PAEDIATRIC NEPHROLOGY RESIDENT

HANDBOOK

FIRST EDITION

PAEDIATRIC NEPHROLOGY
RESIDENT HANDBOOK
 FIRST EDITION

2021

CANADIAN ASSOCIATION OF
PAEDIATRIC NEPHROLOGISTS
AUTHORS
Laura Betcherman University of Toronto
Fahd AlShammri
McMaster University
Tom Blydt-Hansen University of British
Columbia
Sarah AlTamimi
McMaster University
Rahul Chanchlani McMaster University

Abdulaziz Bamhraz McMaster University

Janis Dionne
University of British Columbia
Rahul Chanchlani McMaster University

Laura Kaufman
Susannah Jenkins McMaster University
University of Calgary

REVIEWERS Valerie Langlois

Abdullah Alabbas University of Alberta University of Toronto

Steven Arora Amrit Kirpalani

McMaster University Western University
 University of Manitoba
Charushree Prasad
McMaster University Seetha Radhakrishnan
University of Toronto
Magdalena Riedl
University of Toronto Sara Rodriguez-Lopez
University of Alberta
Cal Robinson
University of Toronto Michelle Ruhl
University of Saskatchewan
Subhrata Verma
Western University Chia Wei Teoh
University of Toronto

Gabrielle Weiler
Damien Noone University of Ottawa
University of Toronto

1
Kristen Pederson
University of Manitoba

Maury Pinsk
HANDBOOK University of Calgary

COMMITTEE
Amrit Kirpalani
Fahd AlShammri
McMaster University Western University

Sarah AlTamimi Charushree Prasad McMaster

McMaster University University

Abdulaziz Bamhraz Seetha Radhakrishnan University of

McMaster University Toronto

Laura Betcherman Magdalena Riedl

University of Toronto University of Toronto

Rahul Chanchlani Cal Robinson

McMaster University University of Toronto

Susannah Jenkins Subhrata Verma

McMaster University Western University

Laura Kaufman
HANDBOOK LAYOUT AND DESIGN
Jason McConnery
University of Toronto

SENIOR EDITORS
Véronique Phan
Damien Noone
Centre Hospitalier Universitaire Sainte-Jusine
University of Toronto

Kristen Pederson
University of Manitoba

SUPERVISING EDITOR
Charushree Prasad
McMaster University

2
Copyright © 2021 Canadian Association of Paediatric Nephrologists. All rights reserved.
This publication is protected by copyright and permission should be obtained from the
publisher prior to any prohibited reproduction, storage in retrieval system, or transmission in
any for or by any means, electronic, mechanical, photocopying, recording, or likewise. To
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permissions, please submit a written request to [email protected].

All tables, figures and diagrams were either used with permission from the author and
publishing journal and are cited, or were modified from available sources and referenced
accordingly, or created by the authors.

Aside from academic illustrations (otherwise cited when used), all images used in the
design of this work were obtained under a Creative Commons License as free for
educational use, or for unrestricted use. Credit to the following creators:

• Kidney Cover - Suzakar(page 0)

INTRODUCTION

Welcome to your paediatric nephrology rotation! Kidneys are arguably one of the most
important (if not the most important!) organs in our body and have many integral functions –
management of fluid balance, acid-base homeostasis, electrolytes, toxin/waste removal,
blood pressure regulation, bone health, anemia, growth and more! A basic understanding of
kidney disease and manifestations in children is crucial as a general paediatrician.

We hope you will find this handbook a helpful guide to key concepts in renal physiology and
the clinical practice of paediatric nephrology.

We are interested in your feedback on the guide – please email

[email protected] with any comments or questions. If you would like to
provide any feedback anonymously, please visit the following link: https://shorturl.at/ikDE5 or
QR code below.

This handbook will be revised and updated every 3 years, to ensure the content is up to
date.

CONTENTS
1. History & Physical Exam ...................................................7 1

History by Chief Complaint .........................................................7

N

Physical Examination.................................................................11 O

2. Diagnostic Tests ...............................................................14 T

Bloodwork ...............................................................................14 E

Urine Testing ............................................................................15 S

Diagnostic Imaging...................................................................19
3. Kidney Development.......................................................22 Human Kidney
Development .....................................................22 Anatomy of the Kidney
.............................................................22

4. Fluids and Electrolytes.....................................................27 Maintenance

Fluids...................................................................27 Hyponatremia
..........................................................................27
Hypernatremia.........................................................................32 Hyperkalemia
..........................................................................35
Hypokalemia............................................................................37 Acid-Base
Disorders..................................................................38

5. Acute Kidney Injury ........................................................45 2

Overview.................................................................................45
Diagnostic Evaluation of AKI.....................................................49 N

ManagemenT of AKI ................................................................50

O

6. Approach to Proteinuria .................................................55 C

Overview.................................................................................55 S

Making the Diagnosis ...............................................................55 1

Etiologies .................................................................................57
Management & Follow Up ........................................................61

7. Hypertension in Children.................................................65
Overview.................................................................................65
Etiologies .................................................................................68
Diagnostic Evaluation of HTN....................................................70
Management & Follow Up ........................................................71
Hypertension in Hospitalized Children .......................................73
Acute Severe Hypertension .......................................................73
 8. Approach to Hematuria/Glomerulonephritis...................76
Overview.................................................................................76
Upper Urinary Tract (Renal) Causes ..........................................78
Lower Urinary Tract & Systemic Causes......................................94

9. Chronic Kidney Disease...................................................98

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Overview.................................................................................98
Making the Diagnosis ...............................................................99 N

Management & Follow Up.......................................................101 O

10. Renal Replacement Therapy ........................................114 C

Overview ...............................................................................114 E

Modalities ..............................................................................115
Apheresis ...............................................................................118

11. Basics of Kidney Transplantation .................................121

Overview ...............................................................................121
Pre-Kidney Transplant Work-Up ...............................................122
Management & Follow Up ......................................................125
Complications.........................................................................126
Immunosuppression.................................................................131

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Post-Transplant Surveillance.....................................................133

12. Thrombotic Microangiopathy ......................................135

Overview...............................................................................135
Making the Diagnosis .............................................................136
Etiologies ...............................................................................136

13. CAKUT and Cystic kidney disease................................142

4

Unilateral Kidney Agenesis .....................................................142

Hypoplastic Kidney.................................................................142 N
 Dysplastic Kidney ...................................................................142 O

Multicystic Dysplastic Kidney ...................................................143 T

Abnormalities of Position.........................................................143 C

Hydronephrosis ......................................................................143 S

UPJ Obstruction......................................................................146 UVJ

Obstruction .....................................................................147
Vesicoureteral Reflux ..............................................................147
Posterior Urethral Valves.........................................................148
Prune Belly Syndrome.............................................................149
Kidney Cysts ..........................................................................149
Genetic Cystic Kidney Diseases ...............................................150

14. Urolithiasis ..................................................................153

Overview...............................................................................153
Etiologies ...............................................................................153
Making the Diagnosis .............................................................156
Management & Follow Up.......................................................161

15. Tubular Disorders ........................................................167 General

Approach..................................................................167 General
Investigations ............................................................168 Renal
Tubular Acidosis ............................................................169

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Tubular Transport Disorders.....................................................173
Nephrogenic Diabetes Insipidus ...............................................174

16. Urinary Tract Infections and Vesicoureteral Reflux .....177

Overview...............................................................................177
Investigations..........................................................................178 UTI
Treatment .........................................................................179
Vesicoureteral Reflux ..............................................................180
Enuresis..................................................................................181
 4

Nephrology

1 OUTLINE
SECTION 1
Foundations of Paediatric
1. History & Physical Exam
2. Diagnostic Tests
3. Kidney Development
4. Fluids and Electrolytes

5
C/S = Cesarean section
CFU = colony forming units
CKD = chronic kidney disease
Abbreviations Cl = chloride
CM = centimeter
ABC = airway breathing circulation CNS = central nervous system
ADH = antidiuretic hormone CT = computerized tomography
ADPKD = autosomal dominant polycystic CVS = cardiovascular system
kidney disease D5W = 5% dextrose in free water
AKI = acute kidney injury DCT = distal convoluted tubule
ARPKD = autosomal recessive polycystic DKA = diabetic ketoacidosis
kidney disease DMSA = dimercapto succinic acid DTPA
BMI = body mass index = diethylenetriamine pentaacetate EDTA
BSA = body surface area = ethylenediaminetetraacetic acid ECG =
electrocardiogram NICU = neonatal intensive care unit
ESKD = end stage kidney nMol = nanomole
disease FWD = free water deficit NPO = nil per os (nothing by mouth)
G = gram NS = normal saline
GFR = glomerular filtration rate pCO2 = partial pressure of carbon dioxide
GI = gastrointestinal PCT: proximal convoluted tubule
H = hydrogen RBC = red blood cell
H+N = head and neck RTA = renal tubular acidosis
HCO3 = bicarbonate SIADH = syndrome of inappropriate
Hr = hour antidiuretic hormone

1 TBW = total body water

TTKG = transtubular potassium gradient
US = ultrasound
UTI = urinary tract infection
VCUG = voiding cystourethrogram
IUGR = intrauterine growth restriction VUR = vesicoureteric reflux
IV = intravenous WBC = white blood cell
K = potassium
Kg = kilogram
L = litre
MAG = mercaptoacetyltriglycine

mEq = milliequivalent
mL = milliliter
Na = sodium
NH4 = ammonium 6

1
1. HISTORY & PHYSICAL EXAM

HISTORY BY CHIEF COMPLAINT

Key elements of a renal-specific history are outlined below. Please remember that kidney
disease can manifest in a variety of ways and sometimes can be completely
asymptomatic. Therefore, the astute clinician may need to pick up on subtle signs such as
poor growth, polyuria, or fatigue.

Questions to be asked when taking a general renal history might include the antenatal
history, family history, growth and development, lower urinary tract symptoms, urine colour
and quantity. However, more specific history questions based on chief complaint are listed
below:

Concern for nephritic syndrome/glomerulonephritis (gross hematuria, hypertension,

edema): • What is the colour of the urine? Does it occur with every void? How many
times has the colour changed? Ever happened before?

• Clarify if the urine is bright pink/red or tea/cola coloured, or presence of clots? • If

there is gross hematuria, is it present at the start but clears, noted at the end of the
urinary stream (terminal) or throughout the whole stream?

• Any associated dysuria, abdominal/flank pain, urinary urgency, frequency, swelling/

edema?

• Clarify amount of fluid intake and urine output (any changes/decrease in output)? •
Difficulty breathing

• Intercurrent illness or recent illness?

• General review of systems, including specific focus on autoimmune symptoms
(associated joint pain/swelling, rashes, Raynaud’s phenomenon, mouth ulcers,
pleuritis)

• Medications, nephrotoxins
• Family history of autoimmune/rheumatological disease (including Lupus, vasculitis),
renal disease, sensorineural hearing loss, dialysis, or kidney transplantation

7
Concern for proteinuria/nephrotic syndrome:

• Any swelling/edema – ask about eyelids, abdomen, peripheral limbs, scrotal/genital

swelling? Any sudden weight gain? Any associated gross hematuria? Ever happened
before?

• Fluid intake, and urine output?

• *Note, parents may not equate decreased urine output being associated with their
condition (as they would with dehydration/vomiting) and so this is important to clarify.

• Foamy, frothy urine?

• Any intercurrent illness?
• General review of systems
• Family history of autoimmune/rheumatological disease
 • For congenital nephrotic syndrome: weight of placenta, elevated alpha-fetoprotein
level during pregnancy

Concern for chronic kidney disease:

• When was the increased creatinine noted? Any history of acute kidney injury? • Any
issues with failure to thrive/poor growth, short stature, decreased appetite? • Any
fatigue? Pruritus? Nausea/vomiting?

