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Sleep Apnea and the Kidney

Sleep Apnea and the Kidney Purpose of Review There are some uncertainties about the interactions between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). We critically reviewed recent studies on this topic with a focus on experimental and clinical evidence of bidirectional influences between OSA and CKD, as well as the effects of treatment of either disease. Recent Findings Experimental intermittent hypoxia endangers the kidneys, possibly through activation of inflammatory path- ways and increased blood pressure. In humans, severe OSA can independently decrease kidney function. Treatment of OSA by CPAP tends to blunt kidney function decline over time, although its effect may vary. OSA may increase cardiovascular complications and mortality in patients with end-stage renal disease (ESRD), while it seems of little harm after renal transplan- tation. Excessive fluid removal may explain some of the improvements in OSA severity in ESRD and after transplantation. Summary Severe OSA and CKD do interact negatively, mainly through hypoxia and fluid retention. The moderate mutually interactive benefits that treatment of each disease exerts on the other one warrant further studies to improve patient management. . . . . Keywords Sleep-disordered breathing Renal function Hemodialysis Kidney transplantation CPAP Introduction On the one hand, OSA is associated with intermittent hyp- oxemia, increased blood pressure and sympathetic activity, Both obstructive sleep apnea (OSA) and chronic kidney dis- obesity, and metabolic alterations [3], all of which may en- ease (CKD) are common in the general population [1, 2]. An danger renal integrity and lead to increased albumin excretion interrelationship between the two diseases is increasingly rec- and accelerated decline in glomerular filtration rate (GFR) ognized, but interdisciplinary approaches to their treatment are over time. These mechanisms could lead to an increased inci- highly variable, since both are usually managed by different dence of CKD and to a more rapid trajectory towards end- medical specialists. Despite the fact that the evidence gathered stage renal disease (ESRD) in OSA patients. On the other from clinical and epidemiological observations conducted so hand, uremia and metabolic acidosis associated with renal far still leave some room to uncertainty about independent dysfunction may increase chemoreceptor reactivity and desta- interrelations between OSA and CKD, there is a large body bilize breathing patterns, predisposing patients to both ob- of biological data that support the plausibility of these structive and central apnea. Besides, fluid retention due to interactions. inefficient glomerular filtration may be followed by rostral fluid shift when assuming a recumbent posture, leading to decreased cross-sectional pharyngeal area and obstructive ap- This article is part of the Topical Collection on Sleep and Sleep Apnea at the Extremes neas, or, particularly in patients with cardiac disease, to inter- stitial lung edema, hyperventilation, and central apneas [4]. * Maria Rosaria Bonsignore Nowadays, the attention of physicians managing patients marisa.bonsignore@irib.cnr.it with OSA is mainly directed to symptoms and possible car- diovascular complications, and to a much lesser extent to the Istituto per la Ricerca e l’Innovazione Biomedica, National Research possible kidney involvement. Actually, the importance of ad- Council (CNR) of Italy, Palermo, Italy dressing renal effects of OSA is not entirely clear. Renal con- Respiratory Sleep Clinic, Dipartimento di Promozione Della Salute, sequences of OSA are less known than cardiovascular com- Materno-Infantile, Medicina Interna e Specialistica di Eccellenza “G. plications. Besides, direct evidence of the independent detri- D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy mental effects of untreated OSA, and of benefits of OSA 86 Curr Sleep Medicine Rep (2020) 6:85–93 treatment, on the kidneys is less strong compared to data ob- damage. In a complex experimental model of alanine- tained in animal experiments. As nephrologists are concerned, induced CKD followed by exposure to chronic IH, blocking screening and treatment of OSA in CKD and ESRD have not endothelin (ET)-a and ET-b receptors prevented hypertension entered general clinical practice yet. but not tissue injury [14�� ]. Conversely, Angiotensin 1–7, In this review, we summarize recent data obtained in ani- which counters the effect of Angiotensin-2, was found to blunt mal models on the pathogenesis of CKD in OSA, highlight the the effects of chronic IH on renal sympathetic activity, inflam- current evidence that may support a direct influence of OSA mation, and fibrosis [8]. Moreover, recent studies in which on kidney function, and try to account for the uncertainties and telmisartan and losartan were administered during chronic contradictory interpretations found in the current literature. In IH exposure suggested protective effects of these drugs on addition, we will examine the clinical implications of sleep- kidney injury [15, 16]. More studies are clearly needed to disordered breathing (SDB) in patients with renal disease, understand to what extent IH-induced kidney damage may paying particular attention to those with ESRD or receiving be at least partly mediated by hypertension. transplantation. We will illustrate the present knowledge on the effects of dialysis and transplantation on SDB, as well as of OSA treatment on kidney function, which are topics still requiring extensive investigation. Epidemiology of the Association Between OSA and CKD Evidence of Renal Damage in Experimental Despite unquestionable evidence of risk factors for CKD in Models of OSA OSA, the presence of confounders makes an independent link between the two conditions difficult to demonstrate in human OSA typically causes intermittent hypoxia (IH) during sleep. patients. These confounders include advanced age, obesity, Several studies in mouse and rat models assessed the impact of and especially comorbidities like arterial hypertension and IH on the kidney. A major advantage of animal