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Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
1
Nephrotic Syndrome in Children
Definition
Nephrosis (i.e. the nephrotic syndrome) is a condition characterized by proteinuria with resultant
hypoproteinemia and edema
Pathophysiology
Edema
Proteinuria ⇒ Hypoproteinemia ⇒ Decreased Oncotic Pressure ⇒ Edema & Vascular Hypovolemia
Hyperlipidemia
• Decreased oncotic pressure results in increased hepatic production of VLDL
• Urinary loss of heparin sulfate and LCAT results in decreased lipoprotein lipase activity with a
decreased metabolism of VLDL
• Urinary loss of HDL and LCAT results in an increased LDL/HDL ratio
Hypercoagulability
• Increased plasma levels of fibrinogen, factor V, and factor VII
• Decreased plasma levels of antithrombin III
• Increases in platelet number and aggregation
• Decreased intra-vascular volume
Immunodeficiency
• Hypogammaglobulinemia secondary to urinary losses
• Hypocomplementemia secondary to urinary losses
• Decreased cellular immunity, potentially secondary to urinary losses of Zn and Fe
Miscellaneous
• Artifactual hypocalcemia secondary to hypoalbuminemia
• True hypocalcemia secondary to urinary losses of vitamin D
• Copper, zinc, and iron deficiencies secondary to urinary losses of carrier proteins
• Artifactual hypothyroidism secondary to urinary losses of thyroxine-binding globulin
Differential Diagnosis (General)
Primary Nephrotic Syndrome
• Minimal Change Nephrotic Syndrome (MCNS) 76%
• Focal & Segmental Glomerulosclerosis (FSGS) 9%
• Membranoproliferative Glomerulonephritis (MPGN) 7%
• Membranous Glomerulonephritis (MGN) 2%
• Other glomerulopathies 6%
Secondary Nephrotic Syndrome
• Myriad etiologic agents
Artifactual Nephrotic Syndrome
• Hypoproteinemia unassociated with proteinuria
Specific Diseases
Minimal Change Nephrotic Syndrome (MCNS)
• No changes in light microscopy
• Loss of foot processes in electron microscopy
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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Most common in children
Usually responds to immunosuppressive therapy
Does not lead to renal failure
May cause problems with frequent relapses
Focal and Segmental Glomerulosclerosis (FSGS)
• Mesangial matrix expansion with loss of normal glomerular structures
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•
•
•
Second most common in children
More frequent in adolescents and African Americans
May present with only proteinuria
Usually leads to progressive renal failure
Membranoproliferative Glomerulonephritis (MPGN)
• Mesangial cell proliferation and splitting of GBM
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Third most common in children
A glomerulonephritis which causes nephrosis
Associated with a low C3
Will cause renal failure unless treated with steroids
Histopathology by Age
% of New Cases
20%
MCNS
15%
FSGS
MPGN
10%
5%
0%
0
5
10
Age in Years
Laboratory Evaluation
Initial
• Urinalysis
• Total protein and albumin
• Electrolytes, calcium, BUN, and creatinine
• Cholesterol (±triglycerides)
• Blood pressure
• C3
• PPD
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Pediatric Nephrology Handout
Revised May-00
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Evidence of Complicated Nephrotic Syndrome
• Age≥6 years
• Hematuria
• Hypertension
• Low serum C3
• Normal serum cholesterol
Therapy
Primary Therapy
• Prednisone (high dose with slow taper)
• Cyclophosphamide
• Cyclosporine
Response to Steroid Therapy
Response of Minimal Change (J Peds 98:561, 1981)
Fail
8%
Respond
92%
Histopathology of responsive patients (J Peds 98:561, 1981)
MCNS (92%)
FSGS (5%)
MPGN (1%)
Other (2%)
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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Histopathology of non-responsive patients (J Peds 98:561, 1981)
MCNS (29%)
FSGS (27%)
MPGN (26%)
Other (18%)
Adjunctive Therapy
• Mild diuretic therapy (e.g. HCTZ 1 mg/kg q12°)
• Colloid infusion (e.g. albumin 1 gm/kg accompanied by lasix 1 mg/kg)
• A.C.E. Inhibitors (e.g. enalapril 0.1 mg/kg q12°)
• Pneumococcal vaccine
Evaluation and Therapy of Treatment Failures
• Renal biopsy to determine glomerular histopathology
• Treat MCNS with cyclophosphamide, chlorambucil or cyclosporine
• Treat MPGN and MGN with alternate day steroids for a prolonged course
• Limit treatment of FSGS to symptomatic therapy
Glomerulonephritis (GN) in Children
Definition
GN is an inflammatory glomerular lesion characterized by…
a) hematuria
- >1 RBC/µl in fresh urine
- >5 RBC/hpf on a spun urine
- trace blood or higher by dipstick
b) proteinuria
- 1+ or higher by dipstick
- >150 mg/1.73 M2/day
- >4 mg/M2/hour
- urine protein/creatinine>0.2
c) azotemia
Creatinine Clearance <100 ml/min/1.73 M2
estimated as
[Ht(cm) x 0.5]
creatinine
d) oliguria
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
- <500 ml/1.73 M2/day
- (F.E.Na)<1%
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Pediatric Nephrology Handout
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e) hypertension
Pathophysiology
Process
Glomerular
Inflammation
⇓
Decreased
G.F.R.
⇓
Increased Distal
Tubular Na+ and
H2O Reabsorption
Manifestation
Hematuria &
Proteinuria
Azotemia
Oliguria,
Edema, &
Hypertension
Differential Diagnosis of GN in Children
Low Complement
• Post Streptococcal GN
• Membranoproliferative GN
• Systemic Lupus Erythematosus
Normal Complement
• IgA Nephropathy
• Henoch-Schönlein Purpura
• Idiopathic Vasculitis
• Rapidly Progressive GN
Initial Evaluation of GN
Goal: To distinguish Post Streptococcal GN from other forms of GN
Hx=>
Duration of symptoms, infection, rash, arthralgia, family history
P.E.=>
B.P., edema, purpuric rash
Lab=>
U/A, SMA-6, CBC, ASO, ANA, & C3
Symptomatic Therapy of GN
• Na+ restriction
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Diuretic Rx (e.g. Lasix 1 mg/kg q12°)
A.C.E. Inhibitor Rx (e.g. Captopril 1 mg/kg q6-8° or Enalapril 0.1 mg/kg/dose q12-24°)
Vasodilator Rx (e.g. Minoxidil 0.2 mg/kg or Diazoxide 5 mg/kg) (should be accompanied by ßblocker and diuretic)
Indications for a Biopsy in GN
• Normal initial C3
• Failure of low C3 to normalize after 8 weeks
• Positive ANA
• Progressive azotemia
Hematuria & Proteinuria in Office Practice
Hematuria
• >1 RBC/µl in fresh urine
• >5 RBC/hpf on a spun urine
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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Trace blood or higher by dipstick
Upper versus Lower
Gross versus Occult
False positive with hemoglobinuria, myoglobinuria, alkaptonuria, porphyria and beet ingestion
Proteinuria
• 1+ or higher by dipstick (large proteins only)
• >150 mg/1.73 M2/day
• >4 mg/M2/hour
• Urine protein/creatinine>0.2
Epidemiology
• ~5% of children will have hematuria and/or proteinuria on screening exam
• ~50% of these will be transient
• Incidence increases with age
• Incidence is higher in females than in males
Hematuria Alone, Non-Glomerular (Differential Diagnosis)
• Urinary Tract Infection
• Idiopathic Hypercalciuria
• Presents with isolated hematuria
• Diagnosis by urine calcium/creatinine≥0.21
• Hypercalciuria and hematuria resolve with thiazides
• May lead to nephrolithiasis or recurrent UTIs
• Nephrolithiasis
• Sickle Cell Disease
• RBCs sickle in high osmotic medulla of kidney
• 2° papillary necrosis
• Also seen in trait
• Coincident with poor concentrating ability
• Trauma
• Renal Malformations
• Common presentation of UPJ obstruction is gross hematuria after minor trauma in adolescent
• Neoplasia
• Rare but important
• Interstitial Nephritis
• Usually also with proteinuria and pyuria
Hematuria Alone, Glomerular (Differential Diagnosis)
• Benign Hematuria
• Familial or Recurrent
• Due to thin or irregular basement membrane
• Benign condition
• Glomerulonephritis
• Usually also with proteinuria
• IgA, late post-streptococcal or mild SLE may have only hematuria
• IgA without proteinuria does not warrant biopsy
Hematuria Alone (Management)
• Physical exam (with blood pressure)
• U/A x 3 (over 1 to 3 months)
• U/C x 1
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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U/A on 1st degree relatives
Electrolytes, BUN, and creatinine
Urine calcium/creatinine Ratio (nl≤0.21)
ASO, C3, and ANA
Ultrasound and/or IVP
Proteinuria Alone (Differential Diagnosis)
• Transient (2° to exercise, fever, dehydration, etc.)
