#46: NephMadness 2022: Neonatal AKI

March 16, 2022 | By Sam Masur

NephMadness 2022 Pod Crawl:

Resuscitate your inner nephrology nerd with a bolus of kidney themed podcast episodes in the first annual NephMadness Pod Crawl featuring topics like cardiorenal syndrome, hemodialysis, proteinuria, neonatal AKI, and inequalities in nephrology! The pod crawl starts Monday March 14, 2022 with The Curbsiders Cardiorenal episode and continues all week! Check out the other podcasts in the pod crawl, and fill out your brackets for NephMadness 2022 #nephmadness #NephPodCrawl

Summary

Time to start small as The Cribsiders take their first step into nephrology with Dr. Michelle Starr (Indiana).  For NephMadness 2022, we discuss Neonatal Acute Kidney Injury, including neonatal physiology, diagnosis of AKI, fluids, and dialysis for the tiniest babies. Urine for a real treat!

Credits

• Producer, Writer, Infographic, and Showrunner: Sam Masur MD 
• Executive Producer: Nick Lee MD
• Cover Art: Chris Chiu MD
• Hosts: Justin Berk MD, Chris Chiu MD, Sam Masur MD
• Editor:Justin Berk MD; Clair Morgan of nodderly.com
• Guest(s): Michelle Starr MD MPH

Neonatal AKI Pearls

1. Gestational age determines nephron number. The more premature the infant, the fewer nephrons it starts with
2. Urine output is a poor marker for kidney function in neonates because of immature tubules. They will continue to make urine even if they are volume depleted.
3. Dialysis remains the mainstay of treatment for acute injury when there is no improvement with supportive care. As of 2022, nephrologists can perform hemodialysis in babies as small as 1.3kg
4. If there is no anatomical obstruction, fluids are the initial treatment for AKI
5. Dr. Starr recommends bolusing to achieve goal weight, then using continuous fluids to replace insensible losses while determining how the kidney is responding.
6. UTIs can often cause a mild type 4 RTA due to a pseudo-hypoaldosterone state. If you see high creatinine, low bicarbonate, hyperkalemia, and hyponatremia, you may be able to predict the infection!

SPONSORS: VCU Health CE

We are excited to announce that the Cribsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out cribsiders.vcuhealth.org and create your FREE account!

Neonatal AKI Notes

Newborn Renal Physiology

Nephrogenesis

Gestational age determines nephron number. The more premature the infant, the fewer nephrons it starts with. Post-natal nephrogenesis occurs in the first few weeks after birth, but then quickly trails off. New research on how to maximize post natal nephrogenesis is ongoing.

Glomerular Filtration Rate (GFR)

GFR is the total of the filtration rates of the functioning nephrons in the kidney (National Kidney Foundation). It takes approximately 2 years to fully mature GFR with functioning nephrons. Per Dr. Starr, an ex-30 week neonate probably has a GFR of 20-25 mL/min/1.73m2, which is considered poor kidney function. 

Serum Creatinine

Babies are born with their mother’s serum creatinine (sCr), which they clear over the first week or two of life. According to Dr. Starr, sCr should be approximately 0.2-0.3 by DOL14. On DOL1, the serum creatinine represents a single point in time, but we don’t know if this number is rising or falling without a second value.

Other Biomarkers for Kidney Function

Serum creatinine (sCr) has been the mainstay of estimating kidney function, but it is an imperfect marker determined by muscle mass and clearance. Here are other biomarkers that may be helpful:

• Cystatin C: A protein released by all cells in the body, not affected by age, size, etc, and filtered by the kidney. Dr. Starr will check it in neonates, but uses it as a marker for chronic kidney function rather than acute injury.
• Urinary NGAL (neutrophil gelatinase-associated lipocalin): An iron transport protein that accumulates in the urine in the setting of kidney injury.

Per Dr. Starr, the issue with cystatin c and creatinine is they are markers of kidney damage. Once these biomarkers are elevated, the damage has already been done. The goal is to identify markers which we can act upon before damage occurs, such as uNGAL. 

Acute Kidney Injury in the NICU

Definition

In neonates, AKI is defined by increase in serum creatinine by 0.3mg/dL from baseline level OR decrease in urine output. Both are challenging indicators in neonates, as baseline sCr is difficult to determine, and babies rarely become oliguric (see below).

Urine Output

Urine output is a poor marker for kidney function in neonates because of immature tubules. Without a fully functioning distal convoluted tube (DCT) and collecting duct (CD), babies cannot concentrate their urine. Thus, they will continue to make urine even if they are volume depleted. This should normalize by the time they reach a full-term corrected gestational age.

Preventing AKI in Neonates

Theophylline has been shown to prevent AKI in neonates with Hypoxic Ischemic Encephalopathy (Raina, 2016). By working on adenosine receptors to prevent vasoconstriction, theophylline (adenosine receptor antagonist) improves blood flow to the kidney and improves GFR. 

Caffeine, as a similar compound to theophylline, has also been shown to prevent AKI. In VLBW infants who are already receiving caffeine for apnea of prematurity, researchers found the incidence of AKI to be much lower (Carmody, 2016). Using retrospective data from the AWAKEN trial, giving caffeine within the first week of life to preterm infants decreased the risk of AKI with a NNT of 4!

Differential Diagnosis

Applies for ALL ages, including the neonate through the adult. Nevertheless, the common etiologies in neonatal AKI is prerenal AKI from poor fluid intake and postrenal AKI from anatomic obstruction. 