• Any issues with bowed legs/bony deformities/fractures?

• Polyuria, polydipsia?
• Any history of UTIs?
• Medications, nephrotoxins
• Other co-morbidities (i.e. cardiac disease, CNS, developmental delay, eye
manifestations)

• Previous or in-utero ultrasound findings

• Family history of renal disease, hearing loss, dialysis or transplantation 8

Concern for UTIs:

• History of associated dysuria, flank pain, fever, urgency, frequency, urinary hesitancy,
gross hematuria

• History of sexual activity (for adolescents)

• History of constipation
• Fluid intake
• Voiding history – how often, any holding behaviour/maneuvers, nocturia, any enuresis •
Previous urine cultures (and how they were obtained: urine bag, mid-stream or catheter)

• Any antibiotic prophylaxis

• Previous ultrasound or other imaging

Concern for acute kidney injury:

• Pre-renal: any history of volume loss i.e. vomiting/diarrhea, blood loss, increased
insensible losses, cardiac surgery/poor cardiac function, decreased perfusion
 • Renal: nephrotoxins, sepsis, check for symptoms of glomerulonephritis, any concern
for vascular thrombosis

• Post-renal: urine output, abdominal pain/distension, any history of kidney stones, any
urological history, any concern for neurogenic bladder

Concern for hypertension:

• When was it noted, is the measurement technique correct (correct cuff size, while
patient is calm, and seated, measured in right arm)?

• How high is the blood pressure (please see hypertension section to assess stage of
hypertension)?

• Is the patient symptomatic? Headaches, chest pain, blurry vision, etc. • CNS: any
history of headaches, blurred vision, poor school performance • CVS: difference
between upper and lower limb perfusion, claudication • H+N: symptoms of
obstructive sleep apnea, i.e. any history of snoring, pauses in breathing

9
• Renal: history of renal disease, UTIs, glomerulonephritis etc.
• Endocrine: thyroid symptoms (headaches, tachycardia, GI symptoms, hair loss,
sweating), cortisol (Cushingoid appearance, weight gain, acne, muscle weakness),
pheochromocytoma (headaches, flushing, palpitations, sweating)

• Fluid intake, IV fluids, intake/output and fluid balance

• Medications/Drugs: e.g. caffeine, steroids, amphetamines
• Dietary history – salt intake, juice intake, soft drinks, any junk food, weight gain, BMI •
Physical activity – amount of time, what types of activities, time spent sedentary •
Long-term effects of hypertension: last eye exam (for hypertensive retinopathy), last
echo (looking for left ventricular hypertrophy), and last renal investigations (for
proteinuria, chronic kidney disease)

Concern for congenital anomalies of the kidney and urinary tract:

• Antenatal history including any pregnancy complications, ultrasound findings of the

kidneys and bladder (i.e. degree of pelviectasis, bladder wall thickness, cysts, any note
of pulmonary hypoplasia, or poor respiratory effort on biophysical profile), gestational
age, oligohydramnios/polyhydramnios, IUGR, medications during pregnancy, illness/
infection during pregnancy, maternal diabetes
 • General delivery history specifically focusing on risk of respiratory distress at birth due
to oligohydramnios, lung hypoplasia

• Any associated anomalies at birth/dysmorphic features? Aniridia, hemihypertrophy,

ambiguous genitalia, ear anomalies, cryptorchidism, absent abdominal wall
musculature?

• Urinary stream/flow, when was the first wet diaper after birth?
• Antibiotic prophylaxis being used? UTI symptoms? Enuresis? Bladder emptying?
Urology follow up?

Concern for kidney stones:

• Symptoms of dysuria, gravel/sand/crystals in the urine or diaper, gross hematuria,

flank pain, voiding pattern

• Has this happened before? Any history of surgical interventions (stent placement,
lithotripsy, etc.)

10
• Tubulopathy symptoms: polyuria, polydipsia, poor growth, failure to thrive •
History of UTIs

• Amount of fluid intake

• Mobilization/physical activity
• Diet (including calcium intake to meet DRI, ketogenic diet, salt intake, protein) •
Medications including topiramate, steroids, vitamin D, furosemide

• Co-morbidities (i.e. inflammatory bowel disease, Celiac disease)

• Family history of renal stones, end stage kidney disease

PHYSICAL EXAMINATION

Should include a complete physical examination with special attention to the following: •
Vital signs: Heart rate, blood pressure (need to assess in relation to sex and height),
respiratory rate, temperature, oxygen saturation

• Height, weight, head circumference (also BMI, growth velocity)

• Dysmorphic features, congenital abnormalities, systemic findings
• Some examples may include:
• Aniridia (WAGR syndrome –Wilms tumour, aniridia, genitourinary anomalies,
 and intellectual disability)

• Cataracts (Lowe’s syndrome, sequelae of steroid treatment)

• Uveitis (in association with tubulointersitial nephritis with uveitis) •
Hemihypertrophy, branchial cleft fistulas or cysts, cleft palate, ear anomalies
(Beckwith-Wiedemann syndrome, Branchio-oto-renal syndrome)

• Cryptorchidism, absent abdominal wall musculature (Prune-Belly syndrome)

• Spinal abnormalities (indicative of neurogenic bladder)
• Polydactyly (Bardet-Biedl syndrome)
• Imperforate anus
• Ambiguous genitalia
• Examination for edema: periorbital, facial, sacral, scrotal/labial swelling, abdominal
ascites, peripheral pitting edema

11
• CVS: pulses, blood pressure differential between upper and lower limbs, brachial
femoral delay, murmur, abdominal bruit, jugular venous pressure

• Resp: signs of fluid overload with crackles, tachypnea, work of breathing, stony dull
percussion with pleural effusions

• Abdomen: abdominal distension, scars/ostomies/peritoneal dialysis catheter, ascites

examination (fluid wave/shifting dullness), costovertebral angle tenderness, palpable
kidneys (enlarged with ARPKD/ADPKD, obstructed kidneys, tumour)

• Bones: evidence of renal osteodystrophy i.e. rachitic rosary of chest, lower limb
deformities (bowing of legs), widening of the wrists, frontal bossing

• Joint/skin examination to look for associated findings in autoimmune/vasculitic

conditions or syndrome-related skin manifestations (e.g. angiofibroma, hypopigmented
lesions, café au lait macules, stretch marks, buffalo hump, hyperpigmented areola/
genitalia)
 12
FURTHER READING

Rees L, Bockenhauer D, Webb NJ, Punaro MG. Paediatric nephrology. Oxford University
Press; 2019 Feb 14.
 13

1
2. DIAGNOSTIC TESTS
BLOODWORK

1. Creatinine: a product of muscle breakdown that is excreted by the kidneys. Used as a

marker of kidney function. Should be interpreted with caution.

• In neonates the serum creatinine is reflective of maternal serum creatinine for the
first 72 hours of life after which it slowly falls to reflect neonatal values.

• Creatinine is a less reliable marker in patients with low or above average muscle
mass
2. Urea: a product of many biological pathways that is excreted by the kidneys. It is filtered
in the glomerulus and a portion is reabsorbed in the kidney tubules.

• Uremia can present with nonspecific signs and symptoms including altered mental
status, nausea, vomiting, anorexia.

• Other causes of high urea outside the kidneys include: high protein diet, GI bleed,
steroids, in catabolic states. If high ratio compared with creatinine, suggestive of pre
renal state.

3. GFR: glomerular filtration rate

• Gold standard way of measurement is by measuring inulin clearance (cumbersome

test, not routinely done in clinical practice)

• Other clearance markers used in place of inulin

(1) 51CrEDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriamine
pentaacetate)

(2) 24-hour urine creatinine clearance also used as a surrogate marker for
GFR • Estimated GFR (eGFR) calculated based on different formulas that use
serum creatinine or cystatin C.

(1) A commonly used formula is the bedside Schwartz:

eGFR = 36.5 x height (in cm) / Cr (μmol/L)

4. Electrolytes: important indicator of kidney function. Electrolyte derangements may be

indicative of worsening kidney function or specific disorders. Many abnormalities can be
life-threatening and prompt and careful assessment is necessary! Don’t forget to

14
measure extended electrolytes and save a urine sample for paired urine electrolytes
where possible
 • Basic electrolytes: Sodium, Potassium, Chloride, bicarbonate
• Extended electrolytes: Calcium*, Magnesium, Phosphate
*Total or ionized. If sending total, ensure albumin sent as well to correct for
hypoalbuminemia.

5. Blood gas: Metabolic acidosis or alkalosis may be indicative of kidney pathology

• pH, bicarbonate
6. Albumin: Protein synthesized by the liver, responsible for acting as the transporter for
many compounds and maintaining intravascular volume status.

• Hypoalbuminemia is a key feature of nephrotic syndrome, but it can also be low in

protein losing enteropathy, inflammatory conditions, liver failure, sepsis,
malnutrition

• High albumin in the context of high calcium, hemoglobin and hematocrit may hint at
volume contraction

URINE TESTING

Urinalysis: A great deal of information can be obtained from the urinalysis.

• pH
• Important in diagnosis of renal tubular acidosis
• Alkaline urine may cause false positive protein on dipstick
• Specific gravity
• May provide information about kidney concentrating ability
• When interpreting the dipstick positive for protein or blood, low specific gravity
may result in false negatives while high specific gravity can lead to false positive
for protein/blood.

• Blood
• Urine dip measures hemoglobin, not red blood cells
• Free myoglobin in the urine can create false positive

15
• Microscopic hematuria is defined as >5 RBC per high powered field (as seen on
urine microscopy)
 • Protein
• A urine sample is positive for protein if the dipstick is ≥ 1+ in a urine sample
with a specific gravity of ≤ 1.015

• Proteinuria is an important marker of kidney disease

• Urine dipstick measures predominantly albumin but other forms of protein can
also be lost in the urine

• (i.e. Exclusively tubular proteinuria – typically low molecular weight proteins -

may not result in a positive urine dip for protein)

• Degree of proteinuria is important in diagnosis (ie. ≥ 3+ is nephrotic range –

look for other features of nephrotic syndrome)

• Leukocytes
• Pyuria is defined as ≥ 3 WBC per high power field
• Can be positive in a cystitis or pyelonephritis, but it is important to check how the
sample was taken (catheter sample or suprapubic aspirate would be the most
reliable method of sampling to assess for infection)

• Sterile pyuria is seen in certain viral or fungal infections, and Kawasaki disease
• Nitrites
• Positive in the presence of specific bacteria that convert nitrate to nitrite •
Some organisms that do not do this are Enterococcus, Pseudomonas and
Acinetobacter

• Often falsely negative in infants as urine is not held long enough in bladder for
nitrites to form

Urine culture

• Bacterial growth indicates urinary tract infection, minimum colony counts depend on
method of urine collection

• Clean catch: ≥ 105 CFU/mL

• In-and-out: ≥ 5x104 CFU/mL
• Suprapubic aspiration: ≥ Any growth

16
Urine protein: better quantification of urine protein can be obtained by the following •

24-hour urine protein – most accurate way to quantify proteinuria

• Entire urine volume over 24 hours is collected and measured

 • Difficult to obtain in infants and young children
• Normal < 100 mg/m2/day (or < 150 mg/day)
• Nephrotic Range > 1000 mg/m2/day (or >3.5 g/day)
• Spot Urine protein-to-creatinine ratio (PCR) – a substitute measurement that is
easier to obtain and highly correlates with 24-hour urine protein

• Units: mg or g of protein/mmol of creatinine. Ensure units are correct when

calculating!

