EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: In this study, we examined the history of sleep disorders in chronic kidney disease, 60 years after the advent of hemodialysis and renal transplant of genetically nonrelated organs, which have spurred a critical mass of data.
Materials and Methods: We analyzed selected literature on sleep disorders in chronic kidney disease from 1959 onward.
Results: Sleep disturbances are present in the general population. They cause loss of renal function and progressive nephron loss. Insomnia, sleep apnea, restless leg syndrome, and periodic limb movements represent sleep disturbances in chronic kidney disease. These symptoms manifest early in chronic kidney disease and are a rule in patients on
dialysis and kidney transplant recipients. Sleep disturbances cause fatigue, excessive daily sleepiness, impaired daytime function, impaired health-related quality of life, increased morbidity, and increased mortality.
Conclusions: Sleep disorders affect most patients with chronic kidney disease. No ascertained pharmacological therapy exists, and even a successful transplant
does not totally restore a refreshing sleep. Longer nocturnal hemodialysis is of benefit. Sleep apnea may be cured with continuous positive airway pressure.

Key words : Dialysis, Kidney transplant, Renal transplantation, Sleep disturbances

In the 60 years that have elapsed since the first renal transplant between genetically nonrelated donors and the introduction of effective hemodialysis treatment, a plethora of data on sleep disorders in renal disease has accumulated that can now be scrutinized through the eyes of the historian of nephrology, rather than with the purposes of writing a review. Characterizing such disorders is no small feat but a network of crucial events and curious scientists, the people, and the facts that made history.

To understand the importance of the problem, a systematic review and meta-analysis¹ were conducted on 3708 articles published between January 1, 1990, and September 28, 2018. There were a total of 45 716 patients either with chronic kidney disease (CKD) or treated with hemodialysis, peritoneal dialysis, and transplant. A total of 93 articles were selected with 62 on poor sleep that included 21 180 patients and 31 on insomnia that included 17 010 patients.

Prevalence of poor sleep was 59% in CKD patients, 68% in patients on hemodialysis, 67% in patients on peritoneal dialysis, and 46% in transplant recipients.¹ Corresponding prevalence for insomnia was 48% in CKD patients, 46% in hemodialysis patients, 61% in peritoneal dialysis patients, and 26% in transplant recipients (Table 1).

Sleep disorders in CKD include (1) insomnia with a prevalence of 80% to 100% but 4% to 29% in the general population; (2) sleep apnea syndrome with a prevalence of 17% to 53% but 3% to 7% in the general population; (3) central sleep apnea; (4) restless leg syndrome (RLS), which affects 26% of CKD patients but only 15% of the general population; and (5) periodic limb movements, which can affect up to 70% of the general population.

Start of the History

Sleeping, waking, and uremia attracted the attention of physicians well before the advent of dialysis and transplantation. George Schreiner in 19592 described the uremic patient’s drowsiness during the day, associated with insomnia at night, and their atypical response to sedatives.¹ In 1963, Gonzales and colle-agues were the first to report insomnia in hemodialysis patients and hypothesized that it was of functional origin.³ However, in 1965, Shea and colleagues noted that “soporific effects of dialysis occurred in every patient unless the patient was particularly anxious.”⁴ Passouant and colleagues were the first to use objective methodology (electroencephalographic recordings). Before dialysis, they found that the total sleep duration was diminished, with myoclonic jerks and periods of wakefulness occurring throughout the night. REM sleep was diminished and occurred at irregular intervals. After dialysis, sleep cycles became regular, suggesting that dialysis could completely restore the sleeping disorders.⁵

Daly and Hassall in 1970 reported on sleep maintenance hemodialysis. From their study, subjective estimates of sleep did not show differences between patients treated at home or in the hospital, by day or at night. The accumulation of metabolites between dialyses had no apparent effect. They suggested a psychological rather than a metabolic cause of insomnia in patients on dialysis.⁶

Reichsman and Levy performed the first longitu-dinal study in 1972.⁷ Treatment did not improve sleeping disorders in patients on dialysis. Some years later, Levy coined the term psychonephrology, utilizing the Greek stems psyche (mind) and nephros (kidney), to describe studies of the stresses of the various treatments, the complex and demanding medical regimen, the dependency of patients, and the losses that they encounter.⁸

Sleep Disorders in Chronic Kidney Disease

Cross-sectional studies
Sleep disorders are highly prevalent and occur early^9-14 in CKD (Table 2). Iliescu and colleagues⁹ were the first to disclose a disrupted sleep in 53% of CKD patients by means of the Pittsburgh Sleep Quality Index (PSQI) in patients not needing dialysis (grade IV CKD). The study did not support a direct relation between prevalence of sleep disorders and progression of kidney disease and hypothesized a psychological explanation and noted that 30.2% of poor sleepers were depressed.

