RENAL CHAPTER (Patho)

What is the criteria for diagnosing AKI?

We use Kidney Disease: Improving Global Outcomes (KDIGO) criteria as the standard definition for neonatal AKI in research

Which neonatal population are at high risk of developing AKI and why?

Neonates and infants undergoing cardiac surgery are among the highest risk patients for developing AKI

Because of the complex interaction of risk factors

such as low cardiac output, single ventricle

physiology, ischemic-reperfusion injury, fluid overload (FO), and

nephrotoxic medication (NTX) receipt.

What is the commonalities between NEC & AKI?

Infants with NEC have increased risk for AKI due to the effect of sepsis, hemodynamic instability, NTX receipt, systemic inflammation, increased intrabdominal pressure, and obviously prematurity

What are the top nephrotoxic medications we use in the NICU?

1. Gentamicin (86%)

2. Indomethacin (43%)

3. Vancomycin
   Exposure to nephrotoxic medications interrupts and impairs nephrogenesis by causing AKI.
   
   AKI frequently leads to increased risk of later development of hypertension, proteinuria, and CKD. This occurs through pro-fibrotic healing pathways during AKI recovery

Does AKI increase the chances of IVH? (True or false)

True

While Creatinine is the gold standard for identify AKI, what are some of the challenges ? What are some solutions?

1. It measure Kidney function rather than injury'

2. SCr can also be delayed (48-72hours) of kidney function

Solution
- They are currently testing “novel biomarkers” especially Neutrophil gelatinase associated lipocalin (NGAL - a Protein expressed by multiple tissues including kidney) as it may predict AKI earlier than changes in SCr

How does Methylxanthine Therapy (Theophylline and Caffeine) affect AKI?

Because they are adenosine-receptor antagonists, they prevent the development of AKI by preventing adenosine driven pre-glomerular vasoconstriction and post-glomerular vasodilation.

Theophylline protects the renal tubule, and improves fluid balance, GFR and urine output. 

What does the development of the kidney entails or look like?

Three organs needs to form for the Kidney to be in its known shape or form -

1. Pronephros
   a. Develops first
   b. A small structure of 7 to 10 nephrotomes that develops in the cervical region and regresses by the end of the fourth week of gestation.

2. Mesonephros
   a. Replaces Pronephros when it regresses
   b. It has excretory tubules in an S-shaped loop that includes a glomerulus and Bowman capsule at the proximal end.
   c. it involutes at the second month and its remnant s becomes into the vas deferens in males and vestigial tissue in females.

3. Metanephros (aka definitive kidneys)
   a. Starts to form from the mesoderm when the wolffian duct swells to form the uretic bud.
   b. A signal between metanephric mesenchyme and the uretic bud leads to branching divisions that forms the collecting ducts
   
   A S- shaped is forma the glomeruli, and the cephalic portion forms the tubular elements of the nephron.
   Finally the metanephric kidney ascends up from pelvis to the thoracolumbar region and then the pelvic vasculature from the aorta is replaced with more cephalad vasculature from the aorta.
   
   During the second half of gestation, the metanephric kidney becomes functional and nephrogenesis is complete at 34 weeks’ gestation. Each kidney contains
   800,000 to 1.2 million nephrons

What about the bladder and the urethra ?

• The bladder and urethra develops around the second and third month of gestation

• Between the fourth and seventh weeks of development, the cloaca, which will develop into the urethra and urinary bladder, is separated into the primitive urogenital sinus (ventral portion) and anorectal canal (dorsal portion).

• The primitive urogenital sinus develops into the bladder, prostatic and membranous urethra, and the penile urethra in males.

• In females, it develops into the bladder, urethra, and vaginal vestibule. Subsequently, the ureteral orifices migrate cephalad, and the mesonephric ducts enter the prostatic urethra to form the trigone of the bladder.

What do you think when you hear the word “Hydronephrosis'“?

Basically water in the kidney. Mostly, when something keeps the urine from flowing from the kidney to the bladder. When that happens, one or both kidney swells.

There are three types
1. Vesicoureteral Reflux
- When urine refluxes to various degrees from bladder up into the collecting system. It is caused by abnormal insertion of the ureter into the bladder wall - VUR can happen when the ureter develops an abnormal connection with the bladder, causing the normal one-way valve mechanism to fail. Some cases have a genetic/developmental basis.

The key thing to remember for an exam is: abnormal ureterovesical junction → incompetent anti-reflux valve → urine flows backward → risk of recurrent UTI/pyelonephritis and renal scarring.