• Normal:
• Less than 2 years of age: < 50 mg/mmol
• Greater than 2 years of age: < 20 mg/mmol (< 0.02 g/mmol in some
centres)

• Nephrotic range:
• Greater than 250 mg/mmol creatinine (>0.2 g/mmol in some centres) •
Spot Urine albumin-to-creatinine ratio (ACR) can be used as well. It can help to
distinguish glomerular proteinuria (ACR) from glomerular + tubular proteinuria
(PCR). Used in diabetic nephropathy.

• Units: mg of albumin/mmol of creatinine

• Normal <2.5 mg/mmol
• 2-20 mg/mmol creatinine mildly increased
• 20-220 mg/mmol creatinine moderately increased
• Nephrotic range >220 mg/mmol creatinine

Urine electrolytes:

• Used to investigate many serum electrolyte disturbances, assess for kidney tubular
disorders, fluid status (hypovolemia), monitor progression of kidney function

• 24 hr Urine sodium can sometimes help estimate sodium intake

17
• Fractional Excretion of Sodium (FENa) %
= 100 x Urine sodium (mmol/L) × Serum creatinine (mmol/L)

Serum sodium (mmol/L) x Urine creatinine (mmol/L)

• <1% suggests pre-renal etiologies, >2% suggests intrinsic renal

• *Please see Acute Kidney Injury chapter for further details on how to
 calculate and interpret the fractional excretion of sodium (FENa)

• Other useful formulas:

• Transtubular potassium gradient (TTKG) to assess potassium excretion in the
urine (described further in electrolytes chapter)

TTKG = UrineK/BloodK x Bloodosm/Urineosm

• Should be low in hypokalemia, high in hyperkalemia
• Tubular reabsorption of phosphate (TRP) to assess phosphate reabsorption
1 - Urine phosphate x Serum creatinine x 100
Serum phosphate x Urine creatinine

• Normal should be >82%

Urine microscopy: Visualization of urine under microscope, may provide additional clues to
underlying kidney disease

• RBC casts
• Pathologic, suggests glomerular injury (ie. Glomerulonephritis)
• WBC casts
• Typically seen in tubulointerstitial disease such as acute pyelonephritis or
allergic interstitial nephritis

• Hyaline casts
• A few (1-2) per high powered field are normal
• Increased number can be seen in the context of strenuous exercise or
dehydration

• Granular casts
• Suggests stasis within the nephron
• Can be associated with tubular necrosis
18
Urine stone studies: done when there are concerns for nephrolithiasis

• Urine calcium, oxalate, citrate, uric acid, all normalized for urine creatinine or urine
osmolality

• Urine amino acids can be used to look for cystine (in some centres a urine
nitroprusside may be done as a screening test for cystinuria)

• See Urolithiasis chapter for more details

DIAGNOSTIC IMAGING

Kidney ultrasound can visualize the following:

• Location and size of kidneys

• There are normal graphs for kidney size based on age and child’s height. Kidneys are
normally located in the flanks, but can be ectopic (e.g. in the pelvis)

• Structural abnormalities
• Ex. Hydroureteronephrosis, cysts, horseshoe kidney, duplex collecting systems
• Hyperechoic or hypoechoic areas – may be seen in acute pyelonephritis • Well
defined hypoechoic or anechoic mass and absence of internal flow on power doppler
(may also include loculations or septations) – kidney abscess

• Increased kidney echogenicity – a nonspecific finding that may be indicative of

parenchymal disease

• Dense calcifications, bright echogenic foci with posterior acoustic shadowing,

twinkle artefacts – findings of nephrolithiasis

• Irregular, focal indentations in the cortex overlying the medullary pyramids – suggest
areas of scarring

• Doppler ultrasound - used to assess arterial and venous flow of the kidney, useful if
clinical concern for thrombosis

• Useful to see flow through renal arteries, assess for renal artery stenosis, renal
vein thrombus, arteriovenous malformations

CT Scan

• Can be helpful to see stones that aren’t seen on US

19
• CT angiogram is better than US at detecting renal artery stenosis
• Watch out for contrast with CT, may cause kidney injury!

DMSA (dimercapto succinic acid)

• Static scan that shows uptake of tracer to the kidneys. Gold standard to detect
pyelonephritis. Useful for detecting kidney parenchymal defects/scarring and to
assess differential function.
 • Normal findings are equal uptake to both kidneys (approximately 50% each)
• Areas of scarring may be indicated by reduced uptake of the tracer

MAG-3 (mercaptoacetyltriglycine)/DTPA

• Dynamic scans that can give you a nuclear medicine GFR

• MAG-3 is a tracer better suited to assess renal tubular function and is used to look
for urinary tract obstruction (e.g. UPJ obstruction)

• DTPA is better suited to assess glomerular function (used for GFR determination)

VCUG

• Gold standard to diagnose vesico-ureteral reflux (VUR) and posterior urethral valves
(PUV)

• Fluoroscopic study to assess the lower urinary tract (urethra, bladder, ureters) • Dye
inserted through urethra (via catheter) and images taken to watch flow • Should not be
done during an acute infection as it may falsely overestimate the VUR and increase
risk of sepsis

• In girls, can consider using a nuclear cystogram: less radiation, detects reflux, but
doesn’t provide as detailed anatomy (can’t visualize urethra)

20
FURTHER READING
Dhull RS, Joshi A, Saha A. Nuclear Imaging in Pediatric Kidney Diseases. Indian Pediatr.
2018;55(7):591-597.

Gulati M, Cheng J, Loo JT, Skalski M, Malhi H, Duddalwar V. Pictorial review: Renal
ultrasound. Clin Imaging. 2018;51:133-154. doi:10.1016/j.clinimag.2018.02.012

Kaplan, Bernard S., M.B.B.Ch, and Madhura Pradhan M.D. 2013. Urinalysis interpretation
for pediatricians. Pediatric annals 42, (3) (03): 45-51, https://www-lib-uwo
ca.proxy1.lib.uwo.ca/cgi-bin/ezpauthn.cgi?url=http://
search.proquest.com.proxy1.lib.uwo.ca/docview/1314386564?accountid=15115 (accessed
August 16, 2020).

Porrini E, Ruggenenti P, Luis-Lima S, et al. Estimated GFR: time for a critical appraisal
[published correction appears in Nat Rev Nephrol. 2018 Dec 18;:]. Nat Rev Nephrol.
2019;15(3):177-190. doi:10.1038/s41581-018-0080-9

Utsch B, Klaus G. Urinalysis in children and adolescents. Dtsch Arztebl Int.

2014;111(37):617-626. doi:10.3238/arztebl.2014.0617

21

1
3. KIDNEY DEVELOPMENT

INTRODUCTION
The kidney is a critical organ for eliminating metabolic waste products and maintaining key
homeostasis of pH, ion concentrations, and hormone status, as mentioned in the
introduction.
Nephrons and the collecting duct system perform the daily functioning of the kidney.

HUMAN KIDNEY DEVELOPMENT

• Human kidney development begins in the 5th week of gestation, with the first
functioning nephrons making urine by the 9th week.

• New nephrons continue to form until approximately 32–34 weeks gestation. • Further renal
growth results from the growth and maturation of already formed nephrons rather than new
nephrons.

• In fetal or perinatal renal injury, the developing kidney is incapable of compensating for
irreversible nephron loss.

• The number of nephrons formed at birth is an essential determinant of renal function

later in life.

• Nephron endowment at birth is a crucial fetal factor that may have long term impact on
the development of hypertension and chronic kidney disease (CKD) in adults.

ANATOMY OF THE KIDNEY

The renal anatomy can be described in two basic forms for teaching

purposes: Gross anatomy

• The average renal length by ultrasound in healthy newborns is (4.21 +/- 0.45) cm for the
right kidney and (4.32 +/- 0.46) cm for the left kidney. They grow with age at about 0.5 cm
to 1 cm per year and achieve adult length by approximately by 18 years of age.

22
• Both kidneys are located retroperitoneally, at the posterior aspect of the abdominal wall,
with the right one slightly lower than the left.

• Each kidney has two layers with an outer layer called the cortex and inner brighter red
called the
medulla

• Each kidney
has a
collection of
triangular
renal
 pyramids, or lobes,
with a base bordering
the cortex and an
apex projecting as
renal papillae into the
minor calyces.

• Each renal pyramid

consists of medullary
tissue associated with
the corresponding cap
of cortical tissue.

• Minor calyces join to

form the major
calyces, which Figure used with permission from: Noone
ultimately unite to form the ureter. DG, Iijima K, Parekh R. Idiopathic nephrotic
syndrome in children. The Lancet. 2018 Jul
• The ureter is 25 cm long in an adult but
7;392(10141):61-74.
Figure 3.1. Gross Kidney Anatomy.

has a variable length in children.

• The ureter enters the urinary bladder posteriorly on each side.

• The urinary bladder is a hollow muscular organ located posterior to the symphysis pubis,
and a reflection of the peritoneal lining covers its superior surface.

Microscopic anatomy

• The renal parenchyma consists of functional units called uriniferous tubules, which
consist of two components:

• The nephrons: the “functional units” of the kidney; cleanse the blood and balance
the constituents of the circulation.

23
• The nephron consists of the Bowman capsule (the most proximal structure of
nephron), proximal convoluted tubules (PCTs), the loop of Henle, and distal
convoluted tubules (DCTs).

• Nephrons have highly variable lengths, with the superficial (cortical) nephrons
are shorter, and the deep (juxtamedullary) nephrons are longer, mainly
depending on the length of the loop of Henle.

• Nephrons with glomeruli close to the corticomedullary junction have long loops of
Henle, which participate in the urinary concentration mechanism
 • The collecting tubules:
• The last component of the nephron have squamous epithelium, whereas the
collecting ducts have taller epithelial cells, starting as cuboidal cells in the
cortex but growing taller along the route of descent to the renal papilla

Figure 3.2.
Figure used with permission from: Noone DG, Iijima K, Parekh R. Idiopathic nephrotic
syndrome in children. The Lancet. 2018 Jul 7;392(10141):61-74.

Blood supply of the kidney

• Blood flow through the kidneys is surprisingly extensive (approximately 25% of cardiac
output), ensuring rapid removal of wastes from the blood.

• 90% flows through the cortex and the rest flowing through the medulla. • The renal
artery enters the renal sinus and divides into anterior and posterior branches, forming
segmental arteries.

• Segmental arteries ➔ lobar arteries for each renal pyramid (lobe) ➔ branch further into
interlobar arteries between the renal pyramids

24
• Once the interlobar arteries have penetrated to the corticomedullary junction, ➔ branch
into arcuate arteries, which run parallel to the surface of the kidney.

• At regular intervals along the arcuate arteries, interlobular arteries project radially
toward the most superficial parts of the cortex.

• As the interlobular arteries pass from the deep cortex to the superficial cortex, they send
out branches called afferent arterioles that supply blood to the glomeruli. After leaving
the glomerulus, blood enters the efferent arteriole.

• These blood vessels drain into interlobular veins, arcuate veins, interlobar veins, and
eventually the renal vein.
Important medications to note that act on the afferent and efferent arteriole: • NSAIDs

and calcineurin inhibitors vasoconstrict afferent arteriole & decrease GFR •

Prostaglandins vasodilate afferent arteriole and increase GFR

• Angiotensin II preferentially vasoconstricts efferent, driving up intraglomerular pressure

and increases GFR

• Therefore, Angiotensin converting enzyme (ACE) inhibitors do the opposite,

vasodilating the efferent to lower intraglomerular pressure and decrease GFR

25
FURTHER READING
Pietilä I, Vainio SJ. Kidney development: An overview. Nephron - Exp Nephrol.
2014;126(2):40-44. doi:10.1159/000360659.