• Orthostatic
• Negative first morning urine
• 1° Tubulointerstitial Disease
• Reflux Nephropathy
• Interstitial Nephritis
• Glomerular Disease
• Focal and Segmental Glomerulosclerosis (FSGS)
• Common form of nephrotic syndrome in children
• May present with only proteinuria
• More frequent in adolescents and African Americans
• Usually leads to progressive renal failure
Proteinuria Alone (Management)
• Physical exam (with blood pressure)
• U/A x 3 (over 1 to 3 months)
• 1st morning void
• Electrolytes, BUN, creatinine, and albumin
• Ultrasound and or/IVP
• Renal Biopsy (if ≥0.5 gm/day/1.73 M2)
Hematuria and Proteinuria (Differential Diagnosis)
• Probable glomerulonephritis
• Hypocomplementemic (low C3)
• Post Streptococcal GN (PSAGN)
• Membranoproliferative GN
• Systemic Lupus Erythematosus
•
Normocomplementemic (normal C3)
• IgA Nephropathy
• Henoch-Schönlein Purpura
• Idiopathic Vasculitis
• Rapidly Progressive GN
Hematuria and Proteinuria (Initial Evaluation)
• Goal: To distinguish PSAGN from other forms of GN
• History
• Duration of symptoms, infection, rash, arthralgia, family history
• Physical Exam
• BP, edema, purpuric rash
• Lab
• U/A, Chemistries, CBC, ASO, ANA, & C3
• Indications for Biopsy
• Biopsy all patients unlikely to have post-streptococcal GN as determined by…
• Normal initial C3
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Pediatric Nephrology Handout
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Failure of low C3 to normalize after 8 weeks
Positive ANA
Progressive azotemia
Hypertension in Children
Significance
• Acute hypertension can lead to heart failure and encephalopathy
• Prolonged hypertension predisposes to atherosclerotic disease
• National Heart, Lung and Blood Institute established a Task Force on Blood Pressure Control in
Children in 1977
Definitions
Normal Blood Pressure
Systolic and diastolic blood pressures ≤90th percentile for height, sex and age
High-Normal Blood Pressure
Systolic or diastolic blood pressure between the 90th and 95th percentile for height, sex and age
High Blood Pressure (Hypertension)
Systolic or diastolic blood pressure >95th percentile for height, sex and age on at least three
measurements
Severe Hypertension
Hypertension requiring pharmacologic therapy
Measurement
• Blood pressure should be measured annually on children >3 years old
• Use appropriate sized cuff
• Width >2/3 of the length of the upper arm
• Length > the circumference of the arm
• Palpation
• Measures only systolic blood pressure
• Used only in neonates
• Doppler Ultrasound
• Measures both systolic and diastolic blood pressure
• Auscultation
• Used to establish standards (based on height, age and sex)
• 5th Korotkoff sound used for diastolic if possible
Population Standards
Standards vary by height, age and sex
Boys
Systolic
Age
3
6
10
13
16
Height Percentile
5th
25th
104
107
109
112
114
117
121
124
129
132
75th
111
115
121
128
136
95th
113
117
123
130
138
Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
Diastolic
3
6
10
13
16
10
63
72
77
79
83
64
73
79
81
84
66
75
80
83
86
67
76
82
84
87
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Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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Girls
Systolic
3
6
10
13
16
Height Percentile
5th
25th
104
105
108
110
116
117
121
123
125
127
Diastolic
3
6
10
13
16
65
71
77
80
83
65
72
77
81
83
75th
108
112
120
126
130
95th
110
114
122
128
132
67
73
79
82
85
68
75
80
84
86
Epidemiology of Hypertension
• Incidence usually ~1 to 2%
• Incidence varies with…
• …weight
• …family history
• Incidence does not vary with…
• …age
• …sex
• …race
Symptoms of Hypertension
• Neonates and Infants
• Failure to Thrive
• Irritability
• Feeding problems, especially vomiting
• Cyanosis
• Respiratory distress
• Cardiac failure
• Seizures
•
Older Children
• Hypertension in older children is usually symptom-free
• Severe hypertension may present with headache, seizures or congestive heart failure
Etiology of Hypertension
• Neonates and Infants
• Most Common
• Renal artery thrombosis 2° UAC
• Coarctation of the aorta
• Congenital renal disease
• Renal artery stenosis
•
Less Common
• Bronchopulmonary dysplasia
• Patent ductus arteriosus
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Pediatric Nephrology Handout
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Chris Clardy, M.D.
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Intraventricular hemorrhage
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Pediatric Nephrology Handout
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Older Children
• Most Common
• Renal disease
• Coarctation of the aorta
• Essential hypertension
•
Less Common
• Renal Artery Stenosis
• Hypercalcemia
• Neurofibromatosis
• Neurogenic tumors
• Pheocromocytoma
• Hyperthyroidism
• Mineralocorticoid excess
• 1° hyperaldosteronism
• 11ß-hydroxylase deficiency
• 17α-hydroxylase deficiency
• Syndrome of Apparent mineralocorticoid excess (SAME)
• Liddle’s syndrome
• Status post urologic surgery (transient)
• 2° limb immobilization
• 2° sleep apnea
Evaluation of Hypertension
• History and physical exam
• CBC
• Urinalysis
• Serum electrolytes, BUN, creatinine, cholesterol
• Urine culture
• ±Echocardiogram
• ±Renal ultrasound
Treatment of Hypertension
• Goal is reduction to ≤95th percentile for height, sex and age
• Weight loss and salt restriction when appropriate
• Treat hypertensive crisis with vasodilators
• Use ACE inhibitors and calcium channel blockers for long term therapy
Pharmacologic Therapy
Emergent
Nifedipine
Initial Dose
0.25 mg/kg
Maximum Dose
0.5 mg/kg
Nitroprusside
0.5 µg/kg/min
8 µg/kg/min
Labetalol
1 mg/kg/hr (iv)
3 mg/kg/hr (iv)
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Pediatric Nephrology Handout
Revised May-00
Chris Clardy, M.D.
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Long Term
Captopril
Neonates
Children
Enalapril
Nifedipine XL
Atenolol
HCTZ
Lasix
Initial Dose
Maximum Dose
0.03 mg/kg/day
1.5 mg/kg/day
0.15 mg/kg/day
0.25 mg/kg/day
1 mg/kg/day
1 mg/kg/day
1 mg/kg/day
2 mg/kg/day
6 mg/kg/day
?
3 mg/kg/day
8 mg/kg/day
2 mg/kg/day
12 mg/kg/day
Neonatal Hypertension
Significance
Neonatal hypertension can lead to…
• left ventricular hypertrophy
• retinopathy
• renovascular changes
• encephalopathy
• intraventricular hemorrhage
Epidemiology
• 20 of 10,000 normal newborns are hypertensive
• ~9% of premature infants who are normotensive at discharge from the hospital will be hypertensive
at their first follow-up visit
• 43% of infants with bronchopulmonary dysplasia will develop hypertension in the first year of life
Guidelines
• Blood pressure will vary according to birth weight until about 8 weeks of age
• Blood pressure will vary by post natal age
• In general the systolic blood pressure determination is the most accurate
The following chart was put together using extrapolations of published data (Pediatrics 65:1028, 1980,
Pediatrics 67:607, 1981, and Pediatric Research 18:321A, 1984)
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Pediatric Nephrology Handout
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Upper Limits of Systolic Blood Pressures
120
110
Systolic Blood Pressure
100
90
80
70
>2.5 kg
1.5-2.5 kg
1.0-1.5 kg
60
<1.0 kg
50
1
10
Post Natal Age
(days)
Differential Diagnosis
Vascular
• Renal Artery Thrombosis
• Renal Vein Thrombosis
• Arterial Calcification
• Renal Artery Stenosis
• Coarctation of the Aorta
Renal
• Renal Dysplasia
• Obstructive Uropathy
• Infantile Polycystic Kidney Disease
• Renal Insufficiency
• Renal Tumor
Endocrine
• Adrenogenital Syndrome
• Cushing Disease
• Primary Hyperaldosteronism
• Thyrotoxicosis
100
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Pediatric Nephrology Handout
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Chris Clardy, M.D.
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Pediatric Nephrology Handout
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Chris Clardy, M.D.
