Chapter XIII.3. Cystic Kidney Disease
Rhiana L.A. Lau, MD
October 2013

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Miki E. Shirakawa, MD. This current second edition chapter is a revision and update of the original author's work.


A 48 hour-old full-term female infant was admitted to the NICU shortly after birth for respiratory distress. Her mother reports that she was told there might be a kidney abnormality on a prenatal ultrasound. There is a report of oligohydramnios towards the end of pregnancy. The infant required intubation and ventilation for respiratory distress. She has had one wet diaper and one meconium stool since birth. There is no family history of any kidney disease or inherited disorders.

Exam: Wt 3.5kg, HR 130, RR 50, BP 100/60 The infant is of appropriate size. She is non-dysmorphic. Her HEENT exam is normal. Her lungs are clear bilaterally, ventilated. Her heart is RRR without murmurs. Her abdomen appears distended. There are palpable masses in the flank area bilaterally. There is normal female genitalia. No swelling or edema is noted. There is no significant jaundice or rashes.

Her CBC is normal. Renal function panel demonstrates a K of 6, HCO3 15, BUN 40, and creatinine 1.0. A bag urinalysis shows RBC 25-50/HPF. A renal ultrasound is obtained that shows bilateral enlarged echogenic kidneys. The bladder is decompressed.

Over the next several days, the infant becomes progressively more edematous and hypertensive with oliguria despite furosemide therapy and fluid restriction. She continues to have a rising BUN and creatinine with worsening hyperkalemia and metabolic acidosis. The infant is taken to the OR for bilateral nephrectomies secondary to autosomal recessive polycystic kidney disease and dialysis catheter placement. She begins dialysis shortly thereafter.


Cystic Diseases of the Kidney

Cystic diseases of the kidney comprise a large variety of inherited and acquired disorders involving cyst formation in either one or both kidneys. Many cystic kidney diseases arise from genetic mutations in primary cilia. In this chapter, we will cover the more commonly seen cystic kidney diseases in pediatrics, including cystic dysplastic kidneys, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease. We will also briefly cover other less common pediatric diagnoses including nephronopthisis, simple cysts, tuberous sclerosis (a heritable condition in which renal cysts are involved), medullary cystic kidney disease, and medullary sponge kidney. Other cystic kidney diseases that will not be discussed include acquired cystic kidney disease and other heritable conditions that can involve renal cysts, such as Bardet-Biedel syndrome, glomerulocystic kidney disease, Von-Hippel Lindau disease and Meckel-Gruber syndrome.

The names "Potter's syndrome" (types I, II, III, IV) or "Potter's sequence" may be seen in association with several of the specific cystic kidney disease conditions below. It classically refers to a phenotype of oligohydramnios, pulmonary hypoplasia, Potter's facies, and limb abnormalities.

Multicystic Dysplastic Kidney (MCDK)

MCDK occurs when there is a disruption of normal renal development, which is usually unilateral. Bilateral MCDK is usually a fatal condition. MCDK is a non-inherited condition. The estimated incidence of MCDK is 1 in 4,000 live births. It is the most common cause of a flank mass in an infant. It manifests as a cluster of multiloculated thin-walled cysts that are non-communicating. The parenchyma between cysts is often non-functional and there may be cartilaginous structures. It is often found in the setting of obstructive uropathy. Renal ultrasound often shows nonreniform structures with hyperechoic scant tissue between cysts and there is often no renal artery detectable on Doppler US. Other major findings with MCDK include hypertension. The contralateral kidney may have areas of limited dysplasia or vesicoureteral reflux. It is important to follow the contralateral kidney for adequate growth with serial postnatal ultrasounds. A DMSA (dimercaptosuccinic acid) renal scan can identify foci of dysplasia within the contralateral kidney. The MCDK may undergo partial or complete involution. There is the rare potential for malignant transformation in MCDK that do not undergo complete involution.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the most common heritable renal cystic disease and its incidence occurs in 1 in 400-1,000 live births. ADPKD can arise at any age, but most often occurs in the fourth and fifth decades of life. It affects all races and gender distribution is equal. It involves cystic enlargement that can occur at any point of the nephron and collecting duct; however, only a handful of nephrons and collecting ducts within a kidney are involved. The genes responsible for ADPKD include PKD1 (located on the short arm of chromosome 16 and encoding polycystin 1), PKD2 (located on the long arm of chromosome 4, encoding polycystin 2), and PKD3 (location not definitively known). PKD1 is the gene responsible for the majority of cases of ADPKD.

ADPKD is most commonly diagnosed via ultrasound with identification of one or more renal cysts; however, MRI or CT can also be used to establish the diagnosis. Clinically, patients can exhibit hypertension, even in infancy despite normal renal function. Other clinical features at presentation can include abdominal pain, palpable abdominal masses, hematuria (gross or microscopic), polyuria with a urinary concentrating defect, UTI, or hernias. Extrarenal cysts observed in the liver, pancreas, testicles, ovaries, spleen, and intestine are seen more commonly in adult patients than in pediatric patients. Cerebral aneurysms can occur in about 10% of affected patients.

