Mechanical stress-related haemolysis in a paediatric haemodialysis patient

Abstract

Haemodialysis (HD) is a common kidney replacement therapy (KRT) used in the management of children with end-stage kidney disease (ESKD). We describe the case of a 2-year-old child who developed mechanical intraluminal haemolytic anaemia secondary to the acute angulation of the HD line. In contrast to reports of arteriovenous fistula-associated haemolysis, onset was insidious in nature and detected through review of subtle serial biochemical and haematological changes. Development of hyperbilirubinaemia during HD was modest due to the partial clearance of bilirubin via HD-enabled diffusion. The only persistent and consistent marker was the post-HD rise in lactate dehydrogenase in association with decreasing haemoglobin. We propose that mechanical stress-induced haemolysis should be considered in children on HD who develop unexplained or persistent anaemia with resistance to increasing doses of iron and erythropoiesis-stimulating agent supplementation.

Background

Worldwide, nine per million children develop end-stage kidney disease (ESKD). In the UK, 11.4% of these children receive kidney replacement therapy (KRT) via haemodialysis (HD).^{1 2} Dual processes of diffusion and convection are employed for the removal of excess fluid, waste products, uraemic toxins and electrolyte homeostasis. Haemolysis is a potentially life-threatening event that is rarely witnessed during HD.³ It is often difficult to recognise due to the existing haematological and biochemical disturbances caused by the underlying kidney disease. Its identification is critical considering the additional risks posed by significant anaemia and hyperkalaemia, both of which can result in significant morbidity and mortality.⁴

Case presentation

We describe the case of a 2-year-old child with a background of chronic kidney disease (CKD) stage 5 secondary to Finnish type congenital nephrotic syndrome (NPHS1 mutation). HD was commenced at 17 months of age following failure of peritoneal dialysis due to life-threatening coliform peritonitis. An 8Fr (French gauge) 18 cm length double-lumen haemodialysis catheter (Medcomp) was inserted into the right internal jugular vein (RIJV). HD was commenced with an SF03 dialyser (AK98 Baxter Gambro), using blood flow rates of 80 mL/min for 4 hours, three times per week. The HD line required revision 1 month post-insertion following persistence of bacterial blood culture growths with Raoultella planticola spp. One week later, the line was pulled back to a satisfactory position after plain radiograph demonstrated a low position following concerns with stiffness on flushing during dialysis.

Six months after commencing HD, the patient was noted to have frequent episodes of symptomatic anaemia with mild hyperbilirubinaemia despite optimised haematinics (tables 1 and 2). Over 1 month the patient required three packed red cell transfusions to maintain haemoglobin concentrations above 70 g/L. This was despite weekly intravenous injections of erythropoietin (Aranesp) 30 µg (3 µg/kg) and fortnightly iron sucrose (Venofer) 20 mg (2 mg/kg).

Table 1.

Haematological and biochemical profiles during suspected period of haemolysis

Day	Pre-HD Hb	Post-HD Hb	Retics	Pre-HD SBR	Post-HD SBR	Pre-HD LDH	Post-HD LDH	RBC tx
1	–	113	2.55	–	<3	–	–	No
5	–	85	–	–	4	–	–	No
19	56	77	6.25	4	25	–	–	Yes
33	–	59	11.68	<3	–	–	–	No
34	66	–	–	6	–	–	–	Yes
36	–	112	7.26	–	31	–	–	No
39	–	97	–	–	50	–	–	No
42	–	–	–	8	43	–	–	No
44	–	–	–	4	34	–	–	No
50	58	–	10.19	–	12	2120	–	No
51	93	101	7.19		7	1423	1364	Yes
52	94	–	–	6	6	–	–	No
54	90	92	–	3	5	599	652	No
55	91	92	5.68	4	6	–	555	No

As highlighted in green: on day 39, haemodialysis (HD)-related haemolysis was suspected. On day 50, diagnosis was confirmed and on day 52 single needle HD was commenced. Following this, stabilisation of blood results is observed. Units are expressed as follows: haemoglobin (Hb) g/L (normal range 101–138), reticulocytes (retics) % (normal range 0.2–2), serurm bilirubin (SBR) umol/L (normal range 0–21) and lactate dehydrogenase (LDH) IU/L (normal range 196–314). Packed red blood cell transfusions (RBC tx) were given during HD sessions on the dates highlighted in yellow.

