Angiogenesis in autosomal-dominant polycystic kidney disease.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder that is responsible for approximately 10% of all cases of end-stage renal disease (ESRD). It is characterized by the formation of epithelial cell cysts, an increase in the extracellullar matrix, and vascular alterations believed to be the result of compression by the cysts. Our recent observations demonstrated a rich vascular network on the surface of the cysts, and thus, we postulated that angiogenesis could be a factor in the progression of ADPKD. METHODS: Kidneys removed from patients with ADPKD were studied using (1) angiographs, (2) immunostaining [factor VIII-related antigen, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2), metalloproteinase-2 (MMP-2), and integrin alphavbeta3], and (3) Western blot analysis and enzyme-linked immunosorbent assay. The expression of VEGF165 in ADPKD cells in culture was determined. RESULTS: There was (1) an extensive capillary network in the cyst wall of ADPKD kidneys, (2) morphological evidence of vascular malformations, (3) expression of VEGF165 in cyst cells of VEGFR-2 in endothelial cells and an absence of VEGFR-1 in endothelial cells, (4) secretion of VEGF165 by ADPKD cyst cells in culture, and (5) coexpression of matrix MMP-2 and integrin alphavbeta3 in vessels from ADPKD. CONCLUSIONS: There is angiogenesis in ADPKD. This process may be necessary for cyst cells to grow and may be responsible for increased vascular permeability facilitating fluid secretion into the cysts. Neovascularization may result in the formation of aneurysms responsible for the renal bleeding in this disease.     

Progression of autosomal-dominant polycystic kidney disease in children

BACKGROUND: Although many case reports describe manifestations of autosomal-dominant polycystic kidney disease (ADPKD) in children, no longitudinal studies have examined the natural progression or risk factors for more rapid progression in a large number of children from ADPKD families. METHODS: Since 1985, we have studied 312 children from 131 families with a history, a physical examination, blood and urine chemistries, an abdominal ultrasonography, and gene linkage analysis. One hundred fifteen of 185 affected children were studied multiple times for up to 15 years. Renal volumes were determined by ultrasound imaging. Graphs of mean renal volumes according to age were compared between affected and unaffected children, ADPKD children with and without early severe disease, and children with and without high blood pressure. RESULTS: Affected children had faster renal growth than unaffected children. ADPKD children with severe renal enlargement at a young age continued to experience faster renal growth than those with mild enlargement or normal kidney size for their age, and affected children with high blood pressure had faster renal growth than those with lower blood pressure. Glomerular filtration rate did not decrease in any children except for two with unusually severe early onset disease. CONCLUSIONS: The progression of ADPKD clearly occurs in childhood and manifests as an increase in cyst number and renal size. This study identifies children at risk for rapid renal enlargement who may benefit the most from future therapeutic interventions.     

Treatment prospects for autosomal-dominant polycystic kidney disease

An increased understanding of the molecular genetic and cellular pathophysiologic mechanisms responsible for the development of autosomal-dominant polycystic kidney disease (ADPKD), made possible by the advances in molecular biology and genetics of the last three decades, has laid the foundation for the development of effective therapies. As the concept that a polycystic kidney is a neoplasm in disguise is becoming increasingly accepted, the development of therapies for ADPKD may benefit greatly from the expanding body of information on cancer chemoprevention and chemosuppression. This review summarizes the observations that already have been made and discusses therapies for PKD that deserve investigation.     

Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease

Congenital hepatic fibrosis was found in four families with autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis is commonly though to be characteristic for autosomal-recessive polycystic kidney disease, but the reported families, show that it can also complicate autosomal-dominant polycystic kidney disease. In three families close linkage between the mutation causing the disease and DNA markers on chromosome 16 was demonstrated. The clinical course of the congenital hepatic fibrosis differed considerably; in one family the children with congenital hepatic fibrosis died soon after birth, in the three other families an approximately 20 years follow-up showed no detectable progression of the liver disease.     

Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease

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Determinants of renal volume in autosomal-dominant polycystic kidney disease

The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker.     

Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease

BACKGROUND: Approximately 8% of autosomal-dominant polycystic kidney disease (ADPKD) patients have intracranial aneurysms. The risk of growth and rupture of those discovered by presymptomatic screening is key to the feasibility and success of a screening program. This study was initiated to ascertain this risk. METHODS: ADPKD patients were offered screening with magnetic resonance (MR) imaging that included three-dimensional time-of-flight MR angiographic and three-dimensional phase-contrast sequences. Patients with aneurysms were recommended periodic surveillance, initially at 6 months and yearly, and less frequently after demonstration of their stability. RESULTS: Twenty-two saccular and one fusiform aneurysms were detected at the initial screening in 21 patients from 19 families (seven men and 14 women, 47.9 +/- 10.6 years old). All the saccular aneurysms were small (mean diameter 3.5 mm, range 2.0 to 6.5 mm) and the majority (77%) in the anterior circulation. Two patients died from unrelated causes without further follow-up. One patient was lost to follow-up. A new 2 mm middle cerebral artery aneurysm developed in one patient. One aneurysm increased from a size of 4 mm to 5 mm after a follow-up of 105 months. No aneurysmal development or growth occurred in the remaining 16 patients. No aneurysmal rupture occurred during a mean imaging follow-up of 81 months and a mean clinical follow-up of 92 months. During the period of the study, two additional ADPKD patients, with three intracranial aneurysms detected elsewhere by presymptomatic MR angiographic screening, were referred for surgical treatment. The larger size of these aneurysms (10, 8, and 8 mm) probably reflects referral bias. CONCLUSION: Most intracranial aneurysms detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. The follow-up results do not suggest an increased risk for growth and rupture, compared to those of intracranial aneurysms in the general population. These data do not support widespread screening for intracranial aneurysms in the ADPKD population.     

Recurrence of intracranial aneurysms in autosomal-dominant polycystic kidney disease

BACKGROUND: The natural history of intracranial aneurysms (ICAs) in individuals with autosomal-dominant polycystic kidney disease (ADPKD) is poorly defined. METHODS: We followed twenty ADPKD subjects, eleven with ruptured and nine with intact ICA, for 15.2 +/- 8.1 years (range, 6.0 to 33.2 years). Initial diagnosis was by four-vessel cerebral angiography in eighteen subjects. Follow-up examinations were four-vessel cerebral angiography in fourteen and magnetic resonance angiography (MRA) in six subjects. We examined the occurrence of new ICAs, an increase in size of existing ICAs, recurrent rupture or surgical intervention, and death. RESULTS: Age at initial diagnosis of ICA was 37.7 +/- 10.4 years (range, 20.2 to 53.1 years). Seventeen subjects (85%) had an anterior and three (15%) had a posterior ICA at initial diagnosis. On restudy, five subjects (25%) had a significant change, consisting of new ICAs in a different location in all five and an increase in size of an existing ICA in two of the five. All subjects with ruptured ICA and one subject with intact ICA had undergone surgery at the time of initial diagnosis. Ten subjects (50%) underwent further surgery 8.1 +/- 6.1 years later (1.3 to 17 years). No subject died during follow-up and one subject experienced a recurrent RICA (RICA). We were unable to identify risk factors associated with development of a new ICA or increase in size of an existing ICA. CONCLUSION: Individuals with ADPKD and ICA appear to be at moderate risk for new ICAs and increase in size of existing ICAs; mortality and risk of recurrent rupture, however, appear to be low.     

Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease

Infections involving cysts of patients with autosomal-dominant polycystic kidney disease (PCKD) are often refractory to therapy possibly because of poor penetration of antibiotics into cyst fluid. Ten patients with PCKD had blood urine and cyst fluid sampled at surgery or autopsy for antibiotic concentrations. Cysts were categorized as to their nephron site of origin by cyst fluid sodium concentrations. Drugs active against anaerobes such as metronidazole and clindamycin were present in therapeutic concentrations in both proximal and distal cysts. Ampicillin and trimethoprim-sulfamethoxazole had the best profiles considering likely infecting organisms and the antibiotic concentrations achieved in both type of cysts. It is likely that prolonged therapy with both of these drugs is necessary to insure therapeutic success. Other drugs that can be detected in cysts are lipid soluble, undergo tubular secretion, or have high pKa values. These include erythromycin, vancomycin, and cefotaxime. Aminoglycosides because of their predominant glomerular filtration and thus low filtration rate per single cystic nephron are undetectable in both proximal and distal cysts. Clinically, alternatives to aminoglycosides should be chosen for infected cysts in PCKD.     

