Case Report Article | Open Access

Polycystic kidney disease in a child – A case report

D. Anestakis1*, M. Nikiforou-Lialiampidou1, E. Bountouroudi1, E. Papadopoulou1, S. Bountouroudis1, N. Kifnidis2,
N. Papaioannou3 and E. Zagelidou4

Author Affiliations

*Corresponding author: Doxakis Anestakis
Department of Histopathology, Laboratory of Forensic and Toxicology, Aristotle University of Thessaloniki, Greece; E-mail: anestaki@auth.gr

Received: May 1st, 2017; Accepted: June 6th, 2017; Published: June 12th, 2017

Med Clin Press. 2017; 1(1): 25-32. doi: 10.28964/MedclinPress-1-105

Ⓒ 2017 Copyright by Anestakis D, et al. Creative Commons Attribution 4.0 International License (CC BY 4.0).

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease with a prevalence of about 1:500 and is responsible for approximately 10% of end-stage renal disease in adults. Although, ADPKD is more common among adults, now-a-days it is known that it can present during childhood, even in utero, with important clinical manifestations including progressive structural kidney disease and hypertension. It is unclear why the disease presents early, however early intervention in these children is necessary in order to ameliorate the progression of the disease to chronic kidney failure. The purpose of this article is to present one child with ADPKD and to review the most important aspects of the disease in children such as epidemiology, genetics, clinical manifestations, treatment, early diagnosis and prognosis.

INTRODUCTION

Epidemiology

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human renal disease. This form of polycystic kidney disease affects all racial and ethnic groups and both equally affect males and females, but it is considered to be more severe in males than in females – although the difference is not statistically significant.1

It has an incidence rate of 1:400-1:1000 with 13 million people affected worldwide, and accounts for 7 to 10% of End Stage Kidney Disease (ESKD) in adults and for 7 to 15% of patients on renal replacement therapy. In North America and Europe, ADPKD is responsible for 6 to 10% of End Stage Renal Disease (ESRD) cases. Approximately one per 800-1000 population carries a mutation for this condition.1-5

The Individuals with polycystic disease often show renal failure before the 4-10 years of life and others much later at 60. Only 50-60% of people with polycystic disease will need therapy such as dialysis or transplantation.

Polycystic disease is found in all countries of the world. In Australia it relates to 6% of those who make dialysis (end stage renal failure) and in Greece about 8%.1,5

Genetics

ADPKD is a hereditary disorder. The pattern of inheritance is autosomal dominant. The disorder, as stated before, occurs equally in males and females, thereby each offspring has a 50% chance of inheriting the responsible mutation and, displaying the disease.

ADPKD is a genetically heterogeneous condition with a penetrance of almost 100% that involves at least 2 genes. The genes responsible for autosomal dominant polycystic kidney disease were found to be situated:

  • To the short arm of chromosome 16: 6p13:3(Polycystin 1-PKD1) in 85% of cases
  • The long arm of chromosome 4: 4q21-q22 (Polycystin 2 -PKD2) in most of the remaining cases.1,3,5-7
  • PKD1 codes for a 4304–amino acid protein (polycystin 1) which is a large protein with an extracellular N-terminal region, a short intracellular C-terminal tail and 11 transmembrane domains. The function of polycystin 1 is not yet fully defined, but it is known to interact with polycystin 2. The protein is also involved in cell cycle regulation and intracellular calcium transport. Polycystin 1 localizes in the primary cilia of renal epithelial cells, which functions as mechanosensors and chemosensors.
  • PKD2 codes for a 968–amino acid protein (polycystin 2). It is structurally related to the transient receptor potential (TRP) channel family and to polycystin 1 and co-localizes to the primary cilia of renal epithelial cells. Moreover it is a member of the family of voltage-activated, nonselective cation calcium channels.3,5-7
  • ADPKD1 is more severe than ADPKD2. The dysfunction of these proteins is pathogenetically responsible for the manifestations of autosomal dominant polycystic kidney disease, primarily by renal ciliary dysfunction. A third gene is speculated to account for a small number of patients. Homozygous or compound heterozygous genotypes have been thought to be lethal in utero. Individuals heterozygous for PKD1 and PKD2 mutations usually survive to adulthood but have more severe renal disease. From recent studies it is obvious that standard Mendelian genetics are not adequate to predict the severity of the progression of the renal and extrarenalmanifestations of the disease, as other transcriptional events are responsible (digenic inheritance or trans-heterozygosity; somatic and germline mosaicism; genetic modifiers and epigenetic regulators co-inheritance of mutations in either PKD1 or PKD2).5-7

