Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis (IHD) and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during IHD is safe, feasible, and effective in the attenuation of muscle cramps. Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving IHD who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for 4 weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers. Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180 mm Hg) occurred more often with angiotensin II than with placebo (4/12 sessions, 33% vs. 2/12 sessions, 17% sessions, p = 0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (4/12 sessions, 33% vs. 11/12 sessions, 92% sessions, p = 0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; p < 0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; p < 0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0/12 sessions, 0% vs. 5/12 sessions, 42% sessions, p = 0.037). Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase, or renin. Angiotensin II infusion during IHD appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.

Intermittent hemodialysis (IHD)-related muscle cramps pose a significant challenge to patients receiving maintenance hemodialysis. Such cramps, defined by the sudden and involuntary onset of painful muscle contractions, are reported by up to 80% of patients and can lead to treatment interruption or cessation, which impairs toxin and fluid removal [1‒3]. Importantly, intradialytic cramps have been ranked by IHD patients as one of the three most burdensome physical symptoms [3]. As such, the development of novel strategies to prevent and/or treat intradialytic cramps is a high research priority [4].

The pathophysiology of dialysis-related muscle cramps is poorly understood and likely multifactorial. Their occurrence has been variably attributed to excessive ultrafiltration, hypotension, electrolyte imbalance, or a combination of these factors [2, 5, 6]. However, no interventions targeting these pathways have demonstrated efficacy in preventing or attenuating cramps. Skeletal muscle ischemia induced by an imbalance between circulating angiotensin II, catecholamines, and arginine vasopressin has also been proposed as a potential mechanism in the pathogenesis of intradialytic cramps [7]. In contrast to catecholamines and arginine vasopressin, which preferentially constrict precapillary vessels, angiotensin II constricts both pre- and postcapillary vessels in skeletal muscle, which maintains intracapillary hydrostatic pressure, vessel patency, and functional surface area [8, 9]. Decreased angiotensin II production due to dysfunction of the renin-angiotensin-aldosterone system (RAAS) occurs commonly in IHD patients [10]. This, coupled with the hemodynamic stress of IHD, could contribute to or exaggerate imbalance between vasoactive hormones, resulting in capillary dropout and skeletal muscle ischemia [7, 10]. It is therefore plausible that administration of intravenous angiotensin II during IHD could prevent or attenuate intradialytic muscle cramps.

Accordingly, we conducted a pilot, single-blinded, placebo-controlled, randomized crossover trial to assess the safety and efficacy of intravenous angiotensin II infusion in maintenance IHD patients with a history of frequent intradialytic cramps. We aimed to test the hypothesis that angiotensin II infusion would decrease the occurrence and severity of muscle cramps, with an acceptable safety profile.

Study Design and Population

Cramp Reduction with Angiotensin II in Maintenance Patients on HemoDialysis (CRAMP-HD) was a pilot, single-blinded, placebo-controlled, randomized crossover trial to assess the safety and efficacy of angiotensin II infusion as a means to prevent muscle cramps in IHD patients with a history of frequent intradialytic cramps. It was conducted at Austin Hospital in Australia from August 2023 to March 2024. Adult patients (aged ≥18 years) receiving maintenance IHD (3 times per week) were eligible for inclusion if they had appropriate dialysis access (arteriovenous fistula, arteriovenous graft, or permanent catheter) and a history of painful muscle cramps in the previous month, defined by early termination of a dialysis session due to muscle cramps, a reduction in prescribed ultrafiltration volume, or administration of fluid due to muscle cramps.

Patients were excluded if they (1) had a known or suspected allergy to components of angiotensin II, (2) were presently taking an angiotensin receptor blocker (ARB), (3) had a history of intracerebral hemorrhage or heart failure with a left ventricular ejection fraction less than 20%, (5) recorded a pre-dialysis systolic blood pressure (SBP) greater than 180 mm Hg, or (6) had any other disease or significant laboratory result abnormality that, according to the investigator, could compromise participant safety, interfere with trial participation, or impact the trial objectives. Patients eligible for the study were selected from lists of outpatients receiving hemodialysis. Those who fulfilled all inclusion criteria and none of the exclusion criteria were enrolled in the trial after obtaining informed consent.

