrin clots located on the catheter has been postulated to contribute to this resistance to standard therapy. We, therefore, examined the efficacy of intraperitoneal streptokinase in combination with antibiotic therapy in the treatment of two patients with recurrent bacterial peritonitis. After addition of streptokinase to the therapeutic regimen, no further episodes of peritonitis were observed after 6 to 8 weeks follow-up. These data suggest that intraperitoneal streptokinase may be useful as adjunctive therapy in the treatment of recurrent bacterial peritonitis.

Use of calcium carbonate as a phosphate binder in dialysis patients.

Aluminum-containing phosphate (Al-binders) employed to control serum phosphorus in patients with chronic renal failure can be associated with the development of aluminum toxicity. To obviate the need for Al-binders, we examined the effectiveness of CaCO3 as a phosphate binder in 31 hemodialysis and 8 CAPD patients followed for 2 months while receiving Al-binders, and then, for 3-14 months while receiving CaCO3 (5.8 +/- 0.4 g/day). Monthly serum phosphorus averaged 5.4 +/- 0.2 mg/dl with Al-binders and 5.1 +/- 0.3 to 5.7 +/- 0.4 mg/dl with CaCO3 (p = NS). There were 25.2 episodes of hyperphosphatemia (serum phosphorus greater than 6.5 mg/dl) per 100 treatment months with Al-binders and 19.2 episodes/100 treatment months with CaCO3 (p = NS). Plasma aluminum levels, 105 +/- 21 micrograms/l during ingestion of Al-binders, fell to 34 +/- 11 micrograms/l after 8 months of therapy with CaCO3 (p less than 0.01). Monthly serum Ca averaged 9.5 +/- 0.1 mg/dl during Al administration and was 8.9 +/- 0.8 to 10.0 +/- 0.2 mg/dl with CaCO3 (p = NS). Thirty-four episodes of hypercalcemia (serum Ca greater than 11.0 mg/dl) occurred in 14 patients ingesting CaCO3, but hypercalcemia did not occur with ingestion of Al-binders. Al-related bone disease was found on bone biopsy in 11 of 13 patients who developed hypercalcemia, compared to only 5 of the 11 biopsied patients who remained normocalcemic (p less than 0.01 by chi 2 analysis). Other side effects included diarrhea in 1 patient and constipation in 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo analysis of the Lundia 5 (PRO 5) and Lundia 3 (PRO 3) dialyzers with Gambrane polycarbonate membranes.

The physical, solute transfer and biocompatibility properties of two new parallel plate dialyzers using Gambrane polycarbonate (PC) membrane of 0.8 m2 (L-3 PC) and 1.1 m2 (L-5 PC) were studied in 6 volunteer chronic dialysis patients. Two of these 6 had suffered severe first-use syndromes with Cuprophan. Samples were collected under carefully controlled conditions. Mass transport properties were confirmed by total dialysate collection and found to compare favorably with other standard dialyzers. For the L-3 PC, KUF was 3.59 ml/h/mm Hg TMP-14.5 and standard whole blood clearances were BUN 142, creatinine 121 and inorganic phosphate 69 ml/min. For the L-5 PC, KUF was 6.27 ml/h/mm Hg TMP-28.66 and standard clearances were BUN 155, creatinine 134 and inorganic phosphate 89 ml/min. Using bicarbonate dialysate no consistent hypoxemia occurred and all dialyses were well tolerated. The L-3 PC and L-5 PC dialyzers induced more leukopenia and C3a generation than PAN but less than Cuprophan. Thus these new dialyzers offer conventional mass transfer and ultrafiltration rates with much improved membrane biocompatibility.

Preliminary report on complement activating potential of polycarbonate membrane.

Clinical as well as laboratory studies have been employed to assess the complement activating potential of polycarbonate membrane hemodialyzers. Blood samples from a group of patients undergoing sequential maintenance hemodialysis with cuprophane, polyacrylonitrile and polycarbonate devices were evaluated to define plasma levels of C3a antigen and leukocyte counts during the initial phases of hemodialysis. While polyacrylonitrile dialyzers did not activate complement to a significant extent, we did observe transient elevations in the plasma concentration of C3a and corresponding diminutions in the granulocyte counts of patients dialyzed with both cuprophane and polycarbonate dialyzers. However, polycarbonate devices appeared to activate complement to a lesser degree than cellulosic dialyzers. Laboratory evaluation of these three different types of dialyzers also provided evidence that polycarbonate membranes did not appear to activate human complement as readily as cuprophane. These observations suggest that polycarbonate membranes display complement-related biocompatibility properties that are intermediate between those of cuprophane and polyacrylonitrile.

Performance characteristics of high flux haemodiafiltration.

With the described technique of high diffusive and convective solute transport an almost threefold increase in efficiency over conventional dialysis was clinically demonstrated. Coupled with the better tolerance to high solute and weight removal rates, this approach permits drastic reduction of treatment time, without sacrificing treatment adequacy.

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.

High-flux hemodiafiltration: under six hours/week treatment.

Better utilization of existing high blood flow in mature vascular accesses with the described new technique of simultaneous high diffusion and convection results in a marked increase of treatment efficiency. Coupled with the better tolerance to high solute and weight removal rates, this approach permits drastic reduction of treatment time over conventional hemodialysis without sacrificing treatment adequacy.

Technical aspects of high-flux hemodiafiltration for adequate short (under 2 hours) treatment.

The efficiency of hemodialysis can be more than doubled. This involves deviating from conventional blood and dialysate flows, employing dialyzers with greater surface area and permeability, bicarbonate dialysate, and an apparatus capable of rigid volumetric control of the dialysate. Coupled with the better treatment tolerance described elsewhere in this volume, this self-contained and automated technique providing high diffusive and convective transfer permits drastic reductions in treatment time over conventional dialysis: in our study, to under 6 hrs/wk.

Parathyroid gland responsiveness to acute hypocalcemia in dialysis osteomalacia.

The majority of chronic hemodialysis patients have elevated serum iPTH levels and bone disease characterized by osteitis fibrosa. However, a small group of patients develop osteomalacic bone disease associated with normal or slightly elevated iPTH values and a tendency to hypercalcemia which occurs either spontaneously or after treatment with small doses of vitamin D sterols. To examine the causes of the relatively low iPTH levels, we evaluated the change in serum iPTH levels that occurred in response to acute hypocalcemia, produced by dialysis using a low calcium dialysate, in 11 patients with osteomalacia and 8 control hemodialysis patients. Dialysis against a dialysate free of calcium for 60 to 90 min led to a fall in serum calcium to 7.5 +/- 0.2 and 7.2 +/- 0.2 mg/dl in the osteomalacic and control patients, respectively. Serum iPTH rose in controls from 1380 +/- 287 to 1960 +/- 287 pg/ml (P less than 0.01), whereas in patients with osteomalacia it rose from 360 +/- 58 to 507 +/- 104 pg/ml (P less than 0.05), a value only slightly above normal for this PTH assay. These data suggest that the relatively low basal levels of serum iPTH do not arise as a consequence of physiologic suppression of parathyroid gland function. This reduction in parathyroid function could contribute to the pathogenesis of low turnover osteomalacia.