Screening evaluation of an asymptomatic at risk child with imaging is not currently recommended because of financial and psychosocial factors involved. Asymptomatic at risk children should be evaluated annually for emergence of hypertension, urinary abnormalities, polyuria, or palpable abdominal masses. Positive findings would be an indication for ultrasound. Genetic testing is available for confirmatory diagnosis. Management generally consists of controlling the sequelae of both renal and extrarenal complications, including blood pressure control, pain management, proteinuria reduction, and treatment of urinary tract or cyst infection. Newer therapies are being trialed in cyst reduction, including vasopressin receptor antagonists, mTOR (mammalian target of rapamycin) inhibitors, and somatostatin analogues. Proteinuria is an early marker of severe cystic disease in pediatric patients. About half of adult patients will progress to end-stage renal disease. The most common cause of death in ADPKD patients is heart disease, followed by infection and neurologic complications.

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

ARPKD, a heritable condition, is characterized by cystic dilations of the renal collecting tubules. The incidence of ARPKD is estimated to be between 1 in 10,000-40,000. As in ADPKD, both genders are affected equally and the disease incidence spans ethnic groups. It is the most common childhood-onset ciliopathy. The majority of patients present in infancy, although presentation can occasionally be as late as early adulthood. Extrarenal manifestations of this disorder include congenital hepatic fibrosis or Caroli disease, which involves non-obstructive dilation of intrahepatic bile ducts. The gene responsible for ARPKD is PKHD1 (located on chromosome 6), with most affected patients being compound heterozygotes. The frequency of the gene is estimated at 1 in 70 in the population.

Patients are often diagnosed in utero with suggestive findings of enlarged kidneys, oligohydramnios, and absence of urine in the bladder. Clinically, infants may have Potter’s facies and large palpable flank masses with impaired renal function. Other presenting features may include pulmonary insufficiency, transient hyponatremia, metabolic acidosis, and hypertension. Renal ultrasound is the usual imaging modality for confirmatory diagnosis. The ultrasound characteristically demonstrates bilaterally enlarged, echogenic kidneys with poor corticomedullary differentiation. Multiple small cysts may be visualized on ultrasound, but is not the usual. Imaging of the liver generally demonstrates hepatomegaly with increased echogenicity and difficulty visualizing the periportal veins, as well as findings consistent with portal hypertension. Renal biopsy is generally not required, especially in patients who fulfill the diagnostic criteria for ARPKD or who have positive genetic testing. Liver biopsy may be helpful. Genetic testing may be helpful, but is not required in families who already have one affected child.

Survival of neonates has improved with medical technological advances with an estimated 70% survival in affected infants in the first year of life. Management involves correction of electrolyte abnormalities, respiratory support, nutritional support, and treatment of hypertension. Dialysis in combination with unilateral or bilateral nephrectomy may be required to allow for optimal ventilation of the infant. Urinary abnormalities may be seen including concentrating defects, hematuria, proteinuria, and pyuria. Complications of ARPKD often relate to the hepatic system, including hepatomegaly, esophageal varices, portal vein thrombosis, portal hypertension, hypersplenism, and bacterial cholangitis.

Nephronopthisis

Nephronopthisis is an autosomal recessive disorder with an infantile, juvenile, and adolescent form depending on the age at presentation. It is classified as a medullary cystic kidney disease. The juvenile form is the most common type with symptoms typically developing between 4 to 6 years of age. Nephronopthisis is the most common genetic cause of end-stage renal disease in the first 3 decades of life with an incidence of 9 cases per 8.3 million population in the US. There is no gender preference. There are now 13 different gene mutations (NPHP1 to 13) that have been identified as causing nephronopthisis. Earliest symptoms that patients present with include polydipsia, polyuria, nighttime fluid intake, decreased urinary concentrating ability, and secondary enuresis. Most patients have these symptoms and often start around the age of 6 years. Extrarenal manifestations may be found in association with nephronopthisis in about 10% of cases. These include retinal degeneration in Senior-Loken syndrome, cerebellar vermis aplasia in Joubert syndrome, liver fibrosis, cone-shaped epiphyses, and mental retardation. Anemia and growth retardation develop later in the disease course.

Patients with nephronopthisis have normal or small hyperechoic kidneys with poor corticomedullary differentiation on ultrasound. Medullary cysts are characteristic; however, not always visualized on ultrasound and CT may be necessary. The cysts are progressive and typically arise at the corticomedullary junction of the kidney. Genetic testing is possible in most cases. Most affected patients go on to end-stage renal disease requiring renal transplantation in childhood.

