Congenital renal disorders: Pathology review

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Case study0:00–0:45

Two people came to the Nephrology ward one day. The first is 29 year old Dan, who presents with hypertension, gross hematuria, and flank pain.
Dan’s family history showed that his grandmother died of a berry aneurysm. Next is 35 year old Heather.
She doesn’t present any symptoms, but she has been referred to the nephrology clinic because her primary care doctor discovered that she her kidneys have a “weird shape” on an abdominal x-ray.
Both individuals underwent abdominal ultrasound. Dan had many cysts of different sizes on both kidneys, while Heather’s kidneys are located lower than normal and appear fused together.
Both Dan and Heather have congenital renal disorders. The renal system starts developing during week 4 of intrauterine life.

Pathology0:45–2:20

It comes from the mesoderm, which is one of the three primitive germinal layers. More specifically, it develops from a portion of the mesoderm called the intermediate mesoderm.
The intermediate mesoderm on either side of the embryo condenses to form a cylindrical structure called the urogenital ridge, and a portion of the urogenital ridge called the nephrogenic cord gives rise to urinary structures.
During renal development, the nephrogenic cord gives rise to three sets of structures: the nonfunctional pronephros in the embryo’s head region which regresses by the end of week 4.
Then, the mesonephros forms, appears in the thoracic and upper lumbar region and acts as temporary kidneys until they regress in week 12.
Finally the metanephros develops in the pelvic region, and it forms the permanent kidneys. Ok, the metanephros sprout small buds called the ureteric buds.
At the same time, the intermediate mesoderm gives rise to another tissue called the metanephric blastema. The blastema release growth factors that stimulates the ureteric bud to become the ureter, the renal pelvis, the renal calyces, and the collecting ducts.
Meanwhile, the ureteric bud release growth factors that cause the metanephric blastema to develop into nephrons. At around week 20, the metanephric kidneys take over urine production, this becomes the major source of amniotic fluid.
As they continue to grow, they move up from the pelvis to reach their adult position. Okay, so if there’s a problem during the development of the kidneys we can get oligohydramnios, or a deficiency of amniotic fluid.

Potter sequence2:20–3:31

As a result, a number of things can happen leading to the so called Potter sequence. With less amniotic fluid, there’s pulmonary hypoplasia.
Not only that though, with less amniotic fluid, there’s less space in the amniotic sac, and so the fetus is literally compressed into a smaller space, which causes developmental abnormalities like a flattened face, wrinkly skin, low-set ears, as well as limb abnormalities like clubbed feet.
Some renal conditions make it impossible for urine to be excreted, in which case there will also be renal failure in utero.
Okay, now, one high yield fact is remembering the specifics for Potter sequence. We have a mnemonic for that: P is for Pulmonary hypoplasia, O is for oligohydramnios, first T is for Twisted face, second T is for Twisted skin, E is for extremity defects and R is for renal failure.
Okay, let’s now let’s talk about each of the congenital renal disorders. To make things easier, we can split them into cystic and non-cystic disorders.