Randomization and Blinding

Patients were randomly assigned in a 1:1 ratio to receive either angiotensin II or placebo (0.9% saline) during their first dialysis treatment of the week, based on a computer-generated list. Randomization was performed using an online research electronic data capture program (REDCap Consortium, Vanderbilt University, Nashville, TN database). For the first 2 weeks, patients received either angiotensin II or placebo, and for the following 2 weeks, they switched to the alternate treatment. This ensured that each participant completed two dialysis treatments with angiotensin II and two with placebo, providing a balanced exposure to both interventions across the study period. Patients and dialysis nurses were blinded to group allocation, while an unblinded investigator of the research team was responsible for preparing and administering the study drug infusion.

Intervention

During dialysis sessions assigned to the intervention group, patients received a continuous intravenous infusion of angiotensin II. To prepare the infusion, 1 mL was withdrawn from a 500 mL bag of 0.9% sodium chloride and replaced with 1 mL of angiotensin II (2.5 mg), achieving a final concentration of 5,000 µg/L (5 µg/mL). The study drug infusion began within 15 min of dialysis initiation at a prescribed dose of 1 ng/kg/min. The rate of the infusion was increased in increments of 0.5–2 ng/kg/min every 15 min until the maximum rate of 30 ng/kg/min was reached or the SBP exceeded 180 mm Hg. The goal was to deliver angiotensin II at the maximum tolerated dose between 1 and 30 ng/kg/min while maintaining a SBP less than 180 mm Hg. If the SBP increased above 180 mm Hg, the infusion was paused for 15 min and restarted if the SBP fell below 180 mm Hg. Adjustments to the infusion rates were handled by a member of the study team. For dialysis sessions assigned to the control group, patients received a continuous placebo infusion of 0.9% saline in a 500 mL bag. The titration protocol of the placebo was identical to that for the study drug. The dialyzate sodium concentration was standardized at 138 mEq/L for all participants. This concentration was selected to reflect typical clinical practice at our institution and to ensure consistency across all dialysis sessions.

Data Collection

Demographic data including age, sex, comorbidities, etiology of kidney failure, and laboratory parameters were collected at baseline. Recorded data on dialysis prescription included modality, blood flow rate, dialyzate flow rate, treatment time, type of vascular access, anticoagulation, ultrafiltration rate, and weight (target, pre-dialysis, post-dialysis). The occurrence and intensity of muscle cramps were evaluated every 15 min using the Brief Pain Inventory (BPI), employing a scale from 0 to 10, where 0 indicates no pain and 10 represents the most severe pain (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000543280) [11].

Hemodynamic parameters were collected by the ClearSight device (Edwards Lifesciences, Irvine, CA, USA) at baseline and every 15 min until dialysis cessation. Such parameters included SBP, diastolic blood pressure, mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and cardiac index [12, 13]. Biomarkers of cardiac and muscle injury (troponin I, creatine kinase) were collected pre- and post-dialysis, as was plasma renin activity.

Outcomes

The primary outcome was the safety and tolerability of angiotensin II, defined as the incidence of local and/or systemic adverse events from day 0 to day 7 of each intervention or control period. Adverse events included intradialytic hypertension (SBP >180), access thrombosis, venous thromboembolic event, or arterial thromboembolic event. Evidence of adverse events was identified from patients, dialysis nursing charts, and the medical record.

The secondary efficacy outcomes were (1) occurrence of intradialytic muscle cramps, (2) intradialytic muscle cramp intensity as assessed by the BPI, (3) hemodialysis treatment alteration due to muscle cramps (e.g., fluid bolus administration, reduction in ultrafiltration goal, or treatment termination), (4) intradialytic hypotension defined as a decrease in SBP >20 mm Hg or SBP <90 mm Hg, (5) adverse intradialytic symptoms (e.g., abdominal pain, nausea, vomiting, restlessness, dizziness, fainting, “going flat”). The secondary safety outcomes were changes in hemodynamic parameters (SBP, DBP, MAP, HR, CO, CI) and changes in biomarkers (troponin I, creatine kinase, and renin) from pre- to post-dialysis.

