Complications of Hemodialysis

Fig. 9.1
The step of physiological compensation for hypotension and the related pathologic conditions in each step

There are a number of factors that interfere with these compensation mechanisms. Patient factors include loss of baroreflex and impaired autonomic nervous system in elderly and/or diabetic patients, the intensive use of antihypertensive drugs, structural abnormalities in the heart, arrhythmia , sepsis, bleeding , anemia , venous pooling during dialysis, elevation of core temperature , and meals during dialysis. Factors-related dialysis processes include use of low sodium or low calcium dialysates, use of acetate dialysis or bioincompatible dialyzers (K/DOQI 2005). Humoral Factors

Excessive interdialytic weight gain causes the necessity of excessive UF rate and amount during dialysis. Similarly, excessive accumulation of uremic molecule also causes acute excessive osmolality change. Excessive water removal and acute decrease of osmolality are the common causes of intradialytic hypotension . Elderly or long-term diabetic patients frequently manifest the impaired autonomic function, which can cause intradialytic hypotension by impairing cardiac compensation. Hypoalbuminemia also causes intradialytic hypotension by the impairment in vascular refilling. Low sodium or low calcium dialysates can be a cause of hypotension . Vascular Factors

Intradialytic hypotension occurs when compensations fail such as sympathetic reflex or blood flow redistribution from peripheral to central vasculatures. Diabetic or uremic autonomic neuropathy, especially in the elderly, causes sympathetic failure in which the responsive secretion of norepinephrine is inadequate. Food intake during hemodialysis increases the splanchnic blood flow and reduces the amount of blood in the core vasculatures. Antihypertensive agents taken before dialysis are a common cause of intradialytic hypotension . Severe anemia (hematocrit <20–25%) tends to cause hypotension by hypoxia and consequent vasodilation. High temperature dialysate over 36 ° C causes peripheral vasodilation to reduce core temperature , which results in the decrease of core blood volume and consequently hypotension . In the past, intradialytic hypotension was frequent with use of acetate dialysate through the adenosine-mediated vasodilation and use of bioincompatible dialyzers through the complement activation. Cardiac Factors

Conditions impairing the reflex response of cardiac output and heart rate result in intradialytic hypotension . It is difficult to compensate hypovolemia due to reduced cardiac filling in the patients with diastolic dysfunction such as left ventricular dysfunction or ischemic heart disease. Cardiac contractility is reduced in the patients with congestive heart failure , ischemic heart diseases, hypertensive heart diseases, and arrhythmia . The use of beta-blocker, uremic or diabetic autonomic neuropathy, and the elderly also frequently show the impairment of the reflex increase of heart rate.

9.2.3 Management

Immediate interventions should be performed for restoration of circulatory blood volume and ensuring vital organ perfusion. These include taking Trendelenburg positions, supplying oxygen, immediate cessation of UF and minimization of blood flow, and rapid recovery of circulation with saline or mannitol infusion (Table 9.1). If needed, hemodialysis has to be discontinued. However, it should be remembered that frequent interruption of hemodialysis session may cause chronically insufficient delivered dose of dialysis and chronic blood loss. The returning of blood to the patient’s body should be carefully done in consideration of the risk of air embolism or hemolysis.

Table 9.1
Bedside management of intradialytic hypotension

1. Trendelenburg position

2. Nasal oxygen supply

3. Discontinuation of ultrafiltration

4. Blood flow reduction

5. Saline (or mannitol) administration

6. Cessation of hemodialysis with cautious returning of blood to patient’s body when necessary

9.2.4 Preventive Measures for Controlling Humoral Factors General Measures

Reevaluation of Dry Weight: It is necessary to evaluate whether dry weight is set excessively low. Trial and error method by well-trained nephrologists is generally accepted. Blood volume marker such as ANP, BNP, or cGMP, bioimpedance analysis , and the measurement of inferior vena cava by ultrasound or echocardiograph have been reported helpful.

Restriction of Interdialytic Weight Gain: UF amount should not exceed 3 kg per session. If weight gain is more than this, education for water and diet uptake should be intensified targeting weight gain not exceeding 1 kg per day and/or not exceeding 2 kg for interdialytic period. To prevent excessive weight gain, salt restriction should be emphasized rather than water itself (Agarwal and Weir 2010).

