Peds Nephro for Residents Nov2005

7/29/2019 Peds Nephro for Residents Nov2005

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Pediatric Nephrology Handout 1

Revised May-00

Chris Clardy, M.D.

Nephrotic Syndrome in Children

DefinitionNephrosis (i.e. the nephrotic syndrome) is a condition characterized by proteinuria with resultant

hypoproteinemia and edema

Pathophysiology

EdemaProteinuria 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 ratioHypercoagulability

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 volumeImmunodeficiency Hypogammaglobulinemia secondary to urinary losses Hypocomplementemia secondary to urinary losses Decreased cellular immunity, potentially secondary to urinary losses of Zn and FeMiscellaneous 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 globulinDifferential 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 agentsArtifactual Nephrotic Syndrome Hypoproteinemia unassociated with proteinuriaSpecific DiseasesMinimal Change Nephrotic Syndrome (MCNS) No changes in light microscopy Loss of foot processes in electron microscopy


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Most common in children Usually responds to immunosuppressive therapy Does not lead to renal failure May cause problems with frequent relapsesFocal and Segmental Glomerulosclerosis (FSGS) Mesangial matrix expansion with loss of normal glomerular structures Second most common in children More frequent in adolescents and African Americans May present with only proteinuria Usually leads to progressive renal failureMembranoproliferative Glomerulonephritis (MPGN)

Mesangial cell proliferation and splitting of GBM Third most common in children A glomerulonephritis which causes nephrosis Associated with a low C3 Will cause renal failure unless treated with steroidsHistopathology by Age

0 %

5 %

10%

15%

20%

0 5 10 15

MCNS

FSGS

MPGN

Laboratory EvaluationInitial Urinalysis Total protein and albumin Electrolytes, calcium, BUN, and creatinine Cholesterol (triglycerides) Blood pressure C3 PPD


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Evidence of Complicated Nephrotic Syndrome Age6 years Hematuria Hypertension Low serum C3 Normal serum cholesterolTherapy

Primary Therapy Prednisone (high dose with slow taper) Cyclophosphamide CyclosporineResponse to Steroid TherapyResponse of Minimal Change (J Peds 98:561, 1981)

Respond

92%

Fail8%

Histopathology of responsive patients (J Peds 98:561, 1981)

MCNS (92%)

FSGS (5%)

MPGN (1%)

Other (2%)


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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 vaccineEvaluation 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

DefinitionGN is an inflammatory glomerular lesion characterized by

a) hematuria

- >1 RBC/l 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


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-


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e) hypertension

Pathophysiology

Process Manifestation

Glomerular Hematuria &Inflammation Proteinuria

Decreased Azotemia

G.F.R.

Increased Distal Oliguria,

Tubular Na+ and Edema, &

H2O Reabsorption Hypertension

Differential Diagnosis of GN in ChildrenLow Complement

Post Streptococcal GN Membranoproliferative GN Systemic Lupus ErythematosusNormal Complement IgA Nephropathy Henoch-Schnlein 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 rashLab=> U/A, SMA-6, CBC, ASO, ANA, & C3

Symptomatic Therapy of GN

Na+ restriction 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 -

blocker 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/l in fresh urine >5 RBC/hpf on a spun urine


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Trace blood or higher by dipstick Upper versusLower Gross versusOccult False positive with hemoglobinuria, myoglobinuria, alkaptonuria, porphyria and beet ingestionProteinuria 1+ or higher by dipstick (large proteins only) >150 mg/1.73 M2/day >4 mg/M2/hour Urine protein/creatinine>0.2Epidemiology ~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 malesHematuria Alone, Non-Glomerular (Differential Diagnosis) Urinary Tract Infection Idiopathic Hypercalciuria

Presents with isolated hematuria Diagnosis by urine calcium/creatinine0.21 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 pyuriaHematuria 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