Statistical Analysis

Based on feasibility, we aimed to include a convenience sample of 6 patients with a total of 24 sessions and approximately 50 h of angiotensin II infusion. Descriptive statistics were used to summarize baseline data. Categorical data were presented as frequencies and percentages (%), normally distributed data were presented as means and standard deviations, and skewed data were presented as medians and interquartile ranges. Baseline characteristics were compared using Fisher’s exact test, the unpaired t-test, or the Mann-Whitney U test, as appropriate.

For comparison of parameters during the intervention (i.e., pre- and post-dialysis) and outcomes between groups, analyses were made using the paired t-test, Wilcoxon signed-rank test, or McNemar’s test, depending on data type. Linear mixed models were constructed with patients as a random effect to assess for the interaction between group assignment and pain score, drug dosage, SBP, DBP, MAP, HR, CO, and CI. All analyses were performed according to an intention-to-treat principle using R version 4.2.3 (R Foundation for Statistical Computing) and a two-sided p value <0.05 was considered statistically significant.

Study Population

From 1 August 2023 to 30 March 2024, a total of 12 patients were screened for eligibility. Six patients were excluded since they were either ineligible (n = 2) or declined to participate (n = 4). The remaining 6 patients were randomized and completed a total of 24 study dialysis sessions (shown in Fig. 1). Baseline characteristics of the study population according to their initial allocation are shown in Table 1. The mean age was 68.2 years, and the median dialysis vintage was 5.6 years. The most common comorbidities were hypertension, cardiovascular disease, and chronic lung disease. One patient was previously on an ARB, which was stopped for clinical reasons 1 week prior to the study period. There were no significant differences between groups in terms of baseline demographic, laboratory, hemodynamic, or dialysis parameters, as shown in Table 2.

Fig. 1.

CRAMP-HD study flowchart.

Fig. 1.

CRAMP-HD study flowchart.

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Table 1.

Baseline characteristics of study participants

CharacteristicsStudy participants
all (n = 6)
Age, years 68.2±5.6 
Sex, n (%) 
 Male 4 (66.7) 
 Female 2 (33.3) 
Comorbidities, n (%) 
 Hypertension 6 (100) 
 Cardiovascular disease 3 (50) 
 Chronic lung disease 3 (50) 
 Chronic liver disease 1 (16.7) 
 Cancer 1 (16.7) 
Cause of kidney failure, n (%) 
 ADPKD 1 (16.7) 
 ANCA-associated GN 1 (16.7) 
 Diabetic nephropathy 1 (16.7) 
 Membranous nephropathy 1 (16.7) 
 Reflux nephropathy 2 (33.3) 
Vascular access site, n (%) 
 Arteriovenous fistula 2 (33.7) 
 Arteriovenous graft 1 (16.7) 
 Permanent catheter 3 (50) 
RAAS inhibitor usage, n (%) 1 (16.7) 
Residual urine output, mL/day 0 (0–75) 
Dialysis vintage, years 5.6 (2–9.2) 
Laboratories 
 Urea, mmol/L 17.06±3.68 
 Creatinine, μmol/L 648.3±231.5 
 Potassium, mmol/L 4.5±1.0 
 Phosphate, mmol/L 1.6±0.5 
 Albumin, g/dL 28.8±3.6 
 Hemoglobin, g/L 100.7±17.9 
CharacteristicsStudy participants
all (n = 6)
Age, years 68.2±5.6 
Sex, n (%) 
 Male 4 (66.7) 
 Female 2 (33.3) 
Comorbidities, n (%) 
 Hypertension 6 (100) 
 Cardiovascular disease 3 (50) 
 Chronic lung disease 3 (50) 
 Chronic liver disease 1 (16.7) 
 Cancer 1 (16.7) 
Cause of kidney failure, n (%) 
 ADPKD 1 (16.7) 
 ANCA-associated GN 1 (16.7) 
 Diabetic nephropathy 1 (16.7) 
 Membranous nephropathy 1 (16.7) 
 Reflux nephropathy 2 (33.3) 
Vascular access site, n (%) 
 Arteriovenous fistula 2 (33.7) 
 Arteriovenous graft 1 (16.7) 
 Permanent catheter 3 (50) 
RAAS inhibitor usage, n (%) 1 (16.7) 
Residual urine output, mL/day 0 (0–75) 
Dialysis vintage, years 5.6 (2–9.2) 
Laboratories 
 Urea, mmol/L 17.06±3.68 
 Creatinine, μmol/L 648.3±231.5 
 Potassium, mmol/L 4.5±1.0 
 Phosphate, mmol/L 1.6±0.5 
 Albumin, g/dL 28.8±3.6 
 Hemoglobin, g/L 100.7±17.9 