Pathophysiology-Pathology

The main feature of ADPKD is a bilateral progressive increase in the number of cysts, which may lead to ESRD. Hepatic cysts, cerebral aneurysms, and cardiac valvular abnormalities can also occur. The cysts expand progressively, separate from the parent tubule and eventually create an isolated sac filled with fluid. Secondary and tertiary changes can be provoked in the renal intersitium leading to fibrosis. In children, the typical appearance of ADPKD is one or more renal cysts within enlarged kidneys. In ADPKD children, kidney cysts form in glomeruli and all tubular segments. The cyst formation is commonly asymmetric and may occasionally present as unilateral. Generally, the finding of even a single solidary renal cyst in an at-risk pediatric or adolescent patient should prompt further evaluation as simple cysts are extremely rare in children.1,5-7

Cyst development is a multi-factorial process. Even though the mechanisms that lead to the PKD phenotype are not fully discovered, multiple cellular defects have been identified. Molecularfactorsinclude:

  • Influence of one cyst on neighboring nephrons creating a “snowball effect” leading to cyst development in adjacent tubules
  • Reduction in functional PC1 dosage
  • The developmental timing of PKD1 inactivation
  • Cellular and nephron differences in sensitivity to PC1 dosage1,5
  • Common phenotypic abnormalities define key pathogenic features of a unique phenotype of a cystic renal epithelial cell. These include:
  • Abnormal expression and function of the epidermal growth factor (EGF) (Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway is activated)
  • Increased Cyclic Adenosine Monophosphate (cAMP) which results in the activation of the β-Raf/MEK-ERK pathway and thus both cellular proliferation and fluid secretion are stimulated
  • Abnormal activity of C-terminal Src kinase or cellular Src (c-Src). A critical molecule that mediates cross-talk between the Epidermal Growth Factor Receptor (EGFR) axis and G-protein-cAMP pathways
  • Abnormal structure and function of the primary cilia; disturbance of the fimbriae structure of epithelial tubular cells
  • Alternative activation of renal interstitial macrophages that contribute to the development of progressive fibrosis
  • Increased proliferation of tubular epithelial cells
  • The increased secretion of tubular fluid
  • Disruption of the interaction between cells and matrix
  • Change in the polarity of epithelial tubule cells.1,2,4,5,7

The processes referred above contribute at some point to the formation and the enlargement of the renal cysts in various stages, namely: tubular epithelial proliferation; abnormal tubular secretion; alterations in extracellular matrix structure, and/or function; recruitment of macrophages and inflammatory mediators.1

CASE REPORT

We present the case report of a 7-year-old girl who had a history of vesicoureteral reflux with no apparent cause. She had been operated on twice but both surgeries were unsuccessful. Unfortunately, the girl died of hyperkalemia. A histological examination of certain organs has been performed providing us with the following findings.

MATERIALS

  • two brain tissue blocks (8.5 g & 9.4 g)
  • one myocardial tissue block (6.1 g)
  • two lung tissue blocks (4 g, 4.3 g)
  • one liver tissue block (3.6 g)
  • one spleen tissue block (5.5 g)
  • two renal tissue blocks (2 g & 16.8 g)

RESULTS

The tissue block of the brain presented destruction of the gray matter in various places, inflammatory infiltration, vessels with relative hyperemia and in some areas varying levels of red cells blood clots (Figure 1).

On the myocardial tissue block sites autolytic character as well as interstitial edema was observed. The fibres of the myocard presented with relative ataxia as far as the order is concerned. Moreover, blood clots and arterioles with thickened walls were distinguished (Figure 2).

