Ch 39- Alt of Renal & Urinary Tract Fxn Children

Embryonic Development of the Kidneys

• The Wilms Tumor 1 (WT1) gene is important for kidney development and maintenance.
• The WNT signaling transduction pathway is important for mesenchyme growth and differentiation.

Pronephros

• A nonfunctional structure arises during the 3rd fetal week in the cervical and upper thoracic regions.
• It connects the primitive Wolffian duct to the cloaca, which is the foundation for male sexual development.

Mesonephros

• This begins development around the 4th fetal week, more caudally.
• It starts excretory function in the 6th week.
• Most of the mesonephros degenerates and disappears by the end of the embryonic period.

Metanephros

• It arises distal to the bifurcation of the aorta and develops from two sources.
• The ureteric bud (metanephric duct) grows dorsocranially from the mesonephritic (Wolffian) duct and starts subdividing forming a ureter, renal pelvis, and calyces, eventually forming collecting ducts by the 5th fetal month.
• The metanephrogenic mesenchyme then sits atop the terminal branches of the collecting ducts and develops into primitive glomeruli and uriniferous tubules.
• Genetic information from the metanephrogenic mesenchyme guides the development of the ureteric bud.
• Connection between the uriniferous tubules and the collecting ducts is vital for kidney development; errors can result in polycystic kidneys.
• The external genitalia develops between 8 and 16 weeks, and testicular descent begins in month 7 of gestation.
• Definite kidneys migrate from the caudal position to the lumber region and the ureters connect with the bladder as the embryo grows
• In the 8th week make embryo, the wolffian duct begins to give rise to the epididymis, the seminal vesicles, and the caudal part of the vas deferens
• The tissues organize and progressively differentiate for about 30 days after the glomeruli and tubules form.
• Initial glomerular development is staggered, with some of the first glomeruli formed degenerating later.
• Progressive development continues into the 9th fetal month when all metanephrogenic tissue disappears.
• The kidneys appear to ascend from the sacral area at about 6 weeks to the third lumbar area by the 3rd month, and to the first lumbar area at term as the embryo develops and the vertebral column straightens.
• The kidneys rotate 90 degrees as they ascend so that renal tissue is lateral, and the collecting system is medial.
• The cloaca becomes the urogenital sinus which differentiates into the vesicourethral canal (bladder and upper urethra) and the urogenital sinus (main part of the urethra) as the kidneys mature.
• At birth the kidneys occupy a large portion of the posterior abdominal wall and the ureters are proportionately shorter than those of an adult.
• All the nephrons are present at birth and they do not increase in number as the kidney grows and matures.
• The kidney reaches adult size by adolescence and increases in weight fivefold from the time of birth because of maturation of the tubular system.

Urine Formation

• Urine formation and excretion begin by the 3rd month of gestation.
• In infancy the bladder lies close to the abdominal wall, making urinary bladder aspiration a relatively simple procedure.
• The bladder descends into the pelvis with growth, changing from a cylindrical organ to the adult pyramidal shape.
• Although small amounts of urine are found in the bladder at birth, the newborn may not void for 12 to 24 hours.

Renal Blood Flow and GFR

• Immediately at birth the renal blood flow and glomerular filtration rate (GFR) increase due to decrease in vascular resistance.
• Renal vascular resistance remains higher in newborns and infants; attributed to increased levels of circulating renin.
• Resistance progressively declines during the 1st year of development, with an increasing fraction of cardiac output going to the kidney.
• The GFR continues to increase, achieving adult levels by 2 years of age.
• The infant produces a more dilute urine compared to the adult.
• The combination of higher blood flow and shorter loops produce a more dilute urine up to 6 months of age-approximately 400 to 600 mOsm compared with 800 to 1200 mOsm in adults.

Nephrotic Syndrome Defined

• This describes a symptom complex characterized by proteinuria, hypoalbuminemia, hyperlipidemia, and edema.

