Dialysis evolves as we learn more about the uremic condition. In its earliest versions, the major transport process was diffusion, the spontaneous movement of particles down a concentration gradient. This required concomitant ultrafiltration generated by osmotic, oncotic, or hydrostatic pressures. Consequently, ultrafiltration’s solvent drag effects led to an appreciation of the importance of convective transport and its advantage in enhancing the removal of species of larger molecular size (that is, higher molecular weight plus steric hindrance; Fig 1). Thus, contemporary dialysis uses both diffusive and convective transport, and modern equipment allows for each process to occur independently or in combination. Currently, dialysis cannot replace the endocrine or metabolic functions of the kidney, so our discussion is restricted to solute and fluid removal. Solute removal is measured in mass (eg, grams), which is determined by comparing total-body solute mass before and after dialysis, usually by extrapolation. Measuring the acquisition of solute in effluent dialysate is easier. The difference between the mass acquired in the dialysate and the mass removed from the body is called mass balance error and usually reflects the solute binding to the dialyzer membrane. This can be clinically relevant for antibiotics and cytokines. Solute removal also may be measured as the extraction ratio, which is the fraction of solutes removed from blood in a single pass through the dialyzer. Extraction ratio is determined as (Cin – Cout)/Cin, where Cin is solute concentration in the blood entering the dialyzer and Cout is the concentration in the blood exiting the dialyzer. The extraction ratio is dependent on blood (Qb) and dialysate (Qd) flow rates, the dialyzer membrane, and the intrinsic properties of the solute, such as molecular size and protein binding. The extraction ratio is high in traditional thrice-weekly hemodialysis (HD) and lower in short daily HD. We use a variation of this formula, urea reduction ratio, to measure urea removal during HD. Another method of indirectly assessing solute removal uses the concept of clearance, which is the volume (of plasma, serum, blood, or the entire body) from which all the solute was removed during a specific period; hence, the units are volume/time. Plasma is the fraction of blood that is not cellular, and plasma water makes up ∼94% of plasma. Plasma water is what is dialyzed. When a solute’s concentration gradient is from blood cells to plasma water (eg, potassium), the amount removed during dialysis may exceed the amount in plasma water. For urea, we often evaluate dialysis dose by total-body clearance, which is the K in Kt/V. The t refers to the duration of the clearance period, and the V, to the volume of distribution of the substance (for urea, V = total-body water). The V term normalizes the Kt product to body size. In dialysis practice, in HD, clearance is determined from what was removed from the blood, whereas in peritoneal dialysis (PD), clearance is determined by what is acquired in the dialysate. Instantaneous blood clearance in HD is extraction ratio multiplied by Qb (Fig 2A). In clinical practice, we measure blood urea before and after HD. Clearance does not change during an HD session unless operating conditions are altered. As solute is removed, Cin declines such that the fraction of total removal declines over the course of the dialysis session, but clearance remains constant. Because Cin is highest at initiation, the greatest amount of mass removed is early in the treatment: hence, repeating HD frequently may be very effective in improving total weekly solute removal. Dialysis clearance can never exceed Qb. If all the blood is cleared, clearance equals Qb. Clearance can never exceed the Qd. If the dialysate is 100% saturated (equilibrated) with solute, the clearance equals Qd. This concept is important when dialysate is limited, as it is in PD and some short daily HD systems (eg, NxStage). Figure 2B shows the relationship between clearance, Qd, and molecular size. Comparing clearance across different dialysis modalities is done best by using a week as the interval, adjusting for the continuous nature of PD versus the intermittent nature of HD and accounting for the frequency of the intermittent treatments, as first proposed by Gotch. In short daily HD using the most popular system in the United States, NxStage System 1, and PD, the limit to clearance is the availability of dialysate. In each therapy, the goal is to use dialysate efficiently, which means equilibrating dialysate with the solutes of uremia. In PD, peritoneal blood flow is limited, so saturating dialysate takes more time than in short daily HD, in which Qb is 3 times Qd. Both differ from standard thrice-weekly HD, in which dialysate is relatively unlimited. In PD, the saturation is defined by the dialysate to plasma concentration ratio, whereas in short daily HD, it is derived from the ratio of Qd to Qb, which is called flow fraction. When flow fraction is <40%, dialysate saturation with urea is >90%. The per-treatment Kt/Vurea for short daily HD is about 0.45, so 5 or 6 treatments per week is at least equivalent to thrice-weekly traditional HD. A comparison of weekly standardized Kt/Vurea over different modalities is shown in Fig 3. »Daurgirdas JT. Second generation logarithmic estimates of single pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol. 1993;4:1205-1213.»Gotch FA. The current place of urea kinetic modeling with respect to different dialysis modalities. Nephrol Dial Transplant. 