Hughson M, Farris AB, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and
size in autopsy kidneys: The relationship to birth weight. Kidney Int. 2003;
63(6):2113-2122. doi:10.1046/j.1523-1755.2003.00018.

Karrwal K, H. William Schnaper, Larry Greenbaum .Clinical Pediatric Nephrology 3rd

Edition. 2017 by Taylor & Francis Group.

Osathanondh V, Potter EL. Development of human kidney as shown by microdissection. IV.

Development of tubular portions of nephrons. Arch Pathol. 1966 Nov;82(5):391-402. PMID:
5923462.

Potter EL. Normal and abnormal development of the kidney. Chicago: Year Book Medical
Publishers; 1972.

Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D. Human intrauterine renal
growth expressed in absolute number of glomeruli assessed by the disector method and
Cavalieri principle. Lab Invest. 1991;64(6):777–84.

Rodriguez MM, Gomez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE.
Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants.
Pediatr Dev Pathol. 2004;7(1):17–25.

26

1
4. FLUIDS AND ELECTROLY TES

MAINTENANCE FLUIDS

First rule in nephrology to remember: the 4-2-1 rule is not always the right answer for
maintenance fluids! Maintenance fluid requirements based on the 4-2-1 rule which are used
in other areas of paediatrics were calculated based on healthy children and their calorimetric
losses, which don’t always apply to children in hospital. If children have experienced an AKI,
have polyuria or oliguria, or if they have an electrolyte abnormality, “maintenance” fluids per
the 4-2-1 rule may not be an appropriate treatment.

Therefore, maintenance fluid requirements = insensible losses (skin losses, respiratory

system losses, typical GI water losses) + urine output.

In admitted patients, we may need to consider additional losses in the form of vomiting,
diarrhea, CSF drain, abdominal or chest drains.

Insensible losses in children/day = approximately 400 mL/m2 of Body Surface Area

Formula for Body Surface Area:

HYPONATREMIA

You may have heard that sodium problems are actually water problems…it’s true!
Hyponatremia is a disorder of water balance – mediated by either appropriate or
inappropriate ADH production.

Step by step:

1. Identify hyponatremia (Na+ <135 mmol/L).

2. Check serum osmolality:

• Low = true hyponatremia

27
• Normal = hyperproteinemia/hyperlipidemia
• High = glucose/mannitol (pseudohyponatremia).
3. Next, assess volume status to identify the cause:

• Hypovolemia (Total body water ↓, Total body Na+↓↓)

• Check urine Na+
• Urine Na+ >20 mmol/L: renal losses (i.e. diuretics, mineralocorticoid
deficiency, salt wasting, osmotic diuresis)

• Urine Na+<20 mmol/L: extrarenal losses (i.e. vomiting, diarrhea, third

 spacing, pancreatitis)

• Euvolemia (Total body water↑, Total body Na+ the same)

• Urine Na+ generally >20 mmol/L
• Syndrome of inappropriate anti-diuretic hormone excretion (SIADH), stress,
hypothyroidism, glucocorticoid deficiency, certain medications

• Variable etiologies of SIADH: CNS disorders (infection, stroke, hemorrhage,

trauma), medications, respiratory infections, malignancies, pain, nausea.

• Examples of medications that can cause SIADH: anti-epileptic medications such

as carbamazepine and valproate, chemotherapy such as vincristine, and
cisplatin, antipsychotic medications such as haloperidol and amitriptyline,
NSAIDs, exogenous DDAVP.

• SIADH biochemical features include hyponatremia, evidence of inappropriate

urinary concentration (UOsm > 100 mOsm/kg), low plasma osmolality (<270
mOsm/kg)

• Hypervolemia (Total body water↑↑, Total body Na+↑)

• Check urine Na+
• Urine Na+ >20 mmol/L: Consider AKI/CKD
• Urine Na+ <20 mmol/L: Consider Nephrotic syndrome, cirrhosis, heart failure
4. When assessing hyponatremia, it is important to note the following: fluid balance for the
preceding days (total intake, total output and balance), daily weights, serum sodium, the
sodium content of any fluid/diet intake they have, and urinary sodium to help guide us to
the etiology and management.

5. Treatment – varies according to etiology:

28
• Acute hyponatremia
• Are there severe symptoms, such as seizures, loss of consciousness,
coma, lethargy?

• If yes, then give 3% saline (2-3 mL/kg over 20 min)

• 3% saline = 513 mmol/L of Na+
• Repeat x 2 until symptoms resolve or there has been a 5 mmol/L rise in Na+
• Hypovolemic hyponatremia
• ABC’s come first! Give NS bolus if required from a circulation standpoint and a
volume perspective, and then deal with the sodium correction. Be sure to
 account for the sodium given in your bolus as part of your sodium deficit.

• Avoid rapid correction because in chronic hyponatremia if you correct too

rapidly, can get osmotic demyelination.

• Once symptom free, we want to raise Na+ by no more than 8-10 mmol/L in
first 24 hrs

• Please note: There are multiple formulas that can be used to correct
sodium for hypovolemic hyponatremia. One option is provided below.
Remember that no formula is perfect all the time – there are many
variables that we cannot account for. Always check labs frequently to
ensure you are moving in the right direction, at the right pace, and change
your plan if needed.

• Correcting hypovolemic hyponatremia using the Sodium deficit formula •

Replace the sodium deficit (i.e. the amount of Na missing), and provide a
‘maintenance’ amount of continuing sodium to account for ongoing losses
(~2 mmol/kg/day).

• Sodium deficit = 0.6 x weight (i.e. TBW) x (Desired – current sodium) •

Then, once deficit is determined, use cross multiplication to determine the
volume of normal saline required to correct

• The sodium content of various fluids can be found below.

29
EXAMPLE: Let’s say someone has a serum Na of 112. You want it to raise to
no more than 120 in the next 24 hours.

Sodium deficit = 0.6 x 10 kg x (120-112) = 48 mmol

Using 0.9 NS: 1000 mL/154 mmol = x mL/48 mmol

x = 311 mL/24 hours = 13 mL/hr of NS

• Giving 13 mL/hr of 0.9 NS will replace the sodium deficit over 24 hours •
However, we must also account for ongoing sodium losses. You can do this
by:

• Estimating a ‘maintenance’ sodium of 2 mmol/kg/day

• 2 mmol x 10 kg = 20 mmol/day of maintenance sodium.
 • Using 0.9 NS: 1000 mL/154 mmol = x mL/20 mmol, x = 130
mL/24 hours = 5 mL/hr

• Final script: 13 mL/hr + 5 mL/hr (deficit + maintenance

sodium) = 18 mL/hr of IV NS

• Another way to account for ‘maintenance’ sodium is to measure their

urine sodium and replace the urine output regularly mL:mL with a
solution that matches the urine sodium.

• Keep NPO, measure labs in 2-4h, measure and monitor urine output,
measure urine sodium q 4-6 hrs if possible

• Watch out! If you see the urine output increasing suddenly – this may
indicate that Na is rising rapidly because of excess volume replacement
and ADH getting suppressed too quickly. This may lead to more urinary
free water clearance.

• Euvolemic Hyponatremia (e.g. SIADH)

• Fluid restrict, stop drugs that could cause SIADH and stop hypotonic
fluids

• Restrict fluids to 2x insensible losses = 2x 400 mL/m2/day = max 1 L •

Can also give furosemide to help with free water clearance

• Vasopressin receptor antagonists not routinely used in pediatrics. Urea

supplementation can be considered if chronic.

• Hypervolemic hyponatremia

30
• Increased ADH and aldosterone with salt and water retention, but effective
circulating volume may still be depressed

• Therefore need to fluid restrict, increase free water excretion • If

hypoalbuminemic (e.g. with nephrotic syndrome or liver failure), consider
giving 25% Albumin (0.5-1 g/kg) over 4 hours + Furosemide (1 mg/kg)
midway and at the end of the infusion to mobilize fluid and improve low
extracellular volume
 31
HYPERNATREMIA

Hypernatremia is also a disorder of water balance, usually related to a deficit of free water
(most commonly hypernatremic dehydration). Again, we want to avoid rapid correction
because the brain generates its own osmoles to compensate for the hypertonicity and cells
shrinking. If you correct too rapidly, can get cerebral edema. Sodium should drop by no
more than 8-10/24 hrs, to prevent cerebral edema.

Step by step:
1. Identify hypernatremia (Na+ >145 mmol/L).

2. Causes of hypernatremia: free water deficit due to water loss, or decreased water intake/
salt gain.

• If urine osmolality < serum osmolality: Consider Diabetes insipidus (central/

nephrogenic)

• If urine osmolality > serum osmolality: Consider renal losses, GI losses, skin, lungs,
decreased access to free water, decreased thirst

• Sodium gain due to salt poisoning (very rare)

• Sodium gain due to iatrogenic causes
3. Restore intravascular volume – ABC’s! Bolus with 20 – 60 mL/kg of NS. 4.

Calculate free water deficit (FWD)= 0.6 x weight [(Naactual – Nadesired)/Nadesired] •

EXAMPLE: Weight 9 kg, serum Na+ 174 mmol/L

• Free Water Deficit = 0.6 x 9 kg [(174 mmol/L – 145 mmol/L)/145 mmol/L] = 1080 mL
of free water

• Another strategy:
• A general correction of 4 mL/kg of free water should lower sodium by 1 mmol/L •
Ex: 174-145 = 29.

• 4 mL/kg x 9 kg x 29 = 1044 mL free water (very similar to free water deficit

calculation above)
5. This is the total free water deficit, but we want to correct slowly (no more than 8-10
mmol/24 hours), so this 1080 mL should be given over 3.5 - 4 days = 270 mL of free
water/24 hours

6. Choose the correct fluid to use to replace the free water deficit.

32
• How much Na+ is there in each solution?

• How much free water in each solution?

• The amount of free water depends on the amount of sodium in the solution as
well as the patient’s serum sodium.
 • % Free water in any solution = 1- (SolutionNa/*SerumNa)x100%
• *Use your patient’s serum sodium to determine the amount of free water for
your patient

• Using the above table, you can see for example, that every 1L of 0.2NS would
provide about 800 mL of free water in this case.

• So now we need to figure out how much of each solution you would need in order to
provide 270 mL of free water (that we calculated above)

7. Calculate the insensible losses = 400 mL/m2/day. BSA is approximately 0.4 m2 in this
case. Therefore, insensible losses = 160 mL/day.
8. Add together insensibles + deficit = 160 mL/24 hours + 482 mL of 0.45 NS/24 hours =
27 mL/hr of 0.45 NS. Add dextrose to this fluid to provide glucose.

9. Next, need to account for ongoing future losses (urine/GI). Replace this 1:1 q 2-4 hours
depending on amount of losses. Try to match the sodium content of the replacement

33
fluid to the sodium content of the losses (i.e. if urine sodium is 70 mmol/L, replace with
0.45 NS = 77 mmol/L of Na+).

10. Final prescription = Insensibles + Deficit + Ongoing losses = 27 mL/hr of D5/0.45NS with
mL:mL urine output replacement with 0.45 NS every 2 hours. To be safe, you can start
 replacing urine output with NS instead of 0.45 NS until you can obtain a urine sodium to
confirm the correct solution to replace the urine with, to not drop the sodium too quickly.

11. If able to use the enteral route (no contraindications), can be more physiologic to replace
free water deficit through po/NG route.

12. Make sure you keep checking serum and urine electrolytes frequently, monitor ins and
outs, and adjust prescription as necessary.

34
HYPERKALEMIA

Although hyperkalemia is one of our few true renal emergencies, it can be approached and
treated in a systematic fashion.

Step by step:

1. Identify hyperkalemia (K+ > 5.5 mmol/L).

2. *Confirm sample (i.e. repeat if concerned about hemolysis, thrombocytosis, etc.)

