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Diseases with Liver and Kidney Involvement

  • David MilfordEmail author
Chapter

Abstract

Many congenital and acquired diseases involve both concomitant kidney and liver disease. In these conditions the rate of disease progression is independent in each organ and a co-ordinated approach between nephrologist and hepatologist is essential for management, particularly when considering a need for combined transplantation.

Many congenital and acquired diseases involve both concomitant kidney and liver disease. In these conditions the rate of disease progression is independent in each organ and a co-ordinated approach between nephrologist and hepatologist is essential for management, particularly when considering a need for combined transplantation.

13.1 Primary Hyperoxaluria (PH)

Primary hyperoxaluria type 1 (PH1) is the commonest of the 3 types of PH, presenting in infancy or in mid-childhood, often with chronic kidney disease, nephrocalcinosis and calculi (Fig. 13.1). Failure of liver synthetic function is not a feature but the genetic defect in the peroxisomes of hepatocytes leads to overproduction and accumulation of oxalate with systemic deposition and significant renal damage (Fig. 13.2).
Fig. 13.1

Radiological findings in primary hyperoxaluria: ultrasound coronal section of right kidney shows echogenic medulla and X-ray including the upper abdomen reveals renal calcification of medulla in keeping with nephrocalcinosis

Fig. 13.2

Glyoxylate is normally metabolised via Alanine-glyoxylate aminotransferase (AGT) to glycine in the peroxisome. In PH1 AGT is inactive leading to the conversion of glyoxylate to oxalate by glycolate oxidase. Plasma oxalate is filtered at the glomerulus leading to renal deposition with progressive destruction of renal tissue. Oxalate is also deposited in other tissues

Oxalate binds calcium forming calcium oxalate crystals in many tissues including the kidneys, the retina, blood vessels and myocardium as well as in bones (Fig. 13.3a, b). The progressive loss of renal tissue leads to declining renal function with reduced oxalate excretion and consequently increasing oxalate accumulation. The rate at which this process takes place varies between patients and is determined by the nature of the genetic defect.
Fig. 13.3

(a) Left panel: Oxalate crystals in the kidney, seen here ×400 under polarised light. Right panel: Oxalate crystals in the retina. (b) Nephrectomy specimen showing widespread atrophy and tissue destruction secondary to oxalate deposition

Treatment: Pyridoxine supplementation in those that are pyridoxine sensitive; isolated liver transplantation if renal function is declining but GFR greater than 40 ml/min/1.73 m; combined liver and kidney transplantation when the GFR is less than 40 ml/min/1.73 m.

Children with systemic oxalosis who have successfully undergone isolated liver or combined liver and kidney transplantation no longer produce excessive oxalate but accumulated oxalate is slow to be removed because it is insoluble. The architecture of bones may be disrupted leading to recurrent fractures and bone pain (Fig. 13.4a). In some children who have undergone combined liver and kidney transplantation the oxalate burden is so great that the transplanted kidney becomes damaged as the stored oxalate is mobilised and deposited in the transplanted kidney leading to loss of renal function and a requirement for on-going dialysis (Fig. 13.4b). Unfortunately both haemodialysis and peritoneal dialysis have poor oxalate clearance leading to a slow reduction in the burden of total body oxalate, consequently it may be necessary to treat a child with both dialysis modalities to optimise oxalate removal.
Fig. 13.4

(a) Frontal X-ray of the right tibia and fibula reveals severe demineralization manifested as areas of lucency and also variable remodelling at stress points in proximal and distal shafts due to recurrent fractures with healing resulting from oxalate deposition. (b) Plasma oxalate levels in a child with renal failure from primary hyperoxaluria who underwent sequential liver and kidney transplant. There is an initial fall in plasma oxalate after the liver transplant because of intensive haemofiltration and a subsequent increase when returned to maintenance haemodialysis. There is a transient fall in the oxalate level after kidney transplantation but a subsequent rise after renal transplant failure. The oxalate levels on haemodialysis were undertaken before and after haemodialysis sessions

The other two forms of PH (type 2 and 3) are much less common and tend to have a less severe clinical course.