Etiology

• More common in children than adults.
• No identifiable cause is primary (idiopathic nephrotic syndrome).
• Described by histopathologic results, they include minimal change nephropathy [MCN], focal segmental glomerulosclerosis [FSGS], membranous nephropathy [MN], or membranoproliferative glomerulonephritis [MPGN].
• Found in preschool children, with a peak incidence of onset between 2 and 3 years of age.
• Onset is rare after 8 years of age.
• Boys are affected more than girls.
• There are no prevalent racial or geographic distributions.
• Incidence is approximately 2 to 3 per 100,000 children per year.
• Systemic disease or other cause (drugs, toxins, DM, lupus nephritis) is secondary nephrotic syndrome.
• Same patterns of histopathology but associated with an underlying disease.
• 95% cases occur in the absence of systemic or preexisting renal disease.

Pathophysiology

• Cause is usually idiopathic and includes: MCN, FSGS, or Congenital nephrotic syndrome, Edema (classic symptom), Hyperlipidemia, and Hypercoagulation.

Minimal Change Nephropathy (MCN) or lipoid nephrosis

• Most common cause of nephrotic syndrome in children ages 2 – 6 years old (85%).
• Likely cause: systemic immune mechanism; true etiology unknown.
• Mechanism of increased glomerular permeability is related to release of permeability factors from abnormal circulating T cells injuring glomerular epithelial cells.
• Glomerular appear normal by light microscopy and Immunoglobulin deposition is usually absent.
• Primary injury: fusion of epithelial cell podocyte foot processes is a loss of electrical negative charge and increases permeability within glomerular capillary wall, which causes albuminuria.
• Hyperlipidemia → lipiduria results from hepatic lipid synthesis and decreased plasma lipid catabolism.

Focal Segmental Glomerulosclerosis (FSGS)

• 10% of children with nephrotic syndrome; more common in blacks; frequency is increasing in adults and children.
• Primary injury: effacement (thinning or deletion) of epithelial podocytes with a significant increase in pore size impairs the size selectivity and results in proteinuria.
• Progressive disease: proliferation of endothelial and mesangial cells with occlusion and sclerosis of glomerular capillaries.
• The more severe the proteinuria, the more likely end-stage renal disease will occur.
• Will be steroid-resistent

Congenital Nephrotic Syndrome – Finnish Type

• Cause: autosomal recessive mutation of the NPHS1 gene (encodes an immunoglobulin-like protein, nephrin, at the podocyte slit membrane)
• Nephrin is a transmembrane protein that plays a crucial role in the filtration process in the kidneys.
• Lack of nephrin → heavy proteinuria.
• Disease Time of Onset: before 3 months of life.
• Clinical manifestation: LARGE FONTANELS and SEPERATED CRANIAL SUTURES
• Treatment: intravenous albumin infusions, nutritional supplement, and bilateral nephrectomy, followed by dialysis and kidney transplantation.

Clinical Manifestations for Nephrotic Syndrome

• Onset is insidious.

Edema

• Causative factors: hypoalbuminemia (decreased plasma oncotic pressure) & Na+ retention.
• Movement of fluid from vascular to interstitial space can decrease blood volume, increases activity of aldosterone and ADH (vasopressin), and decrease atrial natriuretic peptide concentration promotes fluid retention.
• First clinical sign is periorbital edema, which is most noticeable in the morning but subsides during the day as fluid shifts to abdomen and lower extremities.
• Pronounced edema can cause respiratory difficulty from pleural effusion, labial or scrotal swelling, or diminished, frothy or foamy urine output.
• Intestinal mucosa edema can cause diarrhea and anorexia.
• Edema marks malnutrition caused by malabsorption and protein loss, and can cause poor absorption.
• Protein deficiency changes the quality of hair, which causes a malnourished state.
• Pallor with shiny skin and prominent veins.
• Blood pressure is normal.
• Increased risk for infection such as Pneumonia, Peritonitis, Cellulitis, and Septicemia.
• Common vague symptoms: irritability, fatigue, and lethargy.
• Edema with nephrotic syndrome is associated with increased aldosterone concentration.
• Movement of fluid from the vascular to the interstitial space can decrease blood volume and increase activity of aldosterone and antidiuretic hormone (vasopressin), and decrease atrial natriuretic peptide, all of which promote fluid retention.
• Nephrotic syndrome produces susceptibility to infection.
• Loss of proteins via the basement membrane includes loss of immunoglobulins, which renders the individual susceptible to infection.