Increasing Dialysis Duration and Frequency: If the restriction of interdialytic weight gain is impossible, it can be considered to extend the duration of dialysis session or to increase the frequency of dialysis to minimize UF per session. Therapeutic Dialysis

Vascular refilling is an important physiological process to avoid hypovolemia during dialysis. Hypotension occurs if this process is inadequate. To achieve adequate vascular refilling, the rapidity of the osmolality change and that of water removal, i.e., UF rate, is most important. Recent dialysis machines can manipulate these two factors by adjusting dialysate sodium concentration and automatic control of ultrafiltration rate.

Sequential Dialysis (Isolated UF + Isovolemic Hemodialysis): Only ultrafiltration is performed for the initial 1 h without removing uremic molecules to keep the osmolality change minimally and to keep vascular volume. After then, hemodialysis is performed for the rest of the session to remove uremic molecules with minimal ultrafiltration . Usually 50% of target UF is achieved for the initial isolated UF time, and the rest is removed for the remaining 3 h of hemodialysis (Fig. 9.2).


Fig. 9.2
Sequential hemodialysis (HD). Rapid decrease of osmolality may interfere the vascular refilling and results in hypotension in conventional HD. In sequential HD, most of target water removal is achieved during initial isolated UF period with minimal osmolality change. Uremic molecules are removed during latter hemodialysis period

Sodium Modeling: It is a method to maintain plasma osmolality, and thus to prevent hypotension by keeping dialysate sodium concentration higher than conventional HD (Zhou et al. 2006). Constant high sodium dialysis higher than 138 mmol/L frequently causes thirst and interdialytic weight gain. Sodium modeling dialysis is introduced to avoid these side effects. In sodium modeling dialysis, dialysate sodium concentration is initially high and decreased to normal or lower level linearly (linear sodium profiling) or stepwise (stepwise sodium profiling) to avoid patients’ hypernatremia after finish of dialysis (Fig. 9.3). In general, it has been regarded to be effective and easy method, but thirst, excessive interdialytic weight gain, and hypertension are still limitation (Song et al. 2002, 2005). Recently, UF profiling is used in combination with sodium profiling (so-called combined sodium and ultrafiltration profiling ) to maximize water removal and minimize hypovolemia (Fig. 9.4). Combination with cool temperature dialysis also is a convenient and effective option (K/DOQI 2005; van Der Sande et al. 2000).


Fig. 9.3
Sodium modeling . In constant high sodium dialysis, dialysate sodium level is maintained higher than usual level, 138 mmol/L. In linear and stepwise sodium profiling, dialysate sodium concentration begins with high level and ends with normal or lower level


Fig. 9.4
Combined sodium and ultrafiltration profiling. UF rate is profiled in parallel with sodium concertation to maximize water removal and minimize hypovolemia

Ultrafiltration Profiling: If vascular refilling rate does not match UF rate, blood volume will drop too early during the dialysis session. UF profiling is a method manipulating UF rate during the session to give the time for vascular refilling and to avoid intradialytic hypotension (Fig. 9.5). Reducing the UF rate sequentially or stepwise and keeping zero at the end of session is done to avoid the vascular refilling failure that usually occurs in the latter part of dialysis. Another method is the periodical stopping of UF, which gives enough time for vascular refilling.


Fig. 9.5
Ultrafiltration profiling. Typical constant UF may cause transient significant hypotension in the patient with impaired plasma refilling ability (a). Stepwise lowering UF can avoid vascular refilling failure that usually occurs in the latter part of dialysis (b). Periodical stopping of UF can give the periodic chance for vascular refilling

Online Blood Volume Monitor and Automated Biofeedback-Controlled Dialysis: Online blood volume (BV) monitor can monitor real-time BV change. It is possible by measuring the hematocrit using optic or ultrasonic devices. Some recent dialysis machines are equipped with these devices, for example, Hemocontrol® (Fig. 9.6) or BVM® (Basile et al. 2001; Leypoldt and Lindsay 1999). Automated biofeedback-controlled dialysis system is a proprietary technology using “fuzzy logic” system (Mancini et al. 2007). These machines can automatically adjust dialysate conductivity, i.e., practically sodium concentration, and UF tracking on-line BV change (Deziel et al. 2007; Colì et al. 2011). This system appears to improve patients’ tolerability to dialysis, but data is inconsistent and still insufficient. Further work is needed before it can be routinely recommended for intradialytic hypotension-prone patients.


