Italian Nephrologists Invent Renal Replacement Machine for Neonates

Italian Nephrologists Invent Renal Replacement Machine for Neonates

Some of the smallest infants with acute kidney injury (AKI) can now seize the day—with a dialysis system specifically designed for them. The Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM) is the first continuous renal replacement therapy (CRRT) designed for neonates.

Speaking at the European Renal Association—European Dialysis and Transplant Association conference in Amsterdam, Claudio Ronco, MD, of the International Renal Research Institute at San Bortolo Hospital in Vicenza, Italy, said that current CRRT systems are often used off-label for infants smaller than 15 kg but are not ideal.

CARPEDIEM, designed for infants weighing 2.5–10 kg, addresses many of the problems with the bigger machines by using a circuit with a priming volume of 27 mL including filter, miniaturized roller pumps providing a flow as low as 5–50 mL/min, and accurate ultrafiltration with a precision of 1 g. Filters with three different surface areas can accommodate patients of different sizes. Laboratory testing showed quite low levels of microhemolysis. The research team’s work was published in The Lancet on May 24.

“It definitely has been needed for a long time,” Benjamin Laskin, MD, MS, assistant professor of pediatrics in nephrology at Children’s Hospital of Philadelphia, told ASN Kidney News. Adult machines that are approved for patients weighing more than 20 kg have been adapted for infants, “but there are some limitations,” such as needing to prime with more blood and alarms calibrated for larger individuals.

CARPEDIEM provides more options than peritoneal dialysis

After completing a 5-year development project, including in vitro testing of the system, meeting regulatory requirements, and then licensing for human use, the clinicians at San Bortolo Hospital treated a 2.9-kg neonate with hemorrhagic shock, multiorgan dysfunction, and severe fluid overload with CARPEDIEM for more than 400 hours using continuous venovenous hemofiltration, single-pass albumin dialysis, blood exchange, and plasma exchange.

The CRRT was started at 3 days after birth. The neonate’s fluid overload was 63 percent, with a body weight of 5.2 kg. Physicians placed a dual-lumen 22 gauge (4 French) catheter into the femoral vein and began postdilution continuous venovenous hemofiltration with CARPEDIEM at a flow rate of 9–13 mL/min and a daily clearance between 2.2 and 2.8 L, which was an exchange volume close to the patient’s total body water.

The researchers reported that there was no clotting or functional decay in the circuit, nor did any blood contact reactions occur during treatments.

By day 10, the fluid overload was brought down to 33 percent, and at the end of CRRT on day 25 it was 12 percent. Similarly, serum creatinine and bilirubin concentrations and severe acidosis were all managed safely and effectively. The baby was discharged from the hospital at 59 days of age with some mild renal insufficiency that did not require renal replacement therapy.

The researchers concluded that CRRT with CARPEDIEM is “feasible, accurate, and safe.” They advised that dual-lumen catheters smaller than 7 or 8 French, often the smallest available, need to be developed.

Incidence of neonatal AKI higher than previously estimated

The incidence of neonatal AKI has been underestimated at about 1–2 percent for many years. But in neonates weighing more than 2 kg and admitted to neonatal intensive care units, the incidence has been estimated in one study at 16 percent, and it may be much higher than that.

Timothy Bunchman, MD, professor and director of pediatric nephrology at Virginia Commonwealth University School of Medicine in Richmond and co-chair of an April 2013 National Institutes of Health workshop on neonatal AKI, told ASN Kidney News, “The incidence is huge. It’s anywhere between 10 to 80 percent, depending on what population you look at and literature you use.” Of those, “maybe only 5 percent” require dialysis.

But that 5 percent is still a large niche for which options have been lacking. “It’s a breakthrough in an area that’s very difficult,” Bunchman said.

Peritoneal dialysis (PD) will still be the treatment of choice for most infants needing renal replacement therapy. “But we can’t use it in all situations,” said Laskin, who wrote an editorial to accompany The Lancet article. He cited situations in which neonates have had abdominal surgery, instances in which metabolic toxins or electrolytes such as potassium need to be removed quickly, or cases of toxic ingestions in which PD does not work as well as hemodialysis.

Besides continuous venovenous hemofiltration, CARPEDIEM can extend the range of extracorporeal treatments, allowing continuous venovenous hemodiafiltration, plasma exchange, blood exchange, and single-pass albumin dialysis, and also provide fluid management after cardiac surgery.

CARPEDIEM advantages and cautions

Bunchman said that a system with a 52-mL extracorporeal circuit is approved in Europe, “but the CARPEDIEM is literally half that volume. It’s 27 milliliters…. It allows one to safely and easily do extracorporeal therapies in kids probably down to about 2 kilos.”

But he thinks that problems with typical larger catheters may be magnified with the smaller ones. “You can have hemolysis. Literally placing the thing is the difficult part—getting a small catheter in some of these small guys,” he said. “So placement, flow characteristics, destruction [of blood elements], occlusion, clotting, infection—all those are risk factors associated with the smaller catheters.”

On the other hand, lower-volume circuits can be a good thing. Laskin said that CARPEDIEM avoids problems associated with larger circuits. “Number one, giving the blood when you prime can cause bradykinin release, which can lead to hypotension,” he noted, “and in the long term, we think, we don’t know, that the more blood products that we expose these kids to may increase their risk of getting sensitized for later transplants.”

The machine appears to remove fluid well, but Laskin said the researchers still need to validate that it adequately clears solutes at lower flow rates and with small catheters. “It will be important in babies that are anuric to make sure we’re removing enough toxins, too.”

Both Laskin and Bunchman said they were disappointed that the research report involved only one patient. “Through the rumor mill, I know they’ve used it on four or five kids,” Bunchman said.

Although PD will remain the most commonly used form of dialysis in infants worldwide because of simplicity and access to resources, “This actually will add a niche, but in only certain countries” with higher incomes and a high level of medical sophistication, said Bunchman. He advised that more nondialytic therapies need to be developed, some of which are already coming along. Even in richer, more developed countries, “This is not going to be in the community [hospitals]. This is going to be at university and tertiary-based centers completely,” he predicted.

Even there, and considering that “the pediatric neonatologists are very excited,” Bunchman foresees that neonatologists may be a barrier to the adoption of a system like CARPEDIEM. “This is a foreign concept to neonatologists. It’s just outside their comfort zone,” he said. But a device specifically designed for some of the smallest patients and that avoids jury-rigging adult dialysis machines may in the end help to raise neonatologists’ comfort level and lessen their resistance.