models is the diabetes mellitus. Therefore, one important requirement for possibility to study the effects of IH without the confounding epidemiological studies on OSA and CKD is a large sample variables occurring in human OSA, but the IH models do not of subjects in order to adjust for multiple confounders. In provide data on the effects of intermittent hypercapnia associ- addition, ideally, the sample sizes of subjects with CKD, ated with IH in OSA. One study assessed the effects of IH and OSA (from mild to severe), and healthy controls should be IH associated with hypercapnia and suggested a possible pro- adequately balanced, which is difficult to obtain. In fact, stud- tective effect of CO on inflammatory markers, but duration of ies performed in general population samples, while showing exposure was short, warranting further study [5� ]. little or no selection bias in subjects’ recruitment, predomi- Acute exposures to IH caused minimal or no pathological nantly included healthy subjects, and the few OSA patients changes and increased renal blood flow and GFR [6]. in the sample had a mild disease with little nocturnal hypox- Conversely, chronic IH was associated with evidence of glo- emia. Conversely, studies on patients with suspected OSA merular and tubular damage [6, 7]. The pathological findings included subjects with worse risk factors for CKD and more included an increase in glomerular area, expansion of severe hypoxemia, with higher probability to show significant mesangial matrix, and increased apoptosis [7, 8]. As for func- effects of OSA on renal function, but low applicability of tional changes, increased albuminuria [7] and reduced renal results to the general population. flow, GFR, and sodium transport were found after chronic IH In the last several years, large epidemiological studies have exposures [6]. been published. Among recent cross-sectional studies on the The molecular mechanisms involved in IH-induced renal general population, a significant increase in the prevalence of injury are complex, with involvement of several pathways, SDB, considered as apnea/hypopnea index (AHI) ≥ 15/h of such as the receptor for advanced glycation end-product total sleep time (hrTST), was observed from non-CKD to (RAGE) [9] and its ligand, the high-mobility group box 1 pro- CKD stages 1–2 to CKD stage 3 subjects in the HypnoLaus tein (HMGB1) [5, 9], toll-like receptor 4 (TLR-4) [10], oxida- cohort in Swtizerland; however, CKD stage and estimated tive stress [11� ] and the NLRP3 inflammasome [12]. Blockade GFR (eGFR) quartile did not independently predict SDB of such pathways resulted in decreased tubular damage, colla- [17]. The other available cross-sectional study observed a sig- gen deposition and apoptosis, lower release of inflammatory nificant effect of AHI on CKD prevalence but, unsurprisingly, cytokines, and blunted albuminuria [9, 10, 11� , 12]. no effect of nocturnal hypoxemia: in fact, hypoxia among the Chronic IH exposure causes hypertension in rodents [8, recruited subjects was very mild [18� ]. The longitudinal study 13]. The studies on kidney function did not always monitor on the general population in the Wisconsin cohort found that blood pressure during chronic IH, raising the question about both the decline in eGFR and CKD incidence were similar in the confounding contribution of hypertension to kidney subjects with and without sleep apnea. However, patients with Curr Sleep Medicine Rep (2020) 6:85–93 87 sleep apnea, defined as AHI ≥ 15/hrTST, were few (90/855 Improvement of SDB, obtained with reduction in body fluids subjects) and oxygen saturation values were not reported [19]. by plasma ultrafiltration, may blunt such deterioration [37�� ]. Among investigations on subjects with suspected sleep ap- Recent studies have shown that, in the long term, OSA may nea, one longitudinal study demonstrated that an increased increase cardiovascular and all-cause mortality in middle-aged rate of decline in eGFR occurred when ≥ 12% of sleep time ESRD patients [39, 40]. This effect was not demonstrated in was spent with oxygen saturation (SaO ) < 90% [20�� ], a older patients who, rather the opposite, showed a lower risk of threshold uncommon in significant proportions of subjects all-cause death, myocardial infarction, and ischemic stroke of general population samples. Accordingly, a multicenter when they had been diagnosed with OSA [41]. This is in cross-sectional study on a sleep laboratory population found agreement with observations in other populations reporting a that lowest nocturnal SaO independently predicted eGFR < lower coronary and mortality risk, if not an advantage, in 60 ml/min/m [21� ]. Both these studies did not find any inde- elderly OSA patients [42, 43]. Mortality risk in middle-aged pendent effect of AHI as a risk factor for CKD. ESRD patients was related to nocturnal hypoxemia, and not to Finally, some recent longitudinal studies analyzed data tak- AHI [40], as already found in a previous small study [44]. en from registries, with the advantage of including very large number of patients with diagnosed sleep apnea and controls. Common pitfalls of these studies are that no polysomnograph- Fluid Overload, Dialysis, ic data were available, and information on continuous positive and Sleep-Disordered Breathing airway pressure (CPAP) prescription, when available, was not associated with data on actual CPAP use. Nevertheless, these Rostral shift of fluids when assuming the recumbent posture studies agreed that OSA is likely to be a risk factor for the has been identified as an important determinant of apnea in kidneys since it was associated with faster annual decline in patients with ESRD. In these patients, overnight change in eGRF [22� ] and higher incidence of CKD [23–25] and of leg fluid volume correlated with apnea/hypopnea time in acute ESRD [26� ]. studies [45]. Over an average 8-month time period, it was ob- Altogether, most epidemiological studies support an inde- served that remission of nephrotic syndrome was associated pendent association between OSA and CKD. This association with a reduction in AHI that was attributed to remission of limb primarily involves patients with