Abstract

Background

Low blood pressure occurring in the absence of volume depletion, anti-hypertensive medication, heart failure or cortisol deficiency occurs in ∼5–10% of haemodialysis patients, and can result in serious complications. The pathophysiology of this syndrome is poorly understood.

Methods

We describe eight cases with dialysis-associated hypotension who underwent renal transplantation. Four patients were severely hypotensive with a systolic blood pressure (SBP) <100 mmHg before and during dialysis, and four had a SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions. All had donor-specific human leukocyte antigen antibodies. Six patients underwent pre-transplant plasmapheresis, which was curtailed in two because of further falls in blood pressure. Two patients experienced clotting of their arteriovenous fistula. In one patient cryofiltration was used, which was tolerated without severe falls in the BP. The remaining patient, who had hypotension-associated retinal vein thrombosis before transplant, was supported with an epinephrine infusion and did not receive plasmapheresis.

Results

Post-transplant, the first patient did not receive pressor therapy and died from bowel ischaemia. The other seven patients were supported with inotropes on critical care. The administration of steroids did not reverse hypotension. The mean pre-treatment SBP was 96 mmHg (range 71–110, SEM 5.0). After inotropes were withdrawn and graft function was established, the mean SBP was 127 mmHg (range 113–149, SEM 4.9) (P < 0.01).

Conclusions

Renal transplantation was performed successfully and safely in patients when pressor therapy was used to treat severe dialysis-associated hypotension and, moreover, the blood pressure normalized rapidly after graft function was established.

Introduction

Low blood pressure in long-term haemodialysis patients, despite receiving no anti-hypertensive medication, optimization of fluid balance and in the absence of heart failure or cortisol deficiency, is a well-recognized but rare problem [1–3]. Two types of hypotension occur; episodic hypotension in which the systolic blood pressure (SBP) is <100 mmHg during dialysis, but >100 mmHg between sessions, occurring in 30–40% of dialysis patients, and less commonly in patients with a SBP <100 mmHg that is sustained between dialysis sessions. The latter is inversely related to time on haemodialysis, occurs in 5–10% of patients [1] and is associated with a poorer clinical condition and quality of life. Patients with this inter-dialytic hypotension are more likely to experience complications during sessions, including fatigue, fainting, sweating, vomiting or fistula thrombosis [3, 4], and are at an increased risk of acute vascular complications, for example, myocardial ischaemia, or retinal vein thrombosis [5], therefore requiring greater medical and nursing care [1, 3]. The amount of fluid that can be removed per session is also limited in these patients as they are unable to tolerate any additional decrease in their SBP [1].

The pathophysiology of chronic inter-dialytic hypotension is not yet well defined; however, it is characterized haemodynamically by reduced total peripheral resistance [1], and several mechanisms for this have been proposed. One is a reduced cardiovascular response to vasopressors associated with a down-regulation of their receptors [1], with a relationship between increased time on dialysis, increased levels of norepinephrine and decreased platelet α2-adrenoreceptor density, all resulting in lower blood pressure [6]. The decreased α2-adrenoreceptor density was also associated with a decreased responsiveness to α1-adrenoreceptors, as demonstrated by the requirement of a higher dose of intravenous phenylephrine to raise the blood pressure in these patients [6]. The authors hypothesized that in long-term dialysis, treatment baroreceptor dysfunction develops, which increases norepinephrine levels, leading to down-regulation of α-adrenoreceptors [6]. Β2-adrenoreceptor densities and β2-adrenoreceptor response have also been reported as decreased in hypotensive haemodialysis patients [7]. Higher levels of vasoactive hormones, including epinephrine, plasma renin activity and angiotensin II, in chronic hypotensive haemodialysis patients when compared with normotensive haemodialysis patients have also been reported [8], probably as a result of the decreased responsiveness to vasopressors.

Another mechanism thought to be responsible for the decreased total peripheral resistance in haemodialysis patients with chronic hypotension is an increased production of vasodilators, possibly induced by cytokines, formed as part of the inflammatory state of uraemia [1, 3]. Adrenomedullin, a known vasodilator, the production of which is induced by cytokines, is inversely correlated with the mean arterial pressure in haemodialysis patients [3, 9], and chronic hypotension is also associated with higher plasma levels of nitrites and nitrates [4]. Therefore, vasodilators such as adrenomedullin and nitric oxide could be responsible for the reduced response to vasopressors previously discussed.