- VUR is classified as grades 1 to 5, with grade 1 being the mildest form and grade 5 being the most severe form. Grading of VUR is based on height of the reflux and degree of dilation of the ureters.

2. Ureteropelvic Junction Obstruction
- Impaired urine flow from the renal pelvis into the ureter and is most commonly secondary to congenital obstruction (especially ureteral hypoplasia)


3. Posterior Urethral Valve

- Posterior urethral valve (PUV)
This is the one we see most in the neonates and the most common cause of lower urinary tract obstruction.

- PUV is an obstructing membranous flap or fold in the lumen of the posterior part of the urethra in males.
It can result in various complications including urinary retention, chronic kidney disease (CKD), and (if present in utero, can lead to pulmonary hypoplasia secondary to low amniotic fluid levels)

What is the difference between primary and secondary Vesicoureteral Reflux?

Primary VUR means there is a short length of the ureter that leads to incomplete or improper closure of the ureteral orifice. It can improve as the baby grows.

Secondary VUR occurs due to bladder outlet obstruction and often leads to bilateral reflux.

How is VUR diagnosed ?

Voiding cystourethrogram (VCUG) delineates the anatomy of the urinary system and is the gold standard for diagnosis of VUR

How is UPJ (Ureteropelvic Junction Obstruction) diagnosed and what is done after diagnoses?

• It is diagnosed antenatally with ultrasound during the second trimester.
  
  After diagnosis
  - When baby is born, a renal ultrasonography should be repeated within 48 hours after birth to see if there is severe hydronephrosis (mild or moderate)

How is PUV diagnosed in utero & post nataly? What would we see to know it is PUV?

PUVs occurs exclusively in boys

Antenatally
- We would see bilateral hydronephrosis, dilated prostatic urethra, and distended bladder with thickened wall greater than 3 mm with poor emptying over 30 minutes in the ultrasound.
- In the past, they have also seen “keyhole sign” with dilated proximal urethra but that is under study

Postnatally
- Postnatally we would see lethargy, poor feeding, delayed voiding, and palpable bladder, to urosepsis in the most severe cases

So what is done after PUV has been diagnosed ?

1. Correction of electrolytes and management of possible respiratory distress or urosepsis.

2. Urinary catheterization (often placed by the urology team) may be necessary if the patient has urinary retention

3. Nephrotoxic medications such as nonsteroidal antiinflammatory drugs and aminoglycosides should be avoided, if possible.

What are some Renal Parenchymal Malformations?

1. Renal Agenesis

2. Renal Dysplasia

3. Multicystic Dysplastic Kidney

When you see renal ageneis what other comorbidity could be present ?

1. It can be associated with VACTERL (vertebral defects–anal atresia–cardiovascular anomalies–tracheoesophageal fistula with esophageal atresia– radial and renal dysplasia–limb defects) association

2. It can slo be associated with a single umbilical artery, or contralateral VUR.

Does renal ageneis have an autosomal dominant pattern of inheritance and can be associated with several gene mutations. (True or false)

True

Does Diabetes mellitus during pregnancy or the use of specific drugs during pregnancy also cause renal agenesis?

True

How does renal agenesis occur?

• Absent kidney and ureter

• It occurs secondary to developmental failure of the uretic bud and the metanephric mesenchyme.

If renal agenesis occur to one kidney, what would need to be do and look out for? Can they function with one kidney?

In unilateral renal agenesis, long-term renal function is retained because of a normal contralateral kidney; however, it requires annual monitoring because of compensatory contralateral renal hypertrophy.

What are some symptoms of bilateral renal agenesis?

1. Flattened facies and defects of the lower extremities and genital tract.

2. Pulmonary hypoplasia and respiratory failure

3. Patients with unilateral renal agenesis are often asymptomatic, but they can develop elevated blood pressure, high protein levels in the urine, and VUR.

4. Renal agenesis has a high incidence of VUR. If renal ultrasonography demonstrates high-grade VUR or if UTIs occur, a VCUG can be obtained as a second-line investigation technique to help determine if antibiotic prophylaxis or surgical correction is required.

5. In female infants, pelvic ultrasonography should be performed to look for mullerian duct anomalies. Upon discharge, infants require € regular follow-up to monitor kidney function and blood pressure. (16)

4 things you know about renal dysplasia?

1. Renal dysplasia is an abnormality in renal development in which renal parenchyma is replaced either partially or completely by cartilaginous tissue or disorganized epithelial structures.

