Abstract
Background: Renal cystic disorders (RCD) constitute an important and leading cause of end-stage renal disease (ESRD) in children. It can be acquired or inherited; isolated or associated with extrarenal manifestations. The precise diagnosis represents a difficult clinical challenge. Methods: The aim of this study was to define the pattern of clinical phenotypes of children with renal cystic diseases in Pediatric Nephrology Center, Cairo University. We have studied the clinical phenotypes of 105 children with RCD [45 (43%) of them had extrarenal manifestations]. Results: The most common disorders were the presumably inherited renal cystic diseases (65.7%) mainly nephronophthisis and related ciliopathies (36.2%), as well as polycystic kidney diseases (29.5%). Moreover, multicystic dysplastic kidneys accounted for 18% of study cases. Interestingly, eight syndromic cases are described, yet unclassified as none had been previously reported in the literature. Conclusion: RCD in this study had an expanded and complex spectrum and were largely due to presumably inherited/genetic disorders (65.7%). Moreover, we propose a modified algorithm for clinical and diagnostic approach to patients with RCD.
Introduction
Numerous disorders share renal cysts as a common feature. These disorders may be inherited or acquired, and their manifestations may be confined to the kidney or expressed systemically. They can present at a wide range of ages. The renal cysts may be single or multiple, and the associated renal morbidity ranges from clinical insignificance to progressive parenchymal destruction with resultant ESRD.Citation1,Citation2 Inherited renal cystic diseases constitute an important subset of these disorders and involve single gene defects that are transmitted as autosomal dominant, autosomal recessive, or X-linked traits.Citation3
Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies that are characterized by a wide spectrum of phenotypes, including polycystic kidney, hepatic disease, malformations in the central nervous system, skeletal defects, retinal degeneration, and obesity.Citation4,Citation5 To date, ciliary disruption has been linked to many human genetic kidney disorders, such as autosomal dominant and recessive polycystic kidney disease (ADPKD and ARPKD), tuberous sclerosis (TSC), medullary cystic kidney disease (MCKD), nephronophthisis (NPHP) and related disorders including Joubert syndrome (JBTS).Citation6,Citation7
Cystic renal dysplasia and other renal phenotypes have also been associated with ciliary dysfunction, mostly within the context of syndromes that affect early development, such as the Meckel–Gruber syndrome (MKS), and the short-rib-polydactyly syndrome. In cystic renal dysplasia, the renal cortex is generally cystic, with distension of the terminal ends of the collecting ducts, and the medullary pyramids are poorly developed and demonstrate dysplastic structures and fibrous tissue.Citation8
To date, mutations in roughly 50 genes have been associated with renal ciliopathies. These genes encode various subsets of ciliary proteins including: nephrocystins, Bardet–Biedl syndrome (BBS) proteins BBSome, nephrocystins and JBTS/MKS proteins, interflagellar transport complexes (IFT A & B); as well as fibrocystin, polycystins, Hamartin (TSC1), Tuberin (TSC2), and uromodulin among others.Citation4,Citation9 Mutations in at least 13 different genes have been associated with the enormously genetically heterogeneous NPHP, nevertheless 70% of patients still remain genetically unexplained. Next generation sequencing (NGS) methods, mostly used for research purposes, are accelerating the process of identifying novel disease genes and gaining more insights into genotype–phenotype correlations in a time and cost effective effort.Citation6–9 Nonetheless, genetic basis of this diverse group of clinically and genetically overlapping disorders is beyond the scope of this article.
The differential diagnosis of renal cystic disease is a difficult challenge. Imaging plays an important role as it helps to detect and characterize many of the cystic diseases based on a detailed ultrasonographic analysis. A cystic disease is suspected by the discovery of a hyperechoic kidney and/or cysts. It can be solved by a careful step-by-step approach using ultrasonic (US) imaging and analysis. Familial and clinical inquiry will further help towards the diagnosis.Citation10
Ultrasound is the cornerstone of imaging and sequential examinations have described the natural history of many of these disorders. At times ultrasound alone is sufficient for diagnosis; however, other conditions require integration of many imaging modalities.Citation11
The aim of this work was to study the clinical phenotypic features of renal cystic diseases presenting to this major national referral center, define the etiology based on examination of clinical characteristics in addition to renal imaging and histopathological findings as helpful tools to categorize these diseases. This is to our knowledge the most comprehensive analysis of renal cystic disease reported from a regional single center.
