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Beyond ADPKD there are many other causes of renal cysts, both congenital and acquired which may present at a variety of time points through life. They can vary from simple, incidentally found cysts with no prognostic implications, to multiple large cysts that result in declining renal function and the requirement of renal replacement therapy.

The commonest renal cystic processes are simple cysts which are seen with increasing age and tend to be rare in young patients but have been reported incidentally in up to 50 % of CT imaging performed in those over the age of 40 years. They have a typical appearance of fluid-filled sacs on ultrasound imaging but are better defined with cross-sectional imaging. Cystic lesions can be categorised using the Bosniak Classification (see Chap. 38).

Acquired Cystic Kidney Disease

Acquired cystic kidney disease (ACKD) occurs in the context of chronic kidney disease (CKD) and therefore may be a concern for primary care physicians and general physicians as well as nephrologists and urologists. As it is a cystic condition associated with CKD, the kidneys are usually small to normal in size in contrast to adult polycystic kidney disease. It is characterised by the development of multiple cysts bilaterally which are usually less than 0.5 cm in diameter and are rarely greater than 2–3 cm [1]. As patients progress through successive stages of CKD and onto renal replacement therapy (RRT), the incidence of ACKD increases with a third of patients affected after 3 years of haemodialysis and occurring in up to 80 % of patients after 10 years of dialysis. Both men and women are affected equally independent of age [2]. Modality of dialysis, peritoneal or haemodialysis, appears to have no influence on the development of cysts. Plasticisers used in dialysis have been implicated in the pathogenesis of renal cyst formation but the mechanisms of the development of ACKD are not yet fully elucidated. Cysts develop in the renal tubules, and analysis of cyst fluid and epithelium suggests an origin in the proximal tubules [1]. It is thought that the process itself is driven by proto-oncogenes [3] and for this reason may explain the increased rate of renal cell carcinoma secondary to unregulated cellular proliferation (see below).

In its early stages acquired cysts are usually asymptomatic and are increasingly discovered incidentally on abdominal imaging; however, occasionally their discovery can result from the investigation of both microscopic and macroscopic haematuria, urinary tract infection, sepsis of unknown origin secondary to cyst infection, back and loin pain secondary to retroperitoneal cyst rupture, erythrocytosis or development of malignancy [1] (see Fig. 42.1). There is no association between the primary cause of renal impairment and the likelihood of development of ACKD.

Fig. 42.1
figure 1

Acquired cystic kidney disease: The CT scan of a long-standing haemodialysis patient who presented with erythropoietin resistance and haematuria. The scan shows the characteristic features of multiple complex cysts with extensive calcification

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Whilst the majority of ACKD runs a benign course, there is up to a 50-fold increase in the risk of development of renal cell carcinoma (RCC) compared to the general population [4]; prospective studies [5, 6] have placed its incidence at 1.7–7 % with time on dialysis (>3 years) being an important risk factor (transplantation appears to reduce risk), this incidence being much lower than the 20 % first reported in the 1970s. RCCs in ACKD are multicentric in 50 % of cases and bilateral in 9 %. It has recently become apparent that clear cell carcinoma which usually accounts for 70–80 % of RCCs only represents 10 % of RCC in ACKD. Sixty per cent of RCCs in ACKD appear to be due to two novel tumour types: (1) acquired cystic disease-associated RCC (ACDARCC) which appears to be unique to ACKD and (2) clear cell papillary RCC of end-stage kidney. ACDARCC tumours are often surrounded by a dense fibrous capsule and characteristically have extensive oxalate crystals within them [7]. These novel renal cancers may explain the rather surprising findings of better outcomes from RCC in patients with ESRD compared to other patients with RCC.

Renal cell carcinoma remains a clinical concern in patients with ACKD post-transplantation, and tumours may behave more aggressively in this setting, so careful monitoring must be considered in these patients [8]. Guidelines on who to screen and when have been inconsistent with some groups advocating screening ‘high-risk’ patients, but do not define high risk [9]. Renal ultrasound may be useful, but sensitivity for detecting small tumours is limited but this is improving with technology, and frequency of screening has not been established with some suggesting twice yearly and others recommending screening should be conducted every 2 years. For those with ACKD yearly screening seems appropriate. Due to a lack of evidence of benefits and the cost-effectiveness of screening, they were unable to recommend a particular method [9]. KDIGO guidelines from 2002 comment that ultrasound screening could be performed but found no data for the optimum frequency.