13.2 Ciliopathies

The ciliopathies are a newly recognised collection of genetic disorders arising from mutations of proteins affecting the structure and function of the primary cilium which is present on the surface of every nucleated cell. This complex structure has mechano- and chemo-sensory functions (Fig. 13.5). The ubiquitous distribution of this organelle leads to defects in multiple apparently unrelated systems and there is great phenotypic variation. It is estimated that more than 1000 proteins comprise the primary cilium, consequently there are increasing numbers of genetic conditions now classed as a ciliopathy.
Fig. 13.5

Diagram showing the complex structure of the primary cilium and the intraflagellar transport (IFT) mechanism that is key to the sensory and excretory function of the organelle (from J Cell Sci. 2010; 123: 499–503)

13.2.1 Jeune Syndrome

Jeune syndrome, also known as asphyxiating thoraco-dystrophy, is now considered one of a group of disorders known as short-rib thoracic dysplasia (SRTD) with or without polydactyly. Presentation can be at birth (or antenatally) but also later in those with a milder phenotype. The first gene identified was mapped to 15.13, and subsequently a further 15 genes have been identified, all of which directly or indirectly influence the function of the primary cilium.

Children present with a restricted thoracic cage, which causes respiratory problems (Fig. 13.6), short ribs, shortened tubular bones, and a ‘trident’ appearance of the acetabular roof. While respiratory symptoms usually predominate, there may be progressive renal disease (juvenile nephronophthisis), a condition in which there is a progressive breakdown of the tubular basement membrane leading to interstitial fibrosis and cystic tubular dilatation. Hepatic fibrosis progressing to biliary cirrhosis with portal hypertension occurs in some children. Prolonged neonatal cholestasis may be an early presenting feature although older children are found to have hepatic lesions with fibrosis, cirrhosis and portal hypertension leading to liver failure. Isolated or combined organ transplantation may be required depending on the rate of decline in kidney and liver function.
Fig. 13.6

Left panel: narrow chest as a result of restricted rib growth in a child with Jeune syndrome. Right panel: frontal chest X-ray of a child with Jeune syndrome reveals short narrow elongated chest, high riding clavicles and irregular costochondral junctions

13.2.2 Bardet Biedl Syndrome

This multi system disease presently has more than 20 identified genes, all impacting on the structure or function of the primary cilium with most having autosomal recessive expression. Affected individuals have hyperphagia-associated obesity (Fig. 13.7), post-axial polydactyly, progressive blindness from rod-cone dystrophy (Fig. 13.8) and varying degrees of developmental delay. Other clinical features include renal structural abnormalities of varying severity in up to 50%, chronic kidney disease in 30–40%, liver disease, bronchiectasis, significant constipation (Hirschprung disease has been identified in some children) and polyuria and polydipsia arising from resistance to AVP. Skeletal abnormalities including genu valgum and pes planus may be marked and progressive, exacerbated by the marked obesity. Type 2 diabetes develops in 15% of adults as a complication of the obesity and may progress to insulin dependency (see also Sect. 7.1.2, Chapter  7).
Fig. 13.7

Growth chart showing early and continuing excessive weight gain in a child with Bardet Biedl syndrome

Fig. 13.8

Colour fundus photograph of right eye showing pale optic disc, attenuated retinal vessels, with depigmentation and granular appearance of the macula in a child with Bardet Biedl syndrome

There is marked phenotypic variability, particularly with regard to the developmental abnormalities, with some affected individuals demonstrating marked autistic behaviour while others have normal educational attainment and develop successful careers.

13.3 Autosomal Recessive Polycystic Kidney Disease

The diagnosis of ARPKD is often made on antenatal scanning when the foetus is noted to have enlarged, echo bright kidneys with poor corticomedullary differentiation and oligohydramnios. ARPKD occurs in 1:20,000 to 1:40,000 live births and is caused by a mutation in the PKHD1 gene which codes for a fibrocystin/polyductin protein complex, a receptor-like protein expressed in the primary cilium of epithelial cells that has been identified in renal collecting ducts and the Loop of Henle, in pancreatic epithelial ducts and in hepatic biliary ducts.

