Review of clinical outcomes in nocturnal haemodialysis patients after renal transplantation

Brendan B. McCormick1, Andreas Pierratos2, Stanley Fenton1, V. Jain1, Jeffrey Zaltzman3 and Christopher T. Chan1

1Division of Nephrology, Toronto General Hospital, 2Division of Nephrology, Humber River Regional Hospital and 3Division of Nephrology, St Michael's Hospital, University of Toronto, Ontario, Canada

Correspondence and offprint requests to: Dr Christopher T. Chan, 200 Elizabeth Street, 12-EN 226, Toronto, ON M5G 2C4, Canada. Email: christopher.chan{at}uhn.on.ca



   Abstract
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 
Background. Nocturnal haemodialysis (NHD) is a novel form of haemodialysis therapy that is associated with improved blood pressure control when compared to conventional haemodialysis (CHD). Current studies suggest that NHD lowers blood pressure through a decrease in peripheral resistance. The graft and blood pressure outcomes of NHD patients who undergo renal transplantation are unknown.

Methods. We reviewed the renal allograft and blood pressure outcomes of 15 NHD patients who underwent renal transplantation. An age and vintage matched cohort of 29 CHD patients was used as controls.

Results. The rate of delayed graft function (DGF) tended to be higher in the NHD group compared to the CHD group (64 vs 41%, P = 0.15), however the 1-year graft function (53±6 vs 59±5 ml/min, P = 0.426) and graft survival (92 vs 95%, P = 0.751) were similar. Intra-operatively, NHD patients had lower minimum systolic (92±5 vs 109±4, P = 0.03) and diastolic (48±3 vs 64±2, P = 0.02) blood pressures in comparison to the CHD cohort. Pathologically, acute tubular necrosis accounted for 100% of DGF in the NHD group in contrast to 75% in the CHD population (P = 0.01). Pre-transplant mean systolic BP (sBP) was significantly lower in the NHD group compared to the CHD group (113±6 vs 145±10 mmHg, P<0.001). At 12 months post-transplant, mean sBP increased from baseline in the NHD group ({triangleup}sBP 22±7 mmHg, P = 0.009) while in the CHD group mean sBP fell ({triangleup}sBP –14±5 mmHg, P = 0.014). Mean arterial and diastolic BP exhibited similar changes. These trends persisted after 24 months of post-transplant follow-up.

Conclusions. One-year graft outcomes and blood pressures are similar for NHD and CHD patients who undergo renal transplantation. Unlike CHD patients, NHD patients experienced a significant fall in their intra-operative blood pressures, which likely contributed towards the delayed graft function in this cohort of patients. Further prospective studies are needed to examine the underlying differences in haemodynamics and long-term graft survival between the two renal replacement modalities.

Keywords: blood pressure; home haemodialysis; nocturnal home haemodialysis; renal transplantation



   Background
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 
Home nocturnal haemodialysis (NHD) is an increasingly popular form of renal replacement therapy. It involves nightly prolonged haemodialysis treatments performed at home with reduced blood pump speed and reduced rate of dialysate flow. Pioneered in the early 1990s in Toronto, it has gained worldwide recognition due to certain clear advantages over conventional haemodialysis (CHD) therapy [1]. Substantial improvement in blood pressure control secondary to increased peripheral vasodilation [2], and associated regression in left ventricular hypertrophy [3] and restoration of impaired left ventricular ejection fraction [4], have been reported with conversion of patients from CHD to NHD. NHD has also been shown to result in improvement in phosphate control without the use of phosphate binders [5], improvement in sleep apnea [6] and improvement in quality of life [7]. Whether these advantages translate into reduced mortality has yet to be determined. Renal transplantation, however, has been shown to clearly improve quality of life and reduce mortality compared to conventional dialysis therapy [8]. Given the established mortality benefit with transplantation, our practice has been to recommend that all end-stage renal disease patients (NHD and CHD) without a medical contra-indication be considered for renal transplantation.

It is not known if NHD patients have equivalent transplant outcomes compared with CHD patients. It is known that dialysis modality may affect transplant outcomes as comparative studies of haemodialysis (HD) and peritoneal dialysis (PD) patients have suggested that PD patients have lower rates of delayed graft function (DGF) [9,10] but have similar long term graft outcomes [11]. It is hypothesized that PD patients may have expanded extracellular fluid (ECF) volume compared with HD patients and that this may reduce the risk of DGF. It is unknown whether the described haemodynamic differences between NHD and CHD patients will predispose to differing short term graft outcomes.

