Clinical aspects of autosomal recessive polycystic kidney disease

Abstracts

INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR) é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts) foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses), com distribuição similar entre os sexos (52% dos pts do sexo feminino). Houve histórico familiar da doença em 20% dos casos (5/25), com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS) em 56% dos Pts (14/25); doença renal crônica estágio > 2 (DRC > 2) em 24% (6/25); infecções do trato urinário (ITU) em 40% (10/25) e hipertensão portal (HP) em 32% dos casos (8/25). Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses), HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce.

rim policístico autossômico recessivo; base de dados; processos patológicos

ORIGINAL ARTICLE

^IFaculdade de Medicina da Universidade de São Paulo - FMUSP

^IIUnit of Pediatric Nephrology of the Instituto da Criança of the Hospital das Clínicas of the FMUSP

^IIIDiscipline of Nephrology of the Department of Internal Medicine of the FMUSP, Laboratory of Cellular, Genetic and Molecular Nephrology of FMUSP

^IVDepartment of Pediatrics of the FMUSP, Unit of Pediatric Nephrology of the Instituto da Criança of the FMUSP

Corresponding author

ABSTRACT

INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum.

METHODS: The clinical presentation and evolution of 25 patients (Pts) were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al. Morbidities associated with the disease were evaluated with respect to their frequencies and age of onset.

RESULTS: The median age at the diagnosis was 61.45 months (0 to 336.5 months), with similar gender distribution (52% of the patients were female). A family ARPKD history was found in 20% of the cases (5/25), two of them associated with consanguinity. On arrival, arterial hypertension (SAH) was diagnosed in 56% of the Pts (14/25); chronic kidney disease stage > 2 (CKD > 2) in 24% (6/25); urinary tract infection (UTI) in 40% (10/25); and portal hypertension (PH) in 32% of the cases (8/25). Eighty percent of the initial abdominal ultrasonograms detected echogenic kidneys with gross cysts and 64% demonstrated normal liver and biliary ducts. ACE inhibitors were used in 36% of the analyzed patients, beta-blockers in 20%, calcium channel blockers in 28%, and diuretics in 36% of them. In the final evaluation, after an average follow-up time of 152.2 months (29.8 to 274.9 months), SAH was detected in 76% of the cases, CKD > 2 in 44%, UTI in 52% and PH in 68%.

CONCLUSION: The high morbidity and mortality associated with ARPKD justify the assembly of an international database, with the aim of establishing an early therapeutic support.

Keywords: autosomal recessive polycystic kidney; database; pathologic processes.

Introduction

Autosomal recessive polycystic kidney disease (ARPKD) is a frequently severe form of pediatric cystic kidney disease that affects the kidneys and the biliary tract. It has an estimated incidence of approximately 1:20,000 live births, as suggested in the most recent analyses by Zerres et al.¹

All typical forms of ARPKD result from mutations in the same gene, PKHD1 (Polycystic Kidney and Hepatic Disease 1). That locus was mapped to the chromosome 6p21.1-p12 in 1994/1995^2,3 and identified by Onuchic et al. and Ward et al. in 2002.^4,5 The first group of researchers used positional cloning, while the other group of researchers used the characterization of that gene's ortholog, mutated in the model of the PCK rat. The PKHD1 gene extends over a genomic segment of at least 469 kb and is highly complex, comprising a minimum of 86 exons. Its exons are assembled in a complicated pattern of splicing, originating a large number of alternative transcripts.⁴

PKHD1 encodes an integral membrane protein with 4,074 amino acids and still poorly known function, called polyductin or fibrocystin.^4,5 However, if many of its alternative transcripts are translated, the proteins encoded by that gene should form two groups: one comprising transmembrane domain products, related to the membrane, and other including proteins without that domain and, therefore, soluble and possibly secreted. Several authors have recently assessed the expression profile of polyductin. In the adult human kidney, its expression has been detected in the cortical and medullary collecting tubules and in the thick ascending limb of Henle's loop.⁶ On the other hand, at the subcellular level, expression of polyductin in the axoneme and basal body of primary apical cilia has been demonstrated, indicating that it is one more protein involved in the pathogenesis of a polycystic kidney disease expressed in that organelle.⁶ Positive labeling in the luminal membrane and cytoplasm of the cells of the collecting duct has also been detected. Those studies have also included embryonal kidney tissue of mouse, showing specific labeling in the branch of the ureteric bud.

The diagnosis of ARPKD can be performed in the intrauterine period, neonatal period or in the first months of life, through ultrasound detection of bilateral diffuse kidney enlargement. Its clinical presentation, however, is highly variable and can be identified in the perinatal, infantile, or juvenile period. Oligohydramnios is a common finding, due to the low fetal urinary output, and is rarely observed before the 20^th gestational week. As a consequence of the oligohydramnios, the fetuses affected develop the Potter sequence, a phenotype comprising lung hypoplasia, typical facies, and extremity anomalies. Regarding histopathology, ARPKD is characterized by a fusiform dilatation of the collecting tubules and dysgenesis of the hepatic portal triad - characterized by hyperplastic biliary ducts and congenital hepatic fibrosis.