De Santo and colleagues^11,14 studied early CKD at the time it was diagnosed for the first time. A minority of patients at the time of CKD diagnosis did not report sleep disorders and slept a mean of 8.38 ± 1.04 hours. Most patients (89.5%) reported sleep disorders and slept a mean of 6 hours or less. At that time, they were not receiving erythropoietin, parathyroid hormone level was still normal, and the Charles Comorbidity Index was 4.1, but 1 of 3 patients (29.8%) needed sleeping pills. A high percentage of patients had insomnia. Sleep disorders in early CKD could not be defined by factors that explain sleep disorders in hemodialysis patients. However, studies on narratives suggest that it may be explained by the effects of a disease on a person who does not feel ill but receives a chronic disease diagnosis with unpredictable outcome for the quality and longevity of life. According to Kierans and Maynooth,¹⁵ the moment of diagnosis is crucial. The patient learns that his body may be ill beyond repair, with long-term loss of autonomy.

Data in Table 2 indicate that patients learn to cope with the disease over time. Thus, the prevalence of sleep disorders, cleared of the psychological component, declines and subsequently levels off high throughout CKD stages and finally affects nearly every patient treated with dialysis.

Longitudinal studies
In a group of 154 patients enrolled in a 3-year perspective longitudinal study, 78 completed the study.16 At 3 years, the mean creatinine clearance dropped by 29.3% over baseline (P < .0001) and PSQI increased significantly (P < .001). Mean arterial pressure increased by 14.5 mm Hg (P < .001), although the number of antihypertensive drugs increased significantly (31%; P < .001). Rate of poor sleepers was 50.4% at baseline and 84% at 3 years (P < .01). Depression was not studied.

In another study, 220 newly diagnosed CKD patients with a low Charles comorbidity index of 4.20 ± 2.21 and estimated glomerular filtration rate (eGFR) of 84.1 ± 11.1 mL/min/1.73 m² were followed up for 4 years under strict blood pressure monitoring.¹⁶ The PSQI and Beck Depression Inventory were measured at baseline and then at 2 and 4 years. At 4 years, patients showed no significant changes in eGFR and no patient needed erythropoietin. At baseline, 15% reported being good sleepers and 50% at follow-up completion (P < .01). Among patients in the study, 30% needed hypnotics at baseline but only 15% required this at 4 years (P < .001). At baseline, 70% of patients had Beck Depression Inventory >11, but this decreased to 30% after 4 years (P < .001). Both systolic and diastolic blood pressure levels improved significantly over time and fell within normal limits. Logistic regression analysis failed to detect significant correlations for putative factors emerging from studies on hemodialysis patients except for depression. The study indicated that chronic disease triggered sleep disorders in patients with early CKD. The high prevalence of sleep disorders in early CKD highlights the initial coping process with the disease.¹⁷

In a third study of 148 CKD patients with eGFR of 43.9 ± 14.3 mL/min2/1.73 m², CKD patients slept 28 minutes less than controls and 31% slept less than 5 hours/day. Sleep efficiency was significantly lower than in controls, whereas the fragmentation index was higher. After 2 years, eGFR was reduced by 4.9 mL/min/1.73 m² (not significant), whereas “the effect of GFR and its progression on various parameters of sleep quality did not reveal any linear pattern. Furthermore, no cogent patterns emerged that related sleep quality to stages of CKD or to the change in stages of CKD.” The longitudinal study found no differences and in general did not find the relationships expected from the cross-sectional study.¹⁸

A bidirectional link between sleep apnea and chronic kidney disease
A bidirectional link between sleep apnea and CKD exists. The prevalence of sleep apnea ranges from 3% to 7% in the general population, is 17% in patients with early CKD (eGFR >60 mL/min/1.73 m²), 41% in CKD patients with eGFR <60 mL/min/1.73 m² BSA, and 57% in patients with end-stage kidney disease.¹⁹ Progression is mediated by hypoxia, leading to tubulointerstitial injury.^20,21 Continuous positive airway pressure (CPAP) reduces hyperfilt-ration by increasing renal plasma flow and reducing filtration fraction. Long nocturnal hemodialysis can reduce the prevalence of sleep apnea, as it does the longer cycler assisted peritoneal dialysis.

Sleep Disorders in Dialysis

Patients on dialysis frequently present with sleep disorders. The prevalence of insomnia has been reported to be 49% to 93% of patients on maintenance dialysis. Sleep disorder symptoms include delayed sleep onset, night time waking, fragmented sleep, early morning awakenings, reduced sleep duration, nightmares, somnambulism, snoring, reduced sleep efficiency, and nonrefreshing sleep.