Risk of intracranial aneurysm bleeding in autosomal-dominant polycystic kidney disease

Patients with autosomal-dominant polycystic kidney disease (ADPKD) carry an increased risk of developing intracranial aneurysms. Bleeding from these sites is a significant complication with the events reported to cluster in some families. In this study we determined if individualized risk of aneurysm rupture can be estimated based on family history using a Bayesian random effects model. Previously reported data were used to define distributions and to construct a model that fit these data. Our results confirm that intracerebral aneurysm bleeding in ADPKD patients tends to cluster in families and that basic family history can provide a simple estimate of family-specific risk.     

Current advances in molecular genetics of autosomal-dominant polycystic kidney disease

Autosomal-dominant polycystic kidney disease results from at least two causal genes, PKD1 and PKD2. The identical clinical phenotype in human patients and targeted Pkd1 and Pkd2 mutant mouse models provides evidence that both gene products act in the same pathogenic pathway. The discovery of direct PKD1 and PKD2 interactions implies that both gene products, polycystin-1 and polycystin-2, play a functional role in the same molecular complex. The spectrum of germ-line mutations in both genes and the somatic mutations identified from individual PKD1 or PKD2 cysts indicate that loss of function of either PKD1 or PKD2 is the mechanism of cystogenesis in autosomal-dominant polycystic kidney disease. A novel mouse model, Pkd2WS25/-, has proved that loss of heterozygosity is the molecular mechanism of autosomal-dominant polycystic kidney disease. Recently, studies on the expression patterns of PKD1 and PKD2 in humans or mice indicate that polycystin 1 and polycystin 2 seem to have their own respective functional roles, even though most of the functions of these polycystins are parallel during human and mouse development. Pkd2-deficient mice have cardiac septum defects, but Pkd1 knockout mice do not have this phenotype. On the other hand, Pkd2 has a very low level of expression in the central nervous system when compared with Pkd1. In addition, the level of expression of Pkd1 is increased during mesenchymal condensation, whereas Pkd2 expression is unchanged. Preliminary data have shown that the PKD1/PKD2 compound trans-heterozygous has a more severe cystic phenotype in the kidney than that of an age-matched heterozygous type 1 or type 2 of autosomal-dominant polycystic kidney disease alone. This finding suggests that PKD1 may be a modifier of disease severity for PKD2, and vice versa. The characteristics of the contiguous PKD1/TSC2 syndrome phenotypes and the data from Krd mice imply that TSC2 and PAX2 may also serve as potential modifiers for the disease severity of autosomal-dominant polycystic kidney disease.     

Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease

BACKGROUND: Left ventricular diastolic dysfunction has been shown in patients with autosomal-dominant polycystic kidney disease (ADPKD). However, there is no study evaluating right ventricular functions in these patients. METHODS: In the present study, diastolic functions of both ventricles in normotensive and hypertensive ADPKD patients with well-preserved renal function were investigated. Fifteen hypertensive and 16 normotensive patients with ADPKD with well-preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Conventional left and right ventricular echocardiographic measurements were performed in all subjects. Left and right ventricular functions were investigated both by myocardial performance index (MPI) [calculated by dividing the sum of isovolumic contraction time and isovolumic relaxation time (IVRT) by ejection time] and by tissue Doppler imaging (TDI). RESULTS: Left ventricular deceleration time and IVRT were significantly prolonged in hypertensive patients with ADPKD compared with patients with essential hypertension and even in normotensive patients with ADPKD compared with healthy subjects. Left and right MPIs were significantly higher in patients with ADPKD compared with healthy subjects, showing systolic and diastolic dysfunction. Moreover, by using TDI, the peak early diastolic mitral annular velocity (Em) to peak late diastolic mitral annular velocity (Am) ratio and the peak early diastolic tricuspid annular velocity (Et) to peak late diastolic tricuspid annular velocity (At) ratio were decreased in patients with ADPKD, suggesting biventricular diastolic dysfunction. CONCLUSION: Both hypertensive and normotensive patients with ADPKD show significant biventricular diastolic dysfunction, suggesting cardiac involvement very early in the course of ADPKD.     