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U/A on 1st degree relatives Electrolytes, BUN, and creatinine Urine calcium/creatinine Ratio (nl0.21) ASO, C3, and ANA Ultrasound and/or IVPProteinuria 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-Schnlein 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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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

DefinitionsNormal 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

BoysHeight Percentile

Age 5th 25th 75th 95th

Systolic 3 104 107 111 113

6 109 112 115 117

10 114 117 121 123

13 121 124 128 130

16 129 132 136 138


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Diastolic 3 63 64 66 67

6 72 73 75 76

10 77 79 80 82

13 79 81 83 84

16 83 84 86 87


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Girls

Height Percentile

5th 25th 75th 95th

Systolic 3 104 105 108 110

6 108 110 112 11410 116 117 120 122

13 121 123 126 128

16 125 127 130 132

Diastolic 3 65 65 67 68

6 71 72 73 75

10 77 77 79 80

13 80 81 82 84

16 83 83 85 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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Intraventricular hemorrhage


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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 11-hydroxylase deficiency 17-hydroxylase deficiency Syndrome of Apparent mineralocorticoid excess (SAME) Liddles 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 ultrasoundTreatment 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 therapyPharmacologic Therapy

Emergent

Initial Dose Maximum Dose

Nifedipine 0.25 mg/kg 0.5 mg/kg

Nitroprusside 0.5 g/kg/min 8 g/kg/min

Labetalol 1 mg/kg/hr (iv) 3 mg/kg/hr (iv)


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Long Term

Initial Dose Maximum Dose

Captopril

Neonates 0.03 mg/kg/day 2 mg/kg/day

Children 1.5 mg/kg/day 6 mg/kg/day

Enalapril 0.15 mg/kg/day ?Nifedipine XL 0.25 mg/kg/day 3 mg/kg/day

Atenolol 1 mg/kg/day 8 mg/kg/day

HCTZ 1 mg/kg/day 2 mg/kg/day

Lasix 1 mg/kg/day 12 mg/kg/day

Neonatal Hypertension

SignificanceNeonatal hypertension can lead to left ventricular hypertrophy

retinopathy renovascular changes encephalopathy intraventricular hemorrhageEpidemiology

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 lifeGuidelines

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 accurateThe 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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100101

50

60

70

80

90

100

110

120

2.5 kg

Differential DiagnosisVascular Renal Artery Thrombosis Renal Vein Thrombosis Arterial Calcification Renal Artery Stenosis Coarctation of the AortaRenal Renal Dysplasia Obstructive Uropathy Infantile Polycystic Kidney Disease Renal Insufficiency Renal TumorEndocrine Adrenogenital Syndrome Cushing Disease Primary Hyperaldosteronism Thyrotoxicosis


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Drugs Ocular Phenylephrine Corticosteroids Theophylline DeoxycorticosteroneOther Increased Intracranial Pressure Fluid Overload Neural Crest Tumor Abdominal Wall Surgery Pneumothorax Hypercalcemia Genitourinary Tract Surgery Bronchopulmonary DysplasiaEvaluation Directed History and Physical Exam Serum Electrolytes, Calcium, BUN, and creatinine CXR Renal Ultrasound DTPA Scan Aortogram Head UltrasoundTreatmentDiuretic 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 g/kg/min (i.v.)-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 EmbryogenesisKidney 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 alongitudinal duct which develops into two vestigial kidneys, the pronephros and the mesonephros, as

well as the permanent kidney, the metanephros.


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Figure #1The development of the permanent kidney occurs when the metanephros interacts with an offshoot of

the cloaca called the ureteric bud (Figure #2).

Figure #2The ureteric bud undergoes a branching process to form the ureter, the renal pelvis, the calyces, andthe collecting tubules (Figure #3).

Figure #3Meanwhile, 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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Figure #4The permanent kidney is formed in the pelvis, however as the fetus develops it migrates to its position in

the lumbar region (Figure #5).