Fig. 9.6
Hemocontrol® continuous intradialytic recording of the blood volume obtained during a biofeedback system (upper panel). Middle and lower panels represent the intradialytic profiles of UF rate (UFR) and dialysate conductivity (DC), respectively, leading to the blood volume changes (∆BV) shown in the upper panel (Basile et al. 2001) (need permission from Basile C, Giordano R, Vernaglione L, Montanaro A, De Maio P, De Padova F. Efficacy and safety of haemodialysis treatment with the hemocontrol biofeedback system: a prospective medium-term study. Nephrol Dial Transplant 2001;16(2):328–34)

9.2.5 Preventive Measures for Controlling Vascular Factors Predialysis Antihypertensive Medication

Antihypertensive agents taken before dialysis are a common cause of intradialytic hypotension . Careful evaluation of the association of the timing and dosing of antihypertensive drugs and inter-, pre-, and postdialytic blood pressure is required in intradialytic hypotension-prone patients. If the association is suspected, it should be considered to skip or reduce the dose of predialytic antihypertensive drugs. It also can be helpful to move the prescription time of antihypertensive drug to evening. Refraining from Food Intake During Dialysis

The food intake during dialysis increases the splanchnic blood flow . Consequently, the reduced blood flow in the core vasculatures may result in hypovolemia. Food intake should be refrained before and during the dialysis session in intradialytic hypotension-prone patients. Bicarbonate Dialysate

Acetate dialysate was a culprit causing frequently dialysis reaction and intradialytic hypotension . Although it is now rarely used, acetate may be present in a small quantity, approximately 3 mmol/L, in some bicarbonate-based dialysates. There have been some reports that acetate, even in small quantities, may cause intradialytic hypotension (Bolasco et al. 2011; Agarwal 2012). Cool Temperature Hemodialysis

When circulating blood volume is reduced, superficial vasculatures are constricted to redistribute blood flow to the core blood flow to compensate central hypovolemia by the sympathetic nervous system activation. During this process, core body temperature is elevated. In hypotension-prone patients, conventional dialysate temperature of 36–37 °C may elevate the core temperature too high to cause paradoxical superficial vasodilatation and hypotension (Fig. 9.7). Cool temperature dialysis with dialysate temperature of 34–36 °C is helpful to avoid intradialytic hypotension in these patients. A recent study suggested cool temperature hemodialysis also ameliorates subclinical myocardial ischemia (Selby et al. 2006). Recent biofeedback technology makes it possible to maintain patient’s body temperature constantly (isothermic hemodialysis) and to profile the temperature as needed (dialysate temperature profile). Some authors reported that it is most effective when sodium modeling is combined with cool temperature dialysis (K/DOQI 2005; van Der Sande et al. 2000).


Fig. 9.7
Reduced blood volume by UF induces the decrease of superficial blood flow and redistribution of blood to body core, which is necessary to maintain hemodynamic stability. Elevated core temperature may paradoxically cause superficial vasodilatation and hypotension in hypotension-prone patients. Cool temperature dialysis can stop the latter response Drug Therapy

Midodrine: Patients with advanced stage of diabetes, long-term uremia , and/or old age do not respond to other methods due to severe autonomic nervous system dysfunction. In these intractable patients, alpha-1 adrenergic agonist, midodrine, can be helpful at a dose of 10 mg orally 30 min before dialysis session. Midodrine is effectively cleared, and its half-life is reduced to 1.4 h by hemodialysis. Since it has specificity for alpha-1 receptor, cardiac or central nervous system effect is minimal. Common side effects are nausea , heartburn, piloerection, scalp itching or tingling, urinary urgency, headache, nervousness, and sleep disturbance. Long-term use has been associated with supine systolic hypertension in less than 10% of patients, which warrants cessation of therapy (Jankovic et al. 1993). The combination of cool dialysate and midodrine may be helpful to decrease intradialytic hypotension .