This early retrospective review of our centres’ results with renal transplantation in NHD patients was undertaken to assess whether there were any observable short- or medium-term effects of the lower blood pressure and putative vasodilated state on graft outcomes when compared to the results in transplanted CHD patients. The short-term outcome of interest is DGF, and the medium-term outcomes of interest are 1-year graft function and graft survival. Our second objective is to compare the natural evolution in blood pressure post-transplant in NHD and CHD patients to determine if withdrawal of NHD therapy is associated with deterioration in blood pressure control.



   Subjects and methods
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 
The study protocol was approved by the research ethics boards at all three participating centres [Humber River Regional Hospital (HRRH), St Michael's Hospital (SMH) and Toronto General Hospital (TGH)].

Subjects included all Toronto-based patients who had performed home NHD for at least 3 months immediately prior to their kidney transplant. NHD is funded as a demonstration project by the Ontario Ministry of Health. Patients are referred to the programme by their attending nephrologist and their eligibility determined after an interview with a NHD nephrologist and nurse specialist. Patients may enter the programme either directly from pre-dialysis clinic or, more commonly, transfer from either in-centre haemodialysis or home peritoneal dialysis. They are followed at either of two centres in Toronto that provide NHD: HRRH and the TGH. The disposition of every patient who had successfully completed NHD training between April 1994 and November 2002 was reviewed, and those who had subsequently received a kidney or kidney–pancreas transplant were identified. All transplanted patients were contacted, and the site of their ongoing transplant or dialysis care was determined. Two centres in Toronto provide routine post-transplant care for adult patients: TGH and SMH.

Pre-transplant blood pressure (BP), weight, and number of vasoactive medications were determined by review of the clinic or hospital record immediately preceding the transplant. Blood pressure was taken by the clinic nurse while the patient was seated and medication profile was reviewed by the same nurse. Ambulatory blood pressure measurements were not routinely performed. Post-transplant outcome (DGF vs no DGF) was determined from a review of the hospital chart. DGF was defined as the need for haemodialysis in the immediate period (0–72 h) after kidney transplantation. Intra-operative blood pressures were determined by review of the anaesthetic record. Renal transplant biopsy was performed if DGF did not resolve. Pathological diagnosis of DGF was identified and reviewed systematically for all patients. By policy, calcineurin antagonist (i.e. cyclosporine or tacrolimus) was withheld if DGF occurred and was started upon resolution of DGF. Blood pressure, weight, vasoactive medication profile and serum creatinine post-transplant were assessed by review of the outpatient transplant clinic chart at 6, 12 and 24 months post-transplant. Blood pressures were taken by the clinic nurse while the patient was seated, and the medication profile was recorded by the same nurse.

Control patients were drawn from patients who received a kidney or kidney–pancreas transplant at TGH during the period of interest. Controls were matched to patients by age (within 5 years), era of transplant (within 6 months), duration of end-stage renal disease (within 5 years) and type of transplant (cadaveric kidney, cadaveric kidney–pancreas, living donor kidney). Where possible, two controls were chosen for each subject. Identical clinical variables were obtained for the control cohort as outlined above.

Data are presented as mean±standard error. A Student's paired t-test was applied to analyse within group comparisons and an unpaired t-test was used for between group comparisons for normally distributed variables. Non-normally distributed variables are presented as median±25th to 75th percentile, or interquartile range (IQR). A Mann–Whitney U rank sum test was used for abnormally distributed variables. A two-tailed P-value<0.05 was employed to determine significance.



   Results
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 
Review of all 114 patients who successfully performed NHD revealed that 16 (14%) had subsequently received a renal transplant. One patient had been switched back to CHD for 2 weeks prior to living donor transplantation and was excluded from the analysis. All 15 patients had previously been treated with CHD prior to entering the NHD programme. Duration of follow-up of subjects varied from 1 to 68 months with a mean follow-up of 25 months. Duration of last renal replacement therapy session to time of renal transplant tended to be shorter in the NHD group (range: 6–12 h) vs the CHD group (12–24 h, P = 0.06). The demographic features of the 15 subjects and the 29 matched controls are shown in Table 1.