Both CT with contrast enhancement and MRI offer greater sensitivity for detecting tumours <1 cm. Despite improved sensitivity there is no data to support their routine use, and therefore decisions on local practice should be guided by consideration of the needs of the patient, potential complications of one modality and the results of previous imaging. A consensus that patients treated with dialysis for 3 years should undergo ultrasound is practical in patients with a reasonable life expectancy. If a mass is detected, then contrast-enhanced imaging should be performed yearly for surveillance unless criteria are reached for intervention [10].

Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) usually manifests in childhood. Its incidence is estimated at 1:10,000 to 1:40,000 and it is seen more frequently in Caucasians [11]. This may be an underestimate however as some children will die in infancy (often secondary to pulmonary hypoplasia as a consequence of oligohydramnios) without a diagnosis. Its characteristic features are of cystic dilatations of the renal collecting ducts and congenital hepatic fibrosis. Whilst predominantly diagnosed in early childhood, often it can be asymptomatic and may not be discovered until later in childhood or adolescence.

ARPKD is the result of mutations in the PKDH1 gene located at 6p21region of chromosome 6 which encodes the transmembrane protein fibrocystin (or polyductin) [12]. It is primarily a disease of ciliary dysfunction. Evidence suggests this dysfunction results in cyst development and expansion as a consequence of its role in intracellular calcium regulation and sodium transport [13].

Around half of cases are diagnosed antenatally [14] the remainder usually diagnosed neonatally or during infancy. Prenatal ultrasound can reveal oligohydramnios in severe cases and markedly enlarged kidneys. Neonates present with large palpable flank masses and the consequences of renal disease, notably hypertension [13]. Whilst there is always hepatic involvement, this may not be clinically evident. Those who present later in life tend to do so as a consequence of hepatic disease (congenital hepatic fibrosis) and will often demonstrate the sequelae of chronic liver disease, portal hypertension and varices but may also present with deteriorating renal function, hypertension, haematuria and mild proteinuria [11]. The more severe cases may present with ultrasound features of Caroli’s disease.

Whilst genetic testing is possible, in clinical practice diagnosis of ARPKD is made on clinical assessment, imaging and biochemistry. Features suggestive include:

  1. 1.

    Bilaterally enlarged, hyperechogenic kidneys with multiple small cysts (1–2 mm) and loss of corticomedullary differentiation and either

  2. 2.

    Signs or imaging compatible with hepatic fibrosis such as dilated bile ducts, evidence of portal hypertension

  3. 3.

    Or ARPKD in a sibling with exclusion of ADPKD in either biological parent

Detailed ultrasound and HIDA scan of children with ARPKD is normally suffice for hepatic assessment without the need for contrast-enhanced CT scanning.

Management of ARPKD is supportive with ongoing care focused on the complications of declining renal function, sepsis from pyelonephritis, infected cysts or ascending cholangitis, liver complications and eventually end-stage renal disease. Parents should be aware that further children will have a 25 % chance of being affected and a 50 % chance of being a carrier for the mutation in PKDH1 [15]. Although a parent may be a carrier as it is recessive, this would not prevent donation. Some patients may require combined liver-kidney transplant and should be jointly assessed if there is significant hepatic involvement.

Medullary Sponge Kidney

Medullary sponge kidney (MSK) is a congenital dilatation of the distal collecting tubules with subsequent enlargement of the affected pyramids; changes are confined to the medulla. It typically affects both kidneys but can also be present unilaterally or variably in different papillae [16]. It generally manifests as nephrocalcinosis and recurrent renal stones [17]; however, it may be diagnosed incidentally on radiological imaging for other indications. In an unselected radiological series, it has been observed in 0.5–1 % of cases, but occurs in up to 20 % of recurrent calcium stone formers [17]. There appears to be no male or female preponderance or racial difference in prevalence and is generally diagnosed in adulthood.