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Drugs
• Ocular Phenylephrine
• Corticosteroids
• Theophylline
• Deoxycorticosterone
Other
• Increased Intracranial Pressure
• Fluid Overload
• Neural Crest Tumor
• Abdominal Wall Surgery
• Pneumothorax
• Hypercalcemia
• Genitourinary Tract Surgery
• Bronchopulmonary Dysplasia
Evaluation
• Directed History and Physical Exam
• Serum Electrolytes, Calcium, BUN, and creatinine
• CXR
• Renal Ultrasound
• ±DTPA Scan
• ±Aortogram
• ±Head Ultrasound
Treatment
Diuretic
• Hydrochlorothiazide 0.5-2 mg/kg/dose q 8 hours (p.o.)
• Lasix 0.5 to 2 mg/kg/dose q 12 hours (p.o., i.v.)
Vasodilator
• Hydralazine 0.15-1 mg/kg/dose q 6 hours (i.v.)
• Diazoxide 2-5 mg/kg/dose (i.v.)
• Nitroprusside 0.25-8 µg/kg/min (i.v.)
ß-Adrenergic Antagonist
• Propranolol 0.2-2 mg/kg/dose q 6 hours (p.o.)
Converting Enzyme Inhibitor
• Captopril 0.2-1 mg/kg/dose q 6 hours (p.o.)
Congenital Uropathies
Normal Embryogenesis
Kidney formation begins in the 3rd week of life when the intermediate mesoderm is formed (Figure
#1A). This subsequently develops into a series of nephrotomes (Figure #1B, left hand side) each of
which in turn develops a lumen (Figure #1B, right side). These nephrotomes join together to form a
longitudinal duct which develops into two vestigial kidneys, the pronephros and the mesonephros, as
well as the permanent kidney, the metanephros.
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Pediatric Nephrology Handout
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Figure #1
The development of the permanent kidney occurs when the metanephros interacts with an offshoot of
the cloaca called the ureteric bud (Figure #2).
Figure #2
The ureteric bud undergoes a branching process to form the ureter, the renal pelvis, the calyces, and
the collecting tubules (Figure #3).
Figure #3
Meanwhile, the metanephric tissue caps form vesicles (Figure #4A and 4B) which elongate to form
glomerulus, the proximal convoluted tubule, the loop of Henle, the and distal convoluted tubule.
These structures join to the previously formed collecting system to form the mature nephron.
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Pediatric Nephrology Handout
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Figure #4
The permanent kidney is formed in the pelvis, however as the fetus develops it migrates to its position in
the lumbar region (Figure #5).
Figure #5
Finally, the bladder is formed when the cloaca separates into an anorectal and urogenital canal (Figure
#6).
Figure #6
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Pediatric Nephrology Handout
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The timing of the events in renal development are outlined below.
Weeks
3 to 4
5
6
8 to 9
10 to 11
14 to 15
20 to 22
32 to 36
Events
Formation of the pronephros and
mesonephros
Formation of the ureteric bud and
initiation of the metanephros
Formation of the urogenital sinus
Renal pelvis and ureter evident, some
nephrons completed, bladder formed
Renal pelvis completed, calyces
initiated
Collecting system completed
Medulla and cortex demarcated
Nephron formation complete
Mechanical Defects
Gross Malformations
Renal Agenesis
Definition:
• Absence of the kidney without any evidence of parenchymal maldevelopment
Pathophysiology:
• Failure of development of the kidney as the result of absence of the ureteric bud
• Bilateral agenesis occurs in 1:6,000 deliveries, unilateral agenesis is more common
Clinical Features:
• Unilateral agenesis usually not detected
• Bilateral agenesis results in the decreased production of amniotic fluid with
consequent oligohydramnios, pulmonary hypoplasia, and a "Potter's facies"
Evaluation:
• Diagnosis is made by either pre- or post-natal ultrasound
Therapy & Prognosis:
• Bilateral agenesis is usually fatal secondary to severe pulmonary disease
• Unilateral agenesis allows normal renal function although there might be some
benefit in a low protein diet
Pelvic Kidney
Definition:
• A kidney arising from the iliac artery instead of the aorta
Pathophysiology:
• Failure of the normal ascent of the kidney
Clinical Features:
• Usually detected only as an incidental finding
Evaluation:
• Renal ultrasound and VCUG
Therapy & Prognosis:
• May have increased incidence of infections or obstruction
Horseshoe Kidney
Definition:
• Fusion of the lower poles of the kidneys, associated with incomplete ascent with
resultant lower lumbar location
Pathophysiology:
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Fusion of the kidneys due to close approximation as they ascend through the arterial
bifurcation
• Occurs in 0.25% of the population
Clinical Features:
• Usually detected only as an incidental finding
Evaluation:
• Renal ultrasound and VCUG
Therapy & Prognosis:
• May have increased incidence of infections or obstruction
•
Microscopic Malformations
Dysplasia, Aplasia, & Multicystic Kidneys
Definition:
• An abnormal parenchymal differentiation reflected by the presence of abnormal
structures including primitive ducts surrounded by collars of connective tissue,
metaplastic cartilage, and less specific lesions such as differentiated glomeruli and
tubules and cystic dilation of tubular structures
• A muticystic, dysplastic kidney is a closely related form of severe dysplasia in which
the kidney is enlarged and variably distorted with cysts.
• Pathophysiology:
• Perturbed development of normal renal architecture as the result of in utero vascular
deprivation or ureteral obstruction (e.g. posterior urethral valves, ureteral vesicular
obstruction, or ureteral pelvic junction obstruction) resulting in failure of the forming
collecting system and glomerulo-tubular apparatus to connect with one another
Clinical Features:
• Unilateral multicystic dysplastic kidney presents as an abdominal mass
• Bilateral dysplasia presents as chronic high output renal failure with an associated
renal tubular acidosis
Differential Diagnosis:
• Dysplastic kidneys are often mislabeled as hypoplastic kidneys, the latter being a
very rare variant of renal agenesis
• Bilateral multicystic dysplastic kidneys may be confused with IPKD ( see below)
Evaluation:
• Diagnosis can be made by post-natal ultrasound
• Severity of disease may be determined by electrolytes, BUN, and creatinine
• In the case of a unilateral multicystic, dysplastic kidney, renal dysplasia must be
suspected in the contralateral kidney
Therapy & Prognosis:
• Therapy and prognosis of a unilateral multicystic, dysplastic kidney is the same as for
unilateral agenesis
• Low potential for malignant transformation of a unilateral multicystic, dysplastic
kidney does not warrant prophylactic nephrectomy
• Bilateral dysplasia usually results in chronic renal failure requiring eventual dialysis
and/or transplantation
Molecular Defects
Polycystic Kidney Disease
Definition:
• Diffuse cystic changes in both kidneys without other evidence of parenchymal
maldevelopment.
• Cysts are centimeter sized
Pathophysiology:
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Infantile polycystic kidney disease (IPKD) is an autosomal recessive disorder
characterized by large fluid filled cysts in the kidney. It presents either at birth or in
the first few years of life and is associated with congenital hepatic fibrosis
• Adult polycystic kidney disease (APKD) is an autosomal dominant disorder (with
frequent spontaneous occurrences) also characterized by large fluid filled cysts in the
kidney. It usually presents in older children and adults and is associated with cysts
of the liver, pancreas, lung, and ovary as well as with cerebral aneurysms.
Clinical Features:
• Initial hematuria (especially APKD) followed by hypertension, abdominal masses,
and azotemia
•
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Differential Diagnosis:
• IPKD may be confused with APKD, obstructive uropathy, bilateral multicystic
dysplastic kidneys, tuberous sclerosis, and renal tumors.
• APKD may be confused with IPKD and tuberous sclerosis
Evaluation:
• Reliable diagnosis of both conditions usually possible with ultrasound
• Renal biopsy occasionally needed with IPKD
Therapy & Prognosis:
• Unrelenting progression to end stage renal disease is seen in both conditions
Medullary Cystic Kidney Disease/ Familial Juvenile Nephronophthisis
Definition:
• Diffuse tubulo-interstitial degeneration either with or without small medullary cysts.
• Cysts are millimeter sized
Pathophysiology:
• Either an autosomal recessive condition, often associated with retinal degeneration,
with onset in younger children or an autosomal dominant condition with onset in older
children and adults.
• Characterized by small cysts formed by dilated distal tubules and collecting ducts.
Clinical Features:
• Inability to concentrate the urine followed by azotemia
Differential Diagnosis:
• May be confused with PKD and medullary sponge kidney.
Evaluation:
• Reliable diagnosis usually possible with ultrasound although renal biopsy
occasionally required
Therapy & Prognosis:
• Unrelenting progression to end stage renal disease
Urinary Tract Infections in Children
Definition
The broad term urinary tract infection (UTI) is used to describe a myriad of conditions which have only
one feature in common, the presence of significant amounts of bacteria in the urine.