Polycystic kidney diseas3:31–6:33

The first cystic congenital renal disorders is polycystic kidney disease. Based on the inheritance pattern, this can further be split into autosomal recessive polycystic kidney disease or ARPKD, and autosomal dominant polycystic kidney disease or ADPKD.
With ARPKD, someone inherits a mutation on both copies of the PKHD1 gene, which codes for the fibrocystin protein. Fibrocystin is found in the collecting ducts, as well as in the epithelial cells of the hepatic bile duct.
The lack of fibrocystin leads to cystic dilation of the collecting ducts in both kidneys. Individuals with ARPKD can develop Potter sequence in utero, and the most common cause of death in these individuals is pulmonary hypoplasia.
If they don’t develop Potter sequence, then after birth, they develop progressive renal failure and systemic hypertension.
The liver is also affected and they can have congenital hepatic fibrosis which leads to portal hypertension. Autosomal dominant polycystic kidney disease, or ADPKD, is more common and symptoms usually develop in adulthood.
ADPKD is an inherited genetic disorder mostly caused by mutations in the PKD1 gene, but mutations can also happen in the PKD2 gene.
Now, PKD1 and PKD2 code for the polycystin 1 and polycystin 2 proteins, respectively. In the nephron, polycystin 1 and 2 inhibit cell growth and proliferation through signaling pathways that’s not well understood.
Now, a person who develops ADPKD would have inherited a single mutation in PKD1 or PKD2. This leaves one functional copy of the gene in every cell, which allows for the production of polycystin 1 or polycystin 2.
However, there is something called the “second hit” theory. This means that a random mutation can occur in the remaining good copy of the gene later in life.
This disrupts the regulation of renal cell growth and proliferation, leading to cyst formation. Overtime, these cysts will fill with fluid and enlarge, causing damage to the surrounding tissue, hypertension, and flank pain.
Eventually this will cause kidney damage. Now, if there’s hypertension and signs of kidney damage like proteinuria, the best treatment is with ACE inhibitors or ARBs.
Now, it’s important to remember ADPKD affects other organ systems too! Individuals can have cysts pop up in the liver too, which will lead to liver failure.
They are also more likely to develop berry aneurysms in the cerebral arteries, usually in the Circle of Willis. These can rupture and cause subarachnoid hemorrhage.
Some individuals may also present mitral valve prolapse or diverticulosis. For you tests, some clinical clues that should make you think of ADPKD include flank pain, hematuria, hypertension and a family history of sudden death due to aneurysms.
If hypertension is present and/or proteinuria develops, the treatment of choice is ACE inhibitors or ARBs. Another cystic disorder is medullary sponge kidney.

Medullary sponge kidney6:33–7:18

Like ARPKD, this is present at birth. Although the precise mechanism is unclear, there’s abnormal induction of the metanephric blastema by the ureteric buds, and cystic tubules develop in the nephrons, which gives the kidney the appearance of a sponge.
The hallmark feature is cysts that form around the collecting ducts in the medulla of the kidney, causing them to dilate.
Even though medullary sponge kidney is present at birth, it’s usually asymptomatic and discovered in adulthood. With medullary sponge kidney, there’s urinary stasis due to the cysts compressing the surrounding structures, and sometimes there’s hypercalciuria which makes the individuals prone to complications like nephrolithiasis.
Next, we have multicystic dysplastic kidney, which is a type of non-inherited congenital kidney disease, where ureteric buds fail to induce differentiation of metanephric blastema.

Multicystic dysplastic 7:18–8:10

As ureteric bud fails to produce ureters, renal calyces, collecting ducts, and collecting tubules, filtered urine is unable to exit kidneys.
This results in a buildup of urine and formation of multiple fluid-filled cysts that are composed of abnormal connective tissue.
In most cases, multicystic dysplastic kidney is unilateral and it can go undiagnosed since the other kidney compensates the renal function.
But, in some neonates, health professionals can detect palpable flank mass, and then an ultrasound must be performed. In rare cases, multicystic dysplastic kidney can be bilateral and then it leads to Potter sequence.
Finally, we have medullary cystic kidney disease. Now, although it’s in our cystic disease section, development of cysts is actually not that common, so the newer term is autosomal dominant tubulointerstitial kidney disease.

Medullary cystic kidney 8:10–8:56

Here, mutations in genes that code for mucin or uromodulin cause dysfunctional proteins synthesis which leads to tubulointerstitial fibrosis and the occasional cysts in the medulla and corticomedullary junction.
Over time, this leads to renal insufficiency with inability to concentrate urine, and eventually renal failure. Now an important clue is that children with this disorder are more likely to develop gout at a young age.
A kidney ultrasound shows small-sized kidneys, while medullary cysts are usually not visualized. Okay, let’s move onto the non-cystic congenital disorders.
First, there’s renal agenesis, which is when one or both kidneys don’t form. With renal agenesis, the ureteric bud fails to induce development of the metanephric blastema, and so either one or both kidneys doesn’t develop.