Recessive autosomal polycystic kidney disease has a poor prognosis, and approximately 30% of the neonates affected die in the perinatal period, usually as a result of respiratory failure. Less severe cases survive and have bilaterally palpable kidneys, arterial hypertension, impaired urine concentration, metabolic acidosis due to impaired distal acidification, and progressive kidney failure. Liver impairment varies and can be asymptomatic or progress to portal hypertension.

Bergmann et al. have shown that most mutations are unique within a family (private mutations), making the establishment of genotype-phenotype correlations difficult and complicating the elaboration of a direct test for molecular diagnosis.⁷ On the other hand, genotype-phenotype correlations have been mainly based on the type of mutation. Almost all patients with both mutations associated with the truncation of the longest open reading frame product of the gene have the most severe phenotype of the disease, while almost all patients with a moderate phenotype have at least one mutation associated with the replacement of amino acids in polypeptide chains.^8,9,10 The mutation most frequently found in the studies performed to this date was c.107 C > T, a missense mutation. The greatest mutation detection rate obtained so far, 87.5%, was achieved by Sharp et al. in a study using the strategy of denaturing high performance liquid chromatography (DHPLC) and sequencing.¹⁰

The present study aimed at assessing the initial and follow-up clinical data of patients diagnosed with ARKPD and followed up at the outpatient clinic of the Unit of Pediatric Nephrology of the Instituto da Criança - HCFMUSP. That assessment was performed by use of initial and follow-up clinical questionnaires developed by Guay Woodford et al. for characterizing North-American patients.¹¹ Such information will be essential for the clinical characterization of ARKPD and its understanding, as well as for establishing genotype-phenotype correlations.

Patients and Methods

The medical records of patients diagnosed with ARKPD were retrospectively assessed. Such patients had been registered at the Instituto da Criança - HCFMUSP, from 1990 to July 2008. Their diagnosis was based on the criteria of initial and follow-up clinical history based on the questionnaire developed by Guay-Woodford et al.¹¹ The guardians of all patients whose medical records were assessed provided written informed consent for their participation in the study, and the study project was submitted to and approved by the Committee on Ethics and Research of the HCFMUSP.

The data obtained underwent a descriptive statistical analysis by using mean (or median), maximum, and minimum values for continuous variables and frequencies for categorical variables.

Results

Description of the cohort and demographic characteristics

The assessment of the patients of the Unit of Nephrology of the Instituto da Criança - HCFMUSP diagnosed with ARPKD was conducted by using a database of SAME, in the period from 1990 to 2008. Of the 98 patients initially listed, 25 had their diagnosis of ARPKD confirmed. Then, each medical record was assessed, and the admission and follow-up forms of each patient were all completed.

The distribution of the disease was similar between genders, with 13 (52%) female patients and 12 (48%) male patients. The ethnicity mostly affected by ARPKD was Caucasian (76%), followed by African (20%) and Asian (4%; 1 patient). Prenatal diagnosis was established in 5 cases (20%), by use of fetal ultrasound scan. Consanguinity between parents was evidenced in only two cases and family history of ARPKD in five (20% of the cases). Two patients died because of septicemia due to dialysis complications.

Clinical Characteristics

The mean age at diagnosis was 61.45 months (0 to 336.5 months).

Regarding the gestational age, four cases were premature (16%), 13 cases were full term (52%), while in the remaining eight cases (32%) no information was provided. Neonatal mechanical ventilation was required in two premature newborns (50%) and one full-term patient (5%), but none of them developed chronic pneumopathy.

Table 1 shows the frequencies of identification of the clinical characteristics upon diagnosis and final analysis of the cases, after a mean follow-up of 152.2 months (29.8 to 274.9 months).

To control arterial hypertension diagnosed upon presentation, 36% of the patients used angiotensin-converting enzyme inhibitors (ACEI); 20% used betablockers; 28% used calcium-channel blockers; and 36% used diuretics. Recombinant human erythropoietin was introduced upon presentation in 8% of the cases for the treatment of anemia secondary to chronic kidney failure. By the time of final assessment, 68% of the patients had used ACEI to control arterial hypertension (17/25), 44% had used betablockers (11/25), 48% had used calcium channel blockers (12/25), and 36% had used diuretics (9/25). Recombinant erythropoietin was administered to 20% of the patients (5/25) to treat anemia associated with chronic kidney disease.

Radiologic findings

Initial radiologic assessment revealed, in 80% (20/25) of the kidney ultrasound scans, echogenic kidneys with gross cysts, while only 40% of the ultrasound scans with no gross cysts (2/5) showed an increase in kidney size. Liver ultrasound scan was normal in 64% of the patients (16/25), while 28% of the patients (7/25) had echogenic liver, and 16% (4/25) had dilated biliary ducts.

Histopathological findings

Two patients underwent unilateral nephrectomy prior to dialysis. The histological analysis of that material showed dilated distal and collecting tubules. Thirteen liver biopsies were performed, six of which (46.1%) revealed biliary dysgenesis and five (38.5%) showed congenital hepatic fibrosis.