Classification
• UTIs may be divided in the following manners…
• those limited to the bladder (cystitis) versus those involving the renal parenchyma
(pyelonephritis)
• symptomatic infections versus asymptomatic bacteriuria detected on screening urine cultures
• primary, uncomplicated infections versus those with complications such as…
• …persistence despite appropriate antibiotic therapy
• …frequent recurrence despite appropriate antibiotic therapy
• …vesicoureteric reflux
• …obstruction
Incidence
• The risk of a newborn girl's falling ill with a symptomatic UTI during childhood is at least 3%; for a
boy, about 1%.
• Approximately 7% of febrile children ≤6 months old will have UTIs.
• The incidence of asymptomatic bacteriuria in girls of pre-school and school age is ~1%.
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•
•
•
24
UTIs are more common in males in children ≤6 months old and more common in females in all other
age groups.
The incidence of UTIs in uncircumcised males is ~10 times that in circumcised males.
About 50% of children with symptomatic UTIs and about 80% of those with asymptomatic bacteriuria
will develop one or several recurrent infections.
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Significance
• Some 5% to 7% of children with symptomatic, febrile UTIs during the first year of life will acquire a
renal scar. This incidence is increased by such factors as…
• obstruction
• gross vesicoureteric reflux
• intrarenal reflux
• increased bacterial virulence
• therapeutic delay
Diagnosis
Clinical Presentation:
• Neonates and infants in the first year of life tend to present with signs of a systemic illness, i.e., fever,
lethargy or irritability, decreased perfusion, etc. In addition, they may have vomiting, abdominal
tenderness and distention, foul smelling urine or hematuria.
• Older children tend to present with frequency, urgency, burning and diurnal enuresis. N.B. dysuria in
females may result from vulvovaginitis unassociated with a UTI.
• All children suspected of having a UTI should be examined for increased blood pressure, fever,
abdominal masses and costovertebral angle tenderness.
Laboratory Presentation:
• A urinalysis with pyuria (≥10 to 20 WBC/hpf on an unspun urine) is adjunctive to the diagnosis of UTI.
50% of patients with pyuria do not have a UTI and 50% of patients with a UTI do not have pyuria.
• An urinalysis with bacteriuria (≥1 organism/hpf on an unspun urine) is adjunctive to the diagnosis of
UTI.
• The presence of nitrites and leukocyte esterase by dipstick are 90% specific for a UTI.
• The only absolute diagnostic criteria for UTI is the presence of significant amounts of bacteria in the
urine. This is defined as either any growth in a urine obtained by bladder aspiration or urinary
catheterization or ≥100,000 colonies/ml in a "clean catch" urine. N.B. Urine must be plated out within
30 minutes if at room temperature or within 24 hours if refrigerated.
• As most antibiotics are concentrated and excreted unchanged in the urine, any pre-treatment is likely
to result in a potentially false negative urine culture.
• The most common pathogens are…
Enterobacteriaceae (EMB plate)
E. coli
Klebsiella
Proteus
Enterobacter
"White" Staph (Blood agar plate)
S. epidermidis
S. saprophyticus
Cystitis vs. Pyelonephritis:
• Most reliable sign of pyelonephritis is a high fever.
• CVA tenderness is often not present, especially at ≤5 years of age.
• Abdominal pain and vomiting suggest pyelonephritis.
• Laboratory tests (e.g. urinary LDH or antibody coated bacteria) are not usually helpful but an elevated
ESR or a low urine specific gravity may indicate pyelonephritis.
Therapy
•
Pyelonephritis in children ≤6 months old should be treated with iv ampicillin and gentamicin (or a 3rd
generation cephalosporin) pending culture results. IV therapy should be continued until the child has
had negative urine cultures for 48 hours. Thereafter and in older children, treatment should be oral
(see below) for a total antibiotic course of 10 days.
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•
Asymptomatic bacteriuria and cystitis can be treated for 10 days with oral…
Antibiotic
TrimethoprimSulfamethoxazole
Amoxicillin
Nitrofurantoin
•
26
Dose (mg/kg/day)
6
30
25-50
3
# Doses/Day
2
3
4
Recurrent UTIs can be prophylaxed with…
Antibiotic
Trimethoprim
Sulfamethoxazole
Nitrofurantoin
Dose (mg/kg/day)
2
10
1
Follow-Up
• Follow-up urine cultures should be obtained 2 to 3 days after the discontinuation of therapy, again at
2 to 3 weeks and 3 more times during the next year.
• Radiographic visualization of the kidney (IVP or Renal US) and the vesicoureteric dynamics (VCUG
or Nuclear Reflux-o-gram) should be obtained after…
• any UTI in a male
• 2 symptomatic UTIs in a female ≤ 5 years
• persistent UTIs in older females
• The goal of radiologic evaluation is to…
• detect factors predisposing to infection and kidney damage, principally congenital or acquired
obstructions of the urinary flow, calculi, vesicoureteric reflux and intrarenal reflux. N.B. ~10% of
children with UTIs will have reflux.
• detect and outline narrowing of renal parenchyma and calyceal dilation, which may be an early
sign of progressive renal scarring.
• determine the rate of growth of the kidney, which may be a valuable aid in assessing the effect of
treatment.
• Radiologic evaluation is not emergent but should be obtained without delay
• Renal scan for function (DTPA) or for detection of a scar (DMSA) are not useful.
• Referral to a urologist for…
• gross vesicoureteric reflux with dilation of the collecting system (grade IV or V).
• reflux associated with frequent recurrence of UTIs which can not be adequately treated with
prophylactic antibiotics.
• any reflux in a child ≥9 years old.
Systemic Lupus Erythematosus
Definition
An autoimmune disease characterized by at least 4 of the 11 following manifestations…
1)
malar rash
2)
discoid rash
3)
photosensitivity
4)
oral ulcers
5)
arthritis
6)
serositis (pleuritis/pericarditis)
7)
renal disorder (proteinuria>500 mg/day or cellular casts)
8)
neurologic disorder (seizures or psychosis)
9)
hematologic disorder (hemolytic anemia, leukopenia, lymphocytopenia, or thrombocytopenia)
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10)
11)
27
immunologic disorder (positive LE cell test, anti-DNA antibody, anti-Sm antibody, or false
positive serologic test for syphilis)
positive anti-nuclear antibody test
Epidemiology
90% female
peak incidence in the third decade of life
1 in 500 adult females afflicted
35% to 90% have renal involvement depending on how it is defined
Classification
W.H.O. Classification:
Normal Glomeruli (Class I)
Mesangiopathic Glomerulonephritis (Class II)- E.M. deposits in the mesangium either without (IIa)
or with (IIb) mesangial cellularity
Focal and Segmental Proliferative Lupus Glomerulonephritis (Class III)- diffuse mesangial
hypercellularity with focal and segmental accentuation, with mesangial and sub-endothelial
deposits in <50% of the glomeruli
Diffuse Proliferative Lupus Glomerulonephritis (Class IV)- same as II but in >50% of glomeruli
Membranous Lupus Glomerulonephritis (Class V)- membranous lesion secondary to sub-epithelial
deposits either alone (Va), with mesangial hypercellularity (Vb), with segmental hypercellularity
(Vc), or with diffuse hypercellularity (Vd)
Glomerular Sclerosis (Class VI)
Cliniopathologic Correlations in Lupus Glomerulonephritis
Class II
Class III
Class IV
Class V
No Clinical
40%
30%
25%
≤5%
Findings of
Renal Involvement
Renal Involvement
7%
16%
65%
12%
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Treatment/Outcome
Most patients developing ESRD will have had W.H.O. Class IV or Vd (DPGN/MPGN)
Effect of Treatment on High Risk SLE
100
IV Cytoxan,
~0.8% ESRD/year
80
%
Survival
60
40
Prednisone Rx,
~12% ESRD/year
20
0
0
20
40
60
80
100
Month
IgA Nephropathy in Children
Definition:
IgA Nephropathy (IgAN) is a clinical/pathological entity defined by…
- hematuria, usually episodic, ± proteinuria
- mesangial IgA deposits
- after SLE, HSP, and liver disease have been ruled out
120
140
160
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Pathology:
Light Microscopy
29
Minimal Change
Focal, Segmental Glomerulosclerosis
Diffuse Proliferation
Immunofluorescence
Microscopy
Mesangial IgA, ± IgG and/or C3
Electron Microscopy
Mesangial Electron Dense Deposits
Epidemiology:
- Statistics vary with study and population
- Potentially the most common form of glomerulonephritis
- 2:1 male predominance
- Increased incidence in Caucasian and Asian populations
- Peak incidence in the 1st and 2nd decade of life
- Increased incidence in family members
Clinical Presentation:
- High coincidence with upper respiratory infections
- High coincidence with loin pain
- Clarkson et al. (Clin Nephrol 8:459, 1977) found…
Macroscopic Hematuria
Proteinuria ± Microscopic Hematuria
Nephrotic Syndrome
Acute Nephritis
Hypertension
Chronic Renal Failure
Acute Renal Failure
…as the initial presentation in 50 patients with IgAN.