Hyperlipidemia

• Occurs in inverse proportion to the decrease in plasma proteins (albumin).
• Causes high concentrations of triglycerides, low-density lipoprotein (LDL), and very-low density lipoprotein (VLDL) cholesterol.
• Results in HDL decreases, Hypoalbuminemia causes deficiency in carrier protein for transport of fatty acids, which remain elevated in serum.
• Hepatic compensation increases synthesis of lipoproteins to maintain plasma oncotic pressure.
• Hypoalbuminemia increases hepatic stimulus for synthesis of LDL and VLDL cholesterol by liver.
• Serum lipids remain elevated 1 to 3 months after remission of proteinuria.

Hypercoagulation

• Abnormalities in coagulation pathways during nephrotic syndrome causes risk for arterial or venous thrombosis.

Diagnosis

• Diagnosis is evident from clinical presentation and findings of proteinuria, hyperlipidemia, edema.
• Diagnostic tests including kidney biopsy (determine cause is an intrinsic renal disease or a consequence of systemic disease).

Treatment

• Intravenous rituximab (monoclonal antibody) shown to induce and prolong remissions in some children with steroid dependent or -resistant nephrotic syndrome.
• Children with minimal change disease tend to have a very favorable prognosis, whereas those steroid-resistant nephrotic syndromes may develop end-stage kidney disease
• Goals of treatment are to reduce excretion of protein, and maintain a protein-free urine.
• Aspects of treatment involves prevention or treatment of infection, control edema, establish balanced nutritional state, and restore normal metabolic process.
• In basic management, administer glucocorticosteroids (prednisone), adhere to a low-sodium, well-balanced diet, and perform good skin care.
• If edema is problematic, administer diuretics (furosemide, metolazone).
• ACE Inhibitors help inhibit formation of angiotensin II and aldosterone, which decreases blood pressure and renal sodium reabsorption.
• Nephrotic syndrome is described by its response to steroid therapy; steroid-sensitive nephrotic syndrome remits with steroid therapy alone.
• Steroid-resistant nephrotic syndrome: children will fail to respond to prednisone within 8 weeks and are treated with noncorticosteroid immunosuppressive agents (cyclophosphamide) or combo of corticosteroids and noncorticosteroid immunosuppressive help prolong remission.

Vesicoureteral Reflux

• Retrograde flow of bladder urine into the kidney and/or ureters; allows infected urine from the bladder to reach the kidneys.
• Reflux prevents complete bladder emptying as reflexed urine drains back into it at the end of each void, which causes infections to develop.
• Combination (reflux and infection) is an important cause of pyelonephritis – especially in children younger than 5 years old.
• Occurs congenitally abnormal or ectopic insertion of the ureter into the bladder, with occasional heredity.
• Maximal intravesical pressure: transmitted to renal calyces and pyramids

Etiology

• Occurs more often in girls; ratio of 10:1.
• Less common in blacks
• Incidence is unknown; in absence of UTI, VUR is often undiagnosed.
• Siblings of those affected have a 27% to 51% chance of reflux.
• Children with parents who have VUR have a 70% chance of reflux.
• Secondary reflux can develop in association with infection, malformations or the ureterovesical (UV) junction, increased intravesical pressures, voiding disorders, or surgery on the UV junction.