2. It is the most common cause of CKD and renal failure in neonates.

3. Renal dysplasia occurs frequently in infants with obstructive uropathy and various congenital disorders such as VACTERL association, CHARGE (coloboma, congenital heart disease, choanal atresia, mental and growth retardation, genital anomalies, and ear malformations and hearing loss) syndrome, brachio-oto-renal syndrome, Jeune syndrome, or trisomies 13, 18, and 21. (

4. There is no specific treatment available for renal dysplasia, and management includes monitoring blood pressure and kidney function at regular intervals.

4 things about Multicystic Dysplastic Kidney ?

1. It is a severe form of renal dysplasia that results in a nonfunctioning kidney due to abnormal renal architecture is absent and, instead, replaced by multiple large cysts that resemble a cluster of grapes.

2. It affects predominantly males and the left kidney.

3. If MCDK is bilateral, it is usually fatal. Most patients with MCDK undergo partial or complete involution over time.

4. Postnatal management is conservative, and patients are monitored with serial ultrasonography to ensure involution and appropriate compensatory growth of the contralateral kidney.

What are some disordered renal migration and collecting system formation?

1. Ectopic Kidney

2. Horseshoe Kidney

3. Duplication of the Collecting System

What do you know about ectopic kidney?

• During the first 8 weeks of development, the kidney normally ascends, rotates 90 degrees, and concludes with a medial rotation toward the renal hilum. In renal ectopy, the kidney is abnormally located and does not cross the midline.

• The most common presentation of renal ectopy is a pelvic kidney.

• In crossed renal ectopy, 1 kidney crosses the midline and usually lies inferior to the contralateral kidney.

• Diagnosis may also be made postnatally by palpation of a pelvic mass on physical examination.

• Renal ectopia can be associated with other urologic abnormalities such as VUR, contralateral renal dysplasia, cryptorchidism, and hypospadias in males and agenesis of the uterus and vagina or unicornuate uterus in females.

• Once identified, management should include evaluation for other anomalies, serial serum creatinine levels to monitor kidney function

What is a horse shoe kidney?

• Mostly in male.

• Mainly kidneys that are fused at the inferior lobes and located lower in the abdomen than usual.

• The connection between the 2 kidneys can be in a midline or lateral position, with the lateral producing an asymmetric horseshoe kidney.

• This isthmus consists primarily of renal parenchyma with a minority composed of fibrous bands. Further ascent of the kidney is often prevented by the inferior mesenteric artery at L3.

• The HNF1B gene has been associated with horseshoe kidneys

• Horse shoe has been associated with Edward and Turner syndromes.

• Because infants are often asymptomatic, this condition is typically identified incidentally on ultrasonography or computed tomography (CT).

• Higher incidence of nephrolithiasis and increased risk of some renal cancers including transitional cell cancer and Wilms tumor.

What does duplication of the collecting system mean?

• The most common congenital kidney abnormality is duplication of the collecting system.

• Mostly female predominance,

• It occurs when there is incomplete duplication of the collecting system that can be associated with VUR and ureteroceles, which increase the risk of UTIs.

• Postnatal diagnostic imaging to confirm duplication can include intravenous urography, renal ultrasonography, or CT.

• For patients with a duplication of the collecting system, management can range from observation to surgical intervention and depends on the segment affected and its native function

What does a physical examination of a suspected renal disease look like?

1. Evaluate BP and volume status evaluate blood pressure and volume status.

2. Nutrition and growth monitoring as well (especially chronic Kidney disease)

3. Hypertension will be seen in…
   Polycystic kidney disease
   Acute kidney injury (AKI)
   Thrombosis, or obstructive uropathy

4. Hypotension will be seen in…
   Sepsis
   Hemorrhage
   Volume depletion

5. Hydrops fetalis, AKI, or congenital nephrotic syndromes can be present as edema.

6. Congenital nephrotic syndromes, as well as urinary tract obstruction or volume overload, can present as ascites.

7. Assess the baby paying close attention to the abdomen
   - A mass may identify hydronephrosis
   - You examine the abdomen for the absence of or laxity in the abdominal muscles (this may suggest Eagle-Barrett (prune belly) syndrome)
   Deficiencies in mesoderm during the 6th to 10th weeks of development may explain the abnormalities seen in prune-belly syndrome. The transient lower urinary tract obstruction occurring at a specific point in fetal development results in massive dilation of the lower ureteral tract. This causes abdominal distention

8. The bladder should be examined as well, and if it is distended, it may suggest a lower urinary tract obstruction or spinal cord lesion.