1998;13(suppl 6):10-14.»National Kidney Foundation. DOQI Clinical Practice Guidelines for Peritoneal Dialysis Adequacy. New York, NY: National Kidney Foundation; 1997:96-106. To be removed by HD, solute must move from its production/storage site to the blood, then to the dialyzer, and then to the dialysate. Each of these sequential steps is affected by the properties of the molecular species itself, as well as the dialytic operating conditions. These concepts are described using urea as an example. Urea, a 60-Da, unbound, uncharged, water-soluble end product of protein catabolism, distributes from the liver to nearly all tissues. It is generated slowly enough for equilibration to occur between extracellular (interstitial and plasma) and cellular water. During HD, blood levels decrease sharply, but re-equilibrate as urea is recruited from the body. However, urea movement out of tissues into blood may be limited by poor tissue perfusion, as well as other forms of intercompartmental transport delays, which is postulated as the cause of dialysis disequilibrium syndrome. Hypotension during dialysis may lead to underperfusion of solute-rich tissue such as skeletal muscle. After HD, tissue beds slowly equilibrate with blood over a course of minutes to hours and urea levels increase, a process called urea rebound. Blood levels immediately after dialysis do not perfectly reflect urea levels in all tissues, which gives rise to 2 different indexes: single-pool Kt/V (spKt/V) based on urea level at the conclusion of HD and equilibrated Kt/V based on urea levels measured 30-60 minutes after HD. A roller pump pushes blood through the HD circuit with probably 95% of the accuracy displayed by the machine. Dialysate moves from the proportioning system to the dialyzer, and a second pump moves it out of the dialyzer and into a drain. The difference in pumping rates between these 2 pumps determines the amount of fluid that gets ultrafiltered. A sensor evaluates conductivity as a surrogate for ionic strength to ensure proper proportioning. Another sensor detects blood in dialysate, which would indicate a rupture in the circuit, usually in the hollow fibers. Most modern dialyzers use hollow fibers made of highly biocompatible synthetic material that maximizes surface area, does not expand under pressure, and has a relatively small extracorporeal blood volume commitment. Solute transport within the dialyzer is a function of blood flow distribution, blood-membrane interactions, membrane characteristics, and dialysate flow distribution. Efficiency ratings refer to urea clearance, which is almost exclusively dependent on dialyzer surface area and Qb. The manufacturer reports a dialyzer’s ability to remove urea as the KoA using milliliters per minute. Conceptually, KoA can be considered the urea clearance at infinitely high Qb and Qd; it is meant to reflect intrinsic dialyzer characteristics. In actual use, dialyzers may have significantly impaired performance when contrasted to manufacturers’ reported values. Low-efficiency units have KoA < 450 mL/min, whereas high-efficiency units have KoA > 700 mL/min. The flux definition is not precise, but the HEMO (Hemodialysis) Study chose β2-microglobulin (12,800 Da) clearance of at least 20 mL/min as their definition of high flux, whereas β2-microglobulin clearance < 10 mL/min was defined to be low flux. High-efficiency and high-flux dialyzers are very water permeable and must be used in conjunction with ultrafiltration rate controllers. The ability of a dialyzer to remove “middle molecules” (500-5,000 Da) must be balanced by the requirement that the dialyzer not leak important polypeptides. The sizes and shapes of the pores within the membrane are governed by the thermodynamics of the polymer, and advancements have gradually achieved this goal. Uremic solute clearance depends on whether the solute is small enough to pass through the membrane's pores. Urea passes freely, albumin is reflected, and β2-microglobulin is partially blocked. Smaller species diffuse faster than larger, while size effect is less significant with convection, leading to the use of convective or mixed convective-diffusive therapies (see Fig 1). »Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med. 2002;347:2010-2019.»Hauk M, Kuhlmann MK, Riegel W, Köhler H. In vivo effects of dialysate flow rate on Kt/V in maintenance hemodialysis patients. Am J Kidney Dis. 2000;35:105-111.»Trinh-Trang-Tan MM, Cartron JP, Bankir L. Molecular basis for the dialysis disequilibrium syndrome: altered aquaporin and urea transporter expression in the brain. Nephrol Dial Transplant. 