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New approaches in treating complicated childhood polycystic kidney disease

  • - Urology / Nephrology News
  • Apr 27, 2013
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Tags: | arpkd | autosomal recessive polycystic kidney disease | infantile polycystic kidneys | polycystic kidney and hepatic disease type i |

A collaborative team of physician-scientists at the Medical College of Wisconsin (MCW) and Children’s Hospital of Wisconsin Research Institute has developed a new evidence-based, clinical algorithm to help physicians treat complex patients with autosomal recessive polycystic kidney disease (ARPKD).

Their invited manuscript, written by Grzegorz Telega, M.D., associate professor of pediatrics (gastroenterology and hepatology) at MCW and program director of hepatology at Children’s Hospital of Wisconsin; David Cronin, II, M.D., Ph.D., professor of surgery and member of the new Transplantation Institute; and Ellis D. Avner, M.D. professor of pediatrics (nephrology) and physiology at MCW, and director of the Multidisciplinary Childhood PKD Program (MCPP) at Children’s Hospital of Wisconsin Research Institute, appears in the April 17 edition of Pediatric Transplantation http://bit.ly/183bd6Z.

ARPKD is a rare genetic disorder that causes progressive disease of the kidneys and liver. Of the patients with ARPKD who survive the first year of life, more than 85 percent will reach their tenth birthday. However, despite dramatic improvements in overall survival and quality of life, nearly 50 percent of those survivors develop end stage kidney disease during that time.

Based on a comprehensive analysis of published medical literature, unique insights generated from the MCPP (established in 2005 and the only such program in the U.S.) and more than 50 years of clinical experience by the authors in treating complex problems in ARPKD patients, an algorithm was developed to guide patient therapy. Of particular note, the authors recommend an innovative approach for a subgroup of ARPKD patients with severe kidney and liver disease: simultaneous kidney and liver transplantation.

“We believe combined liver-kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with end stage renal disease and clinically significant congenital hepatic fibrosis,” said Dr. Avner. “This is a particularly attractive option at our center, given the rapid growth of the joint solid organ transplantation program between Children’s Hospital of Wisconsin, Froedtert Hospital, the Medical College of Wisconsin, and the BloodCenter of Wisconsin, directed by Dr. Johnny Hong.”

Autosomal recessive polycystic kidney disease
Synonyms: infantile polycystic kidneys, polycystic kidney and hepatic disease type I

(Note: the names of infantile and adult polycystic kidney disease (PKD) are no longer used because they are not an accurate description. Both autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) can involve the presence of renal cysts at any time during an affected person’s life, from the prenatal period to adolescence or older.)

ARPKD is inherited in an autosomal recessive manner. Each sib of a proband has a 25% chance of inheriting both disease-causing alleles and being affected, a 50% chance of inheriting a disease-causing allele and being a carrier, and a 25% chance of inheriting neither disease-causing allele and not being a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing alleles have been identified in the family or if linkage studies are informative. No systematic data are available on the sensitivity and specificity of prenatal ultrasound examination in establishing the diagnosis of ARPKD in pregnancies at 25% risk.

The authors also emphasize that this therapy only be considered in major pediatric organ transplant centers with experienced pediatric transplant surgeons, subspecialty physicians and nurses, and complete pediatric ancillary services. The commentary also includes a “tree” to help guide clinicians making decisions about the appropriate course of treatment for complications of ARPKD.

Autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease is characterized by cystic dilatation of renal collecting ducts associated with hepatic abnormalities of varying degrees, including biliary dysgenesis and periportal fibrosis. Autosomal recessive polycystic kidney disease was first recognized in 1902; however, the histology was not reported until 1947. In 1964, Osathanondh and Potter classified autosomal recessive polycystic kidney disease as type 1 cystic kidney disease. Eventually, because neither parent had the disease and no sex predilection was observed, this disease was concluded to have an autosomal recessive mode of inheritance.