The vasopressor drug midodrine, a selective peripheral α1-adrenergic receptor antagonist, is used to treat some cases of chronic hypotension [10].

One case of renal transplantation reversing intractable hypotension in a diabetic patient has previously been described [11]. A 59-year-old hypertensive, diabetic female, who had been on haemodialysis for 6 years due to diabetic nephropathy, developed dialysis-associated hypotension in the range 80–100/50–60 mmHg. Her cardiac performance was fair and the blood pressure did not respond to mineralocorticoids. On Day 1 post-transplantation the blood pressure normalized to the range 120–140/60–80 mmHg. The authors proposed that the grafted kidney somehow altered either pressor response or vasodilator production [11].

Our study sought to evaluate further the effect of renal transplantation in the treatment of chronic hypotension, by examining a series of cases who underwent renal transplantation through the human leukocyte antigen (HLA) Antibody Incompatible Transplantation (AIT) programme at University Hospital in Coventry (UHCW). Patients undergoing this type of transplant are at a higher than standard risk of mortality and morbidity, as they have generally experienced established renal failure for many years; they may require pre-transplant plasmapheresis, which is associated with further hypotension, and they may receive intense immunosuppression [12, 13]. Therefore, the management and outcomes of these high-risk patients with high-risk transplants is of particular importance.

Patients and methods

Eight patients with dialysis-associated hypotension were identified; four had severe hypotension, with the SBP always below 100 mmHg; in the other four the SBP usually dropped to less than 100 mmHg during dialysis; however, in between sessions, they were usually normotensive. In both cohorts, the hypotension did not respond to fluid loading or steroids, and each patient underwent evaluations to rule out any abnormal cardiac function.

All patients were identified from the AIT programme at UHCW, which they had entered after a prolonged wait for a compatible transplant due to the presence of donor-specific (either ABO or HLA) antibodies (DSA) in their circulation.

In the programme, DSA were removed or at least decreased pre-transplant using a double filtration plasmapheresis (DFPP) technique, as described previously [14]. Antibody levels were then monitored post-transplant, daily for the first 2 weeks and tri-weekly for the following 2 weeks, the technique for which we have also described [14].

Immunosuppression consisted of mycophenolate mofetil 1 g twice daily started 10 days pre-transplant, tacrolimus 0.15 mg/kg/day started 4 days pre-transplant, prednisolone 20 mg OD started at the time of surgery, methylprednisolone 500 mg given once during surgery and basiliximab 20 mg given once on the day of surgery, and once 4 days after.

Patients with hypotension received norepinephrine, dopamine or metaraminol infusions to maintain the SBP between 120 and 130 mmHg, except for the first case in this series, who did not receive pressor therapy in the early post-operative period.

Results

Between June 2003 and May 2010, 90 patients received kidney transplants through the AIT programme at UHCW, eight of whom were identified as having dialysis-associated hypotension.

Characteristics of patients are shown in Tables 1 and 2. It should also be noted that no patient had undergone native kidney nephrectomy, a conventional cause of hypotension, and that seven out of eight patients received a living donor transplantation.

Table 1.

Characteristics of the patients within the cohort with a SBP <100 mmHg before and during dialysis

Patient number Pre-dialytic SBP Sex Cause of renal failure Duration of end-stage renal failure, years Duration of dialysis, years Age at transplant, years Living/deceased donor Previous transplants 
N/A Vasculitis 10 10 66 Deceased 
98 Interstitial nephritis 49 Living 
71 Neurogenic bladder 10 10 47 Living 
86 Hypertension 15 15 41 Living 
Patient number Pre-dialytic SBP Sex Cause of renal failure Duration of end-stage renal failure, years Duration of dialysis, years Age at transplant, years Living/deceased donor Previous transplants 
N/A Vasculitis 10 10 66 Deceased 
98 Interstitial nephritis 49 Living 
71 Neurogenic bladder 10 10 47 Living 
86 Hypertension 15 15 41 Living 
Table 2.