Methods
Cross-sectional study including all patients (up to 18 years of age) with renal cystic diseases presenting to Center of Pediatric Nephrology and Transplantation, Cairo University through the period from April 2009 to November 2010. The clinical records, imaging studies and pathology reports of all patients with a diagnosis of renal cystic disease were reviewed.
Demographic and clinical data were recorded including family history, age and pattern of presentation, renal, visual, hepatic and neurological symptoms, and examination including neurological and ocular examination, estimated GFR by the Schwartz formulaCitation12 and staging of CKD, and the age of onset of ESRD and renal replacement therapy.
Abdominal US examination was performed to categorize renal cystic disease through determining kidney size, echogenicity, and corticomedullary differentiation as well as site and size of cysts.Citation13 Cystic renal diseases, for example, NPHP, ARPKD, ADPKD and MCDK were categorized according to the diagnostic US criteria for these diseases.Citation14 US examination was not restricted to the kidneys to exclude extrarenal abnormalities, for example, congenital hepatic fibrosis (General Electric, Vivid 3 Pro, SyncMaster 591S device with a 3.5–7-MHz probe, Wauwatosa, WI). Abdominal computed tomography (CT) examination was only performed in some selected cases where ultrasonography was non-conclusive.
Other imaging studies (e.g., voiding cystourethrography VCUG, brain CT, brain or urinary tract magnetic resonance imaging (MRI)) were employed when additional urinary tract and/or neurological involvement were suspected.
In patients with equivocal renal phenotype and/or evident hepatic involvement, histopathological examination of US guided renal and/or liver biopsy enabled properly identifying renal cystic disease (e.g., NPHP) and confirming associated congenital hepatic fibrosis, respectively
Data analysis
Data were tabulated and subjected to computer-assisted statistical analysis using Microsoft Excel version 2003 and the Statistical Package for Social Science (SPSS) for Windows version 16.0. Nominal data were expressed as frequency and percentage and were compared using chi-squared tests. Numerical data were expressed as mean and standard deviation and were compared using independent samples t tests. p Values <0.05 were considered significant.
Results
Demographics and diagnoses
The present series comprises 105 patients belonging to 100 families, including 59 males (56%) and 46 (44%) females. Their ages ranged from 1 day to 17 years (median 2.7 years). Twenty-two cases (21%) had prenatal ultrasonographic evidence of renal cysts and/or renomegaly of whom two had oligohydramnios as well, five patients (5%) were diagnosed at birth during initial neonatal physical examination, whereas the remaining 78 (74%) presented at a median age of 4.2 years (range 3 days–10 years).
Nine cases were accidentally discovered during ultrasonography for an unrelated condition, four during the screening of siblings of a proband case, Twenty-two patients were already in renal failure when they first came to medical attention, and 18 patients had extrarenal manifestations. Studied patients had strikingly significant family history and 45 patients had extrarenal involvement as shown in . Of the ESRD patients, 10 children underwent renal transplantation of whom 9 have functioning renal grafts, while one patient with nephronophthisis had graft failure associated with interstitial fibrosis and tubular atrophy (chronic allograft nephropathy) requiring maintenance hemodialysis.
Table 1. Clinical characteristics of the studied cases.
Ultrasonography could determine the pattern of renal cystic disease in 95 patients (90.5%). The 10 patients who required additional renal imaging included four cases with autosomal recessive polycystic kidney disease (ARPKD), one case with hypoplasia/dysplasia, another case best categorized as glomerulocystic kidney disease, one case with solitary autosomal dominant polycystic kidney disease (ADPKD), another case with posterior urethral valve and calyceal cysts and, two cases were unclassified syndromic cases. Renal ultrasound scans of some of the studied cases are presented in .
Figure 1. Renal ultrasound scans of: (a) Ten-month-old boy, autosomal recessive polycystic kidney disease: enlarged hyperechoic solitary kidney with poor corticomedullary differentiation and multiple scattered tiny cysts. The arrow points to hypoechoic cortical rim devoid of renal cysts. (b) Fifteen-year-old girl, autosomal dominant polycystic kidney disease: enlarged kidney with multiple variable-sized cysts scattered all through the renal parenchyma. (c) Six-year-old girl, juvenile nephronophthisis: normal-sized hyperechoic kidneys with multiple small corticomedullary cysts. (d) Three-month-old girl, bilateral cystic renal dysplasia: small-sized hyperechoic kidneys with poor corticomedullary differentiation and multiple variable-sized scattered cysts; some are cortical and subcapsular.
