Pathology of Renal Cystic Disease

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Classification of Renal Cystic Diseases

The genetics of some cystic diseases are known, with both pediatric and adult onset of disease. A general classification system is as follows:

  • Pediatric Onset

    • Autosomal Recessive Polycystic Kidney Disease (ARPKD)

      • Large kidneys

      • Cortical cysts

      • PKHD gene encodes fibrocystin

    • Nephronophthisis

      • Small kidneys

      • Corticomedullary cysts

      • NPHP gene encodes nephrocystin

    • Multicystic Renal Dysplasia

      • Variably sized kidneys

      • Variably zized cysts, heterologous tissues

      • No specific gene defect

  • Adult Onset

    • Autosomal Dominant Polycystic Kidney Disease (ADPKD)

        Large kidneys

      • Large cysts throughout

      • PKD1 and PKD2 genes encode polycystin

    • Medullary Sponge Kidney

      • Normal sized kidneys

      • Medullary cysts

      • No gene defect identified

    • Medullary Cystic Disease

      • Small kidneys

      • Corticomedullary cysts

      • MCKD gene mutations

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

This condition is inherited in an autosomal recessive pattern, giving a 25% recurrence risk for parents having subsequent children. The kidneys are affected bilaterally, so that in utero, there is typically oligohydramnios because of poor renal function and failure to form significant amounts of fetal urine. The most significant result from oligohydramnios is pulmonary hypoplasia, so that newborns do not have sufficient lung capacity to survive, irrespective of any attempt to treat renal failure.

Grossly, the kidneys are markedly enlarged and tend to fill the retroperitoneum and displace abdominal contents. The kidneys tend to be symmetrically enlarged. The cysts are quite small and uniform, perhaps 1 to 2 mm on average. Microscopically, the characteristic finding in the later third trimester is cystic change with the cysts elongated and radially arranged. The few remaining glomeruli are not involved by the cysts, and the intervening parenchyma is not increased. In the second trimester, the cysts may not be as well-developed.

ARPKD results from mutations in the PKHD1 gene that encodes for a membrane-associated receptor-like protein called fibrocystin. This protein is involved in ciliary signaling required for regulation of proliferation and differentiation of renal and biliary tract epithelial cells. Abnormalities lead to dilation of renal collecting ducts. In the liver there is expansion of portal tracts from ductal plate malformation with increased numbers of dilated bile ductules in expanded fibrous connective tissue, called congenital hepatic fibrosis.

In cases of ARPKD where a fibrocystin gene mutation leads to less severe defects, then enough renal function can be present for survival. In those cases, over time, the hepatic abnormalities become more prominent. There is more fibrosis, and dilation of bile ducts may become apparent with imaging studies. Into adulthood, even some macroscopic hepatic cysts are possible, but by then the fibrosis is the most prominent component.

  1. Normal fetal kidneys, gross
  2. Normal fetal kidneys, low power microscopic
  3. ARPKD in situ, gross
  4. ARPKD, cut surface, gross
  5. ARPKD in situ, gross
  6. ARPKD, cut surface, gross
  7. ARPKD, low power microscopic
  8. Congential hepatic fibrosis in liver, high power microscopic

Multicystic Renal Dysplasia

This condition has a sporadic inheritance pattern. It is perhaps the most common form of inherited cystic renal disease. It results from abnormal differentiation of the metanephric parenchyma during embryologic development of the kidney. However, in many cases it can be unilateral, so the affected person survives, because one kidney is more than sufficient to sustain life. In fact, with absence of one functional kidney from birth, the other kidney undergoes compensatory hyperplasia and may reach a size similar to the combined weight of two kidneys (400 to 500 gm).

Multicystic renal dysplasia was termed "Type II" in the Potter classification. There are two main subgroups. If the affected kidney is large, then it is termed "Type IIa". If the affected kidney is quite small, it can be termed "hypodysplasia" or "Type IIb". Different combinations are possible, so that only one kidney or part of one kidney can be affected and be either larger or small; both affected kidneys can be large or both can be small, or one can be larger and the other small. It is quite common for asymmetry to be present.

Grossly, the cysts are variably sized, from 1 mm to 1 cm in size, and filled with clear fluid. There are few recognizable glomeruli and tubules microscopically, and the remaining glomeruli are not affected by the cystic change. The hallmark of renal dysplasia is the presence of "primitive ducts" lined by cuboidal to columnar epithelium and surrounded by a collagenous stroma. This increased stroma may contain small islands of cartilage. The liver will not show congenital hepatic fibrosis.

Multicystic renal dysplasia is often the only finding, but it may occur in combination with other anomalies and be part of a syndrome (e.g., Meckel-Gruber syndrome), in which case the recurrence risk will be defined by the syndrome. If this disease is bilateral, the problems associated with oligohydramnios are present, with pulmonary hypoplasia the rate limiting step for survival.