Characteristics of the patients within the cohort with a SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions

Patient number Pre-dialytic SBP Sex Cause of renal failure Duration of end-stage renal failure, years Duration of dialysis, years Age at transplant, years Living/deceased donor Previous transplants 
103 Renal dysplasia 21 27 Living 
110 Renal dysplasia 16 35 Living 
106 Membranous nephropathy 33 Living 
99 Haemolytic-uraemic syndrome 11 50 Living 
Patient number Pre-dialytic SBP Sex Cause of renal failure Duration of end-stage renal failure, years Duration of dialysis, years Age at transplant, years Living/deceased donor Previous transplants 
103 Renal dysplasia 21 27 Living 
110 Renal dysplasia 16 35 Living 
106 Membranous nephropathy 33 Living 
99 Haemolytic-uraemic syndrome 11 50 Living 

ECGs and echocardiograms were performed on each patient to rule out any abnormal cardiac function, although it should be noted that the assessment of systolic contractile function is more difficult in the presence of low SBP, due to the linear relationship between the end-systolic volume and the end-systolic pressure. In all eight patients, the ECG displayed normal sinus rhythm with a normal rate, and the mean pulse readings were between 64 and 92 for the six patients for whom they were available. Echo findings were available for all patients except Patient 1. Patients 2, 4 and 5 displayed mild left ventricular hypertrophy, Patient 3′s echo showed evidence of mild mitral and tricuspid regurgitation, and Patient 4 had some calcification on the mitral valve, but none of these findings would explain hypotension, and other than these every echo displayed normal cardiac function. No patient had overt cardiac failure post-transplant, but echos were not repeated post-operatively. None of the cases included in our study had extensive vascular calcifications.

Pre-transplant

Prior to treatment, one patient lost vision in both eyes from retinal vein thrombosis, and another had transient visual disturbance with normal results on fundoscopy and CT of the brain. Both patients had inter-dialytic SBP persistently in the range 50–60 mmHg.

Of the eight patients, six underwent DFPP pre-transplant. In total, only two out of the six patients could tolerate the full five sessions of DFPP, as a direct result of worsening hypotension during treatment. Two patients experienced fistula thrombosis.

Of the two patients who did not undergo DFPP pre-transplant, one had recent visual loss secondary to retinal vein thrombosis, and received norepinephrine for several days between developing complete blindness and being transferred to our centre for transplantation; thus DFPP was excluded to avoid the risk of further hypotension. The other patient underwent cryofiltration (an alternative to DFPP) pre-transplant, in which plasma is filtered out of blood, anticoagulated with heparin, added with citrate and cooled to 0°C for 6 min, and the resulting cryogel filtered out, before re-warming the plasma to be returned to the patient [15]. This procedure was well tolerated by the patient.

Post-transplant

The first patient experienced a SBP of 50 mmHg post-transplant, resulting in bowel ischaemia, which was found to be too extensive for resection at laparotomy, and she subsequently died. This level of blood pressure had been usual for the patient during her home dialysis therapy, and inotrope therapy had not been given at the ward. Subsequent patients received inotrope therapy in the form of norepinephrine, dopamine or metaraminol peri-operatively to maintain the SBP above 100 mmHg.

The duration and dose of inotrope therapy varied between patients; for example, Patient 2 was started on norepinephrine 0.2 mg/h immediately post-operatively, and this infusion was continued between 0.2 and 1 mg/h for 44 h, until the first dialysis was performed. This lasted 4h, then norepinephrine was continued for a further 38 h between 0.2 and 0.6 mg/h, before being stopped. Creatinine at this time was 495. The patient continued to receive dialysis for a further 16 days, and although the SBP was intermittently <100 mmHg, this was tolerated well, and therefore further inotropes were not given. The day after the final dialysis, creatinine had fallen to 160, while the SBP had risen to 170 mmHg, and this patient was discharged.

For patients 3–8, the aim of inotrope therapy was to keep the SBP >100 mmHg.

Patient 3 received a norepinephrine infusion at between 0.15 and 0.5 mg/h for 34 h pre-operatively; this was then continued for 21 h post-operatively at between 0.3 and 0.8 mg/h until dopamine was added at an infusion rate of 3 µg/kg/h. Both norepinephrine (0–1.6 mg/h) and dopamine (3–5 µg/kg/h) were continued for a further 100 h. After this, norepinephrine was stopped completely and then dialysis 4h later, and dopamine infusion alone was continued at 2.5–5 µg/kg/h for a further 22 h. When all inotrope support was withdrawn, creatinine had fallen to 307 and SBP was 136 mmHg.

