The editors and current authors 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 third edition chapter is a revision and update of the original author’s work.

A 48-hour-old, full-term female 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: T36.8, HR 130, RR 50, BP 100/60, weight 3.5 kg. The infant is of appropriate size. She is non-dysmorphic. HEENT exam is normal. Lungs are clear bilaterally, ventilated. Heart regular without murmurs. Her abdomen is distended. There are palpable masses bilaterally. She has normal female genitalia. No swelling, edema, jaundice, or rash noted.

CBC is normal. Chemistry shows potassium 6 mEq/L, bicarbonate 15 mEq/L, BUN 40 mg/dL, and creatinine 1.0 mg/dL. A bag urinalysis shows 25 to 50 RBCs per high HPF (high power field). A renal ultrasound 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 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 nephronophthisis, 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 (1).

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 (1). The prognosis of affected infants is poor, often related to complications of pulmonary hypoplasia and renal failure.

Multicystic Dysplastic Kidney (MCDK)

MCDK is a severe form of renal dysplasia with complete disruption of normal renal development. It is a non-inherited condition with an estimated incidence of 1 in 2,000 making it the most common cystic disorder in children and one of the most common causes of an abdominal mass in the newborn (1). Though more commonly occurring unilaterally, resulting in a congenital solitary functioning kidney (SFK), bilateral MCDK is also possible and often a fatal condition. MCDK manifests as a cluster of multi-loculated, non-communicating, thin-walled cysts with non-functional parenchyma in between (2). Renal ultrasound typically shows non-reniform structures with hyperechoic scant tissue between cysts, often without a detectable renal artery on Doppler US. Other major findings with MCDK include hypertension. There is an increased risk of abnormalities in the contralateral kidney, which may include vesicoureteral reflux or less commonly, ureteropelvic junction (UPJ) obstruction and ureterovesical junction (UVJ) obstruction (2). It is important to follow the contralateral kidney for appropriate compensatory hypertrophy and to monitor natural, expected involution of the MCDK with serial postnatal ultrasounds. The MCDK may undergo partial or complete involution; however, in cases that do not undergo complete involution, there is the rare potential for malignant transformation.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the most common heritable renal disorder, and it occurs in 1 in 400 to 1,000 live births (3). Although it can arise at any age (some fetuses may already display mild renal enlargement), ADPKD does not usually present until the fourth and fifth decades of life (4). Cystic enlargement 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 primarily responsible for ADPKD include PKD1 (responsible for the majority of cases; located on the short arm of chromosome 16 and encoding polycystin 1) and PKD2 (located on the long arm of chromosome 4, encoding polycystin 2) (3).

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. It is characterized by the progressive development and enlargement of bilateral cysts (3). Clinically, patients can exhibit hypertension, even in infancy despite normal renal function. This manifestation is prevalent in at least 20% of children with ADPKD, though the average age of onset is 30 years. A urinary concentration defect is also seen in up to 60% of children (3). Other clinical features at presentation may include abdominal or flank pain, palpable abdominal masses, hematuria (gross or microscopic), UTI, or nephrolithiasis. 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 8% of all adult patients; however, is seen in about 20% of adult patients with a family history of intracranial aneurysm (3).

Screening evaluation of an asymptomatic at-risk child with imaging is not currently recommended related to potential associated financial and psychosocial factors involved. However, at-risk children should be evaluated by the age of 5 for hypertension with subsequent screenings at 3-year intervals if negative (3). Children may also be monitored for 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 that directly target cystogenic mechanisms are becoming more available. The vasopressin receptor 2 antagonist, tolvaptan, has been shown to slow the rate of kidney growth and decline of estimated GFR in patients with ADPKD (3). Proteinuria is an early prognostic marker of ADPKD in pediatric patients. About half of patients will progress to end-stage renal disease (ESRD) by age 60. In patients with ADPKD who receive renal replacement therapy, the most common cause of death is cardiac disease and infections (3).

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

ARPKD is an infantile form of hereditary polycystic diseases, characterized by cystic dilations of the renal collecting tubules in addition to a range of hepatic abnormalities beginning in utero (5). It has an incidence of 1 in 20,000 live births (4). As in ADPKD, both genders are affected equally, and the disease incidence spans ethnic groups. The majority of patients present in infancy, although presentation can occasionally be as late as early adulthood. ARPKD results from mutations in the PKHD1 gene (located on chromosome 6), with most affected patients being compound heterozygotes. The carrier frequency of the gene is estimated at 1 in 70 in the population (6).