ARPKD is the most common genetic cystic renal disease occurring in infancy and childhood. However, it is nonetheless a rare disorder and is much less common than ADPKD. It is an autosomal recessive disorder due to mutation of the number 6 chromosome at gene map locus 6p21.1-p12, a gene encoding fibrocystin.

A single gene defect leads to differing degrees of renal and hepatic involvement, with very different phenotypes and clinical outcome within even one affected family. Kidneys are bilaterally enlarged and contain large numbers of cysts throughout the organ, due to the dilatation and elongation of renal collecting ducts. At birth, the interstitium and the rest of the tubules are normal but they may later develop interstitial fibrosis and tubular atrophy that can cause renal failure. There may be hepatic as well as renal involvement:

  Hepatic involvement with bile duct ectasia is sometimes called Caroli’s disease.
  Generally, the later the manifestation of the renal disease, the more marked the liver disease. The renal and hepatic disease tend to show opposite degrees of severity
  Severe cases of liver disease may progress to cirrhosis with portal hypertension and oesophageal varices.


About the Medical College of Wisconsin

The Medical College of Wisconsin is the state’s only private medical school and health sciences graduate school. Founded in 1893, it is dedicated to leadership and excellence in education, patient care, research and service. More than 1,200 students are enrolled in the Medical College’s medical school and graduate school programs. A major national research center, it is the largest research institution in the Milwaukee metro area and second largest in Wisconsin. In FY 2011 – 12, faculty received more than $166 million in external support for research, teaching, training and related purposes, of which more than $152 million is for research. This total includes highly competitive research and training awards from the National Institutes of Health (NIH). Annually, College faculty direct or collaborate on more than 2,000 research studies, including clinical trials. Additionally, more than 1,350 physicians provide care in virtually every specialty of medicine for more than 425,000 patients annually.

Polycystic Kidney Disease, Autosomal Recessive
Synonyms: ARPKD; Polycystic Kidney Disease, Infantile
The majority of individuals with autosomal recessive polycystic kidney disease (ARPKD) present in the neonatal period with enlarged echogenic kidneys. At initial presentation, approximately 45% of infants have liver abnormalities, including hepatomegaly, dilated intrahepatic (and occasionally extrahepatic) biliary ducts, and mildly increased echogenicity. Pulmonary hypoplasia resulting from oligohydramnios occurs in a number of affected infants. Approximately 30% of affected infants die in the neonatal period or within the first year of life primarily of respiratory insufficiency or superimposed pulmonary infections. More than 50% of affected children progress to end-stage renal disease (ESRD), usually in the first decade of life. With neonatal respiratory support and renal replacement therapies, the ten-year survival of those who live beyond the first year of life has improved to 82%. Fifteen-year survival is estimated to be 67%-79%, and may be improving. A minority present in older childhood or young adulthood with hepatosplenomegaly and evidence of portal hypertension.

About Children’s Hospital of Wisconsin

Children’s Hospital of Wisconsin is the region’s only independent health care system dedicated solely to the health and well-being of children. The hospital, with locations in Milwaukee and Neenah, Wis., is recognized as one of the leading pediatric health care centers in the United States and is ranked No. 4 in the nation by Parents magazine. Children’s Hospital provides primary care, specialty care, urgent care, emergency care, community health services, foster and adoption services, child and family counseling, child advocacy services and family resource centers. In 2011, Children’s Hospital invested more than $100 million in the community to improve the health status of children through medical care, advocacy, education and pediatric medical research. Children’s Hospital achieves its mission in part through donations from individuals, corporations and foundations and is proud to be a member of Children’s Miracle Network Hospitals.


New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney - liver complications

Improved neonatal medical care and renal replacement technology have improved the long-term survival of patients with ARPKD. Ten-yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra- and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto-systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat-soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato-biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age-matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato-biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to

<10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver - kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver - kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.

  Grzegorz Telega,
  David Cronin,
  Ellis D. Avner

Article first published online: 17 APR 2013

Maureen Mack
.(JavaScript must be enabled to view this email address)
Medical College of Wisconsin

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