The samples of the lung tissue presented signs of pulmonary edema, hemorrhagic and inflammatory infiltrations. There were also areas of fibrotic tissue and some damaged alveoli and bronchioles (Figure 3).

The liver’s tissue block exhibited somewhat broadened sinusoids, hemorrhaging infiltrations, small sites of necrosis and autolysis whilst between the portal spaces phagocytes and granules of hemosiderin were observed (Figure 4).

The spleen sample presented dilated splenic trabeculae, hemorrhagic infiltrations, red thrombi, phagocytes and hemosiderin granules (Figure 5).

The renal parenchyma presented hyalinization of glomeruli in various places, with a colloidal eosinophilic content. There were necrotic areas, areas of fibrotic connective tissue, extensive inflammation and blood vessels with thickened walls. Red thrombi were observed in some of these vessels. There were also cysts in various places. The kidney’s condition justifies the girl’s history of hyperkalemia (Figure 6).

Figure 1: Brain tissue (H/E X40).

Figure 2: Myocardial tissue (H/E X100).

Figure 3: Lung tissue (H/E X40).

Figure 4: Liver tissue (H/E X100).

Figure 5: Spleen tissue (H/E X40).

Figure 6: Kidney tissue (H/E X40).

DISCUSSION

Clinical Characteristics

Although, most pediatric patients with Autosomal Dominant polycystic Kidney Disease (ADPKD) are asymptomatic and cysts are usually noted when screening those with strong family history, some of them appear symptomatic, as in our case.8 In neonatal age, ADPKD may appear with massive renal enlargement, hypertension, oliguria and pulmonary hypoplasia.9

The clinical spectrum of childhood Autosomal Dominant Polycystic Kidney Disease (ADPKD) is wide. Renal involvement is characterized by unilateral or bilateral cyst formation in nearly normal or mildly enlarged kidneys. Other renal manifestations include micro and gross hematuria and proteinuria.1,8 Hematuria can be occurred when cyst hemorrhage either spontaneously or due to trauma. Overt proteinuria is associated with more advanced structural kidney disease. In addition, acute or chronic flank, back or abdominal pain can also exist as a result of capsular stretch, cyst hemorrhage or infection, pyelonephritis or passage of stones. Renal infections and urolithiasis affect children with ADPKD at increased frequency compared with the general population.1,2

Renal insufficiency in children with ADPKD has been reported but is rare and usually develops later in adulthood.1 Most children with ADPKD maintain a normal GFR (Glomerular filtration rate), as a decrease in GFR requires an extensive renal structural destruction. The rate of kidney enlargement has been associated with a faster decline in GFR, therefore TKV (total kidney volume) is utilized as a factor of disease progression.1,2

The cardinal extrarenal manifestation is hypertension which affects 10-35% of children with ADPKD. The major mediator of hypertension is thought to be dysregulation of the renin-angiotensin system (RAS), possibly through cyst compression causing local ischemia and RAS activation. Hypertension often precedes clinical manifestations of ADPKD and is used as a screening measure for at risk children. There is also a strong correlation between hypertension and larger kidneys observed in multiple cohorts of ADPKD children. It is also associated with a decrease in GFR over time. It also occurs earlier and more frequently in PKD1 than in PKD2 and in those ADPKD whose parents also have hypertension.1,2,10,11

The use of ambulatory blood pressure monitoring (ABPM) has also revealed that nearly 33% of children with ADPKD present nocturnal hypertension. Additionally, a significant proportion of normotensive children have “prehypertension” (blood pressure in the upper range of normal).1,2

Cardiovascular disease is also a major feature of ADPKD. Hypertensive and pre-hypertensive children with ADPKD have a significantly higher left ventricular mass index (LVMI) than children with normal blood pressure. There are also cardiac valve abnormalities such as mitral valve prolapse in higher frequency compared with the general population. Impaired endothelium-dependent dilation and increased arterial stiffness, important factors of future cardiovascular events and mortality are evident very early in children with ADPKD.1,2,8

Other extrarenal manifestations including cysts in liver, pancreas, thyroids and intracranial aneurysm which are observed in adults with ADPKD are less common in children.