2005;20:1984-1988. The components of the necessary prescriptions for HD are discussed throughout the remainder of this Core Curriculum (Box 1).Box 1Components of the Hemodialysis Prescription•Type of access and needle size•Qb•Qd•Duration (time)•Frequency•Dialyzer size•Dialyzer membrane material•Anticoagulation regimen•Dialysate composition of Na, K, bicarbonate, Ca•Estimated dry weight•Limitations to UFR•Special medicationsAbbreviations: Ca, calcium; K, potassium; Na, sodium; Qb, blood flow rate; Qd, dialysate flow rate; UFR, ultrafiltration rate. •Type of access and needle size•Qb•Qd•Duration (time)•Frequency•Dialyzer size•Dialyzer membrane material•Anticoagulation regimen•Dialysate composition of Na, K, bicarbonate, Ca•Estimated dry weight•Limitations to UFR•Special medications Abbreviations: Ca, calcium; K, potassium; Na, sodium; Qb, blood flow rate; Qd, dialysate flow rate; UFR, ultrafiltration rate. The National Cooperative Dialysis Study, the HEMO Study, and observational epidemiology of the US Renal Data System have led to a “guideline” expectation that each episode of thrice-weekly HD achieve a minimum spKt/V of 1.2. To minimize treatment time, Qd is twice Qb, allowing urea clearance and total removal to be a strong function of achieved Qb. The major clinical factors to consider in selecting a dialyzer are membrane material, sterilization method, surface area, and preferred flux. Cellulosic membranes perform adequately; choice is driven primarily by idiosyncrasies and cost. Angiotensin-converting enzyme inhibitors predispose patients to anaphylactic reactions when exposed to polyacrylnitrile membranes, and rare reactions to polysulfone or polyethersulfone occur. Dialyzers are sterilized by ethylene oxide, steam, radiation, or chemical reprocessing. Ethylene oxide and reprocessing chemicals must be completely flushed from the device because remnants are toxic. Consequently, using steam- or radiation-sterilized dialyzers may be simpler than mandating the additional maintenance and practice activity. The failure to deliver thrice-weekly spKt/V > 1.2 deserves attention (Box 2). The blood pump is rarely an issue. Thus, the first concern is if the access is adequate to deliver Qb > 300 mL/min. At this rate, a Qd to Qb ratio of 2 with a moderate or large surface area dialyzer should lead to dialyzer Cout urea level < 10 mg/dL. If this does not occur while Qb and dialyzer size are maximized, it is necessary to increase dialysis time. Many clinicians think that increasing time should be an earlier step because longer sessions mean slower (and safer) ultrafiltration rate and a better chance to clear molecules larger than urea. Staff costs and patient reluctance are the main barriers to increasing time.Box 2Items to Assess When Solute Clearance Per Session Is Marginal•Adequacy of blood flow from the access•Blood pump speed•Qd•Dialyzer surface area•Duration of dialysis•Fiber bundle clotting•Dialysate pathway stagnationAbbreviation: Qd, dialysate flow rate. •Adequacy of blood flow from the access•Blood pump speed•Qd•Dialyzer surface area•Duration of dialysis•Fiber bundle clotting•Dialysate pathway stagnation Abbreviation: Qd, dialysate flow rate. The HEMO and Membrane Permeability Outcomes (MPO) studies could not prove a clear benefit of high- versus low-flux dialyzers, but a subgroup analysis of the HEMO Study showed a statistically significant decrease in all-cause mortality in the high-flux arm with dialysis vintage longer than 3.7 years. It may take years of end-stage renal disease for conditions attributed to middle-sized molecules to emerge. Because the cost is hardly different, the only reason to use low-flux dialyzers would be when water purity is suspect. Weight-based unfractionated heparin is the most commonly used anticoagulant because it is inexpensive and has a short half-life. Recurrent exposure risks bleeding and heparin-induced thrombocytopenia. Alternatives include low-molecular-weight heparins, direct thrombin inhibitors, regional anticoagulation with citrate or prostacyclin, and anticoagulation-free treatment, which often is accompanied by frequent saline flushes. Regional anticoagulation with prostacyclin is not commonly performed in the United States. Regional anticoagulation with citrate and calcium infusions is too tedious and expensive for routine use and thus often is limited to the intensive care setting. Citrate-containing dialysate solutions substitute citrate for acetate in the bicarbonate concentrate and may reduce heparin requirements. Below is a section on longer and/or more frequent HD. The rationale for such therapies is that urea levels may not represent removal of the molecules that contribute to uremia. These molecules may be considerably larger and their removal may be limited by slow diffusion from tissue to blood (eg, as is the case with phosphorus). Plasma inorganic phosphorus levels decrease precipitously during HD and then rebound to nearly predialysis levels. Thus, the limiting step in removing phosphorus by HD is intercompartmental transfer, and this also may be true for other uremic toxins. »Cheung AK, Levin NW, Greene T, et al. Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO Study. J Am Soc Nephrol. 2002;14:3251-3263.»DeSoi CA, Umans JG. Phosphate kinetics during high-flux hemodialysis. J Am Soc Nephrol. 1993;4:1214-1218.»National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for 2006; updates: hemodialysis adequacy, peritoneal dialysis adequacy and vascular access. Am J Kidney Dis. 2006;48(suppl 1):S1-S322.»Locatelli F, Martin-Malo A, Hannedouche T, et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009;20:645-654.»Sands J, Kotanko P, Segal J, et al. Effects of citrate acid concentrate (Citrasate™) on heparin N requirements and hemodialysis adequacy: a multicenter, prospective noninferiority trial. Blood Purif. 2012;33:199-204.»Spalding EM, Chamney PW, Farrington K. Phosphate kinetics during hemodialysis: evidence for biphasic regulation, Kidney Int. 2002;61:655-667. The most abundant exchangeable plasma cation is sodium. Sodium is the primary determinant of plasma and extracellular osmolality, which can be regulated in HD patients by controlling sodium and fluid intake and by the dialysate sodium concentration. Epidemiologic studies have shown that a reduction in sodium intake can significantly reduce blood pressure (BP), cardiovascular morbidity, and mortality. We extrapolate this concept to HD patients. Therefore, dietary sodium restriction has been a major management strategy to help reduce interdialytic weight gain (IDWG), antihypertensive medications, and mortality. Before the advent of modern dialysis machines with safe and predictable ultrafiltration controls, sodium concentration in dialysate was ∼126 mEq/L and much of the sodium removed was due to diffusion. Modern nonexpanding dialyzers withstand greater hydrostatic pressures, require a smaller extracorporeal blood volume commitment, and achieve greater ultrafiltration in a shorter time. Thus, sodium removal shifted primarily to convection. As a consequence of faster and more aggressive ultrafiltration with shorter dialysis times, side effects such as muscle cramps, hypotension, thirst, and dialysis disequilibrium increased in frequency and severity. To counteract these effects, dialysate sodium concentration is increased by either fixing dialysate sodium at a higher concentration for the entire HD session or systematically varying the dialysate sodium concentration over the course of the HD session, a process called sodium modeling. The goal of sodium modeling is to shift water from intracellular to extracellular compartments, where this added water supports circulation. Potential benefits include reduced incidences of dialysis disequilibrium, vascular instability, and muscle cramps. As an example, cycling a dialysate sodium concentration of 160 mEq/L in the first period of dialysis and 120 mEq/L in the second equal period and then repeating the cycle throughout the session leads to an average dialysate sodium concentration of 140 mEq/L. Periodic infusions of 50% dextrose in water (D50W), 0.9% sodium chloride, or 23% sodium chloride solutions provide other means for treating intradialytic hypotension and muscle cramps attributed to sodium removal. Some of these techniques can lead to an intradialytic accumulation of sodium, which may cause greater thirst, IDWG, and hypertension. Repeated high IDWG increases cardiovascular morbidity and mortality. Tightly regulating sodium metabolism is crucial for preventing excessive IDWG. Small uncontrolled trials have suggested that individualizing dialysate sodium concentration decreases IDWG and BP and may offer a mortality benefit. The DOPPS (Dialysis Outcomes and Practice Patterns Study) observed a 45% higher risk of death in patients with predialysis plasma sodium levels < 137 mEq/L compared with levels ≥ 140 mEq/L. However, there was a survival benefit in using higher dialysate sodium concentrations, speculated to be due to increased cardiovascular stability. Sodium removal in HD patients presents a challenge. Dietary sodium is restricted and the amount of sodium delivered at dialysis must be minimized. Increasing sodium removal convectively means increasing ultrafiltration, which may be intolerable. Advances in dialysis technology may help individualize dialysate sodium concentration based on plasma sodium concentration. Dialysis machines can monitor and alter dialysate inlet and