Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis

Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited disorder characterized by the progressive enlargement of fluid-filled cysts in the kidneys and liver. Since the cystic fibrosis transmembrane conductance regulator (CFTR) Cl--channel may mediate the secretion of Cl--and fluid into the cysts, it is conceivable that coexisting cystic fibrosis (CF) in patients with ADPKD could attenuate their development. We previously reported that two patients with ADPKD coexisting with cystic fibrosis (CF) had a milder cystic phenotype than that of kindred without CFTR mutations. A subsequent report failed to confirm this protective effect. We now have identified another family with coexisting type 1 ADPKD and CF. The kidney volumes and the number and size of renal and hepatic cysts were markedly less in a member of this family with ADPKD (PKD1 mutation C508R) and CF (homozygous DeltaF508 mutation) than in her sister with ADPKD alone at comparable ages.     

CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease

Disease-modifying genes might participate in the significant intrafamilial variability of the renal phenotype in autosomal dominant polycystic kidney disease (ADPKD). Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a chloride channel that promotes intracystic fluid secretion, and thus cyst progression, in ADPKD. The hypothesis that mutations of the CF gene, which encodes CFTR, might be associated with a milder renal phenotype in ADPKD was tested. A series of 117 unrelated ADPKD probands and 136 unaffected control subjects were screened for the 12 most common mutations and the frequency of the alleles of the intron 8 polymorphic TN: locus of CF. The prevalence of CF mutations was not significantly different in the ADPKD (1.7%, n = 2) and control (3.7%, n = 5) groups. The CF mutation was DeltaF508 in all cases, except for one control subject (1717-1G A). The frequencies of the 5T, 7T, and 9T intron 8 alleles were also similar in the ADPKD and control groups. Two additional patients with ADPKD and the DeltaF508 mutation were detected in the families of the two probands with CF mutations. Kidney volumes and renal function levels were similar for these four patients with ADPKD and DeltaF508 CFTR (heterozygous for three and homozygous for one) and for control patients with ADPKD collected in the University of Colorado Health Sciences Center database. The absence of a renal protective effect of the homozygous DeltaF508 mutation might be related to the lack of a renal phenotype in CF and the variable, tissue-specific expression of DeltaF508 CFTR. Immunohistochemical analysis of a kidney from the patient with ADPKD who was homozygous for the DeltaF508 mutation substantiated that hypothesis, because CFTR expression was detected in 75% of cysts (compared with <50% in control ADPKD kidneys) and at least partly in the apical membrane area of cyst-lining cells. These data do not exclude a potential protective role of some CFTR mutations in ADPKD but suggest that it might be related to the nature of the mutation and renal expression of the mutated CFTR.     

Role of CFTR in autosomal recessive polycystic kidney disease

An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/+/-). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.     

Liver cysts in Congolese patients with autosomal dominant polycystic kidney disease follow a family pattern.

BACKGROUND: It is now well established that at least two genes are associated with autosomal dominant polycystic kidney disease (ADPKD). OBJECTIVE: To analyse the clinical expression of ADPKD in Congolese patients and to compare ADPKD expression between families. METHODS: Following informed consent, ADPKD patients admitted to Brazzaville University Hospital (Congo) were reviewed and their relatives aged 20 years and older were screened by means of a clinical examination, abdominal ultrasound, urinalysis and determination of serum creatinine. RESULTS: We found 7 patients with ADPKD, belonging to 7 distinct families, and identified 100 relatives of whom 50, aged from 20 to 68 years, were diagnosed as having ADPKD. Polycystic kidney disease was associated with polycystic liver in 4 families. In the remaining 3 families no liver cysts were found. No family had a mixture of members with kidney cysts only and members with kidney and liver cysts. This finding was age-independent. CONCLUSION: Liver cysts follow a family pattern in our ADPKD patients. We suggest that our patients may carry at least two different genes for ADPKD, one of which may be associated with renal cysts alone and other with both renal and liver cysts.     

多囊肾囊内感染与肾移植

常染色体显性多囊肾病（ADPKD）是一种常见的单基因遗传性肾病,可进展为终末期肾病（ESRD）。ADPKD患者常反复发生囊内感染,抗生素治疗所产生的耐药性问题日益突出,肾移植手术方式也需根据多囊肾的感染情况进行选择。本文从肾囊肿起源、囊肿的分类及囊液的来源、囊液内细菌类型及其耐药性、ADPKD患者囊内感染与肾移植治疗等方面进行综述,为ADPKD患者囊内感染的诊治提供参考。     

Octreotide reduces hepatic,renal and breast cystic volume in autosomal-dominant polycystic kidney disease

A 43-year-old woman with autosomal-dominant polycystic kidney disease (ADPKD) received octreotide for 12 months, and this was associated with a 6.3% reduction in liver volume, an 8% reduction in total kidney volume and stabilization of renal function. There was also a reduction of cyst size in fibrocystic disease of breast. These data suggest that the cyst fluid accumulation in different organs from patients with ADPKD is a dynamic process which can be reversed by octreotide. This is the first report of a case of simultaneous reduction in hepatic, renal and breast cystic volume with preservation of renal function in a patient with ADPKD receiving octreotide.     