Figure #5Finally, the bladder is formed when the cloaca separates into an anorectal and urogenital canal (Figure

#6).

Figure #6


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The timing of the events in renal development are outlined below.

Weeks Events3 to 4 Formation of the pronephros and

mesonephros

5 Formation of the ureteric bud andinitiation of the metanephros

6 Formation of the urogenital sinus8 to 9 Renal pelvis and ureter evident, some

nephrons completed, bladder formed10 to 11 Renal pelvis completed, calyces

initiated

14 to 15 Collecting system completed

20 to 22 Medulla and cortex demarcated

32 to 36 Nephron formation complete

Mechanical DefectsGross Malformations

Renal AgenesisDefinition:

Absence of the kidney without any evidence of parenchymal maldevelopmentPathophysiology:

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 aortaPathophysiology:

Failure of the normal ascent of the kidneyClinical Features:

Usually detected only as an incidental findingEvaluation:

Renal ultrasound and VCUGTherapy & Prognosis:

May have increased incidence of infections or obstructionHorseshoe Kidney

Definition:

Fusion of the lower poles of the kidneys, associated with incomplete ascent withresultant lower lumbar location

Pathophysiology:


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Fusion of the kidneys due to close approximation as they ascend through the arterialbifurcation

Occurs in 0.25% of the populationClinical Features:

Usually detected only as an incidental findingEvaluation:

Renal ultrasound and VCUGTherapy & Prognosis:

May have increased incidence of infections or obstructionMicroscopic Malformations

Dysplasia, Aplasia, & Multicystic Kidneys

Definition:

An abnormal parenchymal differentiation reflected by the presence of abnormalstructures 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 uterovascular

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 dialysisand/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 disordercharacterized 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 cystsof 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 azotemiaDifferential Diagnosis:

May be confused with PKD and medullary sponge kidney.Evaluation:

Reliable diagnosis usually possible with ultrasound although renal biopsyoccasionally 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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UTIs are more common in males in children 6 months old and more common in females in all otherage 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

DiagnosisClinical 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 infemales 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 ofUTI.

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 likelyto result in a potentially false negative urine culture.

The most common pathogens areEnterobacteriaceae (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 elevatedESR 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 3rdgeneration 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 oralAntibiotic Dose (mg/kg/day) # Doses/Day

Trimethoprim- 6 2

Sulfamethoxazole 30

Amoxicillin 25-50 3Nitrofurantoin 3 4

Recurrent UTIs can be prophylaxed withAntibiotic Dose (mg/kg/day)

Trimethoprim 2

Sulfamethoxazole 10

Nitrofurantoin 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 oftreatment.

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) immunologic disorder (positive LE cell test, anti-DNA antibody, anti-Sm antibody, or false

positive serologic test for syphilis)

11) positive anti-nuclear antibody test

Epidemiology

90% femalepeak 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 glomeruliMembranous 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 In-

volvement

Renal In- 7% 16% 65% 12%

volvement


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Treatment/OutcomeMost patients developing ESRD will have had W.H.O. Class IV or Vd (DPGN/MPGN)

160140120100806040200

0

20

40

60

80

100

IV Cytoxan,

~0.8% ESRD/year

Prednisone Rx,

~12% ESRD/year

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


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Pathology:Light Microscopy Minimal Change

Focal, Segmental Glomerulosclerosis

Diffuse Proliferation

ImmunofluorescenceMicroscopy 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 34%

Proteinuria Microscopic Hematuria 30%

Nephrotic Syndrome 6%

Acute Nephritis 10%

Hypertension 8%

Chronic Renal Failure 6%

Acute Renal Failure 6%

as the initial presentation in 50 patients with IgAN.