outlet conductivity and ionic dialysance (effective solute clearance). Knowing the sodium concentration and ultrafiltration rate, the machine’s software can alter plasma conductivity, a surrogate for plasma sodium concentration. Interstitial storage of sodium contributes to hypertension. Rat studies demonstrate that sodium is stored in muscle and skin, and lowering sodium intake can reverse this. This “osmotically inactive” sodium is a substantial portion of total-body sodium. Recently, tissue sodium content has been measured in healthy and hypertensive humans using sodium magnetic resonance imaging and is higher in muscle and skin of older and hypertensive individuals. Emerging evidence suggests that tissue stores may provide other pathologic effects besides IDWG and volume overload. Validating sodium magnetic resonance imaging is required before clinical implementation. »Hecking M, Karaboyas A, Saran R, Sen A, Hӧrl WH. Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2012;59:238-248.»Kopp C, Linz P, Wachsmuth L, et al. 23Na magnetic resonance imaging of tissue sodium. Hypertension. 2012;59:167-172.»Manculu J, Gallo K, Heidenheim PA, Lindsay RM. Lowering postdialysis serum sodium (conductivity) to increase sodium removal in volume-expanded hemodialysis patients: a pilot study using a biofeedback software system. Am J Kidney Dis. 2010;56:69-76.»Mann H, Stiller S. Sodium modeling. Kidney Int Suppl. 2000;58:S79-S88.»McCausland FR, Waikar SS, Brunelli SM. Increased dietary sodium is independently associated with greater mortality among prevalent hemodialysis patients. Kidney Int. 2012;82:204-211.»Stiller S, Bonnie-Schorn E, Grassmann A, Uhlenbusch-Kӧrwer I, Mann H. A critical review of sodium profiling for hemodialysis. Semin Dial. 2001;14:337-347. Dialytic potassium removal depends on the gradient created between extracellular fluid and dialysate. Intracellular potassium effluxes extracellularly to re-establish equilibrium as extracellular potassium is removed by dialysis. Liver and skeletal muscles are rich in potassium. If either is atrophied, there may be decreased post-HD extracellular potassium replenishment. The absorption of dialysate glucose decreases potassium removal by stimulating insulin, which drives potassium into cells and thus renders it unavailable for dialytic removal. Extracellular acidosis leads to cellular potassium efflux, which increases extracellular potassium concentration and enhances dialytic potassium removal. Dialytic acidosis correction results in a cellular influx of potassium to re-establish equilibrium. Rapid correction of acidosis in the setting of a low potassium dialysate concentration will quickly reduce extracellular potassium levels and can result in serious hypokalemia. The same consequence can occur from long-term excessive bicarbonate administration. The prescribed dialysate potassium concentration depends on the patient’s predialysis potassium concentration. The “rule of 7s” is a basic approach that states that the patient’s potassium level plus dialysate potassium concentration should equal approximately 7. This approach is acceptable as long as individual care is taken in patients with a propensity for arrhythmias. A dialysate potassium concentration of zero should be used for only very short periods with monitoring and close surveillance, if at all. A stepped approach of progressively lowering the bath potassium concentration over the course of the treatment may be less arrhythmogenic. The range of most commonly used dialysate concentrations is 2-4 mEq/L. Lower concentrations can be used in the setting of life-threatening acute hyperkalemia, but only with extreme caution and frequent intradialytic potassium measurements. As potassium blood levels decrease to <3 mEq/L, weakness and muscle pain develop; further decreases cause rhabdomyolysis, paralysis, cardiac arrhythmias, and cardiopulmonary arrest. In patients prone to cardiac arrhythmias or those receiving digoxin, even mild hypokalemia can induce serious arrhythmias. Immediate postdialysis hypokalemia does not warrant treatment unless symptoms are present because a rebound increase in serum potassium level will occur within 1-2 hours. Premature correction could result in hyperkalemia. There is no absolute recommended predialysis potassium level. Better survival is associated with predialysis serum potassium levels of 4.6-5.3 mEq/L. Individualized potassium management demands redundant safety systems so that no patient receives another person’s potassium prescription. »Kovesdy CP, Regidor DL, Mehrotra R, et al. Serum and dialysate potassium concentrations and survival in hemodialysis patients. Clin J Am Soc Nephrol. 2007;2:999-1007.»Sherman RA, Hwang ER, Bernholc AS, Eisinger RP. Variability in potassium removal by hemodialysis. Am J Nephrol. 