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Table 1. Demographic features

 
There was a trend towards a higher rate of DGF with cadaveric kidney transplantation among those patients previously treated with NHD compared to those treated with CHD (64 vs 41%, P = 0.15). As shown in Table 2, there were no significant differences in traditional risk factors for DGF between the two groups. However, intra-operative blood pressures differed significantly between the two groups. Mean maximum (126±4 vs 144±4 mmHg, P = 0.02) and minimum (92±5 vs 109±5 mmHg, P = 0.033) systolic blood pressures were significantly lower in the NHD group compared with the CHD group. Similar differences existed in mean maximum (64±3 vs 80±3 mmHg, P = 0.03) and minimum (48±3 vs 61±2 mmHg, P = 0.02) diastolic blood pressures between NHD patients and the CHD group. There was a significantly higher percentage of acute tubular necrosis accounting for the pathological diagnosis of DGF in the NHD group in contrast to the CHD cohort (100 vs 75%, P = 0.01). Acute rejections accounted for the remainder of DGF pathological diagnoses. Induction with anti-lymphocyte products was not used and all patients received calcineurin inhibitors post-transplant upon resolution of DGF. One patient in the NHD group was switched to a sirolimus-based regimen after prolonged DGF. When analysed based on era of transplantation, the rate of DGF in the earlier era (1994–1998) was not different in the NHD group compared with the CHD group (33 vs 17%, P = 0.57). The rate of DGF in the later era group (1999–2003) showed a higher trend for the NHD group compared with the CHD group (73 vs 48%, P = 0.17).


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Table 2. Delayed graft function and risk factors among cadaveric transplants

 
Twelve-month graft function as estimated by Cockcroft–Gault creatinine clearance did not differ significantly between the NHD and CHD groups (53±6 vs 59±5 l/min, P = 0.426) and 12-month graft survival was similar in both groups (92 vs 95%, P = 0.751). One graft was lost in the NHD group due to chronic allograft nephropathy. In the CHD cohort, one patient died with a functional renal allograft.

As shown in Figure 1, pre-transplant mean systolic BP (sBP) was significantly lower in the NHD group compared to the CHD group (113±6 vs 145±10 mmHg, P<0.001). The median number of antihypertensive medications per patient was also significantly lower at baseline in the NHD group [0 (IQR 0–1.0) vs 2.0 (IQR 1.0–2.0), P<0.001]. At 12 months post-transplant, mean sBP had increased from baseline in the NHD group ({triangleup}sBP 22±7 mmHg, P = 0.009) while in the CHD group mean sBP fell ({triangleup}sBP –14±5 mmHg, P = 0.014). At 12 months, the antihypertensive medication requirement per patient increased [from median 0 (IQR 0–1.0) to 1.0 (IQR 0.5–1.5), P = 0.082] in the NHD group, but remained stable in the CHD group [median 2.0 (IQR 1.0–3.0) medications]. At 12 months post-transplant, sBP was similar in the two groups (134±5 vs 127±9 mmHg, P = 0.278), but the CHD group continued to require more antihypertensive medications than the NHD group [median 2.0 (IQR 1.0–3.0) vs 1.0 (IQR 0.5–1.5), P = 0.025]. Mean arterial and diastolic BP exhibited similar trends (Figures 1 and 2). These trends persisted after 24 months of post-transplant follow-up. Mean body weight was similar in both groups pre-transplant (72.4±4.8 vs 71.2±3.7 kg, P = 0.851) and rose similarly over time in both groups (mean {triangleup}weight at 6 months, +2.7±1.9 vs +3.0±1.1 kg, P = 0.904).



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Fig. 1. Changes in systolic and diastolic blood pressures after renal transplantation. Dotted line, conventional haemodialysis cohort; solid line, nocturnal haemodialysis cohort. *Within group comparison compared to baseline value, P<0.05; **between group comparison, P<0.05.

 


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Fig. 2. Changes in mean arterial blood pressure after renal transplantation. Dotted line, conventional haemodialysis cohort; solid line, nocturnal haemodialysis cohort. *Within group comparison compared to baseline value, P<0.05; **between group comparison, P<0.05.

 


   Discussion
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 
Hypertension and delayed graft function are risk factors contributing to the development of chronic allograft nephropathy [12]. This study is the first to report that graft and blood pressure outcomes may be different in transplanted NHD patients compared with a control group of CHD patients. Intra-operative blood pressures were significantly lower in the NHD cohort when compared with the control CHD group. As a result, there was a higher percentage of acute tubular necrosis accounting for the majority of the DGF pathological diagnoses in NHD patients. The marked difference in pre-transplant blood pressure between the NHD and CHD groups is in keeping with the superior blood pressure control previously reported among NHD patients. The fall in post-transplant blood pressure among the CHD patients is also consistent with some [13,14] but not all published reports. The phenomenon of intra-operative hypotension followed by a marked increase in post-transplant blood pressure among NHD patients has not been previously reported and requires explanation.