Values are presented as n (%), mean ± standard deviation, and median (interquartile range).

ADPKD, autosomal dominant polycystic kidney disease; ANCA, antineutrophil cytoplasmic antibody; Cr, creatinine; GN, glomerulonephritis; RAAS, renin-angiotensin-aldosterone system.

Table 2.

Characteristics of dialysis and clinical parameters according to treatment assignment

Angiotensin II (12 sessions)Placebo (12 sessions)p value
Pre-dialysis parameters 
 SBP, mm Hg 134.2±16.2 123.2±20.8 0.161 
 DBP, mm Hg 58.9±10.7 55.8±9.9 0.474 
 MAP, mm Hg 79.2±11.3 79.1±11 0.985 
 HR, min 68.1±10.3 68.4±11.2 0.940 
 CO, L/min 4.9±0.9 4.2±1.1 0.149 
 CI, L/min/m2 2.5±0.7 2.5±0.3 0.956 
Post-dialysis parameters 
 SBP, mm Hg 139.1±21.2 133.3±32.5 0.608 
 DBP, mm Hg 65.4±12.5 64.9±13.3 0.925 
 MAP, mm Hg 87.8±16.7 88.8±15.3 0.880 
 HR, min 84.7±8.5 78.8±9.9 0.134 
 CO, L/min 4.5±0.9 4.5±1.1 0.938 
 CI, L/min/m2 2.4±0.6 2.4±0.3 0.356 
Dialysis prescription 
 Dialysis time, h 4.5 (4–4.5) 4.5 (4–4.5) 
 Blood flow rate, mL/min 300 (300–300) 300 (300–300) 0.514 
 Dialyzate flow rate, mL/min 500 (500–500) 500 (500–500) 
 Anticoagulation, n (%)   0.605 
  No 2 (16.7) 4 (33.3)  
  Heparin 4 (33.3) 3 (25)  
  Enoxaparin 6 (50) 5 (41.7)  
 Ultrafiltration rate, mL/kg/h 10.1 (7.0–10.7) 9.2 (8.2–10.0) 0.686 
 Total ultrafiltration volume, mL 2,760 (2,300–3,925) 2,925 (2,375–3,625) 0.912 
 Target weight, kg 69.8 (65.4–88.1) 69.8 (65.2–88.1) 0.976 
 Pre-dialysis weight, kg 74.1 (66.9–90.8) 74 (66.8–91.7) 0.977 
 Post-dialysis weight, kg 71.1 (65.4–88.6) 71 (65.6–88.6) 0.908 
Volume and dose of study drug 
 Total drug volume, mL/session 7.8 (3.8–21.5) 33.2 (29.1–57.6) <0.001* 
 Maximal drug dosing, ng/kg/min 2.5 (1.6–4.8) 16.6 (10–30) <0.001* 
Angiotensin II (12 sessions)Placebo (12 sessions)p value
Pre-dialysis parameters 
 SBP, mm Hg 134.2±16.2 123.2±20.8 0.161 
 DBP, mm Hg 58.9±10.7 55.8±9.9 0.474 
 MAP, mm Hg 79.2±11.3 79.1±11 0.985 
 HR, min 68.1±10.3 68.4±11.2 0.940 
 CO, L/min 4.9±0.9 4.2±1.1 0.149 
 CI, L/min/m2 2.5±0.7 2.5±0.3 0.956 
Post-dialysis parameters 
 SBP, mm Hg 139.1±21.2 133.3±32.5 0.608 
 DBP, mm Hg 65.4±12.5 64.9±13.3 0.925 
 MAP, mm Hg 87.8±16.7 88.8±15.3 0.880 
 HR, min 84.7±8.5 78.8±9.9 0.134 
 CO, L/min 4.5±0.9 4.5±1.1 0.938 
 CI, L/min/m2 2.4±0.6 2.4±0.3 0.356 
Dialysis prescription 
 Dialysis time, h 4.5 (4–4.5) 4.5 (4–4.5) 
 Blood flow rate, mL/min 300 (300–300) 300 (300–300) 0.514 
 Dialyzate flow rate, mL/min 500 (500–500) 500 (500–500) 
 Anticoagulation, n (%)   0.605 
  No 2 (16.7) 4 (33.3)  
  Heparin 4 (33.3) 3 (25)  
  Enoxaparin 6 (50) 5 (41.7)  
 Ultrafiltration rate, mL/kg/h 10.1 (7.0–10.7) 9.2 (8.2–10.0) 0.686 
 Total ultrafiltration volume, mL 2,760 (2,300–3,925) 2,925 (2,375–3,625) 0.912 
 Target weight, kg 69.8 (65.4–88.1) 69.8 (65.2–88.1) 0.976 
 Pre-dialysis weight, kg 74.1 (66.9–90.8) 74 (66.8–91.7) 0.977 
 Post-dialysis weight, kg 71.1 (65.4–88.6) 71 (65.6–88.6) 0.908 
Volume and dose of study drug 
 Total drug volume, mL/session 7.8 (3.8–21.5) 33.2 (29.1–57.6) <0.001* 
 Maximal drug dosing, ng/kg/min 2.5 (1.6–4.8) 16.6 (10–30) <0.001* 