Diagnosis

The diagnosis is relatively easy for people with a family history. The formation of cysts already starts from the natal life. Nevertheless, no symptoms are usually displayed in childhood.1

Three key variables must be taken into account when determining the diagnosis:

  1. People at risk for PKD1, age >30 years and without found cysts in Ultrasound (U/S), have <5% chance of having the disease.
  2. The required number for the diagnosis of the disease is as follows:
    • age <18 years: two cysts in total age
    • age 18-30: 3 cysts overall in both kidneys
    • age: 30-60 years: 4 cysts overall in both kidneys
    • age >60 years: 8 cysts overall in both kidneys
  3. The U/S kidneys cannot safely exclude the presence of ADPKD in individuals younger than 30-year-old (Table 1).3,12,13 In patients with ADPKD the definitive diagnosis is done with ultrasound after the age of 30-35. If after 30-35 no cysts on ultrasound are detected, the patient is not suffering. Computed Tomography (C/T) detects even small cysts, so if there are no cysts at age 20 to 25, the disease is excluded. In some cases of negative family history, diagnosis will be established due to the ultrasound findings within an investigation of a hematuria episode or the finding of renal failure. The negative background can cause several people who have the disease die of other causes without ever been diagnosed.1,3,12,14

Table 1: Unified criteria for ultrasound diagnosis of ADPKD.

Usually, the diagnosis is made accidentally during an imaging control which is done for another reason. The imaging tests that are used are analyzed here:

Ultrasound of the Kidneys

It is a simple, safe and painless test that is used on a broad basis. In most cases, it can determine that the problem is a simple renal cyst. If there are suspicious signs of something more serious, the doctor will ask the patient to undergo further testing. Cysts of diameter 1-1.5 cm can be diagnosed by ultrasound.15 Ultrasound provides a safe method for diagnosis and screening of people with a high likelihood of ADPKD, but the cost will prevent this screening from being applied to the whole population.3,12,13

Computed Tomography (CT)

This examination may, more precisely, investigate a suspicious renal cyst and rule out the presence of malignancy. It defines the cysts with diameter of 0.5cm or less.1,2

Magnetic Resonance (MRI)

It has the same indications of CT in the investigation of renal cysts. It is more appropriate than the ultrasound and it is capable of differentiating the kidney carcinomas from the cysts.3

If the diagnosis remains unconfirmed however, there may be assigned additional tests, (an analysis of chromosomes might be requested to determine if the person in question has the gene associated with the polycystic kidney disease) such as the Direct DNA analysis. In this case, the patient’s DNA is tested for the gene panel. This includes genetically programmed tests for identification of the gene responsible for the disease PKD1. They can be used on young people with a family history who have cysts on ultrasound and are interested in becoming renal transplant donors.3,5,14

The clinical symptoms that will make the doctor to speculate the disease include:

  • The presence of high blood pressure, (diastolic blood pressure (BP) greater than 90 mmHg)
  • Increase in the size of the kidneys,
  • Enlargedliveror
  • Blood in the urine
  • Proteinuria
  • and being on multiple antihypertensive medications3

As far as the children with ADPKD are concerned, the clinical spectrum of pediatric ADPKD is especially broad and at some point it may be difficult to distinguish ADPKD from ARPKD especially in newborns. However, ADPKD in early childhood is generally presented as unilateral or bilateral renal cysts in a normal or in mildly enlarged kidneys. Unfortunately, it is still difficult to predict how ADPKD will progress in children with this presentation with the disease becoming more clinically symptomatic or the disease remaining asymptomatic in childhood and in some cases adulthood. ARPKD is speculated when there are clinical findings in the patient and the absence of renal disease in the patient’s biological parents. Identification of biallelic pathogenic variants in PKHD1 in the affected individual establishes the diagnosis ARPKD.1,3

Treatment

Unfortunately, no disease-specific therapies are currently available for Autosomal Dominant Polycystic Kidney Disease (ADPKD), although many novel therapies targeted at specific pathogenic process are in clinical trial. Currently treatment aims at managing or preventing complications of the disease as discussed below.10