Abdominal CT examination was performed in 19 cases and contributed additional information over ultrasonography in only three cases with ARPKD, two of whom had non-conclusive US and CT examination revealed scattered cysts and the characteristic striated nephrogram due to entrapment of the contrast within the dilated collecting tubules. In addition, hepatic fibrosis was evident by CT but not US in one patient. Magnetic resonance urography (MRU) was performed in two patients with solitary kidneys and confirmed the diagnosis of ADPKD and ARPKD.
Renal histopathological examination in 12 patients with presumable diagnosis of NPHP, lacking cysts on US scan, demonstrated the typical histological triad in 9 of them, while 2 cases with infantile NPHP only featured interstitial changes and tubular microcyst formation but no basement membrane changes. Advanced glomerulosclerosis and interstitial fibrosis were present in a patient with juvenile NPHP and ESRD. Other than NPHP, a patient with unclassified syndromic cystic renal disease showed mild mesangial and interstitial infiltration and two patients with ARPKD were biopsied; one because abdominal CT suspected malignant infiltration and the other was an excision biopsy of a large kidney at the time of transplantation.
The classification of the studied patients is shown in . NPHP and related ciliopathies were the most common disorders (38 cases), closely followed by PKD. Advanced CKD (stages 4–5) was present at the time of presentation in 81.5% of cases of NPHP, significantly higher (p < 0.0001) than either PKD (27%) or MCDK (10%).
Table 2. Clinical classification of the studied cases.
Clinical manifestations
Polyuria and/or enuresis were present in 94.7% of cases of NPHP and 66.7% of PKD (p = 0.001), hypertension in 15.8% and 54.5%, respectively (p = 0.0003) and urinary tract infections in 21% and 39.4% (p = 0.04). Extrarenal manifestations were detected in 16 cases (42%) of NPHP and related ciliopathies. Ten had neurological manifestations mostly mental and/or psychomotor retardation (8 cases), hypotonia and truncal ataxia (4 cases), myopathy (1 case) and radiological abnormalities mostly molar tooth sign (4 cases). Retinal dystrophy was present in eight cases (including six with pigmentary retinopathy of whom one also had retinal flecks and choroidal coloboma) while seven had dysmorphic features. One case of Joubert syndrome-related disorders (JSRD) (with a renal phenotype of juvenile NPHP) had congenital hepatic fibrosis, two cases of infantile NPHP had cholestasis (one with liver cyst and the other with neonatal hepatitis). Hypothyroidism was associated with a case of juvenile NPHP.
With respect to hepatic involvement in PKD, one patient with ADPKD (16.7%) had multiple liver cysts detected by US. Hepatic involvement was evident in 11 cases with ARPKD (40.7%), including a case of hepatomegaly and ESRD, 8 cases of hepatic fibrosis (including evident portal hypertension in four), one with dilated intrahepatic biliary radicles (Caroli disease) and another with cholestasis who died of neonatal sepsis and could not be biopsied.
A tuberous sclerosis patient presented with ADPKD, brain tubers and seizures, cardiac rhabdomyoma and arrhythmia. Interestingly, three other patients had neurological involvement: one patient had Dandy–Walker malformation whereas the other two cases had ventriculomegaly that was associated with seizures in one patient and with psychomotor retardation and microcephaly in the other. About 18.5% of the ARPKD subgroup died, all in the first year of life, sepsis and arrhythmia were the principal defined causes of death.
Most patients with PKD and MCDK had palpable renal masses (72.7% and 80%, respectively), while of the 20 cases of MCDK, UTI was reported in only 9 patients. A renal phenotype of right MCDK, left Pelviureteric junction obstruction (PUJO) and CKD stage 4 was reported in one patient along with facial dysmorphy, microcephaly, mental retardation and proximal insertion of the thumb. To the best of our knowledge this syndrome had not been previously reported in the literature.
Finally, we propose a modified algorithm to assist in the diagnostic approach and clinical phenotyping of patients presenting with kidney cysts ().