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 6 th 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 (14

th

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--vis Henoch-Schnlein 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 thehistopathology 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

GeneralTaken 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 sub-

problems 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 500 ml/M2/day

Urine 650 ml/M2/day

Stool 50 ml/M2/day

"Extra" 800 ml/M2/day

2,000 ml/M2/day

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 Causes of Dehydration

Oliguria Polyuria

e.g. SIADH, ATN e.g. DKA, DIExcess Intake 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 Causes of Hypernatremia

Loss of Na+ Alone Excess of Na+ Alone

e.g. Inappropriate e.g. Hyperaldosteronism,

formula dilution Iatrogenic

Excess H2O Alone Loss of H2O Alone

e.g. Polydipsia, SIADH e.g. DI

Losses of H2O & Na+ Losses of H2O & Na

+

(Na+>H2O) (H2O>Na+)

e.g. Diuretic abuse, e.g. Diarrhea

3rd space losses

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 bodys weight


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Hyponatremia

Example:

3 Kg child with [Na+]=123 mEq/LGoal:

To increase [Na+] by 12 mEq/LConcept:

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/LGoal:

To decrease [Na+] by 12 mEq/LConcept:

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 H2O} Give supplemental H2O of 165 mlAcid (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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CO2 & H2O

Cell

H+ & HCO3-

H2CO3

CO2 & H2O

Extra-Cellular Space

HCO3-

CO2

Blood

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 aslactate.

0

20

40

60

80

100

120

140

160

OTHER

NA

CATION

HCO3

CL

ORGANIC

ANION

NORMAL

ACIDOSIS

HIGH

ANION

GAP

HCO3

CL

ORGANIC

ACIDOSIS

NORMAL

ANION

GAP

HCO3

CL

ORGANIC

Figure #2

Causes of Acidosis

(Normal Anion Gap)


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GI Loss of HCO3-

e.g. Diarrhea,

Pancreatic fistula

Renal Loss of HCO3-

e.g. Proximal RTADefective 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.

Na

K,H

DISTAL TUBULE

ALDOSTERONE

MEDIATED

PUMP

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 Causes of Hyperkalemia

(No Body K+) Pseudohyperkalemia

Alkalosis Excess Intake

-Adrenergic drugs Redistribution

e.g. Acidosis,

( Body K+) Cell breakdown

Poor Intake Excretion

e.g. Anorexia nervosa e.g. Renal failure Cellular Incorporation Hypoaldosteronism

e.g. Refeeding

GI Loss

e.g. Vomiting, Diarrhea

Renal Losse.g. Diuretic abuse,

Hyperaldosteronism

Renal Tubular Acidosis

DefinitionRenal 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 ofnon-carbonic acids.

Although respiratory variation of the PCO2 may transiently buffer these acids, the only means ofremoving 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

versus7.4 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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Proximal RTA is associated with other tubulopathies (e.g. renal phosphate wasting) and with theaminoacidopathies.

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).

Failure toreabsorb

NaHCO3

Failure to swap

Na+ for H+

Swap of

Na+for K+

Proximal

Tubule

Distal

Tubule

Na+ K+

Na+ H+

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 5.5which 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 HCO3-. 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 Factorseg. hypovolemia

cardiac insufficiencyRenal 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 nephropathyInterstitial

eg. acute interstitial nephritis

pyelonephritis

Postrenal Factorseg. congenital or acquired obstruction

Complications of Renal Failure

Hyperkalemia Acidosis

Arrhythmia Impaired Cellular Function

Cardiac Arrest Death

Death

Fluid Overload Uremia

Hypertension & Impaired Cardiac, Cerebral,

Congestive Heart Failure & Thrombotic Function

Inadequate Cardiac Function Death

Death

Initial EvaluationBlood 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+

OtherChest X-Ray

Renal Ultrasound

E.K.G.

Initial Management of Acute Renal FailureN.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 pH7.20 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 (FENA1%) 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. Twoconditions 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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Semi-permeableMembrane

BloodDialysisSolution

HighB.U.N.,

Creatinine,otherN2 products

Diffusionof N2 waste

Across aConcentrationGradient

Dialysis

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.