In itself MSK is symptomless, but presentations often result from its complications, most frequently renal stones and urinary tract infections. It may be associated with hemihypertrophy. There is almost universally microscopic haematuria, but macroscopic haematuria can result from urinary tract infections and stones.

Stones are predominantly calcium phosphate and calcium oxalate as a consequence of hypercalciuria, of which the mechanism is not understood. In the majority of cases, urinary acidification is inadequate with a resultant acidosis; however, this is usually incomplete and rarely does a full distal tubular renal acidosis occur.

The pathogenesis of MSK is poorly understood but appears to be congenital and is considered sporadic. To support this it has been noted to be associated with a number of congenital renal disorders as well as non-renal developmental abnormalities including hemihypertrophy, Beckwith-Wiedemann syndrome, Wilm’s tumour, ADPKD, Marfan’s syndrome, Ehlers-Danlos syndrome and horseshoe kidney. Given this, it is postulated that the pathogenesis lies in the renal morphogenesis, and mutations in glial cell line-derived neurotrophic factor, a protein involved in renal development, have been demonstrated in MSK [17].

Diagnosis of MSK is usually made radiologically with IV urogram the gold standard. Contrast is seen collecting in dilated papillary ducts with a resultant blush in mild cases, or in more severe cases the typical ‘bouquet’ or ‘bunch of grapes’ appearance is seen (see Fig. 42.2). In a proportion of cases, nephrocalcinosis will be revealed. Unenhanced CT has replaced IV urograms in most hospitals but unfortunately has a poorer sensitivity, so making the diagnosis of MSK is one of the few reasons to request an IV urogram over a CT KUB.

Fig. 42.2
figure 2

Intravenous pyelogram in a patient with medullary sponge kidney showing the characteristic ‘bunch of grapes’ appearance

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There is no treatment for the condition per se, and management revolves around treating and preventing the complications, be that infective or stone related. Thiazide diuretics can be used to reduce urinary calcium excretion and decrease risk of stone formation. Given the partial distal renal tubular acidosis, some have advocated treatment with alkali citrate, with increments in dosage until 24-h collection urinary pH <7.5 demonstrating a decreased frequency of stone formation and improvement in bone mineral density [17].

Nephronophthisis

Nephronophthisis is the commonest genetic cause of end-stage renal failure in the first two decades of life. It is an autosomal recessive condition resulting from one of the NPHP genes (currently 1–11), most commonly a large deletion in exon 2 of the NPHP gene and affecting about 1 in 50,000 individuals. The mutations result in a ciliopathy, and in some cases this is associated with significant extra-renal manifestations as well as nephronophthisis (see Table 42.1) [18].

Table 42.1 Syndromes and conditions associated with nephronophthisis
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Homozygous deletion of NPHP1 gene represents the commonest known mutation (20 %) of isolated nephronophthisis, but the mutation may not be known for many affected cases where clinical diagnosis is necessary.

Histologically there is tubular basement membrane disintegration (expansion and thinning), interstitial cell infiltration with fibrosis and later tubular atrophy with cyst generation, predominantly at the corticomedullary junction [19].

The commonest form of nephronophthisis results in ESRD by 13 years of age with infantile forms and adolescent forms reaching ESRD before 4 years and 19 years of age, respectively. Initial presentation is often with polyuria and polydipsia as a result of inadequate urinary concentration and disproportionate anaemia with progressive CKD. Kidneys usually maintain a normal size in contrast to PKD or other forms of CKD. Poor growth is common in children with nephronophthisis.

Genetic screening may be diagnostic, but more often the diagnosis will be suggested by a combination of clinical features, (polyuria and polydipsia, enuresis, renal impairment, anaemia) imaging and histology. Renal ultrasound (or MRI) can aid diagnosis and demonstrate medullary cysts with loss of corticomedullary differentiation and normal- to slightly small-sized kidneys. If the diagnosis is entertained, then retinal screening is important.