Table 2.

Investigations undertaken at time of suspicion of haemodialysis-related haemolysis.

Investigation	Result
Platelets	356×109 /L (normal range 150–550)
Direct coombs test (DCT)	Transiently positive following RBC transfusion-resolved when repeated after 24 hours
Haemoglobinopathy screen	Thalassaemia and sickle cell disease excluded
Ferritin	496 µg/L (normal range 13–150)
Iron	14.5 µmol/L (normal range 10–25)
Transferrin	2.3 g/L (normal range 2.2–3.37)
Vitamin B12	1022 ng/L (normal range 197–1999)
Folate	>20.1 µg/L (normal range 3.9–20)
Reticulocytes	10.19% (normal range 0.2%–2%)
G6PD	Rejected by laboratory as patient female
Pyruvate kinase level	15.5 U/gHb (normal range 6.2–14.2)
Co-oximetry	No methaemoglobinaemia
Hepatitis B	Not detected
Hepatitis C	Not detected
Epstein-Barr Virus (EBV) PCR	Not detected
Cytomegalovirus (CMV) PCR	Not detected
Parvovirus B19 PCR	Not detected

Investigations

During one particular HD session the patient became acutely irritable with pallor, sweating and bradycardia. Dialysis was terminated and the circuit was washed back with immediate improvement in skin perfusion and observations. A significant drop of 15 g/L in haemoglobin over a 3-day period with mild hyperbilirubinaemia of 50 µmol/L and altered, macroscopically darkened haematuria was identified (table 1). Of note, no thrombocytopenia or disturbance in the coagulation cascade was detected. During subsequent HD sessions the patient remained clinically asymptomatic despite persistent haematological and biochemical disturbances. A working diagnosis of HD-related haemolysis was thus formulated and bloods were subsequently obtained prior to and following each HD session. Following HD, an acute rise in serum bilirubin, lactate dehydrogenase (LDH) and a drop in haemoglobin was noted. Haptoglobin levels were also assessed in this manner on day 50 (table 1). This identified a baseline low haptoglobin level of 0.11 g/L prior to the HD session, indicating chronic haptoglobin consumption, consistent with haemolysis. Following HD this further dropped to an undetectable concentration (<0.08 g/L), confirming the suspicion that haemolysis was occurring during HD sessions.

On identification of HD-related haemolysis a contrast chest fluoroscopy of the HD line was undertaken (figure 1). This identified an acute angulation of the red proximal lumen with maintained patency of the blue distal lumen. Mechanical stress-induced haemolysis secondary to the partial obstruction of blood flow was thus diagnosed.

Figure 1.

Contrast fluoroscopy highlighting the angulation of the proximal red haemodialysis lumen.

Differential diagnosis

Before the diagnosis of mechanical intraluminal HD-related haemolysis was made, other common causes of haemolysis were tested for and excluded (table 2). These include pyruvate-kinase deficiency, haemoglobinopathy disorder, heparin-induced thrombocytopenia, methaemoglobinaemia, hypophosphataemia, cytomegalovirus (CMV) viraemia, parvovirus viraemia and acute epstein-barr virus (EBV) infection. Bacteriaemia was excluded through frequent negative blood and urine cultures with persistent absence of a rise in inflammatory blood markers.

A G6PD screen was rejected by the laboratory team due to the patient’s female gender. Since the underlying cause of their haemolysis was identified and rectified with no further episodes of haemolysis, a decision was made to not send a formal G6PD genotype. Further attempts at G6PD enzyme activity phenotyping would be equally unfeasible due to acquisition of multiple packed red blood cell transfusions. Drug-induced haemolysis was considered as the patient was treated with prophylactic phenoxymethylpenicillin and aspirin. However, this was similarly rejected following resolution of the underlying aetiology despite lack of medication change.