severe OSA, while it is much edema [46]. Two more recent studies found that patients with a more uncertain for mild cases of sleep apnea. So far, attention high AHI had a higher extracellular fluid volume in non- has been paid mainly to the possible importance, as risk dialysis days [47] and a higher interdialytic weight gain [48]. markers, of classic polysomnographic variables, i.e., AHI Patients undergoing hemodialysis acutely reduce fluid re- and hypoxemia parameters. Future studies may explore roles tention and, at the same time, remove uremic toxins thus im- of other factors that are often altered in OSA, like 24-h blood proving their metabolic status. Interestingly, if in a non- pressure profile or insulin sensitivity. dialysis day ESRD patients are submitted to plasma ultrafil- tration, leading to fluid removal without alterations in acid base balance or plasma metabolic components, their AHI de- Sleep Apnea and ESRD creases proportionally to the reduction in extracellular fluid volume [49� ]. Such data strongly support a major role of fluid Sleep apnea is common in patients with CKD, and its preva- removal as responsible for the beneficial effect of dialysis on lence progressively increases with CKD severity [27]. Patients SDB. However, only minor, non-significant changes in AHI with ESRD show the highest prevalence, possibly because in have been reported between nights preceding and following ESRD, some risk factors for SDB, such as fluid retention and dialysis [28, 32, 50�� ]. One recent study showed that changes high chemoresponsiveness, are more common and severe than in obstructive AHI after dialysis were correlated to changes in in milder CKD. ESRD patients with OSA have higher BMI and fluid overload but confirmed that the average difference in neck circumference than those without OSA [28–30], but they AHI between nights before and after dialysis was not signifi- are thinner compared to typical OSA patients seen in sleep cant [51]. laboratories, and more rarely report typical OSA symptoms, Different results have been reported with a stable change in like heavy snoring or excessive daytime sleepiness [31–33]. dialysis regimen. After transition from conventional (three- ESRD patients report poor sleep quality, but periodic leg move- diurnal sessions per week) to nocturnal (six nights per week) ments [34]rather than SDB [35, 36] likely play a role. [50 ], as well as from continuous ambulatory peritoneal dial- However, several observations suggest that sleep apnea ysis to nocturnal dialysis [52], AHI significantly improved, may be detrimental also in patients with ESRD (Table 1). with decrease in both central and obstructive apneas. One effect of occurrence of SDB in ESRD may be an over- Nocturnal dialysis, besides better reverting physiological per- night decrease in systolic and diastolic myocardial function turbations of uremia [53], more effectively decreases sympa- [37 ], as already observed in patients with heart failure [38]. thetic activity than conventional dialysis [54]. The lower �� �� 88 Curr Sleep Medicine Rep (2020) 6:85–93 Table 1 Recent studies on effects of sleep apnea in patients with end stage renal disease (ESRD) Authors No. of subjects recruited Sleep apnea No. of subjects with OSA Follow-up duration Outcomes diagnosis Tuohy et al. [41] 184,217 patients ≥ 67 years Diagnosis based on 15,121 SDB Mean 1.6 years SDB associated with lower old starting hemodialysis ICD-9 criteria in risk of all-cause death, the 2 years myocardial infarction and before starting ischemic stroke; no effect hemodialysis on atrial fibrillation Kerns et al. [39] 558 incident hemodialysis Chart reviews of 66 OSA Mean 23.2 months OSA associated with all-cause patients, mean age 56 clinical medical and cardiovascular records available mortality and with sudden in the year prior cardiac death to dialysis initiation Inami et al. [37�� ] 15 ESRD patients Polysomnography 6 OSA 1 day (evening to Sleep apnea associated with 2CSA morning, and night overnight decrease in pre-post plasma systolic and diastolic ultrafiltration) function in ESRD; improved SDB after body fluid removal Jhamb et al. [40]Stage4–5CKD (n =88) Polysomnography 45 mild Median 9 years Relationships of mortality and ESRD (n = 92), 42 moderate with nocturnal hypoxemia, mean age 54 41 severe but not with AHI predominantly obstructive sleep apnea sympathetic activity could be associated with a greater de- Evidence of unfavorable effects of sleep apnea in transplanted crease in chemoresponsiveness, which, in turn, could contrib- patients is scant (Table 2). It relies mainly on a paper showing ute tothe improvementin SDB [55]. that subjects transplanted after 2008 who were diagnosed with Children on dialysis show poor sleep quality [56–58]and sleep apnea had a higher risk of graft loss, although their risk of prevalence of sleep-disordered breathing is estimated around death with functioning graft was not increased [63]. Three other 40% [56, 59]. One study reported higher AHI in patients com- studies, while confirming the lack of any influence of OSA [64, pared to controls [58], but another study in children on auto- 65� ], or risk of OSA [66], on mortality in transplanted patients, matic peritoneal dialysis found mild SDB in children with did not find any effect of OSA on rate of decline in eGFR [64]or ESRD [57]. In summary, positive effects of dialysis on SDB in return to dialysis or retransplantation [65� ]. Harmlessness of in adult patients with ESRD are likely, but their mechanisms sleep apnea after transplantation has been hypothesized to be a and the effects of pediatric ESRD are still incompletely consequence of the denervation of the transplanted kidneys, understood. which may blunt apnea-induced sympathetic overactivation [64, 65� ]. According to another theory, ischemic preconditioning due to recurrent apneas could determine long-term benefits in transplanted patients [65� ], as already hypothesized for ischemic Kidney Transplant and Sleep Apnea cardiac disease [42]. In transplanted children, 61% of the sample showed evidence After kidney transplantation, reversal of uremia and fluid of OSA that was moderate-severe in 38.5% and associated