Congenital Kidney Disease 2024 PDF

Congenital and Cystic Diseases of the Kidney  General Features of Congenital Disorders ~10% of population born with a potentially significant urinary tract malformation Frequent cause of chronic renal disease in children Can be inherited or acquired developmental defec...

Congenital and Cystic Diseases of the Kidney  General Features of Congenital Disorders ~10% of population born with a potentially significant urinary tract malformation Frequent cause of chronic renal disease in children Can be inherited or acquired developmental defect during organogenesis Normal term infant kidneys; note the fetal lobulations and the smooth cortical surfaces with some attached adipose tissue  Congenital Anomalies: Renal Agenesis Organ fails to develop during embryogenesis due absent primordial tissue. Bilateral: incompatible with life most infants are stillborn, and mothers have oligohydramnios associated with Potter sequence Unilateral is compatible with normal survival opposite kidney undergoes compensatory hypertrophy some patients develop glomerular sclerosis due to adaptive changes in hypertrophied kidney, leading to chronic renal failure  Congenital Anomalies Renal Hypoplasia failure of kidney to develop to normal size may be unilateral or bilateral kidney has six or fewer pyramids and overlying cortex; should be differentiated from atrophy  Ectopic Kidneys Abnormally located kidneys Pathogenesis: Kidney fails to ascend from its origin in the true pelvis or, Metanephros develops in abnormal location Located usually low; at pelvic brim or within pelvis Can be in thoracic cavity (rare) majority of patients with an intrathoracic kidney are asymptomatic, with normally functioning kidney, often discovered in evaluation of mass discover on chest X-ray  Pelvic Kidney Abnormal position predisposes to ureteral tortuosity and ureteropelvic junction (UPJ) obstruction obstruction of flow, hydronephrosis chronic infections and stones scarring and renal failure Treatment: Ureteroplasty or reposition kidney to improve flow Remove, if severely damaged  Horseshoe Kidney Fusion of kidney poles across the midline, anterior to aorta 90% involve lower pole Isthmus can consist of functional parenchyma or fibrous tissue Common defect Incidence: 1 in 400-800 live births Associated with Turner Syndrome and Trisomy 18 May be asymptomatic, or ureters may kink or take an abnormal course across the "bridge" of renal tissue > partial obstruction > hydronephrosis, increased UTIs or renal  Overview of Cystic Renal Diseases Group of pathologic conditions (hereditary, developmental, or acquired) associated with the development of renal cysts Cyst is an epithelial-lined cavity Common renal abnormalities that can vary from being clinically insignificant to > end-stage renal disease Most common inherited disease in adults is autosomal dominant polycystic kidney disease (ADPKD) Most common acquired kidney cyst is a simple renal cyst Normal adult kidney with capsule removed; pattern of some persistent fetal lobulations and a simple cyst (common)  Polycystic Kidney Disease (PKD) Collection of mainly genetic disorders characterized by development of kidney cysts originating renal tubules or collecting ducts May be accompanied by cysts in the hepatic and pancreatic ducts (ADPKD) or hepatic fibrosis (ARPKD) Cysts disrupt renal parenchyma > obstruction and eventual kidney failure  Proteins Associated with Gene Mutations in PKD Polycystins (Adult PKD) Large transmembrane proteins localized to cilium of tubular epithelial cells Abnormal polycystin protein function > altered calcium flux and altered cell-cell or cell-matrix interactions Results in altered tubular growth/differentiation and cyst formation Fibrocystin (Childhood PKD) Unknown function, but structure suggests a cell surface receptor with a role in collecting duct and bile duct cell differentiation Normal cellular function of nephrocystin (medullary cystic disease complex) is largely unknown, and molecular defects underlying disease pathogenesis remain obscure  Genetic Polycystic Kidney Disease Autosomal Dominant (adult) PKD Frequency: 1 in 400-1000 live births PKD1 gene mutation (polycystin-1 protein) 85-90% of cases PKD2 gene mutation (polycystin-2 protein) 10-15% of cases Older onset, more slowly progressive than PKD1 Autosomal Recessive (childhood) PKD Frequency: 1 in 20,000 live  Genetic Polycystic Kidney Disease Nephronophthisis/ Medullary cystic disease complex Frequency (1:10,000) Nephrocystin gene mutation  ADPKD Systemic disorder, comprising cystic and non-cystic involvement of multiple organs, including kidney, liver, pancreas, spleen, heart, brain Always bilateral kidney involvement Responsible for ~10% of ESKD requiring dialysis or transplantation  ADPKD Autosomal dominant disorder with high degree of penetrance PKD1 gene mutation (polycystin-1 protein) 85-90% of cases Mean age to ESKD – 54 years PKD2 gene mutation (polycystin-2 protein) 10-15% of cases More slowly progressive with mean age to ESKD – 74 years Inheritance pattern similar to tumor suppressor gene inheritance in that an individual usually inherits one gene mutation and acquires the second mutation (loss of heterozygosity) in somatic cells of kidneys Disruption of calcium cellular homeostasis increases cAMP cytosolic levels and affects cell cycle, leading to increased cell proliferation and transepithelial fluid secretion Cysts probably develop secondary to abnormal epithelial cell proliferation, growth and polarity, and Pathogenesis Robbins, Fig. 20-42, modified  ADPKD Course Kidney cysts: not evident at birth but enlarge gradually over time as individual ages > compression of functioning areas and blood vessels until most renal function is lost, about fifth decade or later; patients then develop signs of renal failure  ADPKD May be associated with other anomalies, including cysts of other organs (liver, pancreas, spleen, usually asymptomatic), berry aneurysm of the circle of Willis (may rupture > subarachnoid hemorrhage), mitral valve prolapse (usually asymptomatic) ~40% of patients die due to IHD or hypertensive heart disease; 25% die due to infection; 15% due to subarachnoid or intraparenchymal brain hemorrhage); remainder due to other causes ADPKD p. 943 Morpholog y bilateral enlargement, distortion of cortical surface by numerous cysts that persist on the cross surface; micro reveals functional nephrons dispersed between cysts  Associated Extrarenal Lesions Polycystic liver disease (40% of pts) – usually asymptomatic Cysts in pancreas, lung, spleen – usually asymptomatic Mitral valve prolapse (20-25% of pts) – usually asymptomatic Berry aneurysms (10- p. 943 30% of pts; cause of death in 4-10% of pts)  ADPKD Clinical Features may be asymptomatic until renal failure occurs other signs and symptoms include back pain, hematuria, abdominal mass, hypertension renal failure is usually slowly progressive to uremia; dialysis or transplantation for survival death is due to ischemic or hypertensive heart disease (40%), infection (25%), ruptured berry aneurysm or hypertensive intracerebral hemorrhage (15%) or other causes  ARPKD Rare disease (~1 in 10,000 to 50,000 live births) most cases present during infancy exceptional cases present in older children ~ 75% of affected infants die in perinatal period due to renal failure  Autosomal Recessive PKD Subcategories: Perinatal and neonatal Most common Renal failure usually present at, or soon after, birth 60-90% of collecting ducts involved Infantile and juvenile Renal failure symptoms present later (if at all) 10-25% of collecting ducts involved patients living beyond infancy develop hepatic fibrosis, Hepatic disease is the predominant clinical problem in older children  ARPKD Morphology Gross: enlarged kidneys with smooth cortical surface During early fetal development, kidneys undergo transient phase of proximal tubule cyst formation With progression, site of cystic dilation > distal tubules, and typical renal pathology in postnatal kidneys is fusiform dilatation of the collecting ducts cysts occur in the cortex and medulla (with loss of corticomedullary definition), appearing as elongated channels at right angles to the cortical surface, giving the kidney a sponge-like appearance p. 943  ARPKD Microscopic Morphology Cysts fill most of the parenchyma, and it is hard to find glomeruli Many cysts are elongated and radially arranged from the center of the kidney on the right, much like spokes on a wagon wheel Cysts are lined by cuboidal cells, originating in the collecting tubules  ARPKD Morphology patients living beyond infancy develop hepatic fibrosis, characterized by proliferation of bile ducts, periportal fibrosis, which may lead to portal hypertension congenital hepatic fibrosis, as seen here in which a portal area is expanded with increased bile ducts radially arranged around the perimeter. Dark clusters of cells in the hepatic parenchyma are islands of extramedullary hematopoiesis typical for fetal liver.  AR-PKD Clinical Course Perinatal form: ~90% of kidney affected Represents 75% of AR-PKD cases In utero involvement or presents at birth Massively enlarged kidneys Oligohydramnios, Potter sequence, pulmonary hypoplasia Minimal liver involvement Death within first week of life Neonatal form: ~60% of kidney affected Presents within first few weeks of life Progressive renal failure – death within a few months Mild liver fibrosis  AR-PKD Clinical Course Infantile form: ~25% of kidney affected Presents after first few months of life Moderate hepatic fibrosis – hepatosplenomegaly and portal hypertension Progressive renal failure by adolescence Juvenile form: ~10% of kidney affected Presents age 6 mos – 5 yrs Little renal involvement Severe hepatic fibrosis Hepatosplenomegaly Portal hypertension – variceal bleeding Best prognosis - 80% survive beyond adolescence  Cystic Diseases of the Medulla Medullary Sponge Kidney Nephronophthisis Medullary Sponge Kidney Numerous, small, collecting ducts cysts lined by cuboidal or columnar epithelium Both kidneys are affected in the majority of cases Often asymptomatic and discovered incidentally Renal function usually normal If symptomatic, disease occurs between 30 and 60 because of development of calculi, hematuria, infection pathogenesis is unknown Nephronophthisis - Medullary Cystic Disease Complex Group of disorders, typically with onset in childhood characterized by medullary cysts, sclerotic kidneys, progressive renal failure (accounts for ~20% of chronic renal failure in children and adolescents) Cortical tubulointerstitial atrophy and fibrosis are main cause of renal insufficiency Clinical presentation reflects deteriorating tubular function such as impaired concentrating ability, sodium wasting, with polyuria, polydipsia, and progressive renal failure Disease should be considered in children or adolescents with unexplained renal failure, positive family history and biopsy showing chronic tubulointerstitial fibrosis Nephronophthisis - Medullary Cystic Disease Complex Several variants of nephronophthisis: sporadic (non-familial); autosomal recessive juvenile nephronophthisis (most common, with mutation of several genes encoding nephrocystins); autosomal recessive renal-retinal dysplasia, associated with ocular lesions; Autosomal dominant adult-onset medullary cystic disease, is less frequent, and terminal renal failure appears later in life. Nephronophthisis - Medullary Cystic Disease Complex Morphology Bilateral shrunken kidneys with multiple cysts at the cortico-medullary junction, cortical atrophy, interstitial fibrosis, preservation of glomeruli p. 944 Multicystic Renal Dysplasia Sporadic disorder May be unilateral or bilateral Results from an abnormality in metanephric differentiation Patients present with large, palpable flank mass shortly after birth Unilateral is treated by removal of the affected kidney Bilateral is incompatible with life because of renal failure  Multicystic Renal Dysplasia p. 945 Morphology characterized by persistence of undifferentiated Cystic Renal mesenchyme, islands Dysplasia of cartilage, p. 963 rudimentary glomeruli and tubules, multiple cysts ranging from microscopic to several Acquired Cystic Kidney Disease seen in patients with chronic renal failure who undergo long- term dialysis (after about 5 years) bilateral involvement; often atrophic kidneys with microcysts lined by flat to cuboidal epithelium affecting cortex and medulla, often contain calcium oxalate crystals probably due to tubular obstruction by scar or crystals small percentage of patients develop renal cell carcinoma in cyst wall after many years Simple Renal Cysts very common incidental finding in persons over 50 rarely symptomatic unless very large may be solitary or multiple lined by flattened epithelium and filled with clear fluid occasionally, hemorrhage into cyst may cause pain Main clinical importance is differentiation from renal neoplasms