Hypertension is the major extra-renal manifestation, which needs to be controlled, in order to prevent deterioration of cardiac and renal function. Blockade of the renin-angiotensin-aldosterone system with ACEI (angiotensin-converting-enzyme inhibition) or ARB (angiotensin-receptor blockade) are the first option treatment in pediatric ADPKD. The use of ACEI in hypertensive children and young adults has shown to prevent the decline in glomerular filtration rate (GFR) and increase in left ventricular mass index (LVMI). However, combined therapy with ACEI and ARB failed to demonstrate any benefit in ADPKD progression, as compared with ACEI alone.1,2,10

Statins in addition to their effect to lower cholesterol, they also enhance renal blood flow and GFR and languish vascular inflammation through vascular and glomerular nitric oxide production. In phase III of a clinical trial in children and young adults (age: 8-22), pravastatin has shown to slow the progression of total kidney volume (TKV) and left ventricular mass index (LVMI) in these children. These results prove that statins play a decisive role in maintaining a good renal function in children with ADPKD.1,2

Flank pain is unusual in children with ADPKD. However, management includes identifying potential causes (e.g., infection, bleeding, urolithiasis) and follow certain treatment according to that. Non-steroidal anti-inflammatory agents (except for cyst hemmorhage) and short term narcotic tratment can be used.1,2,15

Urinary tract infections (UTIs) and renal cyst infection, although rare during childhood, should be treated with certain antibiotics. It is important to mention that antibiotics used to treat UTIs (such as penicillins and aminoglycosides) are not able to penetrate renal cysts. For this reason, fluoroquinolones which have a good cyst penetration are the first line therapy in cysts infections. If the cyst infection insists, laparoscopic drainage may be necessary.2,15

In case of cyst bleeding symptomatic treatment is preffered, consisted of bed rest, analgesics and hydration. In case of persistent bleeding further treatment is necessary, including intravenous fluids, packed red cells in case of anaemia, endovascular catheter to avoid ureteric obstruction. Contact sports should also be avoided.10

Supportive measures can be adapted in order to maintain a good renal and cardiac function. The excessive intake of salt, protein, and calories is associated with worsening kidney volume and function in patients with ADPKD, therefore should be avoided. A balanced dietary pattern that is rich in fruits, vegetables, low fat dairy foods, limited in sodium, red meat and added fat has been found to prevent high blood pressure in hypertensive people. High fluid intake can prevent urolithiasis, too. Caffeine due to the inhibition of phosphodiesterase and the increase of cAMP leads to further fluid secretion from cystic epithelium in ADPKD, therefore should be avoided. Lifestyle changes such as maintenance of ideal body weight and regular aerobic exercise should be encouraged to prevent or to treat hypertension, too.2,15

Due to the increased frequency of high blood pressure and valvural abnormalities in children with ADPKD, they should be closely monitored for hypertension and make periodic echocardiographic assessment. Cerebral aneurysms are unusual in children with ADPKD but family history seems to have a strong influence on it. Therefore, young adults with ADPKD and family history of cerebral aneurysms or symptoms should start routine screening with MRA(Magnetic Resonance Angiography) once they reach 18 years of age.1,10

Hyperkalemia

Healthy kidneys have strong regulation of K+ and under normal circumstances, blood potassium level can be controlled within normal range. In case of renal parenchymal damages and when renal functions are damaged such as kidney failure (which can be a result of ADPKD as stated) patients will easily develop hyperkalemia. This can occur due to the fact that the amount of discharged potassium from the kidneys is a lot more than the one taken from the diet. Thereby, it is concluded that excessive potassium in the blood happens in most cases because of a decline of kidney functions and inefficient removing of potassium. In some cases however, hyperkalemia may be caused by dual blockade of the renin–angiotensin–aldosterone system (RAAS), which is implemented due to the implication of RAAS in the generation of hypertension in ADPKD patients. This blockade may include an angiotensin-converting–enzyme (ACE) inhibitor or angiotensin II–receptor blocker (ARB). Increased extracellular potassium levels result in depolarization of the membrane potentials of cells due to the increase in the equilibrium potential of potassium.6,16-18