Bardet-Biedl Syndrome

It is another rare (1:150,000) autosomal recessive ciliopathy associated with retinitis pigmentosa presenting with night blindness in childhood with complete blindness by 15 years. Centripetal obesity is common and can be marked; polydactyl (60–70 %), deafness, hypogonadism in males, genital abnormalities in females and learning difficulties are also common associations. Renal abnormalities occur in 50 % and are most commonly cystic dysplastic changes (including calyceal cysts), histology showing features similar to nephronophthisis, concentrating defects and progression to ESRD common in those affected.

Medullary Cystic Kidney Disease

MCKDs are autosomal dominant conditions now divided into MCKD 1 and 2, causing ESRD in adulthood. Two gene loci have been identified in MCKD, MCKD1 and MCKD2 at 1q21 and 16p12, respectively. MCKD-1 has almost identical histological characteristic to nephronophthisis and is characterised by chronic tubulointerstitial nephritis with cyst development at the corticomedullary junction.

Clinically MCKD-1 has similar features to nephronophthisis with a concentrating defect and otherwise fairly silent progressive CKD, but a median onset of ESRD much later at 62 years and no extra-renal involvement. MCKD should be considered in any patient with otherwise unexplained CKD especially if there is evidence of a family history, polyuria/polydipsia and medullary renal cysts. On imaging the kidneys are either normal sized or only slightly small with corticomedullary cysts. There is no specific treatment apart from maintaining fluid and electrolyte balance, but transplantation is curative.

MCKD-2 is associated with a defect in the uromodulin gene (UMOD) which codes for the Tamm-Horsfall protein and results in hyperuricaemia and juvenile-onset gout. The condition is similar to juvenile hyperuricaemic nephropathy, and because of the autosomal dominance, parents are often alert to the significance of gout in their children. It is not clear if urate reduction therapy slows the rate of ESRD, but it seems prudent to try this not least as a way of reducing the burden of gout. The onset of ESRD in MCKD-2 is early at about 32 years [19], and as with MCKD-1 and nephronophthisis, transplantation is curative and without recurrence.

Renal Coloboma Syndrome

It is a rare autosomal dominant condition with PAX2 mutations causing coloboma (Fig. 42.3), renal cysts and tumours (overexpression) and renal hypoplasia (underexpression).

Fig. 42.3
figure 3

Retinal coloboma in a patient with renal coloboma syndrome

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Glomerulocystic Disease (Associated with Maturity-Onset Diabetes of the Young (MODY)

This autosomal dominant condition associated with hepatocyte nuclear factor (HNF)-1β mutations (as part of renal cysts and diabetes (RCAD) syndrome). It presents antenatally or postnatally with chronic kidney disease, hypertension and early-onset diabetes and is associated with renal magnesium wasting and hypomagnesaemia. Renal ultrasound demonstrates differing renal size with presence of glomerular cysts. A family history or history of MODY should raise suspicions.

Summary

Ciliopathies are responsible for a significant burden of ESRD with many of these cases diagnosed by paediatric nephrologists and then transitioned to adult care. In some there will be significant extra-renal manifestations, and a holistic approach to care will be needed. Some of these conditions may present in adulthood with limited clues to the cause of ESRD. A careful family history, thoughtful imaging for location of cysts and biopsy where appropriate may guide the diagnosis. Our understanding of genetics of renal conditions is improving every year; ante- and postnatal diagnosis increasingly can be confirmed using direct mutational analysis and linkage testing. Consequently genetic counselling is often possible without performing renal biopsies on patients. Even when mutational analysis is not available, it is worth considering storing DNA for the future. Ultimately, transplantation is curative of the underlying renal condition.

Resources

Contact a family. http://www.cafamily.org.uk/. Accessed 18 Mar 2012.

Information sheets for children and adolescents. http://www.gosh.nhs.uk/children/about-your-condition/; http://www.gosh.nhs.uk/teenagers/about-your-condition/. Accessed 18 Mar 2012.

Information sheets for parents. http://www.gosh.nhs.uk/medical-conditions/. Accessed 18 Mar 2012.

RaDaR: National Renal Rare Disease Registry. https://www.renalradar.org. Accessed 18 Mar 2012.

UK Genetic Testing Network. http://www.ukgtn.nhs.uk/gtn/Search+for+a+Test/Search+by+Disease+or+Gene. Accessed 18 Mar 2012.