with overload could be expected to improve pre-existing sleep ap- uncontrolled hypertension. However, SDB was likely to be nea. However, inconsistent results have been reported about overestimated, since prevalence of obesity and metabolic abnor- the effects of transplantation on sleep apnea [60, 61]. Most of malities tended to be higher in children undergoing PSG com- the studies were on small case series and did not adequately pared to children refusing participation to the study [67]. take into account factors such as OSA severity before trans- plantation, reduction in fluid overload, or change in body weight after transplantation. One recent, relatively large, con- Effects of CPAP Therapy on Kidney Function trolled study on patients with a pretransplant AHI ≥ 15/hrTST demonstrated that after transplantation, AHI decreased pro- CPAP is the therapy of OSA that more fully prevents occur- portionally to the decrease in fluid overload, although an in- rence of SDB. Its main limitation is related to variable adher- crease in body fat tended to blunt the change in AHI [62�� ]. ence to its use, which leaves some patients incompletely Curr Sleep Medicine Rep (2020) 6:85–93 89 Table 2 Effects of sleep apnea in patients receiving kidney transplant Authors No. of subjects Sleep apnea diagnosis/ No. of subjects with Follow-up duration Outcomes recruited risk sleep apnea Szentkiralyi et al. [66] 823 adults Berlin questionnaire 226 Median 66 months OSA risk was associated with graft loss after transplant in females, but did not influence all-cause mortality Fornadi et al. [64] 100 adults Polysomnography after 18 mild Median 75 months No effect of AHI or of OSA diagnosis on transplant 11 moderate rate of decline of eGFR or on 14 severe all-cause mortality and time to death Lubas et al. [63] 322 adults Medical records 60 Up to 20 years Sleep apnea did not influence mortality documenting sleep with functioning graft but was apnea before associated with higher risk of graft transplant of after loss in patients transplanted after 2008 transplant before graft loss Tiwari et al. [65� ] 4014 adults Medical records 415 diagnosed before Median 6.1 years No influence of sleep apnea on acute documenting sleep transplant kidney rejection, return to dialysis, apnea 117 diagnosed re-transplantation or mortality after transplant treated. Its favorable effects on patients’ symptomatology are excretion was evident in morning, but not in evening, urine undiscussed, whereas benefits on other health aspects, like samples, suggesting that SDB exerts acute detrimental effects cardiovascular and metabolic manifestations, are small and that may be prevented by treatment [72]. Good compliance to still controversial [68]. CPAP therapy is necessary for a reduction in albuminuria to CPAP therapy is associated with a reduction in common occur [73, 74]. Small studies addressing GFR consistently risk factors for CKD, which could warrant an improvement in found benefits of CPAP therapy, as shown by decreased glo- kidney function. CPAP prevents nocturnal oxygen merular hyperfiltration [70, 75], blunted decline in eGFR [76], desaturations, slightly decreases blood pressure [69], and re- or even increase in eGFR [77]. One large multicenter cohort duces renal RAS activity [70] and circulating inflammatory study compared changes in eGFR over time in patients who markers including IL-18, a marker of acute kidney injury [71]. were untreated or treated by auto-CPAP or by fixed CPAP. All uncontrolled studies support a benefit of CPAP on both While in the first two groups, a larger eGFR decline was albumin excretion and GFR. The decrease in albumin observed in the patients who had a longer follow-up, eGFR remained substantially unchanged irrespective of follow-up duration in those treated by fixed CPAP. The changes in eGFR after fixed, but not after auto-CPAP, significantly dif- fered from the changes after no OSA treatment [78� ]. In con- trast, the only RCT published so far on the effects of CPAP reported that mean changes in eGFR over time were small and did not significantly differ between patients under usual care or CPAP treatment [79� ]. However, even in this study, a non- significant trend to a better evolution of eGFR with CPAP was observed. A large interindividual difference in changes in eGFR after CPAP, which emerged in different studies [78� , 79� ], may make it difficult to clearly demonstrate independent effects of CPAP. Age of the patients, baseline CKD function and OSA severity, duration of follow-up, comorbidities, drug ther- apies, and type of CPAP treatment are some of the factors that can influence the variability in eGFR time course. Discordant results and highly variable interindividual differences have been also reported for blood pressure changes after CPAP, Fig. 1 Summary of the mechanisms by which OSA can worsen chronic and only meta-analyses on a high number of studies have been kidney disease (CKD) and end-stage renal disease (ESRD) can cause able to consistently demonstrate that CPAP decreases blood sleep-disordered breathing. OSA: obstructive sleep apnea. CSA: central sleep apnea pressure, although by a small extent [69]. Similarly, we 90 Curr Sleep Medicine Rep (2020) 6:85–93 permission directly from the copyright holder. To view a copy of this believe that a high number of studies with many patients licence, visit http://creativecommons.org/licenses/by/4.0/. would be necessary to definitely demonstrate benefits of CPAP treatment on kidney function. References Conclusions Papers of particular interest, published recently, have been highlighted as: Experimental studies underpin the existence of biologically � Of importance relevant interactions between OSA and CKD. In animals, �� Of major importance the role of intermittent hypoxia as a factor endangering kidney function is evident, although it is still unclear to what extent 1. Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, the changes observed in kidney structure and function may be Tobback N, et al. Prevalence of sleep-disordered breathing in the at least partly mediated by underlying increased blood pres- general population: the HypnoLaus study. Lancet Respir Med. sure. 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Abstract