34%
30%
6%
10%
8%
6%
6%
Prognosis:
- 10 year renal survival of 75 to 90%
- Outcome worse in…
…persistent as opposed to episodic disease
…older patients
…cases with hypertension, marked proteinuria, or renal impairment
…sclerotic or proliferative disease
…cases with basement membrane deposits
- Significant recurrence after renal transplant
Pathophysiology:
There is no cohesive explanation for the pathophysiology of IgAN. Two lines of evidence are presently
being followed.
Associated Immunologic Abnormalities: The histology of IgAN is consistent with an immune complex
disease. Elevated levels of IgA per se, polymeric IgA, IgA1, and IgA containing immune complexes
have been found in the serum of some patients with IgAN. However these findings are highly
variable and of unclear significance.
Genetic Linkage: Multiple members of the same family may have IgAN suggesting a genetic linkage.
In French and Japanese studies IgAN has been linked to HLA B35 and DR4. This linkage has not
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been associated with extended haplotyes of the short arm of the 6th chromosome. American
studies have shown an increased incidence of null alleles for one of the C4 genes in IgAN. All of
these HLA linkages are associated with a worse outcome. In addition to these HLA linkages,
patients with IgAN have an increased incidence of the fast allele of C3 (19th chromosome) and
have a distinct RFLP for the switch region for IgA (14th chromosome).
Therapy:
- There is no acknowledged therapy for IgAN
- Attempts at therapy have included…
…corticosteroids
…fish oil
…cytotoxic agents
…anti-coagulants
…plasmapheresis
…tonsillectomy
…phenytoin
…none of which has been an unqualified success.
IgAN vis-à-vis Henoch-Schönlein Purpura (HSP):
HSP is an acute vasculitis which affects the mucosa of the gut, the skin, the synovial lining of the joints, and
the glomerulus of the kidney causing abdominal pain, a petechial rash, arthralgias, and glomerulonephritis.
IgAN and HSP have many similarities.
Clinical Presentation:
- 10% to 30% of patients with HSP will have subsequent bouts of gross hematuria with URIs
- 30% of patients with IgAN will have abdominal pain, rash and/or arthralgia
- patients with HSP and IgAN who have similar renal findings (eg. proteinuria, hypertension, renal
insufficiency) will have a similar incidence of chronic renal failure
Histopathology: The glomerulonephritis in HSP is characterized by mesangial proliferation, mesangial
IgA, and occasional sclerosis and crescent formation.
The only difference between the
histopathology of IgAN and HSP is that the cellular infiltrate in IgAN consists of mesangial cells
whereas that in HSP consists of monocytes and T-lymphocytes.
Serology: Several studies have shown an increased serum level of IgA and IgA containing immune
complexes in some patients with HSP
Genetics: HSP and IgAN are often seen in the same families. Patients with HSP have an increased
frequency of C4 null alleles compared to a normal population.
Fluid & Electrolytes
General
Taken as a whole, the maintenance of fluid and electrolyte homeostasis is astoundingly complex.
However, almost all fluid and electrolyte problems can be broken down into relatively autonomous subproblems involving…
Water (H2O)
Sodium (Na+)
Acid (H+)
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Potassium (K+)
As a general rule, the body will prioritize the normalization of fluid and electrolytes in the same order as
that given above. Therefore, it is easiest to approach problems using the same order.
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Water (H2O)
H2O homeostasis depends on both a normal intake and an appropriate output. The former is usually
defined as consisting of…
Insensible
Urine
500 ml/M2/day
650 ml/M2/day
"Extra"
50 ml/M2/day
800 ml/M2/day
∑
2,000 ml/M2/day
Stool
…and the latter is controlled by the renal tubule under the influence of anti-diuretic hormone, aldosterone,
atrial naturetic factor and other mediators. Over hydration can result in hypertension, congestive heart
failure or pulmonary edema whereas dehydration may cause hyperosmia or circulatory collapse.
Causes of Over Hydration
Oliguria
e.g. SIADH, ATN
Excess Intake
Causes of Dehydration
Polyuria
e.g. DKA, DI
Vomiting & Diarrhea
High Insensible Loss
e.g. Burn Injury
Exsanguination
Altered Vascular Tone
e.g. Septic Shock
Sodium (Na+)
Na+ homeostasis depends on a normal intake of approximately 50 mEq/M2/day and a normal output
which is usually via the renal tubule. Hypo- and hypernatremia are deleterious because of their alteration
of the serum osmolality. As there is a blood/brain barrier for Na+, rapid changes in serum [Na+] can lead
to catastrophic swelling or contraction of the brain.
Causes of Hyponatremia
Loss of Na+ Alone
e.g. Inappropriate
formula dilution
Causes of Hypernatremia
Excess of Na+ Alone
e.g. Hyperaldosteronism,
Iatrogenic
Excess H2O Alone
e.g. Polydipsia, SIADH
Loss of H2O Alone
e.g. DI
Losses of H2O & Na+
(Na+>H2O)
e.g. Diuretic abuse,
3rd space losses
Losses of H2O & Na+
(H2O>Na+)
e.g. Diarrhea
Treatment of Hypo-/Hypernatremia
The Baby as a Bucket Theory
•
•
Volume of distribution of sodium is 0.67 L/kg
Therefore sodium space can be conceptualized as a bucket whose volume is 2/3 of the body’s weight
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Hyponatremia
Example:
•
+
3 Kg child with [Na ]=123 mEq/L
Goal:
•
+
To increase [Na ] by 12 mEq/L
Concept:
•
How much extra Na+ is needed to increase the [Na+] of a 2 L bucket of H2O by 12 mEq/L?
Answer:
• Give (2 L x 12 mEq/L) or 24 mEq of Na+
Hypernatremia
Example:
•
+
3 Kg child with [Na ]=157 mEq/L
Goal:
•
+
To decrease [Na ] by 12 mEq/L
Concept:
•
How much extra H2O is needed to decrease the [Na+] of a 2 L bucket of from 157 to 145 mEq/L?
Answer:
•
•
•
New [Na+] = {Total Body Na+} / {Present Body H2O + Supplemental H2O}
145 mEq/L = {2 L x 157 mEq/L}/ {2 L + Supplemental H 2O}
Give supplemental H2O of 165 ml
Acid (H+)
Acid (H+) and alkali (HCO3-) are balanced with each other to maintain the body's pH. An imbalance can
result in either acidosis or alkalosis, which in turn alters the efficiency of biochemical processes in the
body. Of note, too rapid a correction of acidosis may lead to a paradoxical increase in intra-cellular
acidosis with deleterious consequences (Figure #1).
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Cell
35
Extra-Cellular Space
Blood
H+ & HCO3-
HCO3-
H2CO3
CO2 & H2O
CO2 & H2O
CO2
Figure #1
Types of acidosis can be classified by their anion gap ([Na+] - [HCO3-] - [Cl-], Figure #1) which is
normally 8-16 mEq/L. An elevated anion gap indicates the presence of an unmeasured anion such as
lactate.
160
140
OTHER
ORGANIC
mEq/L
120
ORGANIC
ORGANIC
100
80
NA
CL
60
CL
CL
40
20
0
HCO3
CATION
Figure #2
Causes of Acidosis
(Normal Anion Gap)
ANION
NORMAL
HCO3
HCO3
ACIDOSIS
NORMAL
ANION
GAP
ACIDOSIS
HIGH
ANION
GAP
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GI Loss of HCO3e.g. Diarrhea,
Pancreatic fistula
Renal Loss of HCO3e.g. Proximal RTA
Defective H + Excretion
e.g. Distal RTA
(High Anion Gap)
Excess H+ Production
e.g. DKA, Lactic
acidosis
Exogenous H +
e.g. Salicylate
ingestion
The kidney's response to sodium chloride deficiency can cause a secondary alkalosis as shown in figure
#2. Types of alkalosis can therefore be classified by their response to sodium chloride.