Values are presented as n (%), mean ± standard deviation, and median (interquartile range).

CI, cardiac index; CO, cardiac output; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP, systolic blood pressure.

*p value <0.05 is statistically significant.

The total volume of study drug administered was lower with angiotensin II treatments compared to placebo treatments (median, 7.8 mL vs. 33.2 mL per session, p < 0.001). Additionally, the drug dosage varied less during angiotensin II treatments compared to placebo treatments (p = 0.002) (shown in online suppl. Fig. S2).

Primary and Secondary Outcomes

Intradialytic hypertension occurred during 4 angiotensin II sessions and 2 placebo sessions (33% vs. 17%, p = 0.64). No patients developed access thrombosis, venous thrombosis, or arterial thrombosis (Table 3). There was a significantly lower occurrence of intradialytic cramps with angiotensin II compared to placebo (33% vs. 92%, p = 0.009). No patients experienced more than one cramp per session with angiotensin II, compared to a range of one to four cramps per session with placebo (Table 3). In patients who cramped, cramp intensity was less with angiotensin II compared to placebo (median BPI 1.4 vs. 5.3, p < 0.001; maximum BPI 1.4 vs. 6.0, p < 0.001). Moreover, on linear mixed modelling, angiotensin II was associated with a statistically significant reduction in pain scores over time during dialysis compared to the placebo (p = 0.002) (shown in Fig. 2). The patient previously treated with an ARB reported no muscle cramps with angiotensin II and severe muscle cramps with placebo. Cramps were localized predominantly in the lower limbs, especially in the calf (shown in Fig. 3). Fluid bolus administration occurred more frequently with placebo than with angiotensin II (42% vs. 0%, p = 0.037), and there was a trend toward reduction in ultrafiltration goal during placebo compared to angiotensin II (41.7% vs. 8.3%, p = 0.22, Table 2).

Table 3.