Affected foetuses may have oligohydramnios as a consequence of poor urine output and, together with marked renal enlargement, causing lung compression with significant pulmonary hypoplasia leading to a mortality rate of approximately 30% in the neonatal period.

Affected children have a variable renal and liver phenotype. Histologically, there is non-obstructive, fusiform, cystic distension of renal collecting ducts with sometimes massive renomegaly (Fig. 13.9), impaired renal function and hypertension. In some children renal (and liver) enlargement is so great it impacts on feed tolerance as a result of gastric compression.
Fig. 13.9

Ultrasound coronal section of right kidney reveals enlargement with loss of normal architecture due to the presence of multiple tiny cysts in a child with autosomal recessive polycystic kidney disease

Although most neonates (70–80%) have renal impairment, renal failure requiring dialysis or transplantation rarely develops early in childhood and the actuarial renal survival rates are 86% at 5 years, 71% at 10 years, and 42% at 20 years. Hypertension is common (75% affected), especially in children with preserved renal function, and can be severe requiring multi drug therapy or even nephrectomy.

There are varying degrees of congenital hepatic fibrosis (CHF), as a result of a biliary ductal plate malformation. Progressive biliary disease leads to periportal fibrosis or CHF or Caroli’s disease, a cystic widening of the intrahepatic bile ducts and the common bile duct. The main complication is portal hypertension manifested by hepatosplenomegaly, hypersplenism with low platelet count, variceal bleeding and an increased risk of ascending cholangitis. Survival has improved as a result of aggressive management of nutrition, hypertension and isolated organ or combined liver and kidney transplantation during childhood.

13.4 Liver and Kidney Transplant

Simultaneous combined liver and kidney transplantation (CLKT) is a major procedure but has an excellent outcome provided children are carefully selected and the procedure is undertaken in a centre with appropriate experience.

Children with liver disease and chronic kidney disease should be considered for pre-emptive transplantation (before dialysis) if they have an estimated GFR of less than 45 ml/min/1.73 m2 because isolated liver transplantation may cause a decline into established renal failure requiring dialysis.

CLKT is advisable in children with liver disease who are on dialysis and who are at risk of progression of liver dysfunction because the risk of cholangitis is increased in those on immunosuppression after isolated renal transplantation or because of progression of portal hypertension.

CLKT is a proven therapeutic option for children with metabolic disease as a result of defective hepatic enzyme function leading to CKD, as in primary hyperoxaluria type 1.

There is some evidence that the liver provides an immune modulatory function that is beneficial to the transplanted kidney, leading to better long-term renal transplant function and outcome in comparison to isolated kidney transplants (Fig. 13.10).
Fig. 13.10

Renal graft function in 40 combined liver and kidney transplant (CLKT) recipients compared with matched isolated kidney transplants (KT). (From Pediatr Nephrol. 2016; 31: 1539–43)

Further Reading

  1. Bardet Biedl support group. Information leaflet. http://www.lmbbs.org.uk/LMBBS/file/Medical%20Booklet%202016(1).pdf.
  2. Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schoneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Buttner R, Zerres K. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int. 2005;67:829–48.CrossRefPubMedGoogle Scholar
  3. Forsythe E, Sparks K, Best S, Borrows S, Hoskins B, Sabir A, Barrett T, Williams D, Mohammed S, Goldsmith D, Milford DV, Bockenhauer D, Foggensteiner L, Beales PL. Risk factors for severe renal disease in Bardet-Biedl syndrome. J Am Soc Nephrol. 2017;28:963–70.CrossRefPubMedGoogle Scholar
  4. Hulton SA. The primary hyperoxalurias: a practical approach to diagnosis and treatment. Int J Surg. 2016;36(Pt D):649–54.CrossRefPubMedGoogle Scholar
  5. Ranawaka R, Lloyd C, McKiernan PJ, Hulton SA, Sharif K, Milford DV. Combined liver and kidney transplantation in children: analysis of renal graft outcome. Pediatr Nephrol. 2016;31:1539–43.CrossRefPubMedGoogle Scholar
  6. Satir P, Pedersen LB, Christensen ST. The primary cilium at a glance. J Cell Sci. 2010;123:499–503.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NephrologyBirmingham Women’s and Children’s HospitalBirminghamUK

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