Renal agenesis8:56–9:46

Although not completely known, it’s thought that this is a result of a combination of genetic as well as in utero environmental factors such as toxins and infections.
When renal agenesis is bilateral, it leads to renal failure in utero and Potter sequence. This is not compatible with life.
When one kidney is formed and functioning, this is called congenital solitary functioning kidney. The person is usually asymptomatic, but the solitary kidney needs to do all the work, so there will be hypertrophy and over time, there’s a risk of renal failure due to hyperfiltration.
Next, we have duplex collecting system, where the ureteric bud either splits or arises twice from the mesonephric duct. Based on the level of fusion, duplex collecting system can present as bifid renal pelvis; partial ureteral duplication, also known as the Y-shaped ureter; incomplete ureteral duplication, or V-shaped ureter, where ureters join together near or in bladder wall; and complete ureteral duplication, when the duplicated ureter has the separate ureteric opening.

Duplex collecting system9:46–10:38

Now remember that this congenital disorder is highly associated with other abnormalities of the urinary tract, such as ureterocele.
With this condition, the part of the ureter that enters the bladder swells like a balloon, thereby obstructing the flow of urine.
Eventually, ureteral obstruction can lead to vesicoureteral reflux and frequent urinary tract infections. Moving on to posterior urethral valves, or PUV, which is a congenital disorder in genetic males.

Posterior urethral valve10:38–11:22

Normally, the mesonephric duct fuses with cloaca leaving behind the remnants of this process called plicae colliculi. But, in posterior urethral valves, there’s an abnormal fusion of mesonephric duct and cloaca, which leads to the formation of membranous folds, or flaps of tissue.
These membranous folds obstruct the posterior urethra and cause bladder outlet obstruction. Now, it’s important to remember that PUV is the most common cause of bladder outlet obstruction in males, and it can be diagnosed by prenatal ultrasound, which can show a dilated bladder, thickened bladder wall, and bilateral hydronephrosis.
Finally, we have horseshoe kidney where the two kidneys fuse together during fetal development. Between the 4th to 6th week, the kidneys are pretty close together, and it’s thought that some flexion or growth of the developing spine and pelvic organs essentially squish them together.

Horseshoe kidney11:22–12:38

This allows the inferior poles of the kidneys to touch and fuse, forming what’s called a fibrous isthmus. Horseshoe kidney is associated with chromosomal aneuploidy syndromes, like Turner syndrome, trisomies 13, 18 or 21.
They can also be caused by teratogens such as thalidomide or alcohol. Whatever the cause, during the 7th and 8th weeks, the fused-kidneys try to migrate up into the abdomen, but they get trapped under the inferior mesenteric artery, which keeps them lower in the abdomen than normal.
Now the kidneys function normally at first, but due to the abnormal anatomy of the kidneys, there can be urinary stasis which increases the risk for urinary tract infections and kidney stones.
There could also be ureteropelvic junction obstruction that prevents urine from flowing from the renal pelvis into the ureters.
Both kidney stones and UPJ obstruction can block normal urine flow, causing the kidney to swell up, leading to hydronephrosis.
Okay, let’s review now. Renal congenital disorders can be split into cystic and non-cystic.

Review12:38–13:09

Cystic disorders include ARPKD, that can present either in utero or after birth, ADPKD, that mostly presents in adulthood and medullary sponge kidney.
Non-cystic disorders include renal agenesis that can be bilateral, in which case a person develops Potter sequence in utero.
Then there’s unilateral renal agenesis and finally, horseshoe kidney. Coming back to our cases, Dan has ADPKD and the cysts in his kidneys are causing the hematuria and flank pain.

Summary13:09–13:31

Another clue is that Dan also has a family history of berry aneurysms which is common with ADPKD. Regarding Heather, she has an asymptomatic horseshoe kidney, which doesn’t need regular revaluation but she is more likely to develop kidney stones and UTIs.
….And that’s the congenital renal pathology in a nutshell.