Autosomal dominant polycystic kidney disease—type 2. Ultrasound, genetic and clinical correlations

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189

178

Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in ϳ40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

Section: Mutation Screening Dna Sequencing and Founder Effectsmentioning

confidence: 99%

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Voskarides¹,

Damianou²,

Neocleous³

et al. 2007

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189

178

“…In individuals who are older than 60, simple cysts commonly occur and may result in a misdiagnosis, particularly in those without a family history, and more cysts (more than eight cysts present bilaterally) are required to make a diagnosis. A normal ultrasound in an individual who is older than 30 yr and from a family with PKD1 or PKD2 is highly sensitive (97 to 100%) (50,53,54). Agespecific information remains high in those who are between 15 and 30 yr and have a normal ultrasound conferring, a 95 to 97% likelihood of not inheriting ADPKD in individuals with PKD1 and 67% in individuals with PKD2 (55).…”

Section: Approaches To Diagnosis Of Adpkdmentioning

confidence: 99%

Autosomal Dominant Polycystic Kidney Disease

Chapman

2007

Diagnosis and treatment of autosomal dominant polycystic kidney disease (ADPKD) is rapidly changing. Cellular pathways that involve the polycystins are being mapped and involve the primary cilium, intracellular calcium and cAMP regulation, and the mammalian target of rapamycin (mTOR) pathway. With the use of new imaging approaches, earlier diagnosis of hepatic cystic disease is possible, and measurement of kidney and cystic growth as well as kidney blood flow is possible over relatively short periods. PKD gene type, gender, proteinuria, and the presence of hypertension relate to the rate of kidney growth in ADPKD. On the basis of risk factors for progression to ESRD and the pathogenic roles that intracellular cAMP and mTOR play in cystogenesis, novel therapies are now being tested, including maximal inhibition of the renin-angiotensin system, inhibition of renal intracellular cAMP using vasopressin V2 receptor antagonists, and somatostatin analogues, as well as inhibitors of mTOR. This review addresses the current understanding of the pathogenesis and the natural history of ADPKD; accuracy and reliability of diagnostic approaches in utero, childhood, and adulthood; the value of reliable magnetic resonance imaging to measure disease progression early in the course of ADPKD; and novel therapeutic approaches that are being evaluated in ADPKD.

“…However, considerable renal disease variability (age range of onset of ESRD, 40 to 88 yr) was also evident between individual patients. described (17)(18)(19)(20)(21)(22)(23)(24)(25), and the remaining mutations from 21 families are reported here for the first time. The diagnosis of ADPKD in the patients and at-risk individuals from each study family was established using well-established ultrasound-based criteria (26).…”

Section: Study Patientsmentioning

confidence: 99%

“…DNA isolation and mutation screening methods have been previously detailed (17)(18)(19)(20)(21)(22)(23)(24). Single-stranded conformational polymorphism (SSCP), heteroduplex analysis (HA), or direct sequencing was employed to screen all 15 exons and their flanking intronic sequences of PKD2 (28) for PKD2 mutations in one definitively affected individual from each study family.…”

Section: Pkd2 Mutational Analysesmentioning

confidence: 99%

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Magistroni

He²,

Wang³

et al. 2003

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126

Abstract. Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance Յ 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P Ͻ 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.