Sleep apnea is reported in up to 95.5% of patients on dialysis, with RLS and periodic limb movement reported by 20% to 80% of patients on dialysis.²² Sleep disorders predict mortality and are associated with increased systolic hypertension,²³ with a lack of blood pressure at night that is not corrected by achieving target hematocrit levels with erythropoietin. Furthermore, patients on dialysis are known to use sleeping medications. Disordered sleep is more frequent in early morning and late evening. Many factors contribute to sleep disorders in dialysis patients, including (1) demographic and social factors (age, male sex, low education, low economic conditions); (2) lifestyle factors (poor sleep hygiene, obesity, cigarette smoking, alcohol intake); (3) disease-related factors (anemia toxins, inflammation, C-reactive protein, low albumin, melatonin produc-tion and rhythm, hypertension, RAAS activation, endothelial dysfunction, oxidative stress); (4) treatment-related factors (alteration in thermoregu-lation, rapid changes in body fluids and electrolytes, machine-dependent); and (5) psychological factors (anxiety, depression).
Patients on dialysis with sleep disorders note excessive daytime sleepiness and a sense of fatigue.24,25 Excessive daytime sleepiness is found in 10% to 12% of the general population and is defined as the inability to stay awake during the day. It is associated with inadvertent dozing both during passive and active activities. Excessive daytime sleepiness is found in two-thirds of dialysis patients and is alleviated by successful kidney transplant. For excessive daytime sleepiness, many pathogenic factors have been suggested (Table 3).

Sleep Disorders in Kidney Transplant Recipients

For some time, reports on sleep disorders in patients undergoing kidney transplant procedures have been anecdotal. The first study was published in 1993 and was related to 2 patients with sleep apnea syndrome treated with CPAP while on hemodialysis. After transplant, the apnea-hypopnea index was reduced in the first patient from 80 to 9. The second hemodialysis patient, also on CPAP, had successful renal transplant and the apnea-hypopnea index was reduced from 51 to 5.²⁶

Another study described a single patient on hemodialysis with severe sleep apnea-hypopnea syndrome who recovered after a successful kidney transplant and remained free of RLS during a 9-year follow-up.²⁷ Another report²⁸ described 11 patients with RLS on hemodialysis in which RLS symptoms had cleared 1 to 21 days after transplant. Four of 11 patients were completely cleared of RLS, with no further symptoms over the 9-year follow-up. In 3 patients, RLS disappeared after transplant but reappeared with graft loss. The conclusion was that a successful kidney transplant effectively improved RLS symptoms. In a cross-sectional study, Sabbatini and colleagues²⁹ reported that, after a successful kidney transplant, 52.5% of patients were poor sleepers (PSQI >5), calling attention to the various risks involved with sleep disorders even after the best treatment (transplant) for long-lasting quality of life.

Kidney transplant recipients note excessive daily sleepiness and fatigue^30,31 and depression.³² Among transplant patients, 16% had insomnia and 17% used hypnotics. The severity of insomnia was associated with sleep structural changes, namely more slow wake sleep and higher beta power during REM sleep.³³ However, the prevalence of insomnia was no different from the general population (8%) and independent of eGFR. Insomnia was significantly and independently associated with depression, RLS, high risk for obstructive sleep apnea syndrome, and self-reported comorbidities.³⁴

Significant improvements of fluid balance, rostral fluid shift, acidosis, anemia, and load of uremic toxins have been shown after transplant. However, body fluid balance worsens at a later stage. After transplant, there is a trend to obesity in 30% to 50% of patients. In a study from Mallamaci and associates,³⁵ the Apnea Hypopnea Index was below 5 in 75% of patients, between 5 and 15 in 17%, and >15 in 8%. Findings matched those shown in the general population. The percentage of those with Apnea Hypopnea Index >15 increased over time; after a median of 3 years, the rate was 20%, more than double that of the general population. Increased rate paralleled an increase in body mass index. An independent causal relationship was found between Apnea Hypopnea Index >15 and body mass index. Sleep-disordered breathing in this population is a predictor of cardiovascular events and death.

In a prospective study of kidney transplant recipients, no association was found between obstructive sleep apnea, declining GFR, and all-cause mortality. The decline of graft function was comparable in patients with and without obstructive sleep apnea. This disagreed with data in the general population in which a strong correlation was found between GFR and prevalence of obstructive sleep apnea.³⁶ It must be stressed that melatonin concentrations are not affected by transplant.

Sleep disorders are significantly relieved by control of pruritus, pain, hyperparathyroidism, and even more by longer nocturnal hemodialysis and by longer continuous cyclic-assisted peritoneal dialysis. A successful kidney transplant is beneficial but does not represent the ultimate cure. Pharmacology for sleep disorders is still in its infancy, but its role is broadening. The use of CPAP is the treatment of choice for sleep apnea. A bright future is foreseen for cognitive behavioral therapy.³⁷

In this outline of the history of sleep disorders in CKD, we found that sleep disorders are highly prevalent at all stages of CKD and in patients undergoing dialysis. Transplantation is of benefit, although not the ultimate cure. The use of cognitive behavioral therapy for insomnia is gaining acceptance.

Volume: 21 Issue: 6 June 2023 - Supplement - 2

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