Patient 4 received a metaraminol infusion immediately post-operation, and this was continued at between 0 and 3 mg/h for 64 h, then temporarily stopped, but restarted after 11h at between 0.5 and 3 mg/h and continued for a further 52 h until it could be stopped, with the SBP persistently remaining between 120 and 130 mm Hg. At the time the infusion was stopped, the SBP was 123 mmHg and creatinine had fallen to 246.

All patients tolerated the inotropic medications with no problems.

Figure 1 shows the effect of transplantation on the mean blood pressure of the seven successfully transplanted patients, after inotrope therapy had been withdrawn. The data show the mean SBP measured in the immediate pre-treatment period, compared with the mean SBP levels recorded in hospital after inotrope therapy was withdrawn, and in the clinic in the first 2 weeks post-discharge from hospital.

Fig. 1.

Effect of transplantation on the SBP. Figure 1 shows the effect of transplantation on the mean blood pressure of the seven successfully transplanted patients. Patients 2–4 were severely hypotensive with an SBP <100 mmHg before and after dialysis, Patients 5–8 had an SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions. The mean SBP measured in the immediate pre-treatment period is compared with mean SBP levels recorded in hospital after inotrope therapy was withdrawn, and in clinic in the first 2 weeks post-discharge from the hospital.

Fig. 1.

Effect of transplantation on the SBP. Figure 1 shows the effect of transplantation on the mean blood pressure of the seven successfully transplanted patients. Patients 2–4 were severely hypotensive with an SBP <100 mmHg before and after dialysis, Patients 5–8 had an SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions. The mean SBP measured in the immediate pre-treatment period is compared with mean SBP levels recorded in hospital after inotrope therapy was withdrawn, and in clinic in the first 2 weeks post-discharge from the hospital.

In all seven cases, the hypotension resolved within 2–3 days of graft functioning, shown in Figure 1 by the increase in the mean SBP after transplantation. On average, the mean SBP increased from 96 (SEM 5.0) mmHg pre-treatment to 127 (SEM 4.9) mmHg post-transplant (P < 0.01).

All seven patients are still alive with only one graft failure so far, at 32 months due to transplant glomerulopathy, and have remained normotensive long term, although one patient (Patient 5) is receiving 25 mg of atenolol once daily.

Discussion

Our study has shown the clinical importance of severe dialysis-associated hypotension, as demonstrated by blindness, bowel infarction and other episodes of clotting around the time of transplant in our patients.

However, the hypotension was easily corrected by modest doses of inotrope therapy given on critical care. Moreover, blood pressure was normalized rapidly after renal transplantation, within 2–3 days of the establishment of graft function. These findings have practical value for patients with dialysis-associated hypotension.

The rapid resolution of hypotension after transplant function is interesting, given the uncertainty over the pathogenesis of chronic inter-dialytic hypotension. As mentioned in the introduction, there is currently no new understanding on this subject; however, the rapid resolution of blood pressure could indicate that soluble mediators play a bigger role than previously thought, for example, the secretion of vasoconstrictors, or the excretion of vasodilators by the transplanted kidney, and makes several of the theories discussed earlier less likely, for example, those relating to structural arterial changes.

The success of these transplants may also be associated with the use of living donors, as all seven surviving patients were transplanted in this way; therefore it may also be preferable, where possible, to transplant patients with dialysis-associated hypotension from living donors in the future.

Tacrolimus was started 4 days pre-transplant and has a known vasopressor effect; however, it is unlikely that this drug would be responsible for the reversal of hypotension in our study, as there was no increase in the SBP either pre-operatively or during the early post-operative period, when the drug had already been started.

The weakness of this study is that there is no internationally recognized definition of a syndrome of inter-dialytic hypotension, which is why we have divided the patients into groups of increasingly severe hypotension. The syndrome, at least with severe persistent hypotension in patients otherwise fit for transplantation, is rare and we were able to put together a series of cases because of referrals from various hospitals. Indeed the eight patients reported here came from eight different dialysis units. Cardiac screening did not indicate poor cardiac function as a cause of hypotension. Cortisol deficiency was not formally excluded pre-transplant in all cases, but in patients with delayed graft function, the BP did not normalize under the influence of steroid treatment, but only normalized when graft function was established.

In conclusion, the findings of this study may be of great significance for future patients with intractable dialysis-associated hypotension, for whom daily activity is limited and dialysis inadequate, as transplantation could not only reverse renal failure, but intractable hypotension as well.

Conflict of interest statement

None declared.

Acknowledgements

The authors thank Dr Curtis McMurtrey for help with the figures.

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