One hypothesis to consider is that the NHD patients may have lower pre-transplant ECF volume accounting for the lower blood pressure and that post-transplant the ECF volume rises and the blood pressure become similar to the CHD control group. Arguing against this is the fact that previous studies have shown no difference in post-dialysis volume after patients were converted from CHD to NHD [3], and stroke volume, a surrogate for ECF volume, does not decrease among these patients [2]. Indeed, a recent study by Ferris et al. [15] examined the impact of extracellular volume and DGF post-renal transplant. These investigators did not find any significant correlation between these two variables and postulated that other processes must account for the pathogenesis of immediate DGF post-renal transplantation. In this study, we found no difference in pre-transplant weight between the two groups, and peri-transplant weight gain was similar in the two groups, which provides indirect evidence against a significant difference in ECF volumes. We recognize that weight gain is an imperfect surrogate for ECF volume. Potential confounding variables such as nutritional intake do not allow us to draw any conclusion. Further detailed haemodynamic studies will be required in the future.

A more plausible unifying hypothesis is that NHD lowers blood pressure through a decrease in peripheral resistance and that intra-operative hypotension suggests a further fall in cardiac afterload secondary to anaesthesia induction whereas after renal transplantion, there is a reversal of the relative vasodilated state that existed during treatment with NHD. Recent work has shown that conversion of patients from CHD to NHD results in a selective decrease in plasma norepinephrine levels, an improvement in endothelial function and restoration of vasodilator response to nitroglycerin [2]. It was hypothesized that uraemia acts as a direct sympatho-excitatory stimulus causing an elevated total peripheral resistance. Some investigators speculate that the remnant uraemic kidney is associated with the under clearance of endogenous substances, which increase sympathetic nervous system (SNS) activity and/or impair endothelial function [16]. This hypothesis is supported by the observation that the elevated level of muscle sympathetic nerve activity in CHD patients does not appear to be reduced by renal transplantation [17]. It is reasonable to postulate that daily nocturnal haemodialysis may allow enhanced removal of endogenous vasoactive substances or cause a decrease in central sympathetic outflow resulting in an improvement in systemic vascular resistance in the NHD cohort while undergoing dialysis.

Although our early examination of graft outcomes with transplanted NHD patients did not show any statistically significant differences in 1-year graft function when compared with a matched cohort of CHD patients, the observed trend toward increased DGF among NHD patients does, however, deserve further study as our small numbers do not provide sufficient statistical power to exclude a clinically significant increased rate of DGF among these patients. As mentioned previously, patients treated with NHD have an augmented vasodilatory response to nitroglycerine [2], a response that is not seen in CHD patients. We postulate that the trend towards increased rate of DGF in the NHD group may be in part due to an exaggerated response to the vasodilatory effect of anaesthetic agents used intra-operatively which results in relative vascular underfilling and graft hypoperfusion. The higher prevalence of intra-operative hypotension and acute tubular necrosis observed in our NHD cohort supports this hypothesis. In the future, invasive haemodynamic monitoring will be needed to further explore this phenomenon.

Intuitively, renal transplantation should be accompanied by further enhancement in blood pressure control in all end-stage renal disease (ESRD) patients since uraemia control is improved. Our present study suggests that pre-transplant haemodynamics is a critical determinant as to the evolution of blood pressure post-transplant. For CHD patients, renal transplantation offers multiple physiological advantages, including improvements in uraemia control and ECF volume status. Current conventional haemodialysis only delivers 10–15% of renal function in an unphysiological intermittent mode [18]. As a result, haemodialysis associated hypertension in CHD patients is common, involving volume overload, endothelial dysfunction and activation of pressor systems such as the renin–angiotensin–aldosterone axis and the SNS. In contrast, in the NHD group, the haemodynamic benefit of renal transplantation is often counteracted by the vasoconstrictive effect of calcineurin inhibitors. Calcineurin inhibitors are well described to both increase SNS activity [19] and to adversely affect endothelial function [20]. The effect of cyclosporin and tacrolimus on endothelial function appears to be similar [21]. It is reasonable to assume that the two groups of study patients are exposed to the same hypertensive risk factors after renal transplantation. The differing patterns of changes from baseline blood pressures between the two cohorts of ESRD patients highlight a fundamental difference in haemodynamics between the two forms of renal replacement modalities.

In summary, this retrospective study provides the first report of clinical outcomes with renal transplantation in NHD patients. It is noteworthy that both NHD and CHD patients achieved similar blood pressures and renal allograft outcomes 12 months post-transplant despite marked differences at baseline. Intra-operative hypotension and evolution in blood pressure in NHD patients are consistent with current available evidence that NHD lowers blood pressure through a decrease in peripheral resistance. Further careful prospective studies are required to determine the aetiology of this haemodynamic change, and long-term follow-up will determine whether this translates into a clinical advantage for NHD patients to undergo renal transplantation.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Background
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 6. 5.03
Accepted in revised form: 18. 9.03





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