Arachnoid cyst in a patient with autosomal-dominant polycystic kidney disease

We report a case of an arachnoid cyst of the posterior cerebral fossa in a man with autosomal-dominant polycystic kidney disease. No traumatic or infectious etiology for the cyst could be identified.     

Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease

It is known that many tubular proteins are involved in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which causes 8-10% of the cases of end-stage renal disease (ESRD) worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli such as ischemia or toxicity. In the present study, serum and urinary NGAL levels were evaluated in 26 ADPKD subjects. Both levels were significantly higher in patients than in controls (sNGAL 174 +/- 52 vs. 50 +/- 27 ng/ml, p < 0.05; uNGAL 119 +/- 42 vs. 7 +/- 6 ng/ml, p < 0.005) and a close correlation was also found between these parameters and the residual renal function (sNGAL/GFR: r = -0.8, p = 0.006; sNGAL/Creatinine: r = 0.9, p = 0.007; uNGAL/GFR: r = -0.49, p < 0.05; uNGAL/Creatinine: r = 0.84, p < 0.001). Patients were further divided into two groups according to the cystic development assessed with echotomography; subjects with higher cystic growth (HCG) presented higher sNGAL and uNGAL levels with respect to others (sNGAL: 242 +/- 89 vs. 88 +/- 34 ng/ml, p < 0.05; uNGAL: 158 +/- 45 vs. 73 +/- 27 ng/ml, p < 0.05). The strict correlation between NGAL levels and residual renal function is perfectly in accord with recent studies on patients with other ESRD-associated diseases. We can hypothesize that tubular cells produce big quantities of NGAL as a consequence of increased apoptosis following chronic damage or as a compensatory response, similar to that observed in acute stress conditions (ischemia, toxicity ...). Finally, our last finding that patients with HCG showed higher levels of NGAL suggests that this protein could be also involved in the cyst growth process, as previously reported about epithelial and tumoral expansion.     

Cardiac involvement in autosomal-dominant polycystic kidney disease: a hypertensive heart disease

BACKGROUND: There is little information regarding the occurrence and distribution of cardiovascular abnormalities during the course of autosomal-dominant polycystic kidney disease (ADPKD). We conducted a cross-sectional study in three different groups of ADPKD patients to determine the profile and prevalence of cardiac involvement in this population. METHODS: Doppler color echocardiography was performed in 130 ADPKD patients. Patients were divided into normotensive (Group I, n=60), hypertensive (Group II, n=32) and those undergoing hemodialysis (Group III, n=38). RESULTS: There was a progressive increase in left ventricular mass (LVM) index (88.6+/-19.7, 127.6+/-40.4 and 150.5+/-56.5 g/m2, p < 0.0001) and in the prevalence of left ventricular hypertrophy (LVH) (3%, 43%, 62%, p < 0.0001) in Groups I, II and III, respectively. E/A ratio < 1 was found in 2% of normotensives, 46% of hypertensives and 62% of hemodialysis patients (p < 0.0001). Prevalence ofmitral valve prolapse and aortic and/or mitral regurgitation was 4.3% and 8.6%, respectively, in non-dialysis patients. The majority of valvular abnormalities occurred in dialysis patients, and were generally related to annular mitral calcification (28%) or aortic valve calcification (38%). Age, sex, systolic blood pressure (BP) and hemoglobin were independent predictors of LVM index in the entire population, systolic BP and creatinine in non-dialysis patients and systolic BP in dialysis patients. Age, heart rate and diastolic BP in the entire group, and age, heart rate and LVM index in non-dialysis patients remained as independent predictors of abnormal diastolic function. CONCLUSIONS: Cardiac involvement in ADPKD patients is a continuous process that evolves during the course of this disease. It is characterized by a low prevalence of specific valvular abnormalities, a progressive increase in LVM, LVH, and diastolic dysfunction, which are greatest in the latter stages of the disease. This study confirms the major influence of BP on cardiovascular abnormalities of ADPKD patients.