9. Management of CKD focuses primarily on replacing renal functions such as erythropoietin, 1,25-hydroxylation of vitamin D, electrolyte homeostasis/excretion, and, in ESRD, waste product removal

10. 
    

What are some anomalies that will alert an NNP to possible renal defects?

1. Limb deformities

2. Atypical external ears

3. Isolated microcephaly without known etiology

4. Hemihypertrophy

5. Aniridia

6. Imperforate anus

7. Cryptorchidism

8. Abnormality of the external genitalia

9. Cloacal or bladder exstrophy

10. Persistent urachus.

What do you see with Potter’s sequence ? aka Oligo

1. Bilateral renal dysplasia

2. Bilateral urinary tract obstruction

3. Autosomal recessive polycystic kidney disease (due to reduction of fetal kidney function, oligohydramnios, and resultant fetal deformation via compression of the fetus against the uterine wall)

4. Small compressed chest wall

5. Clubfoot

6. Hip dislocation

7. Arthrogryposis
   
   Distinguishing facial features include
   1. Posteriorly low-set ears
   2. Wide-set eyes
   3. Beaked nose
   4. Depressed nasal bridge
   5. Receding chin.
   
   These patients usually have respiratory failure caused by pulmonary hypoplasia.

When we do urinalysis, what are we looking for?

We are looking for the presence of

1. Bacteria

2. White blood cell count to assess for infection.

3. If a urine culture is required, it is best to obtain it via a catheterized sample.

4. Cloudiness of urine may suggest the presence of crystals or a UTI.

Why is the urine specific gravity higher when UTI is suspected?

Specific gravity is usually very low in neonates (<1.004), but may rise secondary to high-molecular weight solutes such as glucose, contrast agents, or other reducing substances

What should you have in mind when it comes to creatinine levels?

• Immediately after birth, the serum creatinine concentration reflects the creatinine concentration of the mother

• In term infants, the serum creatinine level gradually decreases from a range of 0.6 to 1 mg/dL (53.04–88.40 mmol/L) to a mean value of 0.4 mg/dL (35.36 mmol/L) within the first 2 weeks after birth.

• In preterm infants, the decline in serum creatinine is slower and may not reach a nadir for 1 to 2 months.

• If the serum creatinine level remains elevated or increases, there is likely an impairment of renal function.

What is Autosomal dominant polycystic kidney disease (ADPKD),

1. It’s an heritable kidney disease

What is Renal vein thrombosis?

Highly likely with the following

1. Maternal diabetes
   Chorioamnionitis, neonatal polycythemia,
   Inherited thrombophilia, congenital heart disease, male sex, birth asphyxia, hypertonic dehydration, sepsis, and prolonged venous cannulation

The three signs include
1. Hematuria

2. Palpable abdominal/flank mass

3. Thrombocytopenia

Diagnosed the benefit of restoring blood flow through thrombolytic agents or anticoagulants must be balanced with the substantial risk of bleeding, including intraventricular hemorrhage by ulrasound and angiogram

What is the difference bwteen Renal vein thrombosis and Renal arterial thrombosis?

Renal arterial thrombosis
1. less prevalent

2. the most important risk factor for RAT is prolonged use of a femoral or umbilical arterial catheter, but other risk factors include low birth weight, prematurity, sepsis, catheter type, and catheter location

3. RAT prevention methods include removing arterial lines as soon as they are not needed, using an end-hole single-lumen catheter, and placement of the catheter tip above the origin of the renal arteries and celiac axis, at the level of the T6eT9 thoracic vertebrae

4. Hypertension is the most usual presenting feature of RAT

What would the plan of care for CKD?

(1) drugs to replace missing endogenous renal products (erythropoietin, calcitriol)

(2) drugs to mimic the homeostatic functions of the kidney (phosphorus binders, potassium binders, alkali supplementation, sodium supplementation)

(3) administration of vitamins/minerals which are poorly absorbed or utilized in CKD (vitamin D, iron, B vitamins, vitamin C).

Why does babies with CKD need their nutritinal value watched?

Most neonates with CKD don’t have enough appetite and oralemotor skills to take in sufficient calories for appropriate growth.
This is due to the uremic milieu, including higher circulating levels of cytokines and alterations in amino acid balance

What are some genetic and prenatal factors that affects renal development?

1. Maternal factors :
   Maternal diabetes mellitus, older maternal age, gestational hypertension, and obesity.
   Mom using angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) can lead to renin angiotensin system blocker fetopathy, which presents with renal tubular dysgenesis, neonatal anuria, pulmonary hypoplasia, and occasional central nervous system abnormalities, most often after exposure during the second trimester of pregnancy.