1986;6:284-288.»Ward RA, Wathen RL, Williams TE, Harding GB. Hemodialysate composition and intradialytic metabolic, acid-base and potassium changes. Kidney Int. 1987;32:129-135. Dialysis corrects metabolic acidosis by both adding base and removing acid. Between HD treatments, serum bicarbonate level declines as it neutralizes endogenous acid. The predialysis serum bicarbonate level varies depending on the factors elucidated in Box 3. Buffer base loss occurs by convection during ultrafiltration and is proportional to the amount of ultrafiltration. The dialysate buffer concentration should compensate for the bicarbonate needed to buffer interdialytic acid generation plus account for that lost during ultrafiltration.Box 3Influences to Predialysis Bicarbonate Concentration•Postdialysis bicarbonate level•Endogenous acid production•Food content•Food quantity•Time between dialysis sessions•Extent of bicarbonate loss with ultrafiltration •Postdialysis bicarbonate level•Endogenous acid production•Food content•Food quantity•Time between dialysis sessions•Extent of bicarbonate loss with ultrafiltration Managing chronic metabolic acidosis too aggressively may result in acute metabolic alkalosis. A lower base concentration should be used in patients susceptible to alkalosis, such as individuals with poor protein intake, small muscle mass, or persistent vomiting, or those receiving total parenteral nutrition. Symptoms of metabolic alkalosis can range from cramping, paresthesias, and fatigue to hypoventilation, altered mental status, and lethargy. Metabolic alkalosis also can predispose to cardiopulmonary arrest. In HD, the most commonly used dialysate buffer is bicarbonate, which is relatively inexpensive and generally better tolerated than acetate. The usual dialysate bicarbonate concentration is 35 mEq/L. To meet specific individualized requirements, modern dialysis machines are capable of delivering bicarbonate concentrations over the range of 20-40 mEq/L. The National Kidney Foundation’s KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines recommend a midweek predialysis plasma bicarbonate level of 22 mEq/L. Lower mortality risk has been observed in patients with predialysis serum bicarbonate levels of 18-23 mEq/L, with an increase in mortality for both very low (<18 mEq/L) and very high (>27 mEq/L) values. Although low predialysis plasma values usually can be corrected by increasing the dialysate bicarbonate concentration, high plasma values likely reflect decreased protein intake and cannot be corrected by simply decreasing the dialysate bicarbonate concentration. Nutritional status and daily caloric intake should be reviewed thoroughly in this setting. »Bommer J, Locateli F, Satayathum S, et al. Association of predialysis serum bicarbonate levels with risk of mortality and hospitalization in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:661-671.»Fabris A, LaGreca G, Chiaramonte S, et al. The importance of ultrafiltration on acid-base status in a dialysis population. ASAIO Trans. 1988;24:200-201.»Vashistha T, Kalantar-Zadeh K, Molnar MZ, Torlén K, Mehrotra R. Dialysis modality and correction of uremic metabolic acidosis: relationship with all-cause and cause-specific mortality. Clin J Am Soc Nephrol. 2013;8:254-264. Plasma calcium is ∼40% protein bound, 10% anion complexed, and 50% ionized, and only the complexed and ionized portions are dialyzable. The ionized calcium gradient between dialysate and plasma water is the driving force of calcium transfer during dialysis; equilibration occurs by diffusion. The most commonly used dialysate concentrations for HD are 2.5-3.5 mEq/L. Calcium homeostasis is essential for bone health because its disruption leads to secondary hyperparathyroidism and metabolic bone disease. Phosphate binders, vitamin D analogues, calcimimetics, and dialysate calcium concentration are used to maintain normal mineral metabolism while avoiding hypercalcemia, soft-tissue calcifications, and oversuppression of parathyroid hormone with subsequent adynamic bone disease. Like bicarbonate, ionized calcium is removed convectively, so large ultrafiltration volumes must be appreciated. Dialysate calcium concentration also can influence hemodynamics because calcium ion is important for contracting both vascular smooth muscle and cardiac myocytes, which affects BP. Lower dialysate calcium concentrations may cause intradialytic hypotension, acute arrhythmias, and sudden cardiac death. These complications might be avoided in cardiac-compromised patients with a higher dialysate calcium concentration. However, long-term use of higher dialysate calcium concentration increases the risk of calcification. Acidosis decreases and alkalosis increases the binding of ionized calcium to albumin. Acidosis can induce signs of hypercalcemia ranging from mild nausea and vomiting to more serious symptoms, such as confusion and coma. However, care must be taken with acidosis, particularly in the setting of low plasma ionized calcium levels, because rapidly correcting th