3. Obtain ECG and place on cardiac monitor.

• Look for arrhythmia, prolonged PR interval, peaked T waves, absent P wave, widening
QRS, ST depression.
4. Emergency management:

• Stop any sources of potassium

 • Calcium gluconate (50-100 mg/kg, max 2000 mg) x 1 to stabilize cardiac membrane
• To shift the potassium intracellularly:
• Salbutamol (Ventolin) nebulizer (usually the quickest available) <10 kg: 2.5 mg;
>10 kg: 5 mg: repeat back to back x 3

• Sodium bicarbonate (1 mEq/kg IV – max 50 mEq) x 1 (if acidotic)

• Dextrose and Insulin: Dextrose 0.5 g/kg/dose IV over 2-5 min + Insulin
(Humulin R) 0.1 units/kg, max 10 units IV push.

• If non-diabetic, can trial giving just dextrose bolus and patients’ own insulin
surge should also help to shift potassium

• To eliminate potassium:
• Sodium Polystyrene (Kayexalate®) (1g/kg/dose PO, max 15 g) to help excrete
potassium in the stool if no contraindication from GI standpoint/not in the NICU

• Furosemide (1 mg/kg IV).

• Dialysis if all else fails.
5. Assess etiology

• Abnormal GFR – AKI, CKD, excess potassium intake, GI bleed, hemolysis, transfusion,
rhabdomyolysis, drugs impairing potassium excretion

• Normal GFR – low aldosterone, aldosterone insensitivity, medications 3 5

• Transtubular potassium gradient: TTKG = UrineK/BloodK x Bloodosm/Urineosm •

Can be used as a surrogate marker of aldosterone activity
• TTKG <6 = impaired aldosterone bioactivity, TTKG >6 = renal response is intact •
There are questions regarding the validity of this formula due to urea recycling in
the medullary collecting duct, though it is still used. Conditions of use include
urine sodium needs to be >20 mmol/L, and urine osmolality must be greater than
serum osmolality.

• Instead, could consider using urine K/Creatinine ratio (in hypokalemia should be
<1.5, in hyperkalemia it should be >20)

• Low renin/low aldosterone: interstitial nephritis, obstructive uropathy • Normal/high

renin/low aldosterone: primary hypoaldosteronism, congenital adrenal hyperplasia,
medications

• High Aldosterone (aldosterone resistance/insensitivity): obstructive uropathy, drugs,

post-transplant, pseudohypoaldosteronism type 1 or 2
 36
HYPOKALEMIA

Potassium lives primarily intracellularly (concentration = 150 mmol/L intracellularly, 3.5-5

mmol/L extracellularly)

Symptoms: muscle weakness, paralysis, cardiac arrhythmias

Step by step:

1. Identify Hypokalemia, K <3.5. Assess for symptoms.

2. Obtain ECG to look for U waves, ST depression

3. Treat by giving potassium replacement IV (if unable to take oral or symptomatic) or Oral
potassium replacement

• If IV, need ECG monitoring, may need central line if giving larger concentration •
If acidotic – suggest K citrate

• If alkalotic – suggest K chloride

 • If proximal RTA – may need K phosphate
• Can consider using potassium sparing diuretics if not hypovolemic
4. Assess etiology

• Depletion (decreased intake due to malnutrition or malabsorption)

• Increased losses (Renal – urine K >20 mmol/L – due to elevated mineralocorticoid
activity – will see hypertension, or excess tubular losses – i.e. diuretics, Bartter’s,
Gitelman’s)

• Transcellular shift – alkalosis, hypothermia, beta agonist, insulin

• *Special note: Low magnesium releases magnesium inhibition of ROMK channels,
which increases potassium secretion. Therefore, always make sure to correct
hypomagnesemia as well when treating hypokalemia

37
ACID-BASE DISORDERS

This is a general approach you can use for interpreting acid-base problems. Since this is
nephrology, we will focus primarily on metabolic acidosis and metabolic alkalosis.

Overview:

• pH = -log [hydrogen in nmol/L]

• <7.35 acidemia, >7.45 alkalemia
• Free hydrogen is active – destructive, binds to proteins, affects cellular structure and
function

• *Special Note: Hydrogen cations can displace calcium bound to albumin and increase free
calcium level.

• If pH low (acidosis), ionized calcium high, if pH high (alka-LOW-sis), ionized

calcium low.

• When both acidemia and hypocalcemia, must correct calcium first before acidemia. If
 you correct acidosis first, ionized calcium will drop.

• Main hydrogen buffers are bicarbonate, hemoglobin, phosphate and bone

Step by Step:

1. Look at the pH. If <7.35 – acidosis. If >7.45 – alkalosis.

2. If pH <7.35, look at the bicarb (HCO3). If low – metabolic acidosis. If not, look at the
pCO2 – if high – respiratory acidosis.

3. If pH >7.45, look at the bicarb. If high – metabolic alkalosis. If not, look at the pCO2 – if
low – respiratory alkalosis.

4. Next step is to look at compensation. Remember that compensation always corrects the
pH TOWARDS normal – it doesn’t overcorrect.

• Respiratory compensation happens quickly. Metabolic compensation takes

days. • Metabolic acidosis – pCO2 must drop to compensate:

• Expected pCO2 = (1.5 x HCO3) + 8 +/- 2

• Metabolic alkalosis – pCO2 must increase to compensate:
• Expected pCO2 = 0.7xHCO3) + 20+/-1.5

38
• Generally expected compensation
• Acute respiratory acidosis – ↑ HCO3: ↑ pCO2 = 1:10
• Acute respiratory alkalosis – ↓ HCO3: ↓ pCO2 = 2:10
• Chronic respiratory acidosis – ↑ HCO3: ↑ pCO2= 3:10
• Chronic respiratory alkalosis – ↓ HCO3: ↓ pCO2 = 4:10
• Alternative method of approaching compensation:
 • If
the compensation is as expected, then great! Only one acid-base disorder we need to
figure out. However, if it is not, then there is a mixed picture.
• For example, in metabolic acidosis, if the pCO2 is lower than expected for
compensation, then there is concurrent respiratory alkalosis. If it is higher than
expected for compensation, then there is concurrent respiratory acidosis.

5. Next step, assess the etiology.

• Metabolic Acidosis
• Either through loss of bicarbonate (in which chloride must increase to maintain
electroneutrality) OR addition of acid (as an anion, so chloride does not need to
change)

• Calculate the anion gap: Na+ - (Cl-+HCO3-). Normal anion gap is between 8-12. •
Elevated anion gap – think MUDPILES

• Methanol, Uremia, DKA, Paraldehyde/propylene glycol, Iron/inborn errors of

metabolism, Lactate, Ethanol/ethylene glycol, Salicylates

• Normal anion gap – think renal or GI loss of bicarbonate. Usually lost with cation
(Na) – anion gap is unchanged.

39
• GI losses – diarrhea, fistula, stoma losses
• Renal – look at Urine pH and urine anion gap
• Urine anion gap = Na+ + K+ - Cl-. This represents the unmeasured anion in
urine (ammonium, NH4+) which is how the kidney secretes acid.

• If urine anion gap positive, this represents LOW ammonium, could be

representative of RTA

• If urine anion gap neGUTive, this represents HIGH ammonium, appropriate

kidney compensation, and usually GI losses of bicarb.
 • For further details on Renal Tubular Acidosis, please see tubulopathies
chapter.

• Urine pH >5.5 – think about distal RTA

• Urine pH <5.5 + Low K – think about proximal RTA
• Urine pH <5.5 + High K – think about hyperkalemic RTA (Type IV), i.e. low
aldosterone, aldosterone insensitivity, renal failure or obstructive uropathy

• Metabolic alkalosis
• Secondary to Low H+ or High Bicarb
• Causes of low H+
• Transcellular shift. Exchange of hydrogen for potassium. If hypokalemia, K+
comes out of the cell to replace, H+ goes into the cell

• H+ loss through kidney (mineralocorticoid action, or linked to more distal

sodium delivery with diuretics/tubulopathies).

• We reabsorb sodium in exchange for potassium/hydrogen to maintain

balance more sodium reabsorption more K+ and H+ secretion

• H+ loss through GI tract (vomiting)

• Causes of high bicarb
• Excess alkali administration (iatrogenic)
• Chronic respiratory acidosis – if suddenly resp acidosis is corrected, left with
metabolic alkalosis that takes days to reverse

• Combination
• “Contraction” or Chloride-depletion alkalosis

40
• Dehydration leads to decreased GFR which leads to decreased
bicarb excretion

• Dehydration leads to Renin-angiotensin-aldosterone system activation

• Chloride depletion blocks distal bicarb secretion through chloride/
bicarbonate exchanger

• Milk Alkali syndrome – excess calcium carbonate: triad of hypercalcemia, pre

renal AKI, metabolic alkalosis (due to both dehydration AND excess alkali
with the “carbonate”)
 41
FURTHER READING
Faubel S, Topf J. The fluid, electrolyte & acid-base companion. Alert and Oriented Pub.;
1999.

Luke RG, Galla JH. It is chloride depletion alkalosis, not contraction alkalosis. Journal of the
American Society of Nephrology. 2012 Feb 1;23(2):204-7.

Phadke KD, Goodyer P, Bitzan M, editors. Manual of pediatric nephrology. Springer Science
& Business Media; 2013 Dec 13.

Rees L, Bockenhauer D, Webb NJ, Punaro MG. Paediatric nephrology. Oxford university
 press; 2019 Feb 14.

42
Paediatric Nephrology

2 OUTLINE
SECTION 2
Acute Problems in
5. Acute Kidney Injury
6. Approach to Proteinuria
7. Hypertension in Children
8. Approach to Hematuria

43
Abbreviations
eGPA = eosinophilic granulomatosis with
polyangiitis
ANCA = antineutrophil cytoplasmic
antibodies FENa = fraction excretion of sodium FSGS

AKI = Acute kidney injury = focal segmental glomerulosclerosis GBM

ARF = acute renal failure = glomerular basement membrane GN

ATN = Acute tubular necrosis =glomerulonephritis

BUN = blood urea nitrogen GFR = glomerular filtration rate

CNI = calcineurin inhibitors GPA = granulomatosis with polyangiitis

C3G = C3 glomerulopathy Hrs = hours

eCCl = estimated creatinine clearance Hx = history

HUS = hemolytic uremic syndrome

ICU = intensive care unit

KDIGO = Kidney Disease Improving

Global Outcomes

MMF = mycophenolate mofetil

MPA = microscopic polyangiitis

NSAIDs = Nonsteroidal anti-inflammatory

drugs

pRIFLE = Pediatric Risk, Injury, Failure,

Loss, End-Stage Renal Disease

PUV = posterior urethral valve

RAAS = renin angiotensin aldosterone

system

RRT = renal replacement therapy

TFI = total fluid intake

U.O = urine output.

Yrs = years

44

2
5. ACUTE KIDNEY INJURY

OVERVIEW

• Acute kidney injury (AKI) is defined functionally as a rapid decline in glomerular

filtration rate (GFR) that leads to accumulation of waste products such as blood urea
nitrogen (BUN) and creatinine.
• The term acute kidney injury has largely replaced acute renal failure (ARF) because ARF
overemphasizes the discrete event of failed kidney function, whereas AKI accounts for a
continuum of renal dysfunction that better characterizes the clinical spectrum of AKI.
• AKI has been increasingly recognized as an important complication in hospitalized
children.
• AKI occurs in up to 60% of children after cardiac surgery, 10%–80% of all children
admitted to an intensive care unit (ICU).
• It is strongly associated with mortality and long-term health consequences.

