Complications

Most complications of continuous kidney replacement therapy (CKRT) can be classified into three main categories:

Severe allergic reactions to the filter or circuit tubing and circuit-associated haemolysis have been described, but these complications are rare.

Although the relationship between CKRT and thrombocytopenia has been recognised clinically for years, recent observational data have reaffirmed an association between CKRT and reduced platelet counts in treated patients.

The decrease is usually relatively limited, approximately 33%–50% of the baseline value.

Given the many possible causes of thrombocytopenia in critically ill patients, CKRT should be considered its cause only after other causes have been excluded.

Metabolic complications of regional citrate anticoagulation (RCA)

Despite its high efficacy, RCA may cause a variety of metabolic disturbances.

Because each citrate molecule is metabolised to 3 bicarbonate molecules, the most common complication is metabolic alkalosis.

This condition may be termed:

— Citrate excess.

— Or excess alkalinity/base (buffer excess).

It differs from citrate accumulation, and distinguishing the two is essential, as discussed later.

Treating RCA-associated alkalosis

Alkalosis associated with RCA can be treated in several ways:

By increasing the rate of:

The aim is to increase citrate removal through the filter.

The bicarbonate concentration in the other CKRT solutions can also be reduced.

Calcium and magnesium disturbances with RCA

Isolated low or high ionised calcium is relatively common and is usually corrected by adjusting the calcium infusion rate after the filter or through systemic infusion.

Some commonly used citrate formulations, such as:

— Trisodium citrate

— ACD-A

Are hypertonic and may therefore cause mild hypernatraemia.

Finally, RCA may cause hypomagnesaemia because citrate also chelates magnesium (Mg), although less strongly than calcium.

Citrate Accumulation

This is the most concerning complication of RCA and is also termed citrate toxicity or citrate lock.

Because most clinical laboratories do not directly measure plasma citrate concentration, the total-to-ionised calcium ratio (tCa/iCa) is used as a surrogate marker of citrate accumulation; see the details below.

Since approximately 50% of total calcium is normally in the ionised form, this ratio is usually about 2 : 1.

Note that some hospitals measure total and ionised calcium in different units.

Diagnosing citrate accumulation

Clinically important citrate accumulation leads to accumulation of calcium–citrate complexes, resulting in:

— Increased total calcium, tCa.

— And/or reduced ionised calcium, iCa.

A tCa / iCa ratio ≥2.5 indicates important citrate accumulation.

Correction of total calcium for albumin in hypoalbuminaemia is generally not recommended, and at least one study suggests that this correction is probably unnecessary.

Citrate accumulation and acid–base disorders

An increased tCa/iCa ratio usually appears before a clear change in the anion gap. As citrate accumulation continues, a clinically important increase in the anion gap eventually develops.

By definition, this increase in the anion gap represents a form of acidosis.

However, in many cases, sufficient accumulated citrate is metabolised to bicarbonate that frank acidaemia is uncommon if citrate accumulation is diagnosed early.

The patient may therefore typically develop a complex mixed acid–base disorder consisting of:

— High-anion-gap metabolic acidosis.

— With simultaneous metabolic alkalosis.

Which in turn keeps pH approximately normal.

Metabolic disturbances without RCA

When regional citrate anticoagulation is not used, CKRT-associated metabolic disturbances may include:

— Hypokalaemia.

— Hypomagnesaemia.

— Hypocalcaemia.

These complications are usually less frequent because most CKRT solutions contain physiological concentrations of:

— Potassium.

— Magnesium.

— Calcium.

Hypophosphataemia with CKRT

In contrast, most commercial CKRT solutions do not contain phosphate, so hypophosphataemia is common during CKRT.

The greater risk of hypophosphataemia with CKRT than with IHD is related to the kinetics of phosphate movement between body compartments (intercompartmental kinetics).

As with potassium, most phosphate is intracellular. Unlike potassium, which is mainly present inside cells as a free ion, most intracellular phosphate is bound to proteins and other molecules. Intracellular phosphate therefore equilibrates with the extracellular compartment only slowly.

Why does CKRT remove more phosphate than IHD?

Because of these slow kinetics, treatment duration is the principal determinant of the amount of phosphate removed by KRT.

Although IHD efficiently removes phosphate from the extracellular compartment, a single IHD session removes only a modest amount of the body’s total phosphate stores.

The continuous nature of CKRT overcomes slow phosphate redistribution between compartments.

When phosphate-free CKRT solutions are used, hypophosphataemia therefore usually develops approximately 48 hours after starting CKRT.

Complications of severe hypophosphataemia

Severe hypophosphataemia may cause several complications, including:

— Muscle weakness.

— Rhabdomyolysis.

— Impaired myocardial function.

CKRT-induced hypophosphataemia has also been associated with longer mechanical ventilation or a greater need for tracheostomy.

Although no data establish that preventing hypophosphataemia improves clinical outcomes, measures to reduce the risk of CKRT-induced hypophosphataemia are nevertheless recommended.

Preventing hypophosphataemia

Options include using phosphate-containing CKRT solutions or starting scheduled prophylactic phosphate replacement once the initial AKI-associated hyperphosphataemia has been corrected.

In 2015, the US Food and Drug Administration approved premixed phosphate-containing CKRT solutions.

Alternatively, pharmacists can prepare these solutions by adding phosphate to conventional phosphate-free solutions.

In some cases, phosphate preparations can also be added directly to commercially available solutions.

Phosphate-containing CKRT solutions and low glucose

Finally, unlike most other CKRT solutions, which contain physiological glucose concentrations, commercial phosphate-containing CKRT solutions are glucose-free.

This may cause additional complications in patients not receiving nutrition or another glucose source, particularly:

— Hypoglycaemia.

— Or euglycaemic ketoacidosis.

Euglycaemic ketoacidosis during CKRT

Euglycaemic ketoacidosis usually presents with:

— Unexplained metabolic acidosis with an elevated anion gap (AG).

— Normal blood glucose.

— Ketone bodies in the blood.

Treatment requires dextrose and insulin infusions.

Therefore, in any patient receiving CKRT who develops high-anion-gap metabolic acidosis (AGMA) without elevated lactate or evidence of citrate accumulation, euglycaemic ketoacidosis should always be included in the differential diagnosis.

References

[1] Kovvuru K, et al. Complications associated with continuous renal replacement therapy. Semin Dial. 2021. doi:10.1111/sdi.12970.

[2] Zarbock A, Küllmar M, Kindgen-Milles D, et al. Regional citrate versus systemic heparin anticoagulation during CKRT: the RICH trial. JAMA. 2020;324:1629–1639. doi:10.1001/jama.2020.18618.

[3] Baeg SI, et al. Association of Phosphate Containing Solutions with Incident Hypophosphatemia in Critically Ill Patients Requiring CKRT. Kidney360. 2021. PMID:33915554.

[4] Tandukar S, Palevsky PM. Continuous Renal Replacement Therapy: Who, When, Why, and How. Chest. 2019;155:626–638. doi:10.1016/j.chest.2018.09.004.