Grades of Vesicoureteral Reflux

• Grade I: Reflux into a nondilated distal ureter
• Grade II: Reflux into the upper collecting system without dilation
• Grade III: Reflux into dilated ureter or blunting of calyceal fornices
• Grade IV: Reflux into a grossly dilated ureter
• Grade V: Massive reflux with ureteral dilation and tortuosity and effacement of the calyceal details; occurs almost exclusively in male infants
• Secondary reflux: transient or persistent

Clinical Manifestations

• May be asymptomatic or may experience recurrent UTIs; alternatively, they may experience unexplained fever, poor growth and development, irritability, and feeding problems.
• Family history may reveal VUR or UTIs

Diagnosis & Treatment

• Prompt treatment of UTIs in children with reflux is important to minimize the risk of renal scarring.
• Some infants with reflux already have renal scarring at birth.
• Diagnostic imaging may be required for diagnosis and assessment of structural change, scarring, urinary tract function, and risk for future infection and renal damage.
• Identification and resolution of bowel and/or bladder dysfunction is imperative to decrease risk of UTIs and improve the rate of VUR resolution.
• Spontaneous remission of grades I, II, III reflux occurs in 50 to 80% of children and approximately 20% of grade IV and V will resolve.
• Use of prophylactic antibiotics is controversial due to concerns about efficacy and the development of antibiotic resistance.
• Recurrent infection or high-grade reflux may need surgical intervention or endoscopic injection of biomaterials into the bladder wall below the ureteral orifice.
• Surgical repair of reflux has shown to decrease the incidence of pyelonephritis.
• Renal ultrasounds can also be performed only in children with scarring or otherwise abnormal-appearing kidneys

Wilms Tumor Defined

• Embryonal tumor of the kidney that stems from epigenetic and genetic changes which cause abnormal proliferation of renal stem cells (metanephritic blastema).

Etiology

• Incidence remains constant in U.S. with approximately 500 children (between the ages of 1 and 5) are diagnosed per year; peak incidence occurs between 2 and 3 years of age.
• Slightly more common in females and in blacks compared to whites, but it is less common in Asian children.
• Sporadic and inherited origins occurs in children with no known genetic predisposition, although children with congenital anomalies and children with Wilms tumor are likely to have the inherited bilateral form of the disease.
• Composed of stromal blastemic and epithelial cells.
• Blastemic cells are primitive and undifferentiated that partially developed into epithelial or stromal tissue; with each cellular component, varying stages of differentiation may be evident within the tumor.

Pathophysiology

• Most of the inherited cases of Wilms tumor are transmitted in an autosomal dominant fashion.
• “Two hit” hypothesis for development proposes that children who inherit a mutation in one allele of a tumor-suppression gene require just one more somatic mutation for a tumor to form.
• Wilms tumor-suppressor genes WT1 and WT2 are located on chromosome 11.
• Children with Wilms Tumor have losses or rearrangements in chromosomal abnormalities which are often present in Wilms tumors gains in chromosome 1p, 7p, 16q, and 22q.
• WTX is a tumor-suppressor gene located on the X chromosome.
• 10% of children who have Wilms tumor also have deletions or mutations of other genes, and these patients may also have aniridia and hemihypertrophy.
• These patients have genitourinary malformations such as horseshoe kidneys, hypospadias, ureteral duplication, polycystic kidneys, or uterine abnormalities.

Clinical Manifestations

• 90% of Wilms tumors enlarging asymptomatic upper abdominal mass in a healthy, thriving child
• Often discovered by the child's parent who feels or notices an abdominal swelling, usually while dressing or bathing the child
• Other presenting complaints involve vague abdominal pain, hematuria, and fever
• Hypertension may be present due to excessive renin secretion by the tumor

Diagnosis

• Perform a physical examination where tumor feels firm, nontender, and smooth as a solitary mass of varying size that is confined to one side of the abdomen
• Diagnostic Imaging demonstrates a solid intrarenal mass
• Diagnosis is based on surgical biopsy.