Sertraline: A selective serotonin reuptake inhibitor, sertraline, was originally used for idiopathic orthostatic hypotension and neurocardiogenic syncope. Administration of 50–100 mg a day for 4–6 weeks has been reported to improve autonomic function neurocardiogenic syncope. It has been reported that 4–6 weeks of therapy improves the hemodynamic parameters in patients with intradialytic hypotension (Dheenan et al. 1998; Yalcin et al. 2002, 2003). It can be considered for the patient showing clue of paradoxical sympathetic withdrawal, i.e., sudden decrease in blood pressure with bradycardia.

l -carnitine: Carnitine deficiency is associated with several metabolic defects, defined as dialysis-related carnitine disorders, including intradialytic hypotension (Bellinghieri et al. 2003). l-carnitine therapy at 20 mg/kg into the dialysis venous port with each session reduces frequency of intradialytic hypotension and muscle cramps (Ahmad et al. 1990; Riley et al. 1997). It is also effective in improving the quality of life in some patients. Mechanism of beneficial effect is not clear, but it could be due to improvement in vascular smooth muscle and cardiac muscle function.

Caffeine: Caffeine is an adenosine receptor antagonist. It may be helpful when the cause of intradialytic hypotension is increase of adenosine, an endogenous vasodilator, which is released due to anemia or organ ischemia.

Vasopressin: There is a report that the infusion of vasopressin infusion (0.3 mU/kg/min) reduces frequency of intradialytic hypotension and potentiates the removal of fluid although the subject number is too small to be conclusive (Santoro 2007).

9.2.6 Preventive Measures for Controlling Cardiac Factors Identification and Treatment of the Underlying Cardiac Diseases

It is important to check the presence of underlying heart diseases, such as congestive heart failure , arrhythmias , or ischemic heart disease. When it is found, appropriate treatment is mandatory. In particular, it is necessary to check for pericardial diseases. Correction of Anemia

According to K/DOQI guidelines , hemoglobin level should be maintained to 11–2 g/dL. It is an important and effective way to decrease vasodilation due to hypoxia . It also improves cardiovascular and myocardial function, and thus prevents hypotension. Use of High Calcium and Low Magnesium Dialysate

High calcium dialysate (dialysate calcium concentration of 1.5 mmol/L) showed improvement of cardiac contractility and vasoconstriction in the patients with left ventricular ejection fraction of 40% or less or with NYHC III–IV heart failure as compared to low calcium dialysate (1.25 mmol/L) (Gabutti et al. 2009). Low magnesium dialysate (0.25 mmol/L) also may be helpful to improve heart function. The use of these dialysate can be considered for the patient with cardiac dysfunction. It should be made known that hypercalcemia may decrease bone turnover in some patients with the use of dialysate calcium of 1.5 mmol/L or more.

9.2.7 Stratified Approach to Prevent Intradialytic Hypotension

Recently, EBPG guideline has summarized the stratified approach to prevent hemodynamic instability and intradialytic hypotension as in Table 9.2, which can be easily practiced in general dialysis centers (Kooman et al. 2007).

Table 9.2
Stratified approach to prevent intradialytic hypotension from EBPG guideline on hemodynamic instability

First-line approach

• Dietary counselling (sodium restriction)

• Refraining from food intake during dialysis

• Clinical reassessment of dry weight

• Use of bicarbonate as dialysis buffer

• Use of a dialysate temperature of 36.5 °C

• Check dosing and timing of antihypertensive agents

Second-line approach

• Try objective methods to assess dry weight

• Perform cardiac evaluation

• Gradual reduction of dialysate temperature from 36.5 °C downward (lowest 35 °C) or isothermic treatment (possible alternative: convective treatments)

• Consider individualized blood volume controlled feedback

• Prolong dialysis time and/or increase dialysis frequency

• Prescribe a dialysate calcium concentration of 1.5 mmol/L

Third-line approach (only if other treatment options have failed)

• Consider midodrine

• Consider l-carnitine supplementation

• Consider peritoneal dialysis

9.2.8 Resistant Intradialytic Hypotension

K/DOQI Comments for Resistant Intradialytic Hypotension: K/DOQI guideline advised the use of combinations of modalities for resistant cases of intradialytic hypotension as below (K/DOQI 2005):

  1. 1.