Simple Cysts

Solitary and multiple renal simple cysts are the most common cystic lesions found in adults, typically unilateral in nature. It is identified in about 5% of the general population undergoing abdominal ultrasound for a variety of reasons. They are usually located in the cortex and likely arise from the distal convoluted tubule or collecting ducts. They usually arise in non-diseased kidneys. Renal simple cysts are rare in pediatric age patients, but those identified are usually solitary lesions. Prenatally identified simple cysts often resolve during the course of pregnancy. They can occasionally occur in families, which implies a possible autosomal dominant pattern of inheritance.

Tuberous Sclerosis (TS)

TS is a neurocutaneous disorder with an autosomal dominant pattern of inheritance. The prevalence of TS is 1: 6000 individuals. In this syndrome, any part of the nephron can be affected by hyperplastic cystic lesions. TS has been linked to the TSC1 and TSC2 suppressor genes. TS patients most commonly have renal angiomyolipomas; however, they may have severe cystic disease. In these cases, the patients are at risk for developing hypertension and chronic kidney disease. Renal malignancies are a concern in these patients, requiring periodic monitoring with ultrasounds. Extrarenal manifestations of TS include mental retardation, epilepsy, facial angiofibromas, dermatologic findings (shagreen patch, hypomelanotic macules), retinal hamartoma and astrocytoma, cortical tubers, subependymal nodules, giant cell astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis, lymph node angiomyolipoma.

Medullary Cystic Kidney Disease (MCKD)

MCKD is a rare autosomal dominant condition that usually presents in adulthood, but has been known to occur in children. Note that the initials MCKD are very similar to MCDK (multicystic dysplastic kidney). There are two loci MCKD1 and MCKD2 that cause disease. MCKD1 is slowly progressive with end-stage renal disease typically occurring between 25-55 years of age. There may be minimal proteinuria, hematuria, hypertension, and hyperuricemia. MCKD2 also involves hyperuricemia and can present as gout in teenage males. Cysts can sometimes be visualized on ultrasound. Definitive diagnosis can be done through linkage analysis studies. Treatment for both types of MCKD is mainly supportive.

Medullary Sponge Kidney

This is a nonheritable disease, which is usually asymptomatic. It involves ectasia of the papillary collecting ducts, which is thought to be a congenital anomaly. It is usually identified in adulthood, although can be diagnosed in children. Bilateral kidney involvement occurs and they have normal size and function. Other manifestations include nephrolithiasis.


Questions

1. What are extrarenal manifestations of autosomal dominant polycystic kidney disease?
. . . . . A. Congenital hepatic fibrosis
. . . . . B. Liver cysts
. . . . . C. Cerebral aneurysms
. . . . . D. Portal hypertension
. . . . . E. B and C

2. Why is it important to image the contralateral kidney in patients with unilateral multicystic kidney disease?

3. What is the most common childhood-onset ciliopathy?
. . . . . A. Autosomal dominant polycystic kidney disease
. . . . . B. Ciliary kidney disease
. . . . . C. Autosomal recessive polycystic kidney disease
. . . . . D. Nephronopthisis
. . . . . E. Medullary cystic kidney disease

4. True/False: Simple cysts are the most common cystic lesions found in pediatric age patients.

5. A 6 year-old patient presents to your clinic with symptoms of polyuria, polydipsia, and nocturnal enuresis. You check a urine dip and it is negative for glucose and fasting glucose is normal. What heritable cystic condition should you be concerned about?
. . . . . A. Multicystic dysplastic kidney disease
. . . . . B. Autosomal recessive polycystic kidney disease
. . . . . C. Medullary cystic kidney disease
. . . . . D. Nephronopthisis
. . . . . E. Tuberous sclerosis


References

1. Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Pediatric Nephrology, Sixth Edition. Heidelberg, Berlin. Springer-Verlag, 2009.

2. Avni, FE, Hall M. Renal cystic diseases in children. Pediatr Radiol. 2010;40(6):939-946.

3. Bisceglia M, Galliani CA, Senger C, et al. Renal Cystic Diseases. Adv Anat Pathol. 2006;13(1):26-56.

4. Dell KM. The Spectrum of Polycystic Kidney Disease in Children. Adv Chronic Kidney Dis. 2011;18(5):339-347.

5. Loftus H and Ong ACM. Cystic kidney diseases: many ways to form a cyst. Pediatr Nephrol. 2013;28(1):33-49.


Answers to questions

1. E. Both liver cysts and cerebral aneurysms can be seen in ADPKD. In addition to these manifestations, cysts in the pancreas, testicles, ovaries, spleen, and intestine can also be seen. Congenital hepatic fibrosis is seen in ARPKD.

2. In MCDK, there is an increased risk of vesicoureteral reflux or areas of dysplasia in the contralateral kidney.

3. C. Autosomal recessive kidney disease is the most common childhood ciliopathy.

4. False. Simple cysts are the most common cystic lesions found in adults, not children.

5. D. The earliest presenting symptoms of nephronopthisis include polydipsia, polyuria, nocturnal enuresis, decreased urinary concentrating ability, and nighttime fluid intake, often manifesting around 6 years of age.


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