Staging of Wilms Tumor

• System based on surgical findings and the extent of disease at diagnosis that classifies children further as either high or low risk, according to favorable or unfavorable histologic presentation - anaplasia.
• Stage I (40% to 45% of tumors): Tumor limited to the kidney, completely resected
• Stage II (20% of tumors): Tumor is ascending beyond the kidney or into vessels of renal sinus, but appears to be totally resected
• Stage III (20% to 25% of tumors): Residual nonhematogenous tumor confined to the abdomen, positive lymph nodes in renal hila
• Stage IV (10% of tumors): Hematogenous metastases (e.g., lung, liver, bone, brain)
• Stage V (5% of tumors): Bilateral disease either at diagnosis or later, but need to stage each kidney

Treatment

• Primary treatment is usually surgical exploration and resection followed by treatment based on histology OR Chemotherapy followed by surgical resection (limits tumor spillage during surgery)
• Heminephrectomy of the less involved kidney and nephrectomy of the other can be performed if it is in the bilateral disease.
• Radiation therapy may be used for children with higher stages of disease and metastases, patients who have a Survival at 4 years is greater than 90% for localized disease and more than 85% for advanced disease with favorable histology.
• These patients have congestive heart failure, renal failure, hypertension, and secondary malignancies are more frequently in long-term survivors than in the general population.

Poststreptococcal Glomerulonephritis in Children

• One of the most common immune complex-mediated renal diseases in children ages 5 to 15 and is a representative of acute glomerulonephritis.

Etiology

• Most commonly occurs after a throat (pharyngitis) or skin (impetigo) infection with nephritogenic strains of group A betahemolytic streptococci and occurrences have also been observed after viral diseases and bacterial endocarditis.

Pathophysiology

• Glomerulonephritis develops from the deposition of antigen-antibody complexes (immunoglobulin G [IgG] and C3 complement) in the glomerulus; alternatively, it develops from the entrapment of the antigen within the glomerulus, which causes immune complexes to form in situ.
• Lumpy deposits of IgG and C3 on the glomerular basement membrane is shown in immunofluorescence microscopy.
• The thickened glomerular membrane causes decreased GFR and the activated complement, which creates inflammatory cytokines, oxidants, proteases, and growth factors attack endothelial cells and alter membrane permeability, leading to hematuria and proteinuria.
• Hypertension occurs primarily because of fluid retention.

Clinical Manifestations

• Symptoms usually have an ABRUPT onset that begins 1 to 2 weeks after an upper respiratory tract infection (more common during cold weather) as well as 1 to 6 weeks after skin infections - impetigo (more common during warm weather).
• Severity varies with disease and the patient may have urine that is smoky brown or cola colored (presence of red blood cells) and complaints of flank or midabdominal pain, irritability, general malaise, and fever.
• If the patient is experiencing acute hypertension, they may have a headache, vomiting, somnolence, and CNS manifestations can range from seizures - Cardiovascular to dyspnea, tachypnea, and enlarged, tender liver.

Prognosis

• Severly affected children can will have a severe Prognosis if he/she has acute renal failure with oliguria, however, diagnosis usually occurs in 1 month.
• 50% of children are asymptomatic and urine abnormalities may be found in a few test patients for up to 1 year after the onset, but they will be able to recover completely.
• If the child is prolonged and proteinuric, prognosis is more complex and they may potentially worsen.

Diagnosis & Treatment

• Positive throat or skin culture for Streptococcus and Antistreptolysin-O titers confirm recent infection
• Patients often have lab values for Serum complement levels that are ↓ and serum creatinine and BUN levels that are ↑
• Treatment involves monitoring the patients Oliguria and HTN-restricted fluid, NA+ and K+ intake and administering the patient to antihypertensive medication and diuretics on the acute phase.

Hemolytic Uremic Syndrome

• Can be characterized as an acute disorder with microangiopathic hemolytic anemia, thrombocytopenia, and renal Impairment.

Etiology

• Most common community-acquired cause of acute renal failure in young children; more frequent in infants and children under 4 years old the prognosis has improved dramatically in recent years; more than 90% of children survive and regain normal renal function.