Adverse event and IHD-related muscle cramps according to treatment assignment

Angiotensin II (12 sessions)Placebo (12 sessions)p value
Adverse events, n (%) 
 Intradialytic hypertension 4 (33.3) 2 (16.7) 0.640 
 Access thrombosis 0 (0) 0 (0) 1.00 
 Venous thrombosis (DVT or PE) 0 (0) 0 (0) 1.00 
 Arterial thrombosis (AMI or CVA) 0 (0) 0 (0) 1.00 
IHD-related muscle cramps 
 Occurrence of cramps, n (%) 4 (33.3) 11 (91.6) 0.009* 
 Time to first cramps symptom, h 3.5±0.9 2.9±1.2 0.353 
 Total episodes of cramps per session 
  1 episode 4 (100) 7 (63.6) 0.413 
  2 episodes 0 (0) 2 (18.2) 0.478 
  3 episodes 0 (0) 0 (0) 1.00 
  4 episodes 0 (0) 2 (18.2) 0.478 
 Average intensity per session** 1.4±2.1 5.3±2.6 <0.001* 
 Maximal intensity per session** 1.4±2.1 6±2.9 <0.001* 
Hemodialysis treatment alteration due to cramp 
 No changes (maintain same treatment) 3 (25) 2 (16.7) 1.00 
 Fluid bolus administration 0 (0) 5 (41.7) 0.037* 
 Reduction in ultrafiltration goal 1 (8.3) 5 (41.7) 0.220 
 Dialysis termination 0 (0) 1 (8.3) 1.00 
Intradialytic symptoms 0 (0) 0 (0) 1.00 
Intradialytic hypotension 0 (0) 0 (0) 1.00 
Angiotensin II (12 sessions)Placebo (12 sessions)p value
Adverse events, n (%) 
 Intradialytic hypertension 4 (33.3) 2 (16.7) 0.640 
 Access thrombosis 0 (0) 0 (0) 1.00 
 Venous thrombosis (DVT or PE) 0 (0) 0 (0) 1.00 
 Arterial thrombosis (AMI or CVA) 0 (0) 0 (0) 1.00 
IHD-related muscle cramps 
 Occurrence of cramps, n (%) 4 (33.3) 11 (91.6) 0.009* 
 Time to first cramps symptom, h 3.5±0.9 2.9±1.2 0.353 
 Total episodes of cramps per session 
  1 episode 4 (100) 7 (63.6) 0.413 
  2 episodes 0 (0) 2 (18.2) 0.478 
  3 episodes 0 (0) 0 (0) 1.00 
  4 episodes 0 (0) 2 (18.2) 0.478 
 Average intensity per session** 1.4±2.1 5.3±2.6 <0.001* 
 Maximal intensity per session** 1.4±2.1 6±2.9 <0.001* 
Hemodialysis treatment alteration due to cramp 
 No changes (maintain same treatment) 3 (25) 2 (16.7) 1.00 
 Fluid bolus administration 0 (0) 5 (41.7) 0.037* 
 Reduction in ultrafiltration goal 1 (8.3) 5 (41.7) 0.220 
 Dialysis termination 0 (0) 1 (8.3) 1.00 
Intradialytic symptoms 0 (0) 0 (0) 1.00 
Intradialytic hypotension 0 (0) 0 (0) 1.00 

Values are presented as n (%), mean ± standard deviation.

AMI, acute myocardial infarction; CVA, cerebrovascular disease; DVT, deep vein thrombosis; IHD, intermittent hemodialysis; PE, pulmonary embolism.

*p value <0.05 is statistically significant.

**BPI (Brief Pain Inventory) was used to evaluate intensity by rating pain score on a scale ranging from 0 to 10.

Fig. 2.

Time-series boxplot with overlaid jittered points representing Brief Pain Inventory scores at various time intervals after the commencement of dialysis according to treatment assignment. The jittered points represent individual pain score measurements to display the data spread and outliers, while the boxplot summarizes the central tendency and variability. The statistical annotation provides the effect size and p value for the angiotensin II treatment effect.

Fig. 2.

Time-series boxplot with overlaid jittered points representing Brief Pain Inventory scores at various time intervals after the commencement of dialysis according to treatment assignment. The jittered points represent individual pain score measurements to display the data spread and outliers, while the boxplot summarizes the central tendency and variability. The statistical annotation provides the effect size and p value for the angiotensin II treatment effect.

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Fig. 3.

Site of intradialytic muscle cramp according to treatment assignment. Percentages of participants experiencing cramps at each site during the intervention are shown: overall (a), angiotensin II (b), placebo (c).

Fig. 3.