Purpose of Review There are some uncertainties about the interactions between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). We critically reviewed recent studies on this topic with a focus on experimental and clinical evidence of bidirectional influences between OSA and CKD, as well as the effects of treatment of either disease. Recent Findings Experimental intermittent hypoxia endangers the kidneys, possibly through activation of inflammatory path- ways and increased blood pressure. In humans, severe OSA can independently decrease kidney function. Treatment of OSA by CPAP tends to blunt kidney function decline over time, although its effect may vary. OSA may increase cardiovascular complications and mortality in patients with end-stage renal disease (ESRD), while it seems of little harm after renal transplan- tation. Excessive fluid removal may explain some of the improvements in OSA severity in ESRD and after transplantation. Summary Severe OSA and CKD do interact negatively, mainly through hypoxia and fluid retention. The moderate mutually interactive benefits that treatment of each disease exerts on the other one warrant further studies to improve patient management. . . . . Keywords Sleep-disordered breathing Renal function Hemodialysis Kidney transplantation CPAP Introduction On the one hand, OSA is associated with intermittent hyp- oxemia, increased blood pressure and sympathetic activity, Both obstructive sleep apnea (OSA) and chronic kidney dis- obesity, and metabolic alterations [3], all of which may en- ease (CKD) are common in the general population [1, 2]. An danger renal integrity and lead to increased albumin excretion interrelationship between the two diseases is increasingly rec- and accelerated decline in glomerular filtration rate (GFR) ognized, but interdisciplinary approaches to their treatment are over time. These mechanisms could lead to an increased inci- highly variable, since both are usually managed by different dence of CKD and to a more rapid trajectory towards end- medical specialists. Despite the fact that the evidence gathered stage renal disease (ESRD) in OSA patients. On the other from clinical and epidemiological observations conducted so hand, uremia and metabolic acidosis associated with renal far still leave some room to uncertainty about independent dysfunction may increase chemoreceptor reactivity and desta- interrelations between OSA and CKD, there is a large body bilize breathing patterns, predisposing patients to both ob- of biological data that support the plausibility of these structive and central apnea. Besides, fluid retention due to interactions. inefficient glomerular filtration may be followed by rostral fluid shift when assuming a recumbent posture, leading to decreased cross-sectional pharyngeal area and obstructive ap- This article is part of the Topical Collection on Sleep and Sleep Apnea at the Extremes neas, or, particularly in patients with cardiac disease, to inter- stitial lung edema, hyperventilation, and central apneas [4]. * Maria Rosaria Bonsignore Nowadays, the attention of physicians managing patients marisa.bonsignore@irib.cnr.it with OSA is mainly directed to symptoms and possible car- diovascular complications, and to a much lesser extent to the Istituto per la Ricerca e l’Innovazione Biomedica, National Research possible kidney involvement. Actually, the importance of ad- Council (CNR) of Italy, Palermo, Italy dressing renal effects of OSA is not entirely clear. Renal con- Respiratory Sleep Clinic, Dipartimento di Promozione Della Salute, sequences of OSA are less known than cardiovascular com- Materno-Infantile, Medicina Interna e Specialistica di Eccellenza “G. plications. Besides, direct evidence of the independent detri- D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy mental effects of untreated OSA, and of benefits of OSA 86 Curr Sleep Medicine Rep (2020) 6:85–93 treatment, on the kidneys is less strong compared to data ob- damage. In a complex experimental model of alanine- tained in animal experiments. As nephrologists are concerned, induced CKD followed by exposure to chronic IH, blocking screening and treatment of OSA in CKD and ESRD have not endothelin (ET)-a and ET-b receptors prevented hypertension entered general clinical practice yet. but not tissue injury [14�� ]. Conversely, Angiotensin 1–7, In this review, we summarize recent data obtained in ani- which counters the effect of Angiotensin-2, was found to blunt mal models on the pathogenesis of CKD in OSA, highlight the the effects of chronic IH on renal sympathetic activity, inflam- current evidence that may support a direct influence of OSA mation, and fibrosis [8]. Moreover, recent studies in which on kidney function, and try to account for the uncertainties and telmisartan and losartan were administered during chronic contradictory interpretations found in the current literature. In IH exposure suggested protective effects of these drugs on addition, we will examine the clinical implications of sleep- kidney injury [15, 16]. More studies are clearly needed to disordered breathing (SDB) in patients with renal disease, understand to what extent IH-induced kidney damage may paying particular attention to those with ESRD or receiving be at least partly mediated by hypertension. transplantation. We will illustrate the present knowledge on the effects of dialysis and transplantation on SDB, as well as of OSA treatment on kidney function, which are topics still requiring extensive investigation. Epidemiology of the Association Between OSA and CKD Evidence of Renal Damage in Experimental Despite unquestionable evidence of risk factors for CKD in Models of OSA OSA, the presence of confounders makes an independent link between the two conditions difficult to demonstrate in human OSA typically causes intermittent hypoxia (IH) during sleep. patients. These confounders include advanced age, obesity, Several studies in mouse and rat models assessed the impact of and especially comorbidities like arterial hypertension and IH on the kidney. A major advantage of animal models is the diabetes mellitus. Therefore, one