Pathophysiology

• Associated with both bacterial, viral agents, and endotoxins (especially those from Escherichia coli 0157:H7 and recently Escherichia coli 0104:H4) and the potential sources of exposure include animals, unpasteurized beverages, and contaminated meat and vegetables.
• The disease also occurs with cancer and use of chemotherapeutic agents.
• Verotoxin (Shiga toxin) from E. coli is absorbed from the intestines into the blood where it binds to polymorphonuclear leukocytes that are transported to the kidney where it lysis glomerular capillary endothelial cells, separating endothelial cells from the basement membrane, which causes activation and aggregation of platelets, and activation of the coagulation cascade
• Oliguria with renal failure occurs in 50%, and narrow vessels damage passing erythrocytes of the patient.
• Fibrinolysis (process of dissolution of a clot) acts on precipitated fibrin, thus causes fibrin split products to appear in serum and urine where platelet clustering within damaged vessels creates damage and the removal of platelets produces thrombocytopenia.
• Fibrin-rich thrombi can be found throughout the microcirculation (other tissues, including the brain, liver, heart, and intestines as well).

Clinical Manifestations

• Occurs often because of prodromal gastrointestinal (GI) illness with diarrhea (usually caused by Shiga toxin-producing E. coli) and is known as D+ HUS onset that occurs bout 1 to 2 weeks after a GI illness with a symptom-free 1- to 5-day period with a Sudden onset of pallor, bruising or purpura, irritability, and oliguria
• Seizures and lethargy occur in the CNS from renal failure, so Metabolic acidosis, uremia, hyperkalemia, and often hypertension can be expected in CNS.

Atypical HUS (aHUS)

• not associated with diarrhea and is known as D- HUS; dysregulation of the alternative complement pathway is often noted,

Familial aHUS

• very rare that is is only defined as the diagnosis of aHUS given to at least 2 members of the same family at least 6 months apart

Diagnosis

• Diagnosis is based on history of preexisting illness, presenting symptoms, and urine and blood analysis.

Treatment

• Antibiotics should nor be given used in the initial treatment because it increases Shiga toxin release and increase the risk of HUS
• Treatment involves, maintaining nutrition and hydration and controlling hypertension, hyperkalemia, and seizures, but If renal failure occurs in blood, dialysis and transfusions with PRBCs needs to occur to maintain reasonable hemoglobin levels.
• Eculizumab (C5 inhibitor) has shown to be efficacious in the treatment of aHUS.

Prognosis & Complications

• Most children recover, but still develops to high infection and those that develop hypertension proteinuria, or renal insufficiency or failure.
• Most notably, death usually occurs most in complications related to CNS, infectious, or myocardial causes.

Prevention

• The best method is preventing Shiga toxin-producing bacterial infection (i.e., E. coli) prevents D+ HUS

Berger nephropathy (IgA Nephropathy)

• Defined as being a most common form of glomerulonephritis in children and young adults worldwide, the infection also occurs occurs more often in males.

Etiology

• Usually unknown; and is characterized by deposition primarily of IgA and complement proteins in the mesagnium of the glomerulus. Most notably, the abnormal glycosylated IgA-1 (galactose-deficient IgA-1) is produced and created by the bone marrow.

Patho

• Glycan is formed into specific IgA antibodies against the abnormal IgA-1
• Glycan will activate a complement, causing binding to glomerular mesangial stimulating them to generate extracellular matrix injury, cytokines interleukin-6, and tumor necrosis factor-alpha
• The immune response contributes to diffuse mesangioproliferative glomerular injury and glomerulosclerosis (usually reversible that causes specific illnesses

Symptoms

• Concurrent recurrent and gross hematuria will occur specifically with the respiratory tract infection as well as with and recurrent episodes
• There may a microscopic hematuria found and protein

Treatment and Prognosis

• Treatments involve, a supportive method and dealing with proteinuric, hypertension, and some will recover from the chronic illness.