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 syndrome and large palpable flank masses with impaired renal function. Other presenting features may include pulmonary insufficiency, transient hyponatremia, metabolic acidosis, and hypertension. In infants and young children, urinary abnormalities may be seen including concentrating defects, hematuria, proteinuria, and pyuria. Renal ultrasound is the usual imaging modality for confirmatory diagnosis and characteristically demonstrates bilaterally enlarged, echogenic kidneys with poor corticomedullary differentiation. Multiple small cysts in the distal tubules and collecting ducts may also be visualized (5). Extrarenal manifestations of this disorder include congenital hepatic fibrosis or Caroli disease, which involves non-obstructive dilation of intrahepatic bile ducts and/or the common bile duct (5). Imaging of the liver generally demonstrates hepatomegaly with increased echogenicity and difficulty visualizing the periportal veins, as well as findings consistent with portal hypertension (5). 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 (5). 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 (5). Complications of ARPKD often relate to the hepatic system, including hepatomegaly, esophageal varices, portal vein thrombosis, portal hypertension, hypersplenism, and bacterial cholangitis (5).

Nephronophthisis

Nephronophthisis is an uncommon disorder characterized by renal fibrosis, tubular atrophy, and cyst formation. It is classified as a medullary cystic kidney disease and has an infantile, juvenile, and adolescent form. Nephronophthisis is an autosomal recessive (genetic) cause of end-stage renal disease in the first 3 decades of life (7). There is no gender preference. There are many different gene mutations that have been identified as causing nephronophthisis, all related to proteins expressed in the primary cilia of renal epithelial cells (8). The 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 nephronophthisis in more than 10% of cases (7). These include retinal degeneration in Senior-Loken syndrome, cerebellar vermis aplasia in Joubert syndrome, liver fibrosis, cone-shaped epiphyses, and intellectual disability. Anemia and failure to thrive also develop in the disease course (6).

Patients with nephronophthisis have small (but sometimes normal sized), hyperechoic kidneys with poor corticomedullary differentiation on ultrasound. Medullary cysts are characteristic; however, these cannot always be visualized on ultrasound and thin-section CT may be necessary (9). 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 develop end-stage renal disease requiring renal transplantation in childhood.

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

Autosomal dominant tubulointerstitial kidney disease, previously known as medullary cystic kidney disease (MCKD), is a 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); however, they refer to two different conditions. Additionally, ADTKD is very histopathologically similar to nephronophthisis, but is distinguished by its autosomal dominant mode of inheritance and lack of extrarenal involvement with the exception of hyperuricemia, gout, and anemia (7). There are mutations in at least four genes that cause disease: MUC1 (chromosome 1q22), UMOD (chromosome 16p12.3), HNF1B (chromosome 17q12), and REN (chromosome 1q32.1). The median age of end-stage renal disease is 16 to 18 years old in patients with the MUC1 mutation, and 30 to 50 years old in patients with the UMOD mutation (10). Treatment is mainly supportive.

Simple Cysts

Although these are rare in pediatric patients, simple renal cysts are the most common of the renal cystic disorders in children with a mean incidence of 0.22%. Simple renal cysts are non-heritable and much more common in adults. They are generally asymptomatic and incidentally discovered in patients undergoing urinary tract imaging (1). They may be solitary or multiple and are typically unilateral in nature. Simple renal cysts are usually located in the cortex, often arising from the distal convoluted tubule or collecting ducts in non-diseased kidneys. Prenatally identified simple cysts often resolve during the course of pregnancy. Simple cysts may be the first manifestation of an underlying cystic disorder though and should be considered a diagnosis of exclusion and be followed up with at least one ultrasound examination (11).

Tuberous Sclerosis (TS)

TS is a neurocutaneous disorder with an autosomal dominant pattern of inheritance. The incidence of TS is 1 in 6,000 to 10,000 newborns (6). TS has been linked to mutations in the TSC1 (chromosome 9) and TSC2 (chromosome 16) suppressor genes. The most common renal feature of TS is renal angiomyolipoma, which is present in 75% to 80% of patients with TS older than 10 years (12); however, about 40% of children with TS also develop cystic disease with cysts originating in the loop of Henle and distal convoluted tubules (11). In these cases, the patients are at risk for developing hypertension and chronic kidney disease. Renal cell carcinoma is also a concern in these patients, requiring periodic monitoring with imaging (6). Extrarenal manifestations of TS include intellectual disability, epilepsy, facial angiofibromas, dermatologic findings (shagreen patch, hypomelanotic macules), retinal hamartoma, cortical tubers (brain), subependymal nodules, giant cell astrocytoma, cardiac rhabdomyoma, and lymphangiomyomatosis (13).