important requirement for possibility to study the effects of IH without the confounding epidemiological studies on OSA and CKD is a large sample variables occurring in human OSA, but the IH models do not of subjects in order to adjust for multiple confounders. In provide data on the effects of intermittent hypercapnia associ- addition, ideally, the sample sizes of subjects with CKD, ated with IH in OSA. One study assessed the effects of IH and OSA (from mild to severe), and healthy controls should be IH associated with hypercapnia and suggested a possible pro- adequately balanced, which is difficult to obtain. In fact, stud- tective effect of CO on inflammatory markers, but duration of ies performed in general population samples, while showing exposure was short, warranting further study [5� ]. little or no selection bias in subjects’ recruitment, predomi- Acute exposures to IH caused minimal or no pathological nantly included healthy subjects, and the few OSA patients changes and increased renal blood flow and GFR [6]. in the sample had a mild disease with little nocturnal hypox- Conversely, chronic IH was associated with evidence of glo- emia. Conversely, studies on patients with suspected OSA merular and tubular damage [6, 7]. The pathological findings included subjects with worse risk factors for CKD and more included an increase in glomerular area, expansion of severe hypoxemia, with higher probability to show significant mesangial matrix, and increased apoptosis [7, 8]. As for func- effects of OSA on renal function, but low applicability of tional changes, increased albuminuria [7] and reduced renal results to the general population. flow, GFR, and sodium transport were found after chronic IH In the last several years, large epidemiological studies have exposures [6]. been published. Among recent cross-sectional studies on the The molecular mechanisms involved in IH-induced renal general population, a significant increase in the prevalence of injury are complex, with involvement of several pathways, SDB, considered as apnea/hypopnea index (AHI) ≥ 15/h of such as the receptor for advanced glycation end-product total sleep time (hrTST), was observed from non-CKD to (RAGE) [9] and its ligand, the high-mobility group box 1 pro- CKD stages 1–2 to CKD stage 3 subjects in the HypnoLaus tein (HMGB1) [5, 9], toll-like receptor 4 (TLR-4) [10], oxida- cohort in Swtizerland; however, CKD stage and estimated tive stress [11� ] and the NLRP3 inflammasome [12]. Blockade GFR (eGFR) quartile did not independently predict SDB of such pathways resulted in decreased tubular damage, colla- [17]. The other available cross-sectional study observed a sig- gen deposition and apoptosis, lower release of inflammatory nificant effect of AHI on CKD prevalence but, unsurprisingly, cytokines, and blunted albuminuria [9, 10, 11� , 12]. no effect of nocturnal hypoxemia: in fact, hypoxia among the Chronic IH exposure causes hypertension in rodents [8, recruited subjects was very mild [18� ]. The longitudinal study 13]. The studies on kidney function did not always monitor on the general population in the Wisconsin cohort found that blood pressure during chronic IH, raising the question about both the decline in eGFR and CKD incidence were similar in the confounding contribution of hypertension to kidney subjects with and without sleep apnea. However, patients with Curr Sleep Medicine Rep (2020) 6:85–93 87 sleep apnea, defined as AHI ≥ 15/hrTST, were few (90/855 Improvement of SDB, obtained with reduction in body fluids subjects) and oxygen saturation values were not reported [19]. by plasma ultrafiltration, may blunt such deterioration [37�� ]. Among investigations on subjects with suspected sleep ap- Recent studies have shown that, in the long term, OSA may nea, one longitudinal study demonstrated that an increased increase cardiovascular and all-cause mortality in middle-aged rate of decline in eGFR occurred when ≥ 12% of sleep time ESRD patients [39, 40]. This effect was not demonstrated in was spent with oxygen saturation (SaO ) < 90% [20�� ], a older patients who, rather the opposite, showed a lower risk of threshold uncommon in significant proportions of subjects all-cause death, myocardial infarction, and ischemic stroke of general population samples. Accordingly, a multicenter when they had been diagnosed with OSA [41]. This is in cross-sectional study on a sleep laboratory population found agreement with observations in other populations reporting a that lowest nocturnal SaO independently predicted eGFR < lower coronary and mortality risk, if not an advantage, in 60 ml/min/m [21� ]. Both these studies did not find any inde- elderly OSA patients [42, 43]. Mortality risk in middle-aged pendent effect of AHI as a risk factor for CKD. ESRD patients was related to nocturnal hypoxemia, and not to Finally, some recent longitudinal studies analyzed data tak- AHI [40], as already found in a previous small study [44]. en from registries, with the advantage of including very large number of patients with diagnosed sleep apnea and controls. Common pitfalls of these studies are that no polysomnograph- Fluid Overload, Dialysis, ic data were available, and information on continuous positive and Sleep-Disordered Breathing airway pressure (CPAP) prescription, when available, was not associated with data on actual CPAP use. Nevertheless, these Rostral shift of fluids when assuming the recumbent posture studies agreed that OSA is likely to be a risk factor for the has been identified as an important determinant of apnea in kidneys since it was associated with faster annual decline in patients with ESRD. In these patients, overnight change in eGRF [22� ] and higher incidence of CKD [23–25] and of leg fluid volume correlated with apnea/hypopnea time in acute ESRD [26� ]. studies [45]. Over an average 8-month time period, it was ob- Altogether, most epidemiological studies support an inde- served that remission of nephrotic syndrome was associated pendent association between OSA and CKD. This association with a reduction in AHI that was attributed to remission of limb primarily involves patients with severe OSA, while it is much edema [46]. Two more