The spectrum of polycystic kidney disease in children

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are important inherited kidney diseases with distinct clinical features and genetics. Although these diseases have classically been considered "adult" (ADPKD) or "infantile/pediatric" (ARPKD), it is now clear that both diseases can present in children and adults. ADPKD and ARPKD also share important pathophysiologic features, including cilia dysfunction. ADPKD is a systemic disease involving cysts in the kidneys and abdominal organs as well as abnormalities in the heart and vasculature. Although it typically presents in adults, ADPKD has been diagnosed in fetuses, infants, children, and adolescents. The majority of children diagnosed with ADPKD are asymptomatic. Those with symptoms typically present with hypertension or gross hematuria. Routine screening for renal cysts in asymptomatic children who have a parent with ADPKD is generally not recommended. ARPKD is a disorder confined to the kidneys (polycystic kidneys) and liver (a developmental biliary lesion called congenital hepatic fibrosis). Although most children with ARPKD present in infancy with large, echogenic kidneys, a subset present later in childhood and even adulthood, primarily with complications related to the liver disease. As more patients with ARPKD survive to adulthood, these liver complications are likely to become more prevalent.     

Cystic disease in women: clinical characteristics and medical management

Autosomal dominant polycystic kidney disease (ADPKD) is a dominantly inherited systemic disorder equally inherited in men and women characterized by renal cyst development and expansion ultimately leading to renal failure. ADPKD women have a slower rate of progression to renal failure, with a later age of entry into end-stage renal disease (ESRD) as compared with men. Renal cyst growth and renal expansion are the hallmarks of ADPKD, and women will develop renal insufficiency with smaller renal volume than their male counterparts. As well, women have different rates of occurrence of renal and extrarenal complications in ADPKD. Renal complications related to ADPKD, including hypertension and gross hematuria, occur more frequently in men than in women, whereas liver cystic disease occurs earlier and more frequently in women than in men. The presence of polycystic liver disease is related to pregnancy number and oral contraceptive pill use in ADPKD women. Importantly, massive polycystic liver disease requiring surgical intervention occurs primarily in ADPKD women. ADKPD women have a highly successful reproductive course. The chance of a successful pregnancy is excellent in ADPKD women and comparable to healthy unaffected women as long as prepregnancy blood pressure and renal function are normal. Fetal complication rates are no greater than in the general population; however, maternal complication rates in ADPKD women are high with an increased frequency of new or worsening hypertension as well as an increased occurrence of preeclampsia and preterm deliveries. Finally, increasing pregnancy number has minimal or no effect on renal outcome in ADPKD women.     

cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells

Both epithelial cell proliferation and fluid accumulation are responsible for cyst growth in autosomal dominant polycystic kidney disease (ADPKD). It was previously reported that the cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in cysts from ADPKD patients and suggested that cAMP-stimulated Cl(-) and fluid secretion occurs through CFTR. The purpose of this study was to investigate the role of cell proliferation in cyst formation in ADPKD and to explore further the role of fluid secretion in cyst growth. Primary cultures both of ADPKD epithelial cells and a mixed population of normal renal epithelial cells isolated from the cortex (HRCE cells) were used. This study tested whether cAMP was involved both in stimulating cell proliferation and formation of cysts in vitro. (3)H-Thymidine incorporation assays showed that epidermal growth factor stimulated proliferation both in ADPKD cells and HRCE cells. In addition, cAMP stimulated DNA synthesis and cell proliferation in ADPKD, but not HRCE, cells. The effects of cAMP and epidermal growth factor on cell growth in ADPKD cells were additive. cAMP also stimulated cyst enlargement and fluid secretion in ADPKD cells. By contrast, cyst formation and enlargement from HRCE cells occurred without cAMP. Fluid secretion into the cyst lumen was blocked by diphenylamine carboxylic acid (DPC) and glibenclamide in ADPKD cells but blocked only by DPC in HRCE cells. This study showed that ADPKD cells have unique characteristics; cAMP stimulates fluid secretion and cell proliferation, indicating cAMP plays a very important role in cyst growth during the course of ADPKD.     