2. Other potential exposures with an adverse effect on urinary tract development include excessive alcohol consumption, maternal vitamin A or folate deficiency, maternal use of cocaine, use of immunosuppressant medications, use of nonsteroidal anti-inflammatory drugs, and heavy metal exposure.

Can you shed more light on the fetus renal blood flow?

1. Renal blood flow (RBF) is the amount of blood delivered to both kidneys per unit time and In the fetus, only about 3–5% of cardiac output goes to the kidneys (because fetal kidneys have high renal vascular resistance)

2. The kidneys have high renal vascular resistance because of -

   Two important contributors are:
   - Renin–angiotensin–aldosterone system (RAAS) -

   Angiotensin II increases vascular tone leading to vasoconstriction
   - Sympathetic nervous system
   Cause vasoconstriction by α-adrenergic receptors leading to renal arteriolar constriction through

3. RBF rises dramatically after birth.

So Why does renal vascular resistance decrease?

A. Decreased sympathetic/vasoconstrictor influence

After birth, renal vascular resistance decreases, allowing substantially more blood to enter the kidneys.

B. Changes in RAAS

The fetal RAAS is relatively active, contributing to vascular tone.
After birth, the balance of vasoactive systems changes, and renal vascular resistance falls.

C. Increased perfusion pressure

Systemic arterial pressure rises after birth.

Remember:

RBF≈perfusion pressurevascular resistance

So if:

• perfusion pressure ↑

• vascular resistance ↓

then:

RBF ↑↑

This is why the postnatal increase is so dramatic.

How does the GFR change over the days / months / years?

1. The glomerular filtration rate (GFR) of the fetal kidney increases steadily with advancing gestational age.

2. By 32 to 34 weeks’ gestation, a GFR of 14 mL/min/1.73 m ² is achieved, which further increases to 21 mL/min/1.73 m ² at term.

3. The GFR continues to increase postnatally, achieving adult values of approximately 120 mL/min/1.73 m ² by the age of 2 years.

What about the concentration and dilution of Urine in preterm neonates is peculiar?

1. Preterm infants are unable to fully dilute their urine but can achieve urine osmolality of 70 mOsm/kg.

2. But because of their low GFR and their decreased activity of sodium transporters in the diluting segment of the nephron; they can’t handle acute water load

3. Excessive administration of water may place the newborn infant at a high risk for dilutional hyponatremia and hypervolemia.
   
   

What are some “red flag” that you would read on maternal chart that would trigger thought about suspected kidney disease?

• Maternal exposure to angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) - especially in the second and third trimesters, can lead to oligohydramnios, renal failure caused by renal tubular dysgenesis, limb deformities, prolonged hypotension, pulmonary hypoplasia, and hypocalvaria.

• Maternal antenatal exposure to nonsteroidal anti-inflammatory drugs; selective COX-2 inhibitors; mycophenolate mofetil; certain antiepileptic medications; and chemotherapeutic agents, such as doxorubicin and cyclophosphamide.

• A review of the family medical history
  (renal hypoplasia/dysplasia, multicystic dysplastic kidney [MCDK], and vesicoureteral reflux [VUR], polycystic kidney disease and Finnish type congenital nephrotic syndrome,) may have familial clustering.

When assessing the prenatal ultrasonography, what are you assessing?

1. Kidney size

2. Echogenicity

3. Structural malformations

4. Amniotic fluid volume

5. Bladder size and shape

What does urine color might signify?

1. Yellow-brown to deep olive-green color may represent large amounts of conjugated bilirubin.

2. Porphyrins, certain drugs such as phenytoin, bacteria, and urate crystals may stain the diaper pink and be confused with bleeding.

3. Brown urine may suggest AKI, hemoglobinuria, or myoglobinuria

How does the creatinine level change over time?

1. Immediately after birth, the serum creatinine concentration reflects the maternal creatinine concentration.

2. In term infants, the serum creatinine level gradually decreases from a range of 0.6 to 1 mg/dL (depending on the mother’s serum creatinine) at birth to a mean value of 0.4 mg/dL within the first 2 weeks of life

3. In preterm infants, the decline in serum creatinine level is slower and may not reach nadir for 1 to 2 months.

4. In very preterm infants, the creatinine may actually rise transiently because of low GFR and tubular reabsorption of creatinine before falling to reach a nadir value at 2 months of age