recent studies found that patients with a more uncertain for mild cases of sleep apnea. So far, attention high AHI had a higher extracellular fluid volume in non- has been paid mainly to the possible importance, as risk dialysis days [47] and a higher interdialytic weight gain [48]. markers, of classic polysomnographic variables, i.e., AHI Patients undergoing hemodialysis acutely reduce fluid re- and hypoxemia parameters. Future studies may explore roles tention and, at the same time, remove uremic toxins thus im- of other factors that are often altered in OSA, like 24-h blood proving their metabolic status. Interestingly, if in a non- pressure profile or insulin sensitivity. dialysis day ESRD patients are submitted to plasma ultrafil- tration, leading to fluid removal without alterations in acid base balance or plasma metabolic components, their AHI de- Sleep Apnea and ESRD creases proportionally to the reduction in extracellular fluid volume [49� ]. Such data strongly support a major role of fluid Sleep apnea is common in patients with CKD, and its preva- removal as responsible for the beneficial effect of dialysis on lence progressively increases with CKD severity [27]. Patients SDB. However, only minor, non-significant changes in AHI with ESRD show the highest prevalence, possibly because in have been reported between nights preceding and following ESRD, some risk factors for SDB, such as fluid retention and dialysis [28, 32, 50�� ]. One recent study showed that changes high chemoresponsiveness, are more common and severe than in obstructive AHI after dialysis were correlated to changes in in milder CKD. ESRD patients with OSA have higher BMI and fluid overload but confirmed that the average difference in neck circumference than those without OSA [28–30], but they AHI between nights before and after dialysis was not signifi- are thinner compared to typical OSA patients seen in sleep cant [51]. laboratories, and more rarely report typical OSA symptoms, Different results have been reported with a stable change in like heavy snoring or excessive daytime sleepiness [31–33]. dialysis regimen. After transition from conventional (three- ESRD patients report poor sleep quality, but periodic leg move- diurnal sessions per week) to nocturnal (six nights per week) ments [34]rather than SDB [35, 36] likely play a role. [50 ], as well as from continuous ambulatory peritoneal dial- However, several observations suggest that sleep apnea ysis to nocturnal dialysis [52], AHI significantly improved, may be detrimental also in patients with ESRD (Table 1). with decrease in both central and obstructive apneas. One effect of occurrence of SDB in ESRD may be an over- Nocturnal dialysis, besides better reverting physiological per- night decrease in systolic and diastolic myocardial function turbations of uremia [53], more effectively decreases sympa- [37 ], as already observed in patients with heart failure [38]. thetic activity than conventional dialysis [54]. The lower �� �� 88 Curr Sleep Medicine Rep (2020) 6:85–93 Table 1 Recent studies on effects of sleep apnea in patients with end stage renal disease (ESRD) Authors No. of subjects recruited Sleep apnea No. of subjects with OSA Follow-up duration Outcomes diagnosis Tuohy et al. [41] 184,217 patients ≥ 67 years Diagnosis based on 15,121 SDB Mean 1.6 years SDB associated with lower old starting hemodialysis ICD-9 criteria in risk of all-cause death, the 2 years myocardial infarction and before starting ischemic stroke; no effect hemodialysis on atrial fibrillation Kerns et al. [39] 558 incident hemodialysis Chart reviews of 66 OSA Mean 23.2 months OSA associated with all-cause patients, mean age 56 clinical medical and cardiovascular records available mortality and with sudden in the year prior cardiac death to dialysis initiation Inami et al. [37�� ] 15 ESRD patients Polysomnography 6 OSA 1 day (evening to Sleep apnea associated with 2CSA morning, and night overnight decrease in pre-post plasma systolic and diastolic ultrafiltration) function in ESRD; improved SDB after body fluid removal Jhamb et al. [40]Stage4–5CKD (n =88) Polysomnography 45 mild Median 9 years Relationships of mortality and ESRD (n = 92), 42 moderate with nocturnal hypoxemia, mean age 54 41 severe but not with AHI predominantly obstructive sleep apnea sympathetic activity could be associated with a greater de- Evidence of unfavorable effects of sleep apnea in transplanted crease in chemoresponsiveness, which, in turn, could contrib- patients is scant (Table 2). It relies mainly on a paper showing ute tothe improvementin SDB [55]. that subjects transplanted after 2008 who were diagnosed with Children on dialysis show poor sleep quality [56–58]and sleep apnea had a higher risk of graft loss, although their risk of prevalence of sleep-disordered breathing is estimated around death with functioning graft was not increased [63]. Three other 40% [56, 59]. One study reported higher AHI in patients com- studies, while confirming the lack of any influence of OSA [64, pared to controls [58], but another study in children on auto- 65� ], or risk of OSA [66], on mortality in transplanted patients, matic peritoneal dialysis found mild SDB in children with did not find any effect of OSA on rate of decline in eGFR [64]or ESRD [57]. In summary, positive effects of dialysis on SDB in return to dialysis or retransplantation [65� ]. Harmlessness of in adult patients with ESRD are likely, but their mechanisms sleep apnea after transplantation has been hypothesized to be a and the effects of pediatric ESRD are still incompletely consequence of the denervation of the transplanted kidneys, understood. which may blunt apnea-induced sympathetic overactivation [64, 65� ]. According to another theory, ischemic preconditioning due to recurrent apneas could determine long-term benefits in transplanted patients [65� ], as already hypothesized for ischemic Kidney Transplant and Sleep Apnea cardiac disease [42]. In transplanted children, 61% of the sample showed evidence After kidney transplantation, reversal of uremia and fluid of OSA that was moderate-severe in 38.5% and associated with overload could be expected to improve pre-existing