• Pre-Renal Azotemia → impaired perfusion to glomerulus

• Intrinsic Disease/Renal Azotemia → glomerular, tubular, interstitial, or vascular injury

• Post-Renal Azotemia → obstruction distal to the kidney

Dialysis in the NICU 

Dialysis remains the mainstay of treatment for acute injury when there is no improvement with supportive care. Peritoneal dialysis (PD) used to be the only form of dialysis that could be performed on premature infants because of size restrictions, but it did not work very well due to risk of NEC and perfusion complications. With new technology, hemodialysis (HD) in the premature infant has become a reality again. As of 2022, nephrologists can perform HD in babies as small as 1.3kg.

Indications for Dialysis: Everyone’s favorite mnemonic AEIOU

• Acidosis
• Electrolyte abnormalities (hyperkalemia or hyperphosphatemia)
• Intoxication (inborn error of metabolism/hyperammonemia in neonates)
• Overload (Respiratory distress is not the only marker for volume overload. Dr. Starr recommends dialysis for those babies who cannot get adequate nutrition due to fluid restrictions from volume overload)
• Uremia

Most babies placed on dialysis will recover kidney function with time after the initial nephrotoxic insult has passed. But those with congenital renal failure due to dysplasia must be bridged to transplant. Those babies will remain on hemodialysis for weeks until they are large enough for successful peritoneal dialysis, at which point they can remain on home PD until they eventually undergo kidney transplant. 

AKI in the Nursery

Risk Factors

• Birth trauma
• Perinatal asphyxia
• Nephrotoxins, including NSAIDs for PDA, imaging contrast, and antibiotics such as gentamicin

NINJA is a quality improvement program used to decrease incidence of AKI in babies at high risk from nephrotoxins. It involves screening for those who have received 3+ days of an aminoglycoside or 3 total nephrotoxic meds on the same day, obtaining a daily serum creatinine birth, and adjusting future exposures as a result.

Urine Output

The most common cause of anuria in the first 24 hours of life is false alarm – the baby urinated in the delivery room, but it was missed.  Dr. Starr becomes concerned at 48 hours of life without urine output. Until that time, low GFR can explain poor urine output, especially with routine prenatal care and normal prenatal ultrasounds.

Workup

• Renal bladder ultrasound looking for outflow obstruction due to anatomic reasons
• Serum creatinine. We should know mom’s creatinine in order to approximate what to be expected

Treatment

If there is no anatomical obstruction, fluids are the initial treatment as the most common etiology for AKI in this age group is dehydration/poor fluid intake. 

Although urine output is difficult for diagnostic purposes in infants, it can be trended for improvement.

AKI in the Pediatric Emergency Department

Workup

Dr. Starr recommends the following workup in a baby with AKI. She believes the clinical history is much more accurate than FENa in determining etiology of the AKI, especially with immature nephrons. 

• Basic metabolic panel
• Urinalysis
• Urine sodium
• Weight as a marker of volume status
• +/- Renal bladder ultrasound depending on clinical history

Dr. Starr’s Tip: UTIs can often cause a mild type 4 RTA due to a pseudo-hypoaldosterone state → if you see elevated creatinine, low bicarbonate, hyperkalemia, and hyponatremia, you may be able to predict the infection!

Treatment

Fluids are the main treatment for AKI, regardless of age. The goal is to return the child to a normal fluid balance. In an infant, weight can be used as a marker of normal fluid balance. 

• Dr. Starr recommends bolusing to achieve goal weight. Normal Saline is actually an abnormal fluid with high amounts of chloride, so she recommends switching to lactated ringers after any initial resuscitation.
• Then use continuous fluids to replace insensible losses while determining how the kidney is responding. Dr. Starr approximates insensible losses at ⅓ maintenance
• In an infant with actively maturing nephrons, Dr. Starr will order a urine sodium, and match fluids appropriately. For example, if urine Na is 70-80, then half normal saline may be a perfect fluid.

Dr. Starr recommends checking sCr once daily, as it’s a delayed marker of renal function. Urine NGAL is not as delayed as sCr, but it is an inflammatory marker that can be confounded by the underlying illness. Clinical markers such as heart rate, urine output, blood pressure, and weight are more immediately useful.

Disparities in Acute Kidney Injury

Previous calculators have used ethnicity and race to define risk of acute kidney injury. Underrepresented patients, such as black and latinX babies, do experience higher rates of acute kidney injury, but this is not due to their race/ethnicity but rather their social determinants of health. Acute kidney injury is much more prevalent in premature infants, and with higher rates of food insecurity, black and latinX mothers have a higher rate of premature delivery.  Thus, the risk of acute kidney injury comes from risk of prematurity, not race or ethnicity itself. In addition, poor maternal nutrition has been linked to lower nephron number in animal models (Lee 2019), which might explain how food insecurity may have a larger impact on kidney injury than we previously thought.

Consequences of AKI

Every episode of acute kidney injury causes some nephron loss. In addition, all humans lose nephrons over time as they get older. Babies born very premature (< 28 weeks gestation) have a much higher incidence of chronic kidney disease. The thought is if you have fewer nephrons to start with, every kidney injury increases the risk of chronic kidney disease.

Links

Check out the Neonatal Kidney Collaborative!

And don’t forget about Nephmadness 2022, where your team can still win!

Goal

Listeners will learn to diagnose acute kidney injury both in and out of neonatal intensive care, as well as treat most etiologies of kidney disease. 

Learning objectives

After listening to this episode listeners will…  

1. Identify the differences in nephron number by gestational age
2. Be familiar with the diagnostic criteria for acute kidney injury
3. Learn the appropriate workup for acute kidney injury
4. Recall the indications for dialysis and who may receive it
5. Describe the fluid management for acute kidney injury

Disclosures

Dr Starr reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Masur S, Starr M, Lee N, Chiu C, Berk J. “#46: NephMadness 2022: Neonatal AKI”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ March 16 2022.