    Combination of midodrine and dialysate temperature profiling or cold temperature hemodialysis


  2. 2.

    Combination of dialysate temperature profiling or cold temperature hemodialysis and high calcium dialysate


  3. 3.

    Combination of dialysate temperature modeling or cold temperature hemodialysis and sodium modeling


Convective Renal Replacement Therapy: Convective renal replacement therapy such as hemodiafiltration and hemofiltration may reduce the incidence of intradialytic hypotension in patients receiving hemodialysis in long term (Agarwal 2012). A recent randomized trial with 70 hemodialysis patients showed that the frequency of intradialytic hypotension fell from 9.8 to 8% in hemofiltration and from 10.6 to 5.2% in hemodiafiltration. The odd ratio for risk reduction in symptomatic intradialytic hypotension for hemofiltration was 0.69 and for hemodiafiltration was 0.6 (Locatelli et al. 2010). The benefits are thought to be due to improved plasma refill and neurohormonal response to loss of intravascular volume (van Der Sande et al. 2000).

Extended Daily Dialysis or Nocturnal Hemodialysis: These modalities of dialysis therapy have definitely the advantage of slow ultrafiltration rate. However, there is limited data about the benefit of extended daily dialysis or nocturnal hemodialysis . Furthermore, clinical studies are needed to prove the cost-effectiveness of these modalities in the treatment of intradialytic hypotension .

9.3 Other Common Complications

Besides intradialytic hypotension , frequent complications of hemodialysis include postdialysis fatigue syndrome (up to 33%), muscle spasms (5–20%), nausea and vomiting (5–15%), headache (5%), chest pain (2–5%), back pain (2–5%), pruritus (5%), and pyrogenic reaction (1%) in order of frequency. In addition, up to half of dialysis patients still show the uncontrolled hypertension (dialysis-refractory or intradialytic hypertension).

9.3.1 Postdialysis Fatigue Syndrome

Nonspecific fatigue and malaise appear in about 33% of dialysis patients (Abuelo et al. 1993). Possible causes include reduced cardiac output, peripheral vascular diseases, depressed mood, poor conditioning, postdialytic hypoglycemia , hypokalemia , mild uremic encephalopathy, neuropathy, and uremic myopathy.

It tends to be more frequent with non-glucose or acetate dialysate and to be reduced with glucose-containing or bicarbonate dialysate. Complement activation or cytokine production by bioincompatibility of the dialyzer has also been thought to be related, but the exchange of cuprophan with polysulfone dialyzer failed to show symptom improvement in double-blind studies (Group BCDS 1991; Sklar et al. 1998). Carnitine deficiency also causes malaise. Supplementing of L-carnitine has shown improvement of well-being sensation (Lindsay et al. 2006).

9.3.2 Muscle Cramps Clinical Manifestations

Muscle cramps occur at a frequency of about 5–20%. It usually appears within the first month of starting hemodialysis treatment in the elderly, anxious patients, and non-diabetic patients. Symptom appears typically in the legs and/or hands and arms. It usually manifests in the latter half of hemodialysis session, in which skeletal muscle ischemia occurs after water is removed maximally by UF. It may disappear spontaneously within 10 min but sometime last several hours after dialysis. It is one of the common causes of the premature discontinuation of hemodialysis. Etiology and Pathogenic Mechanism

Tissue hypoperfusion by plasma hypovolemia and rapid decrease of osmolality is thought to be the two main pathogenic factors (Canzanello and Burkart 1992). Predisposing clinical conditions include hypotension, excessive interdialytic weight gain, excessively low dry weight, excessive water removal during dialysis, and low dialysate sodium concentration. Electrolyte imbalance such as hypomagnesemia or hypocalcemia , uremic myopathy, peripheral neuropathy, peripheral vascular diseases, and sometimes alcohol or drugs such as clofibrate or nicotinic acid may also predispose to muscle cramps. Management and Prevention

Education should be intensified to avoid excessive interdialytic weight gain. The daily weight gain should not exceed 1 kg. Salt restriction should be more focused than water restriction itself. It has been reported that enalapril, at the dose of 5 mg orally twice a week, may reduce weight gain by suppressing the angiotensin II-mediated thirst (Oldenburg et al. 1988). In patients who show no apparent signs of volume overload , it can be considered to elevate dry weight by 0.5 kg. Bicarbonate dialysate reduces the frequency of muscle cramps comparing to acetate dialysate. Sodium modeling is reported helpful by avoiding acute decrease of osmolality.