Semi-permeableMembrane

BloodDialysisSolution

HighHydrostatic

orOsmoticPressure

Diffusionof H2O

Across aPressureGradient

Ultrafiltration

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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Arteriole inPeritonealMembrane

PeritonealMembrane

Dialysate Solution

SodiumPotassiumChlorideMagnesiumCalciumLactateDextroseOsmolalitypHVolume

130-135 mEq/0-3 mEq/L

96-102 mEq/1.2-1.8 mg/dl6.0-8.0 mg/dl35-40 mEq/L

1.36/2.27/3.86 gm/dl346/396/485 mOsm/kg

5.0-5.15-30 ml/kg

Advantages-

unlikely to cause rapid fluid and electrolyte shifts

does not require systemic anticoagulation

Disadvantages-

ineffective 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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Filter

Proximal

Venous

Access

Distal

Venous

Access

Heparin

Dialysis

Solution

Discard

Advantages-

allows efficient dialysis and ultrafiltration

effective even in low perfusion states

Disadvantages-

requires significant extra-corporeal volumerequires 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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Filter

Arterial

Access

Venous

Access

Heparin

Discard

Advantages-

allows continuous fluid removal in an unstable patient

Disadvantages-

requires 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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Glomerulonephritis (31%)

Reflux Nephropathy (21%)Congenital Dysplasia (19%)

Medullary Cystic Disease (8%)

Cystinosis (8%)

Obstructive

Uropathy (7%)

Glomerulosc

lerosis(6%)

Pathophysiology/Treatment:

Impaired H2O 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 theinsensible 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 acidosiswill 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 -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

[Na]T


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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 versusthe 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

Na

Cl

H2O

Glomerulus

[Na]T


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b) Carbonic Anhydrase Inhibitors

Examples: Acetazolamide, Dichlorphenamide, Methazolamide

PCT

Na

H2O

HCO3

Glomerulus

CarbonicAnhydrase

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

[Na]T [Na]I

Na

Cl

H2O

LOOP OF HENL

DCT

Na

K,H

Blocked byLoop Diuretics


The loop diuretics are a diverse group of drugs which block reabsorption of Na+ and Cl- in the thickascending loop of Henle. This causes a less hypotonic urine to enter the collecting duct with a lowergradient 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 ADHdependent H2O reabsorption and augments their efficacy.

Other Phenomena:

Loop diuretics, particularly ethacrynic acid, perturb endolymph electrolyte composition causingtransient 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)

[Na]T [Na]I

DCT

Na

K,H

Na

Cl

H2O

Blocked byThiazides


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 gradientfor 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 significantdiuresis.

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

Na

K,H


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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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 butinstead 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

versuslasix pharmacokinetics shown below demonstrates this point.

0%

100%

0 2 4 6 8 10

Dobutamine

90% @

7 minutes

Lasix

90% @

6.5 hours

Enuresis In Childhood

Normal Bladder Physiology


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The detrusor muscle of the bladder wall is composed of 3 smooth muscle layers which extend along theurethra. This urethral musculature forms the internal or involuntary sphincter.

The striated muscles of the urogenital diaphragm surround the urethra and form the external orvoluntary sphincter.

The majority of the smooth muscle of the bladder is innervated by parasympathetic nerves arising fromthe sacral portion of the spinal cord.

The smooth muscle in the trigone of the bladder (the infero-posterior portion defined by the ureters andthe 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 pelvis2. 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 aswell 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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Nocturnal enuresis is, to some degree, genetically inherited (e.g.. monozygotic twins have twice theconcordance 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 treatmentoffered.

Treatment regimens include Behavioral modification (Rewards alone versusa reward economy) Wetness alarms Fluid restriction Interval training Medications (e.g.. tofranil 25 to 100 mg qhs or DDAVP 10 to 40 g qhs)

Documents

Peds Nephro for Residents Nov2005