Figure 2. Algorithm for clinical diagnosis of renal cystic diseases (for confirmatory molecular diagnostics when feasible). (1) DMSA scan should be done to confirm non-function; also voiding cystourethrography to exclude contralateral vesicoureteric reflux should the contralateral kidney demonstrate abnormal ultrasonographic findings. (2) If no cysts could be detected by high resolution US, renal biopsy should be done if molecular genetic analysis is not available. Extrarenal manifestations with NPHP can include retinitis pigmentosa and molar tooth sign (Joubert syndrome-related disorders). (3) The presence of evident congenital hepatic fibrosis supports the diagnosis; to be confirmed by PKHD1 genetic mutational analysis. (4) Renal biopsy may be indicated to confirm the diagnosis of GCKD in doubtful cases. For GCKD, a parent may be also affected. (5) The presence of a parent with ADPKD confirms the diagnosis. Nevertheless, absence of renal cysts in both parents does not rule out ADPKD because new mutations account for 8–10% of cases. PKD1 & PKD2 mutational analysis is confirmatory. (6) For confirmatory molecular diagnostics particularly NPHP1 mtational analysis.
Discussion
Since molecular diagnostics are not always a feasible tool for the routine diagnosis of most cystic kidney diseases, physicians must rely upon their clinical skill and knowledge base in order to identify these patients.Citation15 In the current work, examination of clinical characteristics in addition to imaging and histopathologic findings was used to characterize and categorize these diseases in 105 children.
Presumably inherited cystic kidney diseases accounted for 65.7% of study cases. NPHP (and related ciliopathies) represented the largest group (36.2%), followed by PKD (29.5%). It has been previously established that NPHP represents the most frequent genetic cause of ESRD in children and young adults.Citation16 Despite the still-developing practice of national prenatal screening, 22 cases presented antenatally, 5 cases at birth and the rest between 3 days and 10 years of age; indicating how early the onset could be.
The fact that various extrarenal manifestations were present in as many as 43% of cases highlights the clinical heterogeneity of these cases, hence the need for a high index of suspicion and an interdisciplinary approach. The role of cilia as components of almost all cells whose dysfunction can manifest as a protean constellation of features that could include retinal degeneration, renal disease, cerebral anomalies as well as hepatic involvement, is increasingly growing.
The high rate of consanguinity in the study group (63%) and nationally in general (40%)Citation17,Citation18 contribute to a high incidence of autosomal recessive disorders. Ironically, despite the high percentages of familial cystic disease (26%) and sibling death (15%), only 3.8% of our cases were diagnosed by screening. We must therefore emphasize the value of screening siblings of index cases with inherited renal disorders including cystic kidney diseases.
Symptoms including polyuria, polydipsia and/or secondary enuresis were present in a high percentage of our cases (60%), so pediatricians should pay more attention to these symptoms. In addition, the presence of urinary tract infection (UTI) in 31.4% of cases raises the importance of US scanning to rule out underlying renal structural defects in cases of UTI. Genetic disorders of renal growth and structure result in a reduced number of nephrons and/or an abnormal patterning and cellular organization of the renal tissue, for example, PKD and NPHP (early onset/autosomal recessive) – medullary cystic kidney diseases complex (late onset/autosomal dominant).Citation19 Hence, the value of US scanning as a simple and non-invasive tool in suspected cases to reveal the pattern of underlying renal growth and structural defect, if any.
Abdominal US could determine the pattern of renal cystic disease in 90.5% of our cases and abdominal CT examination added new data in only 3 cases with ARPKD out of 19 cases examined. Ultrasonography was, therefore, considered a useful and sensitive tool in this study. To the same effect, Sweeney and Avner, Citation19 stated that CT studies may be used in cases where US imaging is equivocal or when more complicated issues are suspected, such as the possibility of a tumor.Citation19
Regarding the 12 biopsied cases with NPHP, 2 patients with infantile NPHP lacked tubular basement membrane (TBM) disruption, which has been previously reported.Citation20 While O’Toole et al.Citation21 reported that the triad was present in all biopsied cases in their series of 119 families, one patient with juvenile NPHP and ESRD in our series had biopsy evidence of advanced sclerosis lacking this triad, indicating that the classic triad might not be universally demonstrable in all cases of ESRD secondary to juvenile NPHP. This may be due to the sample size of a kidney biopsy and the focal nature of the TBM disruption. It may also be due to the advanced state of renal scarring in our ESRD patient blurring such distinctive feature.