Site of intradialytic muscle cramp according to treatment assignment. Percentages of participants experiencing cramps at each site during the intervention are shown: overall (a), angiotensin II (b), placebo (c).

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SBP, MAP, DBP, and HR increased more over time with angiotensin II compared to placebo (SBP 15.9 mm Hg, p = 0.006; MAP 13.2 mm Hg and DBP 9.7 mm Hg, p < 0.001; HR 3 bpm, p = 0.028) (shown in Fig. 4). There were no significant differences between groups in terms of CO or cardiac index (shown in online suppl. Fig. S3–S4). Changes in troponin I, creatine kinase, and renin before were also not significantly different (shown in online suppl. Fig. S5–S7).

Fig. 4.

a–d Hemodynamic changes during intervention according to treatment assignment.

Fig. 4.

a–d Hemodynamic changes during intervention according to treatment assignment.

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Key Findings

In this pilot, single-blinded, placebo-controlled, randomized crossover trial of maintenance IHD patients who frequently experience intradialytic muscle cramps, we found that angiotensin II appeared to be safe and feasible. We also found that angiotensin II decreased the frequency and intensity of intradialytic muscle cramps. Additionally, it decreased the need for fluid bolus administration and increased blood pressure and HR. Finally, there was no significant impact on cardiac or muscle injury biomarkers or plasma renin activity.

Relationship with Previous Studies

To our knowledge, this is the first randomized controlled trial to examine the safety and efficacy of angiotensin II in the prevention of IHD-related muscle cramps. Previous studies in critically ill patients with vasodilatory hypotension have also found angiotensin II to be safe, even when administered continuously for several days and at much higher doses than in this study [14]. Despite the increase in blood pressure, we observed with angiotensin II compared to placebo, there was no statistical difference in the incidence of intradialytic hypertension between groups. Conversely, angiotensin II may have enhanced hemodynamic status in these patients since fewer patients receiving angiotensin II required fluid bolus administration during their treatment.

Unlike for vasodilatory shock, the optimal dosing and titration regimen for the prevention of cramps in patients undergoing IHD is unknown [15, 16]. Therefore, we opted for a lower starting dose of 1 ng/kg/min and implemented a cautious titration regimen, as described in the Methods, aimed at ensuring blood pressure stability. The median maximal dose required to achieve a satisfactory hemodynamic response (defined as an SBP less than 180 mm Hg) was 2.5 ng/kg/min, which is in keeping with a systematic review that evaluated the safety of intravenous angiotensin II in different study cohorts, including healthy controls [17]. Importantly, the dose of angiotensin II was stable throughout the dialysis session, which has important implications for translation of this intervention to the clinical setting.

Our findings of efficacy in the reduction of cramp frequency and intensity with angiotensin II are supported by the contemporary understanding of intradialytic cramp pathophysiology. The RAAS is believed to play a key role in maintaining skeletal muscle perfusion through the action of angiotensin II on pre- and postcapillary vessel tone [7]. RAAS dysfunction (including failure of RAAS activation) occurs commonly in maintenance IHD patients and may predispose to cramping in this group [18, 19]. Krop et al. [20] discussed the disappearance of renin and prorenin post-nephrectomy, suggesting potential mechanisms that further contribute to the reduced RAS activity observed in IHD patients. Kovarik et al. [21] also provided valuable insights into the molecular regulation of RAS in IHD patients, confirming suppressed RAS activity and altered renin and angiotensin II levels in this population. In the absence of sufficient RAAS activation and augmentation of angiotensin II production, skeletal muscle capillaries undergo derecruitment, which impairs oxygen delivery and increases the risk of skeletal muscle ischemia [7]. Supporting this hypothesis, pharmacological blockade of the RAAS with captopril was found to worsen cramps in a double-blinded, placebo-controlled, randomized trial of IHD patients [19]. Similarly, an observational study of IHD patients reported greater exposure to RAAS inhibitors in patients with cramps compared to patients without cramps [3].