Infusion of hypertonic solutions including 15–20 mL of 23.5% hypertonic saline, 50–100 mL of 25% mannitol, or 25–50 mL of 50% dextrose water can be administered to relieve the cramp (Canzanello et al. 1991). Since high sodium solution may induce sodium load, thirst, and interdialytic weight gain, glucose solution may be a better choice except for diabetic patients. Oral quinine sulfate at the dose of 325 mg at the initiation of dialysis or oxazepam 5–10 mg 2 h before dialysis has been reported to reduce the frequency of muscle cramp (Kaji et al. 1976). Stretch exercise targeting at the affected muscles may be effective during dialysis (Sherman et al. 2015). l-carnitine, vitamin E (400 IU), prazosin, nifedipine, phenytoin, carbamazepine, amitriptyline, and gabapentin have been reported to be effective in some reports.

9.3.3 Restless Leg Syndrome Clinical Manifestations

Restless leg syndrome is typically characterized by paresthesia, drawing and crawling sensation of legs and claves. Patients experience insomnia because of a sense of discomfort and suffer from anxiety and depression. Diabetic or uremic neuropathy, anxiety, and progressive vascular disorders should be excluded. It can be differentiated from other types of peripheral neuropathy that it occurs while resting or in lying positions, such as during dialysis session, and is temporarily subsided by the movement of legs. Some patients also complain of pain near the same site. In general, restless leg syndrome tends to persist lifelong once it appears. It usually disappears after kidney transplantation. Restless leg syndrome of predialysis patients is improved within a few weeks of the initiation of dialysis therapy. Etiology and Pathogenic Mechanism

Electromyography and nerve conduction test usually do not show any remarkable findings. The exact cause is unknown but believed to be associated with uremic toxins since it has been reported that severe restless leg syndrome is relieved by the initiation of dialysis therapy or kidney transplantation (Winkelmann et al. 2002). Management and Prevention

Dialysis adequacy should also be checked. When intractable, benzodiazepines, opiates, and carbamazepine can be administered. Clonazepam acts long and can cause sleeping tendency during the day. Shorter half-life benzodiazepines such as temazepam may be better and tolerable. Opiates may be effective but can lead to abuse and tolerance. Carbamazepine or levodopa has been used successfully but tolerance occurs quickly too. Therefore, some authors prefer the alternative use of these pharmacologically unrelated drugs with 1 or 2 week’s interval to avoid tolerance.

Recently, gabapentin at dose of 200–300 mg after dialysis has been reported effective to improve restless leg syndrome (Thorp et al. 2001). Dopamine receptor antagonists, pramipexole (Montplaisir et al. 1999) and ropinirole (Pellecchia et al. 2004), have showed effectiveness. For the patients not responding to the pharmacological treatments, TENS (transcutaneous electric nerve stimulation) can be an option although sufficient data are not yet reported.

9.3.4 Nausea and Vomiting Clinical Manifestations

Nausea and vomiting are typical uremic symptoms and improved after the initiation of dialysis therapy. However, they continue or newly occur in about 10% of patients even with dialysis. Nausea and vomiting are usually nonspecific manifestations of various pathophysiological processes. Etiology and Pathogenic Mechanism

Usually they appear in association with intradialytic hypotension and may also be the combined manifestation of dialysis disequilibrium syndrome or dialysis reactions. Excessive accumulation of uremic toxins or the electrolyte imbalance may cause nausea and vomiting. If they appear unrelated to dialysis session, adequacy of dialysis or electrolytes level such as calcium should be checked. If there is no reasonable reason, gastroenterological evaluation should be considered.

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Mar 12, 2018 | Posted by in NEPHROLOGY | Comments Off on Complications of Hemodialysis

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