  1. Multicystic renal dysplasia, gross
  2. Multicystic renal dysplasia, gross
  3. Multicystic renal dysplasia, gross
  4. Multicystic renal dysplasia, gross
  5. Multicystic renal dysplasia, microscopic
  6. Multicystic renal dysplasia, microscopic
  7. Pulmonary hypoplasia, gross
  8. Pulmonary hypoplasia, microscopic

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

This condition is inherited in an autosomal dominant pattern, so the recurrence risk in affected families is 50%. It is one of the most common genetic diseases, with an incidence of 1:400 to 1:1000 persons. However, this disease rarely manifests itself before middle age. It may begin in middle aged to older adults to cause progressive renal failure as the cysts become larger and the functioning renal parencyma smaller in volume. This form of cystic disease is rarely manifested prenatally or in children.

ADPKD has been linked with defects in the PKD1 gene, encoding for polycystin-1, and the PKD2 gene, encoding for polycystin-2. The former is more common. The polycystins function in Ca2+ channels and disruption of normal intracellular Ca2+ homeostasis may underlie cyst formation. There are many alleles, explaining variations in onset and severity of ADPKD.

Grossly, ADPKD results in very large kidneys, perhaps up to 3 or 4 kg or more. The affected kidneys are just a mass of large fluid-filled cysts. There is often hemorrhage into the cysts, so that some can be filled with grumous brown organizing hemorrhage. There may be intervening normal renal parenchyma earlier in the disease, or just fibrotic stroma late in the course. If ADPKD is manifested in fetuses and infants, the cysts may involve the gomeruli (so-called "glomerular cysts"). In adults, it is common for all or part of the liver to also demonstrate polycystic disease, and it is possible in some cases for the liver to be more severely affected, so that hepatic failure results. Patients with ADPKD are also prone to have berry aneurysms of the cerebral arteries.

  1. ADPKD, in situ, retroperitoneum, gross
  2. ADPKD, with transplant kidney, gross
  3. ADPKD, gross
  4. Polycystic liver with ADPKD disease, gross
  5. Berry aneurysm of cerebral artery, gross
  6. ADPKD in fetus with glomerular cysts (two views), high power microscopic

Cystic Change with Obstruction

In the fetus and newborn with urinary tract obstruction, it is possible for cystic change to occur in the kidneys, in addition to hydroureter, hydronephrosis, and bladder dilation. Depending upon the point of obstruction, either or both kidneys may be involved. For example, posterior urethral valves in a male fetus, or urethral atresia in a male or female fetus, will cause bladder outlet obstruction so that both kidneys are involved. With bladder outlet obstruction, there will be oligohydramnios and the appearance of pulmonary hypoplasia.

Grossly, this form of cystic disease may not be apparent. The cysts may be no more than 1 mm in size. Microscopically, the cysts form in association with the more sensitive developing glomeruli in the nephrogenic zone so that the cysts tend to be in a cortical location. Thus, "cortical microcysts" are the hallmark of this form of cystic disease, which is "Type IV" in the Potter's classification. There are no accompanying cystic changes in other organs in association with this disease. However, if the obstruction is at the bladder outlet, oligohydramnios with pulmonary hypoplasia can result.

  1. Congenital urinary tract obstruction with hydronephrosis, gross
  2. Obstruction with cortical microcysts, microscopic
  3. Pulmonary hypoplasia, gross

Miscellaneous Cystic Renal Changes in Adults

Perhaps the most common cystic change of all is the appearance of one or more "simple renal cysts" in adults. These cysts may be only a few millimeters in size, or may reach 10 cm or more. They are rarely numerous enough so that intervening normal parenchyma is not recognizable, and they are very unlikely to be the cause for renal failure. These cysts are lined by a flattened cuboidal epithelium and filled with clear fluid. On occasion, there may be hemorrhage into a larger cyst, and it may appear as a mass lesion that can be difficult to differentiate from a renal cell carcinoma (which may undergo necrosis with hemorrhage). However, the finding of clear cells in the cyst is consistent with renal cell carcinoma.

Persons with renal failure who are on long-term dialysis may develop cystic changes in the kidneys. These cysts may be numerous, but never as large as with DPKD, and the kidneys are still generally small, because most diseases leading to renal failure produce small, shrunken kidneys with end-stage renal disease.

Medullary sponge kidney (MSK) is a congenital condition that most often occurs sporadically, without a defined inheritance pattern. It is often bilateral, but incidental and found only on radiologic imaging studies, with an incidence of 0.5 to 1% in adults. MSK may become symptomatic in young adults, with onset of recurrent hematuria and/or urinary tract infection as a consequence of formation of calculi, which develop in 60% of cases. Renal failure is unlikely to occur, but may result from severe pyelonephritis.

  1. Normal adult kidney with single small simple renal cyst, gross
  2. Normal adult kidney with one large simple renal cyst and several smaller cysts, gross
  3. Polycystic change with dialysis, gross
  4. Medullary sponge kidney, gross

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