Medullary Sponge Kidney (MSK)

MSK is a non-heritable benign disease with an incidence of 1 in 5,000 to 20,000 and is usually asymptomatic (6). It involves cystic dilations of the medullary collecting ducts, which is thought to be a congenital anomaly. Bilateral kidney involvement occurs, and they often have normal size and function. The most common presentation is nephrolithiasis, specifically calcium oxalate or calcium phosphate stones. MSK may be associated with Beckwith-Wiedemann syndrome or Ehlers-Danlos syndrome (13). It is usually identified in adulthood, although it can be diagnosed in children.

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 a unilateral multicystic dysplastic kidney?

3. What is the most common heritable renal disorder?
   a. Autosomal dominant polycystic kidney disease
   b. Ciliary kidney disease
   c. Autosomal recessive polycystic kidney disease
   d. Nephronophthisis
   e. Autosomal dominant tubulointerstitial kidney disease

4. True/False: Cystic disease is the most common renal feature found in patients with tuberous sclerosis.

5. A 6-year-old patient presents to your clinic with symptoms of polyuria, polydipsia, and nocturnal enuresis. You check a urine dip stick, and it is negative for glucose and the fasting blood glucose is normal. What heritable cystic condition should you be concerned about?
   a. Multicystic dysplastic kidney disease
   b. Autosomal recessive polycystic kidney disease
   c. Autosomal dominant tubulointerstitial kidney disease
   d. Nephronophthisis
   e. Tuberous sclerosis

References
1. Elder JS. Chapter 552. Congenital Anomalies and Dysgenesis of the Kidneys. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp:2786-2789.
2. Goodyer P, Gupta I. Chapter 5. Renal Dysplasia/Hypoplasia. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Ema F, Goldstein SL (eds). Pediatric Nephrology, 7th edition. 2016. Springer-Verlag, Berlin, Heidelberg. pp:88-110.
3. Bergmann C, Guay-Woodford LM, Harris PC, et al. Polycystic kidney disease. Nat Rev Dis Primers. 2018;4(1):50. doi:10.1038/s41572-018-0047-y
4. Chapter 15. Normal and Abnormal Fetal Anatomy. In: Cunningham F, Leveno KJ, Dashe JS, Hoffman BL, Spong CY, Casey BM (eds). Williams Obstetrics, 26th edition. 2022. McGraw Hill, New York. pp:272-307.
5. Sweeney Jr WE, Gunay-Aygun M, Patil A, Avner ED. Chapter 36. Childhood Polycystic Kidney Disease. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Ema F, Goldstein SL. (eds). Pediatric Nephrology, 7th edition. 2016. Springer-Verlag, Berlin, Heidelberg. pp:1086-1143.
6. Kliegman RM, St. Geme JW, Blum NJ, et al. Chapter 541. Anatomic Abnormalities Associated with Hematuria. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp:2744-2748.
7. Hildebrandt, F. Chapter 35. Nephronophthisis–Medullary Cystic Kidney Disease in Children. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Ema F, Goldstein SL (eds). Pediatric Nephrology, 7th edition. 2016. Springer-Verlag, Berlin, Heidelberg. pp:1060-1085.
8. Bock ME, Blanchette E, Hanna MG. Chapter 24. Kidney & Urinary Tract. In: Bunik M, Hay WW, Levin MJ, Abzug MJ (eds). Current Diagnosis & Treatment: Pediatrics, 26th edition. 2022. McGraw Hill, New York. pp:705-731.
9. Loewen J, Greenbaum LA. Chapter 23. Diagnostic Imaging of the Child with Suspected Renal Disease. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Ema F, Goldstein SL (eds). Pediatric Nephrology, 7th edition. 2016. Springer-Verlag, Berlin, Heidelberg. pp:1891-2995.
10. Srivastava S, Molinari E, Raman S, Sayer JA. Many Genes–One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders. Front Pediatr. 2018;5:287. doi:10.3389/fped.2017.00287.
11. Gimpel C, Avni EF, Breysem L, et al. Imaging of the Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement. Radiology. 2019;290(3):769-782. doi:10.1148/radiol.2018181243.
12. Sahn M, Ullrich N, Srivastava S, Pinto A. Chapter 614. Neurocutaneous Syndromes. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp:3140-3150.
13. Irazabal MV, Torres VE. Chapter 45. Cystic Diseases of the Kidney. In: Lerma EV, Rosner MH, Perazella MA (eds). CURRENT Diagnosis & Treatment: Nephrology & Hypertension, second edition. 2017. McGraw Hill, New York. pp:551-570.

Answers to questions
1. d. 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. a. Autosomal dominant polycystic kidney disease is the most common heritable renal disorder
4. False. Although cystic disease is found in 40% of patients with tuberous sclerosis, renal angiomyolipoma is the most common renal feature.
5. d. The earliest presenting symptoms of nephronophthisis include polydipsia, polyuria, nocturnal enuresis, decreased urinary concentrating ability, and nighttime fluid intake, often manifesting around 6 years of age.