DISTAL TUBULE
Na
ALDOSTERONE
MEDIATED
PUMP
K,H
Figure #3
Causes of Alkalosis
(Chloride Responsive)
GI Chloride Loss
e.g. vomiting
Renal Chloride Loss
e.g. Diuretic abuse
(Chloride Resistant)
Hyperaldosteronism
K+ Deficiency
Excess Alkali Ingestion
Potassium (K+)
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Potassium (K+) levels are balanced by intake, renal and gastrointestinal loss and by redistribution
between the intra- and extra-cellular space. Hypokalemia may cause cardiac conduction defects,
however these are usually not fatal unless a patient is being treated with digoxin. Hyperkalemia, on the
other hand, may lead to ventricular fibrillation.
Causes of Hypokalemia
(No ⇓ Body K+)
Alkalosis
ß-Adrenergic drugs
(⇓ Body K+)
Poor Intake
e.g. Anorexia nervosa
⇑ Cellular Incorporation
e.g. Refeeding
GI Loss
e.g. Vomiting, Diarrhea
Renal Loss
e.g. Diuretic abuse,
Hyperaldosteronism
Causes of Hyperkalemia
Pseudohyperkalemia
Excess Intake
Redistribution
e.g. Acidosis,
⇑ Cell breakdown
⇓ Excretion
e.g. Renal failure
Hypoaldosteronism
Renal Tubular Acidosis
Definition
Renal Tubular Acidosis (RTA) is a disorder of urinary acidification resulting in a hyperchloremic (i.e.
normal anion gap) metabolic acidosis.
Pathophysiology
•
•
•
As a byproduct of normal metabolism the average child produces 1 to 3 mEq H+/kg/day in the form of
non-carbonic acids.
Although respiratory variation of the PCO2 may transiently buffer these acids, the only means of
removing them from the body is via the kidney.
The kidney has two basic mechanisms for handling acid homeostasis:
• Proximal tubular reabsorption of glomerularly filtered HCO3• Distal tubular excretion of H +
Types of RTA
Distal RTA (Type I)
•
•
•
An inability to adequately excrete H+ into the urine against a concentration gradient.
Normal distal tubules can produce a 1,000x concentration gradient of H+ (i.e. a pH of 4.4 in the urine
versus 7.4 in the blood).
Distal RTA is associated with renal dysplasia, medullary cystic disease and hypercalcinuria.
Proximal RTA (Type II)
•
•
An inadequate reabsorption of glomerularly filtered HCO3-.
Normal proximal tubules reabsorb 85% of filtered HCO3-. If this was decreased to 75% in a patient
with a GFR of 125 ml/min and a serum HCO3- of 20 mEq/L an additional 180 mEq of HCO3- would
be lost in the urine each day!
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38
Proximal RTA is associated with other tubulopathies (e.g. renal phosphate wasting) and with the
aminoacidopathies.
Combined Distal and Proximal RTA (Type III)
Acidosis 2° to Hypoaldosteronism (Type IV)
Potassium in RTA
Depending on the type and location the of tubular defect in RTA, a patient may be hypo-, normo- or
hyperkalemic. In hypokalemic RTA the kidney's Na+/K+ exchange pump wastes potassium in order to
retrieve sodium. This is seen in all proximal RTA and in some distal RTA (see figure below).
Proximal
Tubule
Failure toreabsorb
NaHCO3
Na+
Failure to swap
H+ Na+ for H+
Na+
K+
Distal
Tubule
Swap of
Na+for K+
Hyperkalemia is seen mainly in type IV RTA where the aldosterone mediated ability to transport
potassium from the blood into the urine is impaired.
Diagnosis
• Suspected in failure to thrive and nephrolithiasis.
• Diagnosis of RTA made if patient has normal anion gap metabolic acidosis without any other cause of
bicarbonate loss (e.g. diarrhea).
• Diagnosis may be confirmed by urine anion gap ([Na+] + [K+] - [Cl-]). If urine anion gap is positive
•
•
•
(i.e. >0) then this is consistent with RTA.
Distinction between distal and proximal RTA is made by whether urine pH is able to go below 5.5
which excludes distal RTA.
Diagnosis of hypoaldosteronism is made if serum aldosterone level is low.
Evaluation should also include a urine calcium, a urine amino acid screen and a renal ultrasound to
screen for associated anomalies.
Treatment
• The treatment of RTA is always to normalize the serum HCO -.
3
• In hypoaldosteronism the HCO3 is normalized by replacing the aldosterone.
• In all other forms of RTA the treatment is with supplemental alkali in the form of either citrate or
bicarbonate.
Acute Renal Failure
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Etiology
Prerenal Factors
eg.
hypovolemia
cardiac insufficiency
Renal Factors
Arterial
eg.
thromboembolism
arteritis
hemolytic-uremic syndrome
Glomerular
eg. glomerulonephritis
Venous
eg. renal venous thrombosis
Tubular
eg. ischemic acute tubular necrosis
nephrotoxic acute tubular necrosis
crystal nephropathy
Interstitial
eg. acute interstitial nephritis
pyelonephritis
Postrenal Factors
eg. congenital or acquired obstruction
Complications of Renal Failure
Hyperkalemia
⇓
Arrhythmia
⇓
Cardiac Arrest
⇓
Death
Acidosis
⇓
Impaired Cellular Function
⇓
Death
Fluid Overload
⇓
Hypertension &
Congestive Heart Failure
⇓
Inadequate Cardiac Function
⇓
Death
Uremia
⇓
Impaired Cardiac, Cerebral,
& Thrombotic Function
⇓
Death
Initial Evaluation
Blood Laboratories
SMA-6
Blood Gas
Ca++, PO4--, & Mg++
Urate
Total Protein & Albumin
CBC
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Auto-Immune Serology
Urine Laboratories
U/A
Culture
Osmolality, Creatinine, & Na+
Other
Chest X-Ray
Renal Ultrasound
E.K.G.
Initial Management of Acute Renal Failure
N.B. This protocol should only be used as a guideline
1) Obtain a history with specific emphasis on previous health, recent ingestions, fever, arthralgia,
bloody diarrhea, and change in urine amount and/or quality.
2) Do a physical exam with specific emphasis on the blood pressure, estimation of vascular volume,
presence of rash or petechiae, and presence of abdominal masses.
3) Establish an iv and obtain blood laboratories, place EKG leads, insert a foley catheter and obtain
urine laboratories.
4) Treat EKG evidence of severe hyperkalemia (↑ T wave amplitude with ↑ qrs length) with…
10% Calcium Chloride 0.25 ml/kg (maximum 10 ml)
Dextrose 1 gm/kg and Insulin 0.2 unit/kg
Sodium Bicarbonate 1-2 mEq/kg
Kayexalate 1 gm/kg
5) Treat malignant hypertension with…
Minoxidil 0.2 mg/kg p.o.
Hyperstat 5 mg/kg slow iv push over 20 minutes
6) Treat metabolic acidosis resulting in a pH≤7.20 with sodium bicarbonate
7) In the oliguric patient, unless fluid overload exists, give a fluid challenge with 10 ml/kg of normal
saline. Repeat this if there is no increase in urine output after 30 minutes.
8) Call for pediatric nephrology help.
9) While waiting for pediatric nephrology, use the urine and serum concentrations of creatinine and
Na+ to calculate the fractional excretion of Na+ (FENA) in your oliguric patients.
FENA=
([urine Na+] x [serum creatinine] x 100%)
([urine creatinine] x [serum Na+])
This can be used to distinguish pre-renal oliguria (FENA≤1%) from renal oliguria (FENA>1%).
N.B. this test may be falsely elevated for 48° after a patient is given a loop diuretic.
Subsequent Management of Acute Renal Failure
Many cases of acute renal failure can be managed using only the protocol outlined above. Two
conditions require more specialized management…
Uremia requires removal of nitrogenous wastes from the blood. This is accomplished by dialyzing the
blood versus a balanced saline solution across a semi-permeable membrane.
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Dialysis
High
B.U.N.,
Creatinine,
other
N2 products
Blood
Diffusion
of N2 waste
Across a
Concentration
Gradient
Semi-permeable
Membrane
Dialysis
Solution
Fluid Overload require removal of excess H2O from the blood. This is accomplished by ultrafiltering the
blood through a semipermeable membrane using either an osmotic or a pressure gradient.