Increased expression of secreted frizzled-related protein 4 in polycystic kidneys

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disease associated with progressive renal failure. Although cyst growth and compression of surrounding tissue may account for some loss of renal tissue, the other factors contributing to the progressive renal failure in patients with ADPKD are incompletely understood. Here, we report that secreted frizzled-related protein 4 (sFRP4) is upregulated in human ADPKD and in four different animal models of PKD, suggesting that sFRP4 expression is triggered by a common mechanism that underlies cyst formation. Cyst fluid from ADPKD kidneys activated the sFRP4 promoter and induced production of sFRP4 protein in renal tubular epithelial cell lines. Antagonism of the vasopressin 2 receptor blocked both promoter activity and tubular sFRP4 expression. In addition, sFRP4 selectively influenced members of the canonical Wnt signaling cascade and promoted cystogenesis of the zebrafish pronephros. sFRP4 was detected in the urine of both patients and animals with PKD, suggesting that sFRP4 may be a potential biomarker for monitoring the progression of ADPKD. Taken together, these observations suggest a potential role for SFRP4 in the pathogenesis of ADPKD.     

Approach to decortication of simple cysts and polycystic kidneys

Laparoscopic excision and marsupialization of symptomatic of recurrent simple renal cysts is an alternative to open or percutaneous surgery. Such surgery may also be useful for pain relief in patients with autosomal dominant polycystic kidney disease (ADPKD). An occlusion balloon catheter is placed in the renal pelvis at the start of the procedure. Cysts are punctured, and the outer wall of the larger cysts is excised with care not to incise the renal parenchyma. In patients with ADPKD, it is important to mobilize the kidney completely, particularly the upper pole, to treat every visible cyst. A laparoscopic ultrasound probe is used to guide the unroofing of any large cysts within 5 to 10 mm of the renal surface. At the end of the procedure, the integrity of the collecting system is confirmed. Strict criteria must be used in selecting patients with simple cysts for laparoscopic marsupialization to minimize the incidence of unsuspected malignancy, and the cyst wall should be examined by frozen and permanent section. Long-term follow-up is needed to evaluate the effect of laparoscopic decompression in ADPKD.     

The cystic fibrosis transmembrane regulator (CFTR) in the kidney

The cystic fibrosis transmembrane regulator (CFTR) is a Cl - channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl - but also secretes ATP and, thus, controls other conductances such as Na+ (ENaC) and K+ (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.     

Factors predicting decline in renal function and kidney volume growth in autosomal dominant polycystic kidney disease: a prospective cohort study (Japanese Polycystic Kidney Disease registry: J-PKD)

Clinical and Experimental Nephrology - Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly...     

Sequential Liver-Kidney Transplantation for Recurrent Liver Cysts Infection in a Patient With Autosomal Dominant Polycystic Kidney Disease: A Case Report

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Liver cysts are the most common extrarenal manifestation of the disease and usually remain asymptomatic. Liver cyst infection is rare, and its treatment is challenging. Liver transplantation (LT) is the only curative therapeutic option in symptomatic polycystic liver disease associated with ADPKD. Only a few cases of LT for recurrent liver cyst infection have been published. To our knowledge, we report the first case of sequential liver-kidney transplantation for recurrent liver cysts infection in a patient with ADPKD. A 55-year-old woman with ADPKD who had a kidney transplantation (KT) presented with multiple liver cysts infection 9 months after her KT. These episodes started after biliary tract complications due to an ampullary adenoma necessitating multiple endoscopic interventions. Her general status gradually degraded because antibiotic treatment was not effective, and she underwent LT for recurrent liver cysts infection 1 year and 9 months after her KT. LT in this setting turned out to be challenging but was possible. We think that better biliary tract workup before KT may prompt better care in these patients.     

Liver fibrosis in recessive multicystic kidney diseases: transient elastography for early detection

Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant cause of morbidity and mortality in autosomal-recessive polycystic kidney disease (ARPKD), whereas patients with autosomal-dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography [FibroScan?, (FS)] for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (n?=?7) showed no significant difference in liver stiffness (5.3?kPa vs. 4.5?kPa; ns). ARPKD patients (n?=?7) had significantly increased median liver stiffness compared with controls (12.0?kPa vs. 4.5?kPa, p?=?0.002) and ADPKD patients (12.0?kPa vs. 5.3?kPa, p?=?0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease.     