Definitions of AKI:
• The most important advances in the AKI field would not have been possible without a
standardized AKI definition (before 2004, there were >35 definitions).
• Due to lack of a consensus definition, comparisons among studies are difficult, resulting
in a wide range of quoted epidemiology, morbidity, and mortality rates in the AKI
paediatric literature.
• In 2012, Kidney Disease Improving Global Outcomes (KDIGO) AKI Consensus
Conference recommended that the KDIGO AKI definition and staging be used to guide
clinical care and as a standardized criterion and outcome measure in AKI as shown in
(Table 5.1)

45
Table 5.1 Modified Kidney disease improving global outcomes (KDIGO) acute kidney injury
criteria.
Stage Serum Creatinine Urine Output

Stage 0 No change in creatinine or < 0.3mg/dl (26 umol/L) >0.5ml/kg/hour

Stage 1 1.5–1.9 times baseline <0.5 mL/kg/h for
OR 6– 12 hrs
≥0.3 mg/dL rise increase (26 umol/L)

Stage 2 2.0–2.9 times baseline <0.5 mL/kg/h for

≥12 hrs
 Stage 3 3.0 times baseline ≤0.3 mL/kg/h for
OR ≥24 hrs
Increase to ≥4.0 mg/dL (>18 yr of age) (>353 umol/L) OR
OR Anuria for ≥12 hrs
Decrease in eGFR<35 mL/min/1.73m2
(<18 yr. of age)
OR
Initiation of renal replacement therapy

46
Clinical classification of AKI causes:

• Traditionally, AKI has been classified as:

Figure 5.1 Classification of acute kidney injury etiology

47
ACUTE TUBULAR NECROSIS (ATN)
• Occurs with prolonged and/or severe ischemia which can result in histologic changes,
including necrosis, occlusion of the tubular lumen by casts and cell debris.

• It is precipitated by an acute ischemic or toxic event(drugs) or sepsis.

 The workup to differentiate acute tubular necrosis from prerenal (functional) AKI and
other causes of AKI includes:

1. Urinalysis (UA)

• In prerenal AKI: UA normal or may contain hyaline casts.

• In ATN: UA may show muddy brown casts or tubular epithelial cells secondary to
sloughing

2. Fractional excretion of sodium (FENa) = 100 × [urinary sodium(mmol) × serum

creatinine(mmol))/ (serum sodium(mmol) × urinary creatinine(mmol)]

• Pre-renal: less than 1%

• 1-2% FeNa is not conclusive
• ATN/intrinsic renal disease: >2%
• In neonates, FENa >2-3% favours intrinsic kidney disease.
• Not accurate if on diuretics

3. Response to fluid repletion

• In pre-renal: Fluid repletion should cause return of serum creatinine to previous

baseline in 24-72 hours

• Persistent AKI despite adequate fluid repletion can represent ATN 48

DIAGNOSTIC EVALUATION OF AKI

Table 5.2 History and Physical Examination Findings for Categorizing Acute Kidney Injury
Type of History Physical Exam
AKI
 Pre-renal/ ● Volume loss (e.g., history • Weight loss, orthostatic
Functional of vomiting, diarrhea, hypotension delayed capillary
diuretic refill and tachycardia
overuse, hemorrhage, burns, • Poor skin turgor
ostomy losses) • Dilated neck veins, muffled
● Thirst and reduced fluid heart sounds, pulmonary rales,
intake ● Cardiac disease peripheral edema
● Liver disease
• Ascites, jaundice and other
signs of liver failure
Intrinsic renal • Rash, joint swelling, uveitis, • Periorbital, sacral, and
weight loss, fatigue, hematuria, lower extremity edema; rash;
foamy urine, cough, hemoptysis, hypertension, oral/nasal
edema, arthralgia, fever, ulcers, arthritis, fever
infectious illness • Muscle tenderness, high
• Trauma, flank pain volume status
• Prolonged hypotension • Hypertension, fundoscopic
• Trauma or myalgia examination (showing malignant
suggesting rhabdomyolysis. hypertension signs), abdominal
• History of receiving nephrotoxic bruits
medications (including over-the • Oliguria/anuria
counter like NSAIDs, antibiotics
(aminoglycosides) and some
herbals)
• Recent exposure to
radiographic contrast agents
Post-renal • Poor urinary stream, history of • Bladder distention,
oligohydramnios, gross abdominal/ pelvic mass,
hematuria, passing stones, anuria
abdominal
swelling/mass

Investigations
Initial laboratory tests:

1. CBC, differential count, retic. count.

49
2. Serum electrolytes, BUN, creatinine with calcium, magnesium, phosphate, bicarbonate
level and liver function tests with LDH

3. Coagulation profile

4. Urine tests: urinalysis and microscopy, culture, Protein/Creatinine ratio (PCR), urine
 electrolytes (Na, K, Cl, creatinine, urea) – FENa can be helpful (as described above)

5. Cultures*(if hx suggests sepsis/HUS): blood, stool cultures are required

Specific laboratory tests:

1. Peripheral blood smear, Coomb’s test

2. Immunological work up (if hx suggests immune disease/glomerular disorder): ASO titer,

C3, C4, ANA, ANCA (anti-PR3 and anti-MPO), anti-GBM.

3. Drug level for any toxins or nephrotoxic meds and toxicology screen (if history suggest
herbal/toxic ingestions)

Imaging

1. Kidney & Bladder ultrasound + doppler (kidney size, presence of hydronephrosis,

echogenicity, assess perfusion, rule out thrombosis, assess for reverse diastolic
flow).

2. Chest-x-ray (if indicated from the history/Physical exam).

Kidney Biopsy

1. To be ordered by nephrology team if indicated. It is particularly important when clinical

assessment and laboratory investigations suggest a diagnosis that requires confirmation
before disease-specific therapy (e.g., immunosuppressive medications).

MANAGEMENT OF AKI

• Requires a multidisciplinary team approach with paediatric nephrology expert

consultation

• Early discovery of the renal insult

• In general, address the underlying cause (e.g. if post-renal, relief of the obstruction by
catheterization/nephrostomy tube)

50
Management strategies include:

1. Fluid balance

• The fluid status of the child varies depending on the underlying cause, comorbid
conditions, and possible previous therapy.
 • Monitoring patient condition closely with strict intake & output chart, daily weights,
physical examinations (blood pressure and pulse)

• Increase level of monitoring if patient has severe fluid overload.

• Hypovolemia:
• Fluid therapy given as a normal saline bolus (10 to 20 mL/kg over 30 minutes,
repeated after assessment as needed )

• More invasive monitoring in critical area, such as measuring central venous

pressure, may be required to adequately assess the child’s fluid status and help
guide further therapy.

• Euvolemia:
• Maintain euvolemia by calculating maintenance fluid requirement.
• Total fluid intake (TFI) including medications and nutrition = insensible losses
[300 to 500 mL/m2 BSA per day] + urine and gastrointestinal losses.

• Formula for BSA

• Insensible losses can be run as a continues infusion of D5/NS, with urine output/
GI losses replaced mL:mL with NS. If the patient is able to take fluids by mouth,
they could also be advised to drink their insensible losses.

• Hypervolemia:
• Child with signs of fluid overload may require fluid restriction to insensible fluid
[300 to 500 mL/m2 per day] if they are anuric.

• If fluid removal is strongly required like in heart failure or pulmonary edema cases
then may need to consider dialysis. % Fluid overload can be helpful in determining
need for RRT.

• Diuretic therapy: a trial of furosemide may be attempted to induce a diuresis and

convert AKI from an oliguric to a non-oliguric form, though this might not change
the course of AKI.

51
• Trial of furosemide - single high-dose bolus (2 to 4 mg/kg/dose) to children in the
early stages of oliguric AKI with hypervolemia. Stop the furosemide if no response.
2. Electrolytes and acid-base balance

• Hyperkalemia: is the most common electrolyte complication, needs frequent

monitoring especially in the oliguric child. Treatment (discussed separately) is based
 on the severity of hyperkalemia and symptoms present as well as cardiac arrhythmia.

• Hyperphosphatemia and hypocalcemia: Treatment with oral phosphate binders and

dietary restriction of phosphorus are commonly used to decrease intestinal absorption
of phosphorus.

• Metabolic acidosis: often doesn’t require additional treatment and resolves as the AKI
resolves.

๏ May treat metabolic acidosis with IV fluid therapy using lactated ringers’ solution
or the addition of sodium citrate to enteral fluids, with caution taken to avoid
hypocalcemia (alkalosis can lead to decreased ionized calcium)

๏ Although there is controversy regarding the use of sodium bicarbonate because of

its adverse effects, administration of sodium bicarbonate should be considered in
life-threatening situations.

3. Hypertension

• Common complication in children with AKI.

• Several contributing factors: fluid overload and renin-mediated hypertension, often
seen in children with glomerulonephritis.

• Initial management is typically administration of a diuretic.

• Subsequent management is determined by the severity of hypertension, cause of
hypertension, and response to initial therapy

• Typically, ACEi and ARBs are avoided in AKI.

4. Drug management

• Avoidance of nephrotoxic drugs as they may worsen the injury and delay recovery of
function

• Dosing adjustment of renally excreted drugs to avoid toxic accumulation of drugs and
their metabolites, particularly when GFR has dropped below 50 mL/min/1.73 m2

52
• Can estimate the GFR based on Bedside Schwartz equation (36.5 x ht(cm)/creatinine
(μmol/L), https://www.mdcalc.com/revised-schwartz-equation-glomerular-filtration
rate-gfr-2009 or, if severe AKI assume GFR is <10 mL/min 1.73 m2.

• Drug levels should be routinely monitored for medications for which therapeutic
monitoring is available (e.g., vancomycin, aminoglycosides, enoxaparin, and digoxin).
5. Renal Replaxcement Therapy (RRT)
 • RRT in children will be discussed in dialysis section of this handbook.
6. Nutritional Support

• AKI is associated with marked catabolism, and optimal nutritional support is crucial to
enhance the recovery process.

• If adequate protein and calorie nutrition cannot be achieved because of fluid

restriction, RRT should be instituted early in the course of the illness.

Prognosis and outcome

• Many studies report that survivors of paediatric AKI are at risk for chronic kidney disease
(CKD) including hypertension and ESRD.

• Long-term follow-up is necessary based on the long-term morbidity for children who
survive an episode of moderate or severe AKI.

• It is suggested to follow all children with moderate to severe AKI (stage 2 and above) and
those who received renal replacement therapy at least annually for five years, and
continued follow-up until adulthood if any evidence of chronic kidney disease (CKD) is
detected.

53
FURTHER READING
Chanchlani R, Nash DM, McArthur E, et al. Secular trends in incidence, modality, and
mortality with dialysis receiving AKI in children in Ontario a population-based cohort study.
Clin J Am Soc Nephrol. 2019;14(9):1288-1296. doi:10.2215/CJN.08250718.

Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL; AWARE Investigators: Epidemiology of
acute kidney injury in critically ill children and young adults. N Engl J Med 376: 11–20, 2017
5.
Kellum JA, Lameire N, Aspelin P, et al. Kidney disease: Improving global outcomes (KDIGO)
acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury.
Kidney Int Suppl. 2012;2(1):1-138. doi:10.1038/kisup.2012.1

Prasad Devarajan,Tej K Mattoo,Melanie S Kim,.Up-to-date Prevention and management of

acute kidney injury (acute renal failure) in children, 2020.

54

2
6. APPROACH TO PROTEINURIA

OVERVIEW

Proteinuria refers to loss of protein in the urine. While this may be indicative of kidney
damage, the etiology may also be benign. A broad approach to proteinuria, as well as the
common causes, are discussed here. Significant proteinuria may present with nephrotic
syndrome, which will also be discussed.