During the period of episodic haemolysis the patient was dialysed with a dialysate temperature of 36.5°C using an A/231 (1+34) acid concentrate with an electrolyte composition of 135 mmol/L sodium, 2 mmol/L potassium, 1.5 mmol/L calcium, 34 mmol/L bicarbonate and 1 g/L of glucose. These are standard settings used within the department for a patient of their age and size. Haemolysis secondary to high dialysate temperature or hypo-osmolar dialysate was thus excluded. All the dialysis machines used in the dialysis unit are supplied with the same water supply. Since the other children within the department were unaffected by a similar presentation and the symptoms were patient specific over a few days, haemolysis secondary to a contaminated water supply was equally rejected.

Treatment

Due to a background of previous paediatric intensive care unit (PICU) admissions requiring multiple central line insertions, revision of the current HD line was not guaranteed to be successful due to potential vascular stenosis or scarring. Peritoneal dialysis was no longer an option due to previous peritoneal failure. Therefore, removing the HD line may have left the patient without an option for effective dialysis. As a living-related kidney transplant was planned for the near future, subsequent HD sessions were undertaken using a single-needle technique via the blue distal lumen. Since single-needle dialysis is less efficient, HD sessions were increased to 4 days per week to allow for equivalent clearance. No further HD-related haemolysis was subsequently observed. Hyperbilirubinaemia, anaemia and elevated LDH levels all resolved.

Outcome and follow-up

The patient continued to be effectively dialysed on single needle HD. Following bilateral nephrectomies, they progressed to a successful living-related kidney transplantation from their parent.

Discussion

We describe the rare presentation of a 2-year-old child with HD access-related haemolysis secondary to the mechanical shearing stresses of non-laminar, turbulent blood flow in a partially obstructed line lumen. To the best of our knowledge, on review of the literature this has only been reported once in a 13-year-old child and again in a 66-year-old adult.^{3 4} Both cases were severe and acute in presentation and were secondary to mechanical haemolysis within the arteriovenous (AV) fistula rather than within a HD catheter. Previous in vitro studies have equally identified mild degrees of red blood cell fragmentation within HD filters but these were all limited to bovine blood in comparison to human subjects.^{5 6}

In contrast with reported cases, our patient displayed a more insidious onset of often asymptomatic haemolysis which was only noted on retrospective analysis of their haematology and biochemistry records. The level of haemolysis was such that the patient only developed symptoms when this process persisted over a longer period. This illustrates the need to have a high index of suspicion of HD-related haemolysis when children on HD develop unexplained or persistent anaemia despite high doses of iron and erythropoiesis-stimulating agents.

Although bilirubin is an effective biochemical tool in aiding this diagnosis, its partial clearance during HD can result in only modest post-haemolysis rises. LDH is a more sensitive, but non-specific, indicator of red blood cell lysis but is not routinely tested for in patients on HD. We therefore suggest review of LDH levels in children with unexplained HD-related anaemia. With the eventual aim of renal transplantation, frequent use of blood transfusions should be limited in order to prevent unnecessary sensitisation to donor HLA class 1 antigens.⁷ This is undesirable and limits the suitability of available donor organs. HD-related haemolysis should therefore be suspected, identified and treated early in order to minimise the need for recipient HLA exposures.

Patient’s perspective.

Statement from patient’s mother

I was initially very apprehensive when I was informed about her anaemia as my mother died of leukaemia and I was scared she would have the same. While waiting for a diagnosis it was hard as I was bringing her in for blood transfusions and investigations more frequently, meaning my other child was not getting enough attention. However, since going on to single needle dialysis she’s been so much better. Since her transplant it’s been brilliant as I can give more time to all of my children without feeling guilty.

Learning points.

• Haemodialysis (HD)-related haemolysis should be considered in all children on HD presenting with unexplained, persistent or refractory anaemia.

• HD-related haemolysis can be insidious in onset.

• Haemolysis-related hyperbilirubinaemia is often modest in patients with HD due to clearance during dialysis.

• Markers used in the diagnosis of HD-related haemolysis include full blood count, reticulocyte count, lactate dehydrogenase, haptoglobins, bilirubin and blood film. All should be requested when suspecting HD-related haemolysis.

• In addition to exclusion of commonly known medical causes, angulation and partial obstruction of HD lumens should be investigated with fluoroscopy (linogram).

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).