Laparoscopic removal of renal cysts in patients with ADPKD as an alternative method of treatment and patient preparation for kidney transplantation: preliminary results

BACKGROUND: The most frequent genetic disease of the kidneys occurring in 1 of 1000 inhabitants is autosomal-dominant polycystic kidney disease (ADPKD). Growing renal cysts compress the kidney resulting in damage to parenchyma and functional disorders. Around 10% of these patients are dialyzed due to terminal renal insufficiency. With the advent of laparoscopic techniques, the idea of laparoscopic excision of cysts seemed a tempting alternative to nephrectomy. We assessed the preliminary results of laparoscopic treatment of polycystic kidneys compared with open nephrectomy for patients with ADPKD. MATERIALS AND METHODS: Thirty ADPKD patients were treated between 2000 and 2004. Eleven procedures in five men and six women of mean age 51 years included laparoscopic cyst excisions. In the remaining 19 patients (six men and 13 women) of mean age 54 years, nephrectomy was done. Indications for surgery included pain due to compression by large cysts and cyst contamination. Patients after nephrectomy were prepared for renal transplantation when necessary. RESULTS: Laparoscopic polycyst removal produced better effects than nephrectomy. Mean operative time was significantly shorter (86 minutes for cyst removal vs 108 minutes for nephrectomy; P < .05). Postoperative pain measured with the VAS scale was reduced in patients after laparoscopy. Hospital stay was shorter (5 vs 9 days), as well as time to recovery. Other benefits of laparoscopic cyst removal included maintained urination in the patient and no need for erythropoietin substitution, as well as reduced risk of cyst contamination. When eligible for renal transplantation, patients after laparoscopic polycyst removal have smaller kidneys that do not interfere with the graft and the risk of infection during immunosuppression seems lower. CONCLUSION: Although larger series of patients are required in patients with ADPKD, laparoscopic polycyst removal seemed superior to early nephrectomy.     

Coexistence of autosomal dominant polycystic kidney disease and neurofibromatosis: report of a family

Autosomal dominant polycystic kidney disease (ADPKD) and neurofibromatosis are both autosomal dominant heredofamilial disorders. Concurrence of these two diseases is very rare. Herein, we report the coexistence of neurofibromatosis in 3 members, a mother and her 2 sons, of a family with preexisting ADPKD. The chromosomal studies of these patients show no translocation, deletion, or other gross abnormality. It is possible that a mutated neurofibromatosis gene developed in the ADPKD mother with subsequent inherence of both ADPKD and NF genes in her 2 sons.     

Renal transcatheter arterial embolization for autosomal dominant polycystic kidney disease: report of two cases

We report the results of renal transcatheter arterial embolization (renal-TAE) in two patients with autosomal dominant polycystic kidney disease (ADPKD) treated with hemodialysis (HD). A 73-year-old man and a 65-year-old woman on HD visited our department complaining of abdominal fullness, abdominal pain and appetite loss. Abdominal computerized tomography (CT) revealed polycystic kidneys. Both patients underwent renal-TAE. Approximately 1 month later, the symptoms had improved and CT showed decreased cyst volume. These results suggest that renal-TAE is a useful therapy for patients with ADPKD.     

Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells

BACKGROUND: Progressive cyst enlargement, the hallmark of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-recessive (ARPKD) polycystic kidney disease, precedes the eventual decline of function in these conditions. The expansion of individual cysts in ADPKD is determined to a major extent by mural epithelial cell proliferation and transepithelial fluid secretion. This study determined if common receptor-mediated agonists and an anonymous lipid stimulate the production of 3' 5'-cyclic monophosphate (cAMP) in mural epithelial cells from the two major types of human cystic diseases. METHODS: cAMP responses to maximally effective concentrations of renal agonists were determined together with measurements of transepithelial anion current and cellular proliferation and extracellular signal-related kinase (ERK 1/2) expression in primary cultures of epithelial cells from human ADPKD and ARPKD cysts. RESULTS: The rank orders of responses to ligands for ADPKD and ARPKD cells were identical: epinephrine > desmopressin (DDAVP) approximately arginine vasopressin (AVP) > adenosine > prostaglandin E(2) (PGE(2)) > parathyroid hormone (PTH). cAMP concentrations elevated by epinephrine, DDAVP, adenosine, and PGE(2) were diminished by receptor-specific inhibitors. Pools of cyst fluid collected individually from 16 of 19 ADPKD kidneys increased, to varying degrees, cAMP levels in ADPKD and ARPKD cells. PGE(2), beta-adrenergic and AVP antagonists partially inhibited cAMP accumulation in response to fluids from three kidneys, but a large portion of the endogenous activity was attributed to yet-to-be identified bioactive lipid, designated cyst activating factor (CAF). CAF stