Developmental pathology of congenital kidney and urinary tract anomalies

Abstract

Congenital anomalies of the kidneys or lower urinary tract (CAKUT) are the most common causes of renal failure in children and account for 25% of end-stage renal disease in adults. The spectrum of anomalies includes renal agenesis; hypoplasia; dysplasia; supernumerary, ectopic or fused kidneys; duplication; ureteropelvic junction obstruction; primary megaureter or ureterovesical junction obstruction; vesicoureteral reflux; ureterocele; and posterior urethral valves. CAKUT originates from developmental defects and can occur in isolation or as part of other syndromes. In recent decades, along with better understanding of the pathological features of the human congenital urinary tract defects, researchers using animal models have provided valuable insights into the pathogenesis of these diseases. However, the genetic causes and etiology of many CAKUT cases remain unknown, presenting challenges in finding effective treatment. Here we provide an overview of the critical steps of normal development of the urinary system, followed by a description of the pathological features of major types of CAKUT with respect to developmental mechanisms of their etiology.

Keywords: CAKUT; congenital; development; genetics; kidney; urinary tract.

FIGURE 1

Illustration shows events in mammalian kidney development using mouse stages as an example. Pronephros, the first stage, begins at about embryonic day 8 (E8) from intermediate cells. Mesonephros includes mesonephric mesenchyme (MesM) and an epithelial tube called the Wolffian duct (WD). By E10.5, the Wolffian duct has inserted into the cloaca, MesM is degenerating and a bulge on the distal aspect of the WD develops into the UB that grows toward the MM. The portion of the Wolffian duct distal to the UB is called the common nephric duct (CND). At E11.5, the UB invades the MM, causing certain cells in the MM to coalesce around the UB tips. These are called cap mesenchyme cells (CaPM). Interactions between CaPM and UB and other cells in the MM initiate recursive branching called branching morphogenesis. At E12.5, the ureter remodeling process starts to insert into the primitive bladder (UGS) and separate from the Wolffian duct through a process of CND apoptosis (yellow).

FIGURE 2

Hematoxylin and eosin–stained section from a human fetus during the mesonephros stage. Note the linearly arranged primitive glomeruli (arrows).

FIGURE 3

Hematoxylin and eosin–stained section of human perinatal kidney at low power shows organization into lobules (appear as bumps) with outer cortex (darker colored outer layer), medulla and papillae that drain into calyces (crescent-shaped white spaces).

FIGURE 4

VCUG depicts complete duplication of the urinary system. The primary ureter (ureter1) inserts higher in the bladder and drains the lower kidney (kidney1). The dilated ureter2 inserts much lower in the bladder and drains the upper kidney (kidney2). Duplication can arise from failure to repress ectopic budding from the Wolffian duct or multiple UB inductions during metanephros development.

FIGURE 5

Renal dysplasia. (A) Gross morphology of cystic dysplastic kidneys. The image on the left shows the irregular shape of the entire kidney and the image on the right is the cut surface showing multiple cysts and no organization. (B) Histology of renal dysplasia. Both images show no normal renal structures or organization into cortex, medulla and papillae. Numerous cysts are scattered in the kidney. The image on the left highlights collecting ducts in the center surrounded by concentric immature mesenchymal cells (arrows). The image on the right additionally has cartilage (white arrow) in the center that can be seen in about a third of dysplastic kidneys. Dysplasia can arise from abnormal UB budding or branching morphogenesis and nephrogenesis.

FIGURE 6

Obstructive nephropathy. Hematoxylin and eosin–stained section of a kidney from a patient with long-standing urinary tract obstruction shows significant kidney damage. Note that several tubules are dilated with no epithelial lining, thus showing atrophy (arrows). A number of the tubules show proteinaceous eosinophilic material representative of end-stage nephrons. Also note the intense inflammatory infiltrate involving almost the entire parenchyma.

FIGURE 7

Hydronephrosis and obstruction. The radiographic image shows diffuse dilation of the collecting system with dilated pelvis (arrow) due to lower urinary tract obstruction. Obstruction can result from functional or physical abnormalities that are intrinsic or extrinsic to the urinary system.

FIGURE 8

Vesicoureteral reflux (VUR). Vesicoureterocystogram shows high-grade (Grade 5) VUR. Note the dilated, tortuous ureter, with reflux involving the kidney parenchyma, highlighted by the white dye almost spanning each kidney. Primary VUR is due to abnormal development of the ureterovesicle junction so that the valve mechanism to prevent reflux from the bladder into the ureter does not function normally.

FIGURE 9

Ureterocele. The lower abdominal and pelvic ultrasonograph shows a ureterocele (arrow). Note the clear blind ending ureterocele lining (arrow) connected to the dilated ureter (long hypoechogenic tube).

FIGURE 10

Posterior uretheral valves (PUV). The radiograph shows classic findings of PUV in a male child. Note the extreme narrowing of the urethra (arrow) due to persistent valves that lead to a dilated bladder with irregular surface (trabeculations).