Discussion

Our findings represent the beginning of the clinical study of ARPKD in Brazil. The comparison of the present study data with those from the greatest clinical database of ARPKD, representative of the North-American population11, has shown similar sex and ethnic distributions, with a mean age at diagnosis (61.45 months) much greater than that reported in the North-American cohort (1 to 72 days of life).

In our cases, 20% of the diagnoses were antenatal, a figure greater than that reported by Zerres et al.¹ in the German population (10%), but much lower than that of the North-American cohort, in which 45.8% of the live births after 1990 had a prenatal diagnosis of ARPKD. In our study, neonatal mechanical ventilation was required in 2/4 of the premature newborns (50%) and in one full-term patient (5%), but none of them developed chronic pneumopathy. On the other hand, in the above-cited North-American cohort, 40% of births after 1990 required mechanical ventilation, and 11.6% developed chronic pneumopathy.

Portal hypertension was diagnosed in 68.0% of our patients in the follow-up period, while only 34.2% of the North-American patients had it. The frequency of bleeding esophageal varices was also increased in the Brazilian group of patients (24.0%) as compared to that of the North-American patients (10.0%).

Regarding the initial finding of hyponatremia, our data are similar to those of the North-American patients. The same was observed regarding the frequencies of chronic kidney failure and arterial hypertension, the latter being the most frequently diagnosed morbidity in ARPKD. The frequencies of kidney and liver transplantations reported by Guay-Woodford et al. ¹¹ were 22.5% and 7.0%, respectively, while in our population of patients, 5.0% underwent kidney transplantation and none underwent liver transplantation.

The ultrasound findings in the North-American study¹¹ revealed echogenic kidneys with gross cysts in 50.0% of the initial ultrasound scans and echogenic kidneys without cysts in the remaining cases. Regarding the initial liver ultrasound scans, 52.7% were within the normal range. On the other hand, our findings showed echogenic kidneys with gross cysts in 80.0% of the initial kidney ultrasound scans (20/25) and a normal pattern in 64.0% of liver ultrasound scans. However, it is worth emphasizing that, according to Zerres et al.¹, ultrasound alterations frequently pass unnoticed in the prenatal period, the time when almost half of the North-American ARPKD cases are diagnosed.

The histopathological findings of the kidneys in both group of patients were similar. However, in the North-American group, biliary dysgenesis was found in 95.5% of the patients, while in the Brazilian group, 46.1% of the patients had biliary dysgenesis, 38.5% had congenital hepatic fibrosis, and 15.4% showed unaltered hepatic morphology.

Conclusion

In conclusion, our findings show the varied manifestations of ARPKD in the Brazilian population. The patients studied were diagnosed at a late stage, which was complicated by the frequent lack of knowledge about the clinical presentation of ARPKD of the health professionals in our country. Such patients usually had early kidney impairment with subsequent development of liver morbidities.

Our findings represent the beginning of a project aimed at building a database with demographic and initial and follow-up clinical characteristics of ARPKD in the Brazilian population to collect the information needed to establish genotype-phenotype correlations. The next step is the already initiated aggregation of patients from other medical centers from several regions of Brazil. The importance of a national database lies not only on the characterization of the disease in the Brazilian population, but also on the feasibility of the identification of patients for future clinical studies.

References

• 1. Zerres K, Mucher G, Becker J et al Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 1998; 76:137-44.
• 2. Zerres K, Mucher G, Bachner L et al Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet 1994; 7:429-32.
• 3. Guay-Woodford LM, Muecher G, Hopkins SD et al The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: implications for genetic counseling. Am J Hum Genet 1995; 56:1101-7.
• 4. Onuchic L, Furu L, Nagassawa Y et al PKHD1, the policystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple IPT domains and PbH1 repeats. Am J Human Genet 2002; 70:1305-17.
• 5. Ward C, Hogan M, Rossetti S et al The gene mutated in autossomal recessive polycystic disease encodes a large, receptor-like protein. Nat Genet 2002; 30:259-69.
• 6. Menezes LF, Cai Y, Nagasawa Y et al Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int 2004; 66:1345-55.
• 7. Bergmann C, Senderek J, Windelen E et al Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int 2005; 67:829-48.
• 8. Furu L, Onuchic LF, Gharavi A et al Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol 2003; 14:2004-14.
• 9. Bergmann C, Senderek J, Sedlacek B et al Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol 2003; 14:76-89.
• 10. Sharp AM, Messiaen LM, Page G et al Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet 2005; 42:336-49.
• 11. Guay-Woodford L, Desmond R. Autossomal Recessive Policystic Kidney Disease: The Clinical Experience in North America. Pediatrics 2003; 5:1072-80.

Clinical aspects of autosomal recessive polycystic kidney disease (ARPKD)

Natasha Favoretto Dias^I; Vivian Lanzarini^II; Luiz Fernando Onuchic^III; Vera Hermina Kalika Koch^IV

Publication Dates

• Publication in this collection
  25 Oct 2010
• Date of issue
  Sept 2010

History

• Received
  31 May 2010
• Accepted
  04 July 2010