Ultrafiltration
High
Hydrostatic
or
Osmotic
Pressure
Blood
Diffusion
of H2O
Across a
Pressure
Gradient
Semi-permeable
Membrane
Dialysis
Solution
Methods:
Peritoneal Dialysis:
Definition- dialysis across the peritoneal membrane with ultrafiltration using a dextrose osmotic gradient
Access- a single lumen peritoneal catheter
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Peritoneal
Membrane
Dialysate Solution
Arteriole in
Peritoneal
Membrane
Sodium
Potassium
Chloride
Magnesium
Calcium
Lactate
Dextrose
Osmolality
pH
Volume
130-135 mEq/L
0-3 mEq/L
96-102 mEq/L
1.2-1.8 mg/dl
6.0-8.0 mg/dl
35-40 mEq/L
1.36/2.27/3.86 gm/dl
346/396/485 mOsm/kg
5.0-5.5
15-30 ml/kg
Advantagesunlikely to cause rapid fluid and electrolyte shifts
does not require systemic anticoagulation
Disadvantagesineffective in low perfusion states
risk of infection and/or N.E.C.
impairs diaphragmatic motion
Hemodialysis:
Definition- dialysis of extra-corporeal blood across an artificial membrane with ultrafiltration using a
machine generated pressure gradient
Access- a double lumen venous catheter
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Distal
Venous
Access
43
Proximal
Venous
Access
Heparin
Discard
Filter
Dialysis
Solution
Advantagesallows efficient dialysis and ultrafiltration
effective even in low perfusion states
Disadvantagesrequires significant extra-corporeal volume
requires systemic anti-coagulation
may cause rapid fluid and electrolyte shifts
complex procedure requiring specialized personnel
Continuous Arterio-Venous Hemofiltration:
Definition- isolated ultrafiltration of extra-corporeal blood across an artificial membrane using a
biologically generated pressure gradient
Access- a single lumen arterial catheter and a second single lumen venous catheter
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44
Heparin
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Chris Clardy, M.D.
Arterial
Access
Filter
Venous
Access
Discard
Advantagesallows continuous fluid removal in an unstable patient
Disadvantagesrequires significant extra-corporeal volume
requires systemic anti-coagulation
does not allow efficient dialysis
risk of rapid exsanguination via arterial catheter
Chronic Renal Failure in Children
Incidence:
1.5 to 3.0 children per million population will develop End Stage Renal Disease (ESRD)
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Cystinosis (8%)
Glomerulosclerosis (6%)
Obstructive
Uropathy (7%)
45
Glomerulonephritis (31%)
Medullary Cystic Disease (8%)
Congenital Dysplasia (19%)
Reflux Nephropathy (21%)
Pathophysiology/Treatment:
Impaired H 2O and Na+ Excretion:
• May result in fluid retention (eg. glomerulosclerosis) with resultant edema, hypertension, and
congestive heart failure or in the inability to conserve free H2O (eg. congenital dysplasia) resulting in
chronic dehydration.
• Appropriate management consists of prescribing a fluid intake equal to the urine output plus the
insensible fluid loss (~600 ml/M2/day). In fluid retention diuretics and, potentially, dialysis may be
needed.
Impaired H + Excretion:
•
The normal kidney clears 1 to 2 mEq/kg/day of H+ from the body. In renal failure a metabolic acidosis
will develop initially requiring alkali therapy with 10% sodium citrate and, eventually, dialysis.
Excessive Renin Production:
• Dysfunctional renal vasculature may result in hypoperfused segments of the kidney producing large
amounts of renin with resultant hypertension. This can usually be treated using ß-blocking drugs (eg.
propranolol) and A.C.E. inhibitors (eg. captopril) however it may require a nephrectomy.
Impaired Phosphorus Excretion and Vitamin D Production:
• In a complex series of reactions, children with renal failure will develop hyperphosphatemia,
hypocalcemia, hypovitamin D-emia, hyperparathyroidism, and rickets. This can be controlled by
limiting phosphorus intake to 12.5 to 20 mg/kg/day, by using an oral phosphorus binder (eg. CaCO3),
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by assuring that the oral calcium intake is 20 to 80 mg of elemental calcium/kg/day in the form of diet
and calcium supplements (N.B. 100 mg of CaCO3 contains 40 mg of elemental calcium, 100 mg of
calcium lactate contains 12 mg, and 100 mg of calcium gluconate contains 9 mg), and by starting
vitamin D supplementation (eg. rocaltrol).
Impaired Production of Erythropoietin:
• The normal kidney regulates the red cell mass by the production of erythropoietin. This function may
be impaired in renal failure resulting in a profound, normocytic anemia. This may be corrected by
supplementing the patient with exogenous erythropietin.
Impaired Clearance of Nitrogenous Wastes:
• A decreased glomerular filtration rate will result in reduced clearance of the metabolic breakdown
products of amino acid metabolism. This is manifested by an elevation in the BUN and creatinine as
well as by "uremic symptoms" such as lethargy and fatigue. Uremia in and of itself can cause sudden
death as a result of its effect on nerve conduction. The degree of uremia may be controlled by limiting
protein intake to 1 to 2 gm/kg/day, by providing adequate calories from carbohydrate and fat to prevent
protein catabolism (ie. 200 non-protein calories per gram of N2, where 6.5 grams of protein equals 1
gram of N2).
Diuretics
I
Water Physiology of the Kidney
Glomerulus
PCT
CORTEX
DCT
Na
Cl
K,H
[Na]T<[Na]I
Na
H2O
[Na]T=[Na]I
Na
Cl
MEDULLA
COLL.
DUCT
H2O
H2O
LOOP OF HENLE
ADH
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In the proximal convoluted tubule (PCT) active ionic transport, coupled with passive diffusion of H2O,
results in reabsorption of ~70% of the glomerular filtrate. This results in an equal [Na+ ] in the tubule and
interstitium.
In the ascending loop of Henle and distal convoluted tubule active ionic transport occurs uncoupled from
H2O transport resulting in hypotonic tubular fluid and a hypertonic interstitium, i.e. in a lower [Na+] in the
tubule versus the interstitium.
In the collecting duct H2O passively diffuses from the hypotonic tubule into the hypertonic interstitium
under the control of ADH.
II
Types of Diuretics
a) Osmotic Diuretics
Examples: Mannitol, Urea, Glycerin and Isosorbide
Glomerulus
Na
Cl
H2O
H2O
H2O
Mannitol
H2O
H2O
[Na]T<[Na]I
Mechanism of Action:
Osmotic diuretics …
…are freely filterable at the glomerulus
…undergo limited reabsorption by the renal tubule
…are relatively biologically inert
Therefore, their osmotic force retains H2O in the proximal convoluted tubule resulting in a diuresis. The
retained H2O makes the [Na+ ] in the tubule lower then that in the interstitium. This concentration gradient
decreases proximal tubular Na+ reabsorption resulting in a small natriuresis with a net H2O loss.
Other Phenomena:
• Osmotic diuretics result in dehydration of the eye and brain.
• Diuresis is mitigated by subsequent H2O reabsorption in the distal nephron.
• Mannitol increases medullary blood flow, thereby decreasing the medullary urea gradient and
enhancing the diuretic effect.
• Osmotic diuretics may cause hyperosmolality
• Osmotic diuretics may cause fluid overload (e.g. 1 gm/kg of mannitol in a 75 kg person requires an
infusion of 300 to 1,500 ml)
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b) Carbonic Anhydrase Inhibitors
Examples: Acetazolamide, Dichlorphenamide, Methazolamide
Glomerulus
PCT
HCO3
Carbonic
Anhydrase
Na
H2O
Mechanism of Action:
One mechanism of proximal tubular Na+ reabsorption is passive accompaniment with HCO3 , the
reabsorption of which depends on tubular carbonic anhydrase. Therefore, inhibition of carbonic
anhydrase results in…
• diuresis
• natriuresis
• alkaline urine
• normal anion gap metabolic acidosis
Other Phenomena:
• Carbonic anhydrase inhibitors also dehydrate the eye and decrease CSF production.
• Diuretic efficacy is mitigated by subsequent distal HCO3- reabsorption.
• Effectiveness of carbonic anhydrase inhibitors is increased by metabolic alkalosis and decreased by
metabolic acidosis.
+
• Na salvage in the distal nephron results in hypokalemia.
• Inhibition of red blood cell carbonic anhydrase limits CO2 transport and results in hypercapnia.
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c) High-Ceiling (Loop) Diuretics
Examples: Furosemide, Bumetanide, Ethacrynic Acid
DCT
K,H
[Na]T![Na]I
Na
Na
Cl
Blocked by
Loop Diuretics
H2O
LOOP OF HENLE
Mechanism of Action:
The loop diuretics are a diverse group of drugs which block reabsorption of Na+ and Cl- in the thick
ascending loop of Henle. This causes a less hypotonic urine to enter the collecting duct with a lower
gradient for ADH dependent H2O reabsorption. This results in a diuresis and natriuresis. The loop
diuretics also interfere with the generation of a hypertonic medullary interstitium which reduces ADH
dependent H2O reabsorption and augments their efficacy.
Other Phenomena:
• Loop diuretics, particularly ethacrynic acid, perturb endolymph electrolyte composition causing
transient or permanent deafness.