sleep ap- uncontrolled hypertension. However, SDB was likely to be nea. However, inconsistent results have been reported about overestimated, since prevalence of obesity and metabolic abnor- the effects of transplantation on sleep apnea [60, 61]. Most of malities tended to be higher in children undergoing PSG com- the studies were on small case series and did not adequately pared to children refusing participation to the study [67]. take into account factors such as OSA severity before trans- plantation, reduction in fluid overload, or change in body weight after transplantation. One recent, relatively large, con- Effects of CPAP Therapy on Kidney Function trolled study on patients with a pretransplant AHI ≥ 15/hrTST demonstrated that after transplantation, AHI decreased pro- CPAP is the therapy of OSA that more fully prevents occur- portionally to the decrease in fluid overload, although an in- rence of SDB. Its main limitation is related to variable adher- crease in body fat tended to blunt the change in AHI [62�� ]. ence to its use, which leaves some patients incompletely Curr Sleep Medicine Rep (2020) 6:85–93 89 Table 2 Effects of sleep apnea in patients receiving kidney transplant Authors No. of subjects Sleep apnea diagnosis/ No. of subjects with Follow-up duration Outcomes recruited risk sleep apnea Szentkiralyi et al. [66] 823 adults Berlin questionnaire 226 Median 66 months OSA risk was associated with graft loss after transplant in females, but did not influence all-cause mortality Fornadi et al. [64] 100 adults Polysomnography after 18 mild Median 75 months No effect of AHI or of OSA diagnosis on transplant 11 moderate rate of decline of eGFR or on 14 severe all-cause mortality and time to death Lubas et al. [63] 322 adults Medical records 60 Up to 20 years Sleep apnea did not influence mortality documenting sleep with functioning graft but was apnea before associated with higher risk of graft transplant of after loss in patients transplanted after 2008 transplant before graft loss Tiwari et al. [65� ] 4014 adults Medical records 415 diagnosed before Median 6.1 years No influence of sleep apnea on acute documenting sleep transplant kidney rejection, return to dialysis, apnea 117 diagnosed re-transplantation or mortality after transplant treated. Its favorable effects on patients’ symptomatology are excretion was evident in morning, but not in evening, urine undiscussed, whereas benefits on other health aspects, like samples, suggesting that SDB exerts acute detrimental effects cardiovascular and metabolic manifestations, are small and that may be prevented by treatment [72]. Good compliance to still controversial [68]. CPAP therapy is necessary for a reduction in albuminuria to CPAP therapy is associated with a reduction in common occur [73, 74]. Small studies addressing GFR consistently risk factors for CKD, which could warrant an improvement in found benefits of CPAP therapy, as shown by decreased glo- kidney function. CPAP prevents nocturnal oxygen merular hyperfiltration [70, 75], blunted decline in eGFR [76], desaturations, slightly decreases blood pressure [69], and re- or even increase in eGFR [77]. One large multicenter cohort duces renal RAS activity [70] and circulating inflammatory study compared changes in eGFR over time in patients who markers including IL-18, a marker of acute kidney injury [71]. were untreated or treated by auto-CPAP or by fixed CPAP. All uncontrolled studies support a benefit of CPAP on both While in the first two groups, a larger eGFR decline was albumin excretion and GFR. The decrease in albumin observed in the patients who had a longer follow-up, eGFR remained substantially unchanged irrespective of follow-up duration in those treated by fixed CPAP. The changes in eGFR after fixed, but not after auto-CPAP, significantly dif- fered from the changes after no OSA treatment [78� ]. In con- trast, the only RCT published so far on the effects of CPAP reported that mean changes in eGFR over time were small and did not significantly differ between patients under usual care or CPAP treatment [79� ]. However, even in this study, a non- significant trend to a better evolution of eGFR with CPAP was observed. A large interindividual difference in changes in eGFR after CPAP, which emerged in different studies [78� , 79� ], may make it difficult to clearly demonstrate independent effects of CPAP. Age of the patients, baseline CKD function and OSA severity, duration of follow-up, comorbidities, drug ther- apies, and type of CPAP treatment are some of the factors that can influence the variability in eGFR time course. Discordant results and highly variable interindividual differences have been also reported for blood pressure changes after CPAP, Fig. 1 Summary of the mechanisms by which OSA can worsen chronic and only meta-analyses on a high number of studies have been kidney disease (CKD) and end-stage renal disease (ESRD) can cause able to consistently demonstrate that CPAP decreases blood sleep-disordered breathing. OSA: obstructive sleep apnea. CSA: central sleep apnea pressure, although by a small extent [69]. Similarly, we 90 Curr Sleep Medicine Rep (2020) 6:85–93 permission directly from the copyright holder. To view a copy of this believe that a high number of studies with many patients licence, visit http://creativecommons.org/licenses/by/4.0/. would be necessary to definitely demonstrate benefits of CPAP treatment on kidney function. References Conclusions Papers of particular interest, published recently, have been highlighted as: Experimental studies underpin the existence of biologically � Of importance relevant interactions between OSA and CKD. In animals, �� Of major importance the role of intermittent hypoxia as a factor endangering kidney function is evident, although it is still unclear to what extent 1. Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, the changes observed in kidney structure and function may be Tobback N, et al. Prevalence of sleep-disordered breathing in the at least partly mediated by underlying increased blood pres- general population: the HypnoLaus study. Lancet Respir Med. sure. 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