This depolarization opens some voltage-gated sodium channels, but also increases the inactivation at the same time. Since depolarization due to concentration change is slow, it never generates an action potential by itself; instead, it results in accommodation. Above a certain level of potassium the depolarization inactivates sodium channels, opens potassium channels, thus the cells become refractory. This leads to the impairment of neuromuscular, cardiac, and gastrointestinal organ systems. Specifically, the amount of potassium (K+) in the blood determines the excitability of nerve and muscle cells, including the heart muscle or myocardium. When potassium levels in the blood rise, it can result in the reduction of the electrical potential, the inhibition of myocardial contraction and can lead to potentially fatal abnormal heart rhythms and even cause ventricular fibrillation, cardiac arrest, etc.6,16,17

Signs and symptoms of hyperkalemia include weakness, ascending paralysis, and respiratory failure. There are some signs in the Electrocardiogram (ECG) that may suggest hyperkalemia. Mild hyperkalemia can cause peaked T-waves. Moreover, flattened p-waves, prolonged PR-interval, and other anomalies can be caused if hyperkalemia is left untreated. In this case one may see idioventricular rhythms and a sine-wave pattern. Severe hyperkalemia can lead to asystolic cardiac arrest as stated above.6,18,19

Since hyperkalemia often has no obvious symptoms in the early stage, it can cause sudden cardiac arrest, therefore it is very important for kidney failure patients to have close monitoring of their serum potassium level as well as other electrolytes and seek timely and proper measure when potassium is high.16,17

Prognosis

Many factors predict or/and effect Autosomal Dominant Polycystic Kidney Disease progression in children (ADPKD). Several studies have shown that patients with mutations in PKD1 gene have a more severe form of ADPKD than patients with PKD2 mutations. They present a younger age at diagnosis, higher number of cysts, earlier onset of hypertension and faster progression to end-stage renal disease (ESRD).1,10,20

Parental history of hypertension is associated with a higher frequency of hypertension in affected children as well as younger age at diagnosis of hypertension. Hypertension especially in children is contributor to renal function loss and correlates with kidney size and number of cysts. An observational study of children with ADPKD found that those who were diagnosed by ultrasound at age <18 months had larger kidneys, more cysts and more frequent hypertension on follow-up than children diagnosed at age >18 months. Hypertension is also associated with decreased GFR, earlier onset of ESRD and is the main risk factor for early cardiovascular disease.15,20

Early or frequent episodes of gross hematuria, multiple urinary tract infections as well as episodes of cyst rupture are associated with more severe disease and worse renal function. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Levels of urinary albumin excretion in adults are a valuable marker of ADPKD severity before a decline in GFR is evident. Overt proteinuria is also associated with larger renal volume, worse renal function and higher blood pressure.10,20

Low birth weight is associated with a reduced number of nephrons and therefore it is more likely for a child with ADPKD to develop earlier ESRD. Several studies have also shown that male and black racial background are also factors for more severe disease.8,20,21

CONCLUSION

Polycystic kidney disease is a syndrome often hereditary in the autosomal dominant form (although there are cases of autosomal recessive), whose symptoms can be manifested either in childhood or adulthood. In our case, a girl of 7 years, undiagnosed, couldn’t cope with the disease and died of hyperkalemia. This could be explained from the fact that healthy kidneys have strong regulation of K+ and under normal circumstances, blood potassium level can be controlled within normal range. When renal disfunction occurs however, hyperkalemia is established and can result in renal failure, heart problems and eventually death, as happened in our case. Generally, ADPKD can have a wide spectrum of clinical characteristics ranging from renal enlargement, hypertension, oliguria, pulmonary hypoplasia, renal infections, urolithiasis, to extrarenal manifestations such as cysts in liver, pancreas, thyroids, intracranial aneurysm and most common of all, hypertension. Although no disease-specific therapies are currently available for ADPKD, therapies targeted at specific pathogenic process are in clinical trial. Currently, treatment aims at managing or preventing symptoms and complications of the disease, such as hypertension, are supportive methods.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

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Volume 1, Issue 1
June 2017
Pages 25-32

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