How do you measure urine protein? (See Chapter 2: Diagnostic Tests for

details) • Urine dipstick

• Spot urine protein-to-creatinine ratio (ensure correct units – generally mg/mmol)

• 24-hour urine protein (gold standard)

MAKING THE DIAGNOSIS

History and Physical Exam

• Thorough history details can be found in History and Physical Exam
• For proteinuria we also specifically ask about:
• Edema
• When did it begin? Is the patient symptomatic? (ie. Difficulty breathing, difficulty
ambulating, abdominal pain/discomfort)

• Hint: are their eyes puffy in the morning? Have they been diagnosed with “allergies”
because of swollen eye lids? Are they finding it hard to get their socks/shoes on? Do
they notice an imprint from their socks at the end of the day?

• This will help assess severity of presentation and guide decision-making around
inpatient versus outpatient management

• The presence of edema suggests non-benign causes of proteinuria 5 5

• Ask to see a previous photo of the patient to assess for differences in facial
swelling

• Thorough physical exam can be found in History and Physical Exam

• For proteinuria we also pay special attention to signs of fluid overload:
• Vitals
• Hypertension can be a feature of glomerulonephritis or caused by volume overload
in nephrotic syndrome

• Tachycardia may suggest that the patient is intravascularly volume depleted

 • Documentation of weight gain
• Fluid status
• Edema? Where? How clinically significant?
• Mucus membranes, cap refill time
• Cardiovascular
• Gallop may suggest fluid overload
• Distended JVP for fluid overload
• Respiratory
• Crackles for fluid overload, dullness to percussion at bases for pleural effusion
• Gastrointestinal
• Tenderness, distension signs of peritonitis, assessment for ascites

General Investigations
• Urinalysis
• Urine protein-to-creatinine (measures all protein)
• Urine albumin-to-creatinine (measures ‘glomerular’ protein)
• 24-hour urine collection for protein and creatinine that more accurately quantifies the
proteinuria (urine creatinine can help to determine if the collection is adequate).

• Serum electrolytes, albumin

• Urea, Creatinine
• If clinically indicated (signs of glomerular disease, other red flags)

56
• C3/C4
• ANA, dsDNA, hepatitis B and C, HIV
• If presenting with clinical signs concerning for nephrotic syndrome, consider checking
serum lipids and cholesterol (although these are not required to confirm the diagnosis
of nephrotic syndrome)

• Kidney Ultrasound (confirming presence of 2 kidneys, if additional presence of gross

hematuria to rule out thrombosis, helpful for biopsy planning if required)
ETIOLOGIES

Benign Causes of Proteinuria

1. Orthostatic

• Kidney protein excretion increases in the upright position, therefore is more

significant as the day progresses

• Diagnosis:
• A first morning urine negative for proteinuria on 3 consecutive days • a 'split urine’
collection (they fill one container with an entire day’s urine starting with their 2nd
void of the day, and fill another with the next day’s 1st void, then we compare the
‘upright’ vs ‘supine’ urine samples)

• Need to have normal renal function, serum albumin, BP and no hematuria. •

Management: Paediatric patients should be reassured, and counselled to collect first
morning specimens for future urine tests as needed

2. Transient

• Temporary proteinuria that occurs in the context of a febrile illness (temperature >
38.3°C), exercise, dehydration, cold exposure, or stress

• Diagnosis: Requires repeat urine testing after the acute trigger has resolved to
determine is proteinuria is still present.

• Management: None, no ongoing monitoring or follow up required once the proteinuria

has resolved

57
Note: every well-appearing child with isolated proteinuria should have multiple first
morning urine samples to rule out the benign causes before moving towards the more
extensive work-up for pathologic causes

Non-Benign Causes of Proteinuria

3. Tubular

• Many low molecular weight proteins are reabsorbed in the tubules, therefore damage
to the tubules results in urinary loss of these proteins.
 • Tubular proteinuria often occurs in the context of generalized tubular dysfunction
(Fanconi syndrome), which is typically due to an underlying disease

• Consider disorders that affect the tubules

• Cystinosis, Dent disease, Lowe syndrome
• Galactosemia
• Acute tubular necrosis
• Tubulointerstitial nephritis
• Malignancy
• Congenital anomalies of the kidney and urinary tract (CAKUT)
• Reflux nephropathy
• Diagnosis:
• Albumin-to-creatinine ratio compared (ACR) to protein-to-creatinine ratio (PCR)
may help differentiate glomerular versus tubular proteinuria as albumin is typically
lost through the glomerulus while low molecular weight proteins are lost through the
tubules

• You can specifically measure low-molecular weight protein by checking urine

beta-2 microglobulin or urine protein electropheresis

• Referral to paediatric nephrology may be required to determine underlying

diagnosis.

• Management:
• Depends on the underlying etiology.
• Fanconi syndrome is typically managed by correcting the electrolyte abnormalities.
If cystinosis is the diagnosis, cysteamine is part of the therapy.

58
• Tubulointerstitial nephritis may require a biopsy and subsequent steroid therapy,
along with treatment of the underlying cause
4. Glomerular

• Glomerular proteinuria can be divided into nephrotic range which may or may not be
associated with nephrotic syndrome, or non-nephrotic range

• Definition of nephrotic range proteinuria:

• Spot urine PCR greater than 200 mg/mmol (>0.2 g/mmol)
• 24-hour urine protein greater than 3.5g (or greater than 40 mg/m2/hour) •
 The underlying etiology may be a primary kidney condition or secondary to a
systemic/non-kidney condition

• Isolated Proteinuria:
• Minimal change disease
• Most common cause of nephrotic syndrome in children
• Focal segmental glomerular sclerosis
• FSGS is a histological pattern of kidney injury, it’s not in itself a diagnosis • It
may be idiopathic (this is typically related to some immune dysregulation
leading to an FSGS injury pattern, and can cause mild proteinuria up to a full
nephrotic syndrome)

• FSGS can also be secondary to infection (hepatitis B, C, HIV among others),

autoimmune disease, drugs, malignancy, or chronic hyperfiltration (e.g. obesity,
hypertension, heart failure)

• Membranous nephropathy (rare in kids)

• MN is also a histological pattern of injury that may be caused by infection,
autoimmune disease, malignancy, and drugs

• Primary (related to phospholipase A2 receptor antibodies (PLA2R)) or

secondary

• Diagnosed on biopsy
• It can also be seen (very rarely) in neonates due to circulating auto-antibodies
• Treatment dependent on underlying etiology or degree of proteinuria level of
kidney impairment. May consider prednisone, or tacrolimus/calcineurin

59
inhibitor if severe. Renin angiotensin aldosterone system (RAAS) blockade indicated.

• Proteinuria with Hematuria (See section on hematuria)

• Post-infectious glomerulonephritis
• Membranoproliferative glomerulonephritis/C3 glomerulopathy
• Can present with varying severities of nephrotic syndrome and/or
glomerulonephritis

• IgA Nephropathy
• Typically presents with hematuria, but can involve proteinuria
• Glomerulonephritis (Henoch-Schonlein purpura (IgA vasculitis), lupus nephritis,
ANCA, anti-GBM disease)

• Alport syndrome
• Diagnosis is by clinical and biochemical findings, more definitively by kidney biopsy. •
Management dependent on the underlying etiology

• Consider using an ACE inhibitor (or ARB) to help to reduce the

proteinuria (RAAS blockade)

Nephrotic syndrome
1. Nephrotic range proteinuria

2. Hypoalbuminemia

3. Edema

4. ± Hyperlipidemia (not always required for diagnosis)

Figure
6.1 Image from BC Children's Nephrotic Syndrome Physician Handbook) 6 0
*Please note, some centres use g/mmol as their screening units, therefore normal urine
PCR = <0.02 g/mmol, abnormal would be 0.02 – 0.2 g/mmol, and nephrotic range
would be >0.2 g/mmol)*

Patients with uncomplicated nephrotic syndrome may be managed by general

pediatrics, however if there are any concerns for complicated features, they should be
assessed by a paediatric nephrologist. Various factors will be considered when
determining whether management should be as an inpatient or outpatient.

The most likely diagnosis in paediatrics is minimal change disease, and this is often a
presumptive diagnosis (even without biopsy).

You should consider other diagnoses (and biopsy) if:

• The patient is under 1 or over 12 years old

 • There is gross hematuria (not related to renal vein thrombosis)
• They are hypertensive
• They have abnormal kidney function (e.g. low eGFR) not pre-renal in nature • C3 is
low

• There is evidence of systemic disease (e.g. arthritis or rashes)

• They are steroid-resistant
• Defined by the persistence of proteinuria after 4 weeks of steroid therapy (see
management below)

MANAGEMENT & FOLLOW UP

Acute Symptomatic Management

• Is the patient presenting with signs of volume overload (hypertension, edema) or
intravascular volume depletion (ie. Tachycardia, elevated creatinine, edema)?

• May consider diuretics; this should be discussed with a nephrologist • Fluid and salt
restriction (one example in the table below)

• Consideration of 25% albumin infusion if pre-renal or presence of anasarca 61

• FeNa may be helpful to determine if will respond to diuretics alone or need albumin
and diuretic

• Is the patient hypertensive?

• How significant is it and are they symptomatic?
• Consider diuretics if volume overloaded, and possibly short-acting anti-hypertensives
• Considerations for admission:
• Volume overload or depletion requiring IV management
• Severe, symptomatic edema (i.e. significant ascites, pleural
effusions) • Symptomatic hypertension may require admission

• Concerns of acute complications (discussed below)

 Figure 6.2 An example of Fluid/Salt restriction, from BC Children's Nephrotic Syndrome
Physician Handbook

Acute Complications
• Consider the most serious complications of nephrotic syndrome:
• Thromboembolism: Pathophysiology is multifactorial, however the loss of anti
thrombotic protein and protein S, in addition to increased hepatic synthesis of pro
thrombotic factors are thought to play a role

• Spontaneous bacterial peritonitis: stagnant fluid collection in abdomen is prone to

infection (particularly by Streptococcus pneumoniae).

62
• Infection: Multifactorial pathophysiology including urinary losses of proteins involved
in the complement pathway,

• If there are concerns (i.e.. Fever) culture and start empiric antibiotics covering for
pneumococcus (Streptococcus pneumoniae) and gram-negative bacteria
(predominantly Escherichia coli)

Disease Management
• These patients are followed by paediatric nephrology long-term (depending on the
centre, nephrology may only follow complicated cases of nephrotic syndrome)

• Oral steroids are the typical starting therapy for new onset nephrotic syndrome •
Generally started at 60 mg/m2/day (or 2 mg/kg/day) for 6 weeks, then tapered per local
institutional protocols until discontinued

• Example of taper schedule:

 Step 1: 60 mg/m2/day daily for 6 weeks

Step 2: 40 mg/m2/day every other day for 6 weeks, then off

• Parents check urine daily at home to monitor proteinuria and response to therapy

Long-Term Management
• 70-75% of children will relapse and require re-treatment with steroids (usually not as
long)

• If frequently relapsing (2 or more episodes in 6 months, 4 or more in 12 months)

consider low-dose maintenance steroids or second-line immunosuppressive
medications (such as cyclophosphamide, tacrolimus, mycophenolate, rituximab,
levamisole). Occurs in up to 50% of children.

• If steroid dependent (unable to wean or discontinue steroids) consider low-dose

maintenance steroids or second-line immunosuppressive medications

• If steroid resistant (unable to achieve remission after 4-6 weeks of steroids) then plan
kidney biopsy. Management will be dependent on biopsy results. Often may use second
line immunosuppressive medications and consider genetic testing.