It is therefore plausible that infusion of low-dose angiotensin II during dialysis may restore physiological RAAS responses to the circulatory stress induced by IHD and prevent skeletal muscle ischemia. The positive effect of angiotensin II on skeletal muscle perfusion has been previously reported by Fliser et al. [22] who found significantly higher mean leg muscle blood flow in normal subjects receiving angiotensin II at a dose of 5 ng/kg/min compared to those given placebo.

Clinical Implications

Our findings imply that low-dose angiotensin II infusion is likely safe in IHD patients. They also imply that angiotensin II may be an effective way of decreasing the frequency and pain intensity of intradialytic muscle cramps. Moreover, they confirm the effect of angiotensin II on blood pressure and suggest that such treatment may decrease the use of fluid bolus therapy during IHD. Finally, they indicate that the increase in blood pressure with angiotensin II does not adversely affect CO. Whether this therapy can be delivered in the community IHD setting requires exploration in subsequent work.

Strengths and Limitations

This study has several strengths including that it is the first controlled trial to evaluate the safety and efficacy of intravenous angiotensin II in IHD patients who experience frequent intradialytic cramps. Although the sample size was small, its crossover design allowed for more precise estimation of the treatment effect within individual patients. Any concern regarding contamination between study arms was mitigated by a 1-week “washout” period, which was far greater than the half-life of angiotensin II (<1 min). The study also benefited from rigorous bedside monitoring by investigators, which enhanced its internal validity through frequent measurements of cramp intensity using a validated tool. Finally, blinding of patients and dialysis staff to the intervention was performed to minimize bias associated with dialysis treatment alteration and reporting of cramp-related symptoms.

In addition to these strengths, we also acknowledge several limitations with this study. First, the investigators were not blinded to treatment allocation, which may have influenced their perception of adverse events. However, objective definitions were used for all adverse effects, while the reporting of cramps and pain intensity was performed by patients who were blinded to their treatment allocation. Second, the small sample size increases the risk of type 2 error with regards to reporting of adverse events and precludes sex-stratified analyses. Such limitations will be explored in more detail through future work. Third, the absence of skeletal muscle blood flow measurements means we lack direct data on the treatment’s physiological impact on muscle capillaries. We therefore relied on surrogate measures including biomarkers. Fourth, while we demonstrated a degree of safety and efficacy over a 4-week intervention period, the chronic nature of dialysis-related muscle cramps necessitates long-term safety data in the future. Therefore, larger studies are necessary to validate the efficacy and safety of this intervention when given over a prolonged period.

In this pilot, single-blinded, placebo-controlled, randomized crossover trial of IHD patients who experience frequent intradialytic cramps, angiotensin II infusion during dialysis appeared safe. Angiotensin II significantly reduced both the frequency and intensity of muscle cramps, as well as the use of fluid bolus administration. Additionally, it did not impact markers of cardiac or muscle injury. Our study lays the groundwork for future larger studies to investigate the long-term safety and efficacy of angiotensin II therapy as a treatment to prevent or attenuate the frequency and intensity of intradialytic cramps in at risk patients.

We thank the study participants, all participating investigators, and supporting dialysis staff.

Ethical approval was obtained from the Austin Health Human Research Ethics Committee (HREC/94599/Austin-2023). The study was registered in the Australian Clinical Trial Registry (ACTRN12623000980639) and was conducted in alignment with the ethical standards outlined in the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from all participants before enrolment.

J.W. is the C.E.O. and part owner of Proletariat Therapeutics, Inc., who supplied the study drug. L.C. and A.A. are affiliated with Proletariat Therapeutics, Inc. There are no other conflicts of interest to declare.

Study drug was provided by Proletariat Therapeutics Inc. E.S. is supported by a Jacquot Research Establishment Fellowship.

E.S., J.W., M.C., and R.B. contributed to the conception and design of the study. A.P., C.B., G.G., N.P., Y.H., G.E., A.A., P.M., and W.L. were involved in patient recruitment and study conduct. A.C., A.M., A.P., and S.S. provided the data analyses and directly accessed and verified the underlying data reported in the manuscript. A.P., E.S., and R.B. wrote the first draft of the manuscript. All authors contributed to the interpretation of the data and critically revised the manuscript.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (E.S.) upon reasonable request. Requests for data access can be directed to [email protected].

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