• Na+ salvage in the distal nephron results in hypokalemia.
• Loop diuretics decrease systemic vascular resistance thereby augmenting their dehydrating effect.
• Loop diuretics do not differ in their maximal effect.
• Loop diuretics will displace protein bound drugs (e.g. warfarin).
• Nephrotic syndrome decreases loop diuretic efficacy as urinary protein binds and inactivates the
diuretics.
• Loop diuretics decrease urate excretion and may worsen hyperuricemia.
• Loop diuretics may worsen hyperglycemia.
• Loop diuretics increase both Mg++ and Ca++ excretion.
• Loop diuretics may cause idiopathic interstitial nephritis.
• Hypochloremia may decrease loop diuretic efficacy.
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d) Thiazide Diuretics
Examples: Chlorothiazide, Hydrochlorothiazide, Metolazone (thiazide-like)
DCT
K,H
[Na]T![Na]I
Na
Na
Cl
Blocked by
Thiazides
H2O
Mechanism of Action:
The thiazides block a specific site in the early distal tubule which would normally reabsorb Na+ and Cl-.
Like the loop diuretics, this causes a less hypotonic urine to enter the collecting duct with a lower gradient
for ADH dependent H2O reabsorption. This results in a diuresis and natriuresis. Unlike the loop
diuretics, the thiazides do not interfere with the generation of a hypertonic medullary interstitium. This,
and the fact that the majority of the generation of hypotonic tubular fluid occurs before the distal tubule,
makes these diuretic less effective than the loop diuretics.
Other Phenomena:
• Some thiazides have carbonic anhydrase inhibitor activity, but this does not cause significant
diuresis.
• Na+ salvage in the distal nephron results in hypokalemia.
• Thiazide diuretics do not differ in their maximal effect.
• Thiazides decrease urate excretion and may worsen hyperuricemia.
• Thiazides may worsen hyperglycemia.
• Thiazides increase Mg++ excretion but decrease Ca++ excretion.
• Thiazides may cause idiopathic interstitial nephritis.
e) Potassium-Sparing Diuretics
Examples: Spironolactone (aldosterone antagonist), Triamterene (aldosterone independent)
DCT
K,H
Na
Mechanism of Action:
The K+-sparing diuretics block either the aldosterone dependent or independent pumps in the late distal
tubule and early collecting duct. This results in a mild diuresis. In normal conditions there is little change
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in the K+ output, however these drugs are very effective in mitigating an ongoing kaluresis. These drugs
should never be used in combination with K+ supplements.
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52
III Clinical Uses of Diuretics
a) Diuretic Braking Phenomena
With continued bolus doses of diuretics the intra-dose urinary Na+ retention increases, thereby causing
diuretic tachyphylaxis. This effect is not related to aldosterone, angiotensin, adrenergic stimulation but
instead appears to be secondary to autonomous increases in tubular cell function. This effect is
decreased by maintaining a low Na+ intake.
b) Diuretic Resistance
The following may cause edema to be resistant to diuretics…
• Edema not caused by fluid overload (e.g. edema 2° to venous or lymphatic obstruction)
• Excessive Na+ or H2O intake
• Inadequate drug reaching tubular lumen (e.g. non-compliance, inadequate dose, proteinuria)
• Decreased renal response (e.g. low GFR, diuretic braking phenomena, prostaglandin inhibitors)
c) Methods to Increase Diuretic Effect
Combination of diuretic classes (e.g. loop and thiazide diuretic)
Continuous infusion as opposed to bolus dosing:
Continuous infusion of loop diuretics increases the net diuresis. This occurs because the
tubular lumen is continuously bathed with the diuretic, producing a continuous as opposed to an
intermittent blockade of the Na/Cl ATPase in the ascending loop of Henle.
N.B.: A continuous infusion of loop diuretics does not provide the ability to rapidly adjust
the diuretic effect of the drug. The relatively long half lives of the loop diuretics mean that new steady
state drug concentrations will only be achieved after several hours. The comparison of dobutamine
versus lasix pharmacokinetics shown below demonstrates this point.
100%
Lasix versus Dobutamine Pharmacokinetics
Dobutamine
90% @
7 minutes
% of
Steady
State
Lasix
90% @
6.5 hours
0%
0
2
4
6
Hours
Enuresis In Childhood
Normal Bladder Physiology
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•
•
•
•
53
The detrusor muscle of the bladder wall is composed of 3 smooth muscle layers which extend along the
urethra. This urethral musculature forms the internal or involuntary sphincter.
The striated muscles of the urogenital diaphragm surround the urethra and form the external or
voluntary sphincter.
The majority of the smooth muscle of the bladder is innervated by parasympathetic nerves arising from
the sacral portion of the spinal cord.
The smooth muscle in the trigone of the bladder (the infero-posterior portion defined by the ureters and
the urethra, see Figure #10) is innervated by sympathetic nerves arising from the sacral portion of the
spinal cord.
Figure #10
The bladder fills to its normal capacity without any changes in intraluminal pressure. When a certain
volume is reached, the spinal arc "detrusor reflex" occurs. A signal is sent from the bladder to the spinal
cord. In response to this "stretch" signal, the spinal cord initiates the following sequential actions.
1. Relaxation of the voluntary sphincter with the consequent dropping of the bladder in the pelvis
2. Contraction of the trigonal muscles allowing closure at the uretero-vesicular junction and initial opening
of the internal sphincter via the loss of the acute urethral-vescicular angle (see Figure #11)
3. Contraction of the remainder of the detrusor muscles causing both a rise in the intraluminal pressure as
well as a longitudinal pulling of the urethra with consequent further opening of the internal sphincter
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Figure #11
The detrusor reflex can be initiated or inhibited by brain stem and cortical centers.
Development of Bladder Control
• At birth the detrusor reflex is intact, the ability to control this reflex develops in the first 5 years.
• At 1 1/2 years a child can start to defer urination.
• At 2 years a child will "exclaim" while voiding.
• At 2 1/2 years 80% to 90% of children will make known their need to urinate.
• At 3 years a child can be toilet trained, usually urinating 8 to 14 times per day. Night control is achieved
6 to 12 months later.
• At 5 years a child voids only 7 to 8 times per day.
• Achieving dryness is a natural function which will occur independent of training.
Definitions
• Enuresis is the inappropriate voiding of urine in a child who has reached an age at which bladder
control is expected.
• In primary enuresis, a child never achieves dryness. Secondary enuresis is a relapse to wetting after
dryness is achieved.
• Nocturnal enuresis is wetting while asleep whereas diurnal enuresis is wetting while awake.
Epidemiology
• At 5 years, 10% of children wet their beds at least once a month. At 10 years this has decreased to 7%
and by 15 years to only 1%.
• The majority of enuresis is nocturnal as opposed to diurnal.
• The incidence of nocturnal enuresis is increased in certain countries (e.g.. USA and Australia) as
compared to others (e.g.. Sweden).
• Nocturnal enuresis is more common in first borns.
• Nocturnal enuresis is more common in lower socio-economic classes.
• Nocturnal enuresis is more common in children who have had a social or psychological handicap in the
first 4 years of life.
• Up to age 11 years, nocturnal enuresis is twice as common in boys.
• 80% of nocturnal enuresis is primary.
Etiology
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•
•
•
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Nocturnal enuresis is, to some degree, genetically inherited (e.g.. monozygotic twins have twice the
concordance of dizygotic twins). Therefore, 74% of boys and 58% of girls with nocturnal enuresis have
a parent who was enuretic.
Children with nocturnal enuresis have an early detrusor reflex during filling of the bladder and are less
likely to be able to suppress this reflex.
There is no proven association between nocturnal enuresis and depth of sleep.
Organic causes such as bacterial infection, polyuria secondary to renal disease, and abnormalities of
the bladder neck and spinal cord may cause secondary enuresis.
Management
• Initial evaluation should consist of a careful history and physical exam. In addition, children should be
screened with serum electrolytes, BUN, creatinine, urinalysis and, potentially, a VCUG and renal
ultrasound.
• Diurnal enuresis especially if unassociated with nocturnal enuresis, usually requires psychiatric referral.
• The spontaneous remission rate of nocturnal enuresis is 14% per year from 5 to 9 years and 16% per
year from 10 to 19 years.
• 10% of children with nocturnal enuresis will remit after a single visit to a doctor, regardless of treatment
offered.
• Treatment regimens include…
• Behavioral modification (Rewards alone versus a reward economy)
• Wetness alarms
• Fluid restriction
• Interval training
• Medications (e.g.. tofranil 25 to 100 mg qhs or DDAVP 10 to 40 µg qhs)
5