• In these cases, referral to paediatric nephrology should be initiated if not already done

63

FURTHER READING
Bergstein JM. A practical approach to proteinuria. Pediatr Nephrol. 1999;13(8):697-700.
doi:10.1007/s004670050684

Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic

syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012;7(3):513-520.
doi:10.2215/CJN.10131011

Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018 Jul
7;392(10141):61-74. doi: 10.1016/S0140-6736(18)30536-1. Epub 2018 Jun 14. Erratum in:
Lancet. 2018 Jul 28;392(10144):282. PMID: 29910038.

Pediatric Nephrology Program BC Children’s Hospital. Childhood nephrotic syndrome: A

physician’s handbook 2nd Edition http://www.bcchildrens.ca/health-professionals/clinical
resources/renal-program

64

2
7. HYPER TENS ION IN CH ILDREN

OVERVIEW

• Prevalence of hypertension (HTN) among healthy children and adolescents is 3.5%-5%.

• However, prevalence of HTN in various comorbid conditions children is much higher:
3.8-25% in obesity, 3.6-14% in children with obstructive apnea, 50% in those with chronic
kidney disease and 7-10% in children with prematurity.
Importance of Diagnosing HTN in Children and Adolescents
• Elevated BP in childhood increases the risk for adult HTN and metabolic syndrome.
• BP-related cardiovascular damage starts in youth.
• Early detection of HTN is vital to prevent future cardiovascular morbidity and mortality

Definition of HTN

• BP levels in children should be interpreted based on sex, age, and height. New normative
BP tables based on normal-weight children have been introduced by the American
Academy of Pediatrics.

• Hypertension in children is defined as a BP ≥95th percentile for age, sex, and height (in
children 1-12 years) or ≥130/80mmHg (in children ≥13 years) on 3 separate consecutive
occasions.

• Hypertension Canada definition: children can be diagnosed as hypertensive if systolic

or diastolic BP is at the 95th percentile or greater for age, sex, and height, measured on at
least 3 separate occasions, or if systolic or diastolic BP is > 120/80 mm Hg in children
6-11 years of age, or greater than 130/85 mm Hg in children 12-17 years of age

65
Figure 7.1. Blood pressure categories and definitions
Figure used with permission from Saini P, Betcherman L, Radhakrishnan S, Etoom Y. Paediatric
hypertension for the primary care provider: What you need to know. Paediatrics & Child Health. 2021
Apr;26(2):93-8.

Measurement of BP in Children
• It is important to obtain multiple measurements over time before diagnosing HTN. • The
initial BP measurement may be oscillometric (on a calibrated machine that has been
validated for use in the paediatric population) or auscultatory (by using a mercury or
aneroid sphygmomanometer) .

• An appropriately sized cuff should be used for accurate BP measurement. the initial BP is
elevated (≥90th percentile), providers should perform 2 additional oscillometric or
auscultatory BP measurements at the same visit and average them.

66
• If using auscultation, this averaged measurement is used to determine the child’s BP
category. If the averaged oscillometric reading is ≥90th percentile, 2 auscultatory
 measurements should be taken and averaged to define the BP category.

BP Measurement Frequency
• Guidelines recommend annual BP screening for healthy children aged 3 and above •
Some children should have BP measured before 3 years and at every health encounter:
• obesity (BMI ≥95 percentile)
• kidney disease
• diabetes
• aortic arch obstruction or coarctation
• those who are taking medications known to cause HTN
• prematurity

ABPM (Ambulatory BP Monitoring)

• ABPM is more accurate for the diagnosis of HTN than clinic-measured BP, is more
predictive of future BP, and can assist in the detection of secondary HTN.

• For these reasons, the routine application of ABPM is recommended, when available. •
For technical reasons, ABPM may need to be limited to children ≥5 years of age who can
tolerate the procedure and those for whom reference data are available.

• ABPM is indicated in the following scenarios:

• Confirmation of the diagnosis of hypertension in children with repeatedly elevated
office BP readings

• Confirmation of suspected white coat hypertension

• Evaluation for masked hypertension in children
• Evaluation of BP in paediatric transplant recipients, children with CKD and children
on dialysis

• Assessment of treatment effectiveness in children and adolescents receiving

antihypertensive medications

67
ETIOLOGIES

Primary HTN
• Primary HTN is now the predominant diagnosis for hypertensive children and
adolescents.

• General characteristics of children with primary HTN include a) older age (≥6 years), b)
positive family history (in a parent and/or grandparent) of HTN, and c) overweight and/ or
obesity.

• Children and adolescents ≥6 years of age do not require an extensive evaluation for
secondary causes of HTN if they have a positive family history of HTN, are overweight or
obese, and/or do not have history or physical examination findings suggestive of a
secondary cause of HTN.

Secondary HTN
• Children <6 years of age are more likely to have a secondary cause for their hypertension
• Causes of secondary hypertension include:
• Renal (renovascular and renal parenchymal disease, congenital
abnormalities) • Cardiac (coarctation of aorta)

• Respiratory (chronic lung disease-bronchopulmonary dysplasia)

• Iatrogenic (medication, fluid overload)
• Oncological (e.g. neuroendocrine tumours)
• Systemic (e.g. prematurity)
• Endocrine (e.g. hyperthyroidism, Cushing syndrome)

Renal Causes
• Renal disease and renovascular disease are among the most common secondary causes
of HTN in children.

• Renal parenchymal disease and renal structural abnormalities account for 34% to 79% of
patients with secondary HTN. Common causes are acute glomerulonephritis, interstitial
nephritis, renal scarring, obstructive nephropathy, polycystic kidney disease, etc.)

68
• It is appropriate to have a high index of suspicion for renal and renovascular disease in
hypertensive paediatric patients, particularly in those <6 years of age, or teenagers with
low BMI if no other risk factors, particularly with stage 2 hypertension.
• Causes of renovascular disease can be fibromuscular dysplasia (FMD), Takayasu arteritis
(TA), mid-aortic syndrome.

• Renovascular HTN should be suspected in the following scenarios:

• Unexplained hypokalemia with or without high renin
• Sustained diastolic HTN on ABPM
• Clinic BP >150/100 at any age
• Hypertension not controlled on ≥ 2 antihypertensive drugs
• Increase in creatinine (if bilateral renovascular disease) with ACE inhibitor initiation •
Stage 2 HTN in <10 y/o child

• Genetic syndrome associated w/renovascular hypertension

• Known vasculitis or symptoms of vasculitis
• History of renal trauma or vascular insult
• Mid-abdominal bruit on PE
• Severe HTN post-transplant
• Symptomatic HTN w/o defined cause

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DIAGNOSTIC EVALUATION OF HTN

Table 7.1 History, physical and targeted investigations.

Table used with permission from Saini P, Betcherman L, Radhakrishnan S, Etoom Y. Paediatric
hypertension for the primary care provider: What you need to know. Paediatrics & Child Health. 2021
Apr;26(2):93-8.

Imaging
1. ECG: no role of ECG in HTN in children

2. Echo: Necessary for identifying end organ damage such as LVH

• Timing: Start of pharmacologic treatment of HTN, though Canadian guidelines advise

an echocardiogram for all cases

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• Repeat echocardiography performed to monitor improvement at 6- to 12-month
intervals
3. Ultrasound kidney with doppler is recommended for children especially <6 years of age
 with hypertension (Should be done in all children before starting ACE inhibitor/ARB)

4. CT or MR angiography can also be used as they are non-invasive. Sensitivity and

specificity for the detection of RAS is 94% and 93% for CTA and 90% and 94% for MRA,
respectively.
5. Digital subtraction angiography (DSA)is the most reliable way to diagnose renal artery
stenosis (RAS)

MANAGEMENT & FOLLOW UP

In children and adolescents diagnosed with HTN, the treatment goal with
nonpharmacologic and pharmacologic therapy should be a reduction in SBP and DBP to
<90th percentile and <130/80 mm Hg in adolescents ≥ 13 years old.

Lifestyle and Nonpharmacologic Interventions

• Dietary Approach to Stop Hypertension diet (DASH): 4-5 servings of fruit and vegetables
per day, >2 servings of low-fat milk products, 6 servings of whole grains, <2 servings of
fish/poultry and lean red meats, 1 serving of legumes and nuts, 2-3 servings of oils and
fats, avoiding added sugar and sweets, and dietary sodium <2300 mg/day

• Recommend moderate to vigorous physical activity at least 3 to 5 days per week (30–60
minutes per session) to help reduce BP.

Pharmacologic Treatment
• Pharmacologic treatment of HTN in children and adolescents should be initiated with an
ACE inhibitor, ARB, long-acting calcium channel blocker, or a thiazide diuretic. β-blockers
are not recommended as initial treatment in children.

• Common side effects of some of the medications include:

• Calcium Channel Blocker (e.g. Amlodipine): peripheral edema
• ACE inhibitor/ARB: hyperkalemia, increased creatinine. Cough and angioedema are
more common in adults. Adolescent patients should be counselled about teratogenic
effects in pregnancy.

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• Diuretics: Electrolyte disturbances
• β-blockers: bradycardia, hypoglycemia. Should be avoided in patients with asthma. •
Depending on repeated BP measurements, the dose of the initial medication can be
increased every 2 to 4 weeks until BP is controlled (eg, <90th percentile), the
 maximal dose is reached, or adverse effects occur.

• Although the dose can be titrated every 2 to 4 weeks using home BP measurements, the
patient should be seen every 4 to 6 weeks until BP has normalized.

• If BP is not controlled with a single agent, a second agent can be added to the regimen
and titrated as with the initial drug.

• Lifestyle modifications should be continued in children requiring pharmacologic therapy. •

In children with HTN and CKD, proteinuria, or diabetes mellitus, an ACE inhibitor or ARB
is recommended as the initial antihypertensive agent unless there is an absolute
contraindication.

Figure 7.2. Patient management based on office BP

Figure used with permission from Saini P, Betcherman L, Radhakrishnan S, Etoom Y.

Paediatric hypertension for the primary care provider: What you need to know. Paediatrics
& Child Health. 2021
Apr;26(2):93-8.
72
HYPERTENSION IN HOSPITALIZED CHILDREN

• Paediatric HTN has been well studied in the ambulatory setting but not so much in
hospitalized children

• Lack of robust inpatient BP data

• Significance of an elevated BP and the cut-off at which elevated BP evolve into true HTN
is not entirely clear

• First step is to rule out pain, anxiety, fluid overload etc.

• Treatment should be considered:
• Acutely in hospitalized patients who have sustained stage 2 HTN that persists for
greater than a day

• Children experiencing a sudden rise in BP, regardless of whether or not it meets the
stage 2 threshold

• Any patient with hypertensive emergency or encephalopathy should be treated

immediately in an ICU setting

• Children at greater risk for seizures or encephalopathy

• Those at a greater risk for hypertensive complications (recent surgery,
thrombocytopenia, etc.), should be treated at lower thresholds

• Hypertensive emergency: BP elevation is accompanied by evidence of severe

symptoms and end-organ damage

• Hypertensive urgency: Minimal end organ damage

• Hypertensive emergency/urgency have BP >stage 2 hypertension threshold (when child’s
BP increases 30 mmHg or more above the 95th percentile)

• This corresponds to a SBP of above 160 mmHg in children 13 years and older or above
135 mmHg in a 1-year-old child

ACUTE SEVERE HYPERTENSION

Hypertensive emergencies should be treated in an ICU setting with titratable IV

antihypertensive medications. In such situations, the BP should be reduced by no more than
25% of the planned reduction over the first 8 hours, with the remainder of the planned
reduction over the next 12 to 24 hours. The ultimate short-term BP goal in such patients
should generally be around the 95th percentile.

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Treatment options:

• IV hydralazine
• IV labetalol
• IV nitroprusside
• IV nicardipine
• PO nifedipine

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