Kidney biopsy in renal cystic diseases is mainly indicated to verify the diagnosis of nephronophthisis when clinically suspected and ultrasonography is non-conclusive (e.g., normal or slightly reduced kidney size with poor corticomedullary differentiation but lacking cysts). Definitive diagnosis by molecular genetic testing could eliminate the need for biopsy.
While ARPKD is classically described as a disease of infancy with the neonatal presentation of enlarged echogenic kidneys and respiratory distress from pulmonary hypoplasia,Citation22 this typical picture is not always the case as a wide range of presenting features are described including later presentation with evidence of renal insufficiency or liver disease. Although hepatic involvement is invariable, it was evident at presentation in 37% of our cases, while Zerres et al.Citation23 reported an even higher figure of 50%. Manifesting portal hypertension existed in 14.8% of our cases in agreement with Guay–Woodford and Desmond, 2003 who reported a close percentage of 15%.Citation24
Consistent with previous reports of abnormalities in the contralateral kidney in 22% of cases of MCDK,Citation25 VUR (vesico-ureteric reflux) or PUJO were present in 5 of our 20 cases of MCDK and UTI complicated 9 cases. Evaluation of MCDK patients include VCUG to detect contralateral VUR. That being said, VCUG is only recommended when US reveals abnormalities of the contralateral kidney, or failure to show its expected compensatory hypertrophy on serial scans.
Interestingly, the current study included eight, yet unclassified, cases that did not fit any of the previously reported syndromes and could possibly represent newly described clinical phenotypes of ciliopathies. Of note, infantile presentation was a common feature in 7 out of the 8 patients ().
Table 3. Clinical phenotypes of the eight unclassified syndromic cystic kidneys patients.
Mounting evidence suggests that mutations in ciliary genes have been attributed to human genetic disorders particularly cystic kidney diseases at such an accelerating rate that prompted the authors to explore the potential of underlying recessive single gene defects in children with cystic kidney diseases. Therefore, the authors are engaged in collaborative research work combining homozygosity mapping and whole exome resequencing with clinical and ultrasonographical findings to study many of the current study patients. Preliminary unpublished results in our unique community with high rate of consanguineous marriages are encouraging and could be further illuminating in these clinically and genetically heterogeneous disorders.
Cystic kidney diseases in this study included a number of disorders that range from conditions in which the kidney is either the sole organ affected (isolated NPHP), to diverse and pleiotropic clinical phenotypes where cystic kidneys represent one of the observed pathologies along with the extrarenal involvement (NPHP-related ciliopathies).Citation26 The function of the primary cilium and its dysfunction in these diseases remains a focus of intense research investigation. Mutations in genes that affect ciliary structure or function are increasingly recognized, yet they are highly heterogenous with a phenotypic spectrum ranging from dysplasia to degeneration or cystic change.Citation27 It is therefore expected that with the ongoing remarkable progress towards gaining an understanding of the genetic, cellular, and molecular basis of the renal ciliopathies/cystic diseases of the kidney, many of these syndromes will be soon defined.
As shown, renal cystic diseases include a heterogeneous group of disorders that share renal cysts as a common feature. While inherited disorders were the most common in this series, it might not reflect their prevalence in the community since the study represents the experience of a major tertiary referral center. Extrarenal manifestations are common mostly in the context of well defined syndromes, yet occasionally exhibited in unreported constellations possibly representing newly described syndromes. US is a useful screening and initial diagnostic tool with a possible role for additional imaging modalities and shrinking role for renal biopsy. Therefore, in the current study, we propose a modified algorithmCitation28 as a simple tool for characterization of cystic kidney diseases. It is particularly helpful to pediatricians and nephrologists for proper categorization of children with cystic kidney diseases ().
Nonetheless, genetic studies are indicated to confirm the diagnosis in inherited cystic kidney diseases with identified genetic basis, given that mutations in roughly 50 genes have been associated with renal ciliopathies so far. Nevertheless, 70% of NPHP patients still remain genetically unexplained.Citation9 Hence, the continued need to rely on detailed clinical and imaging information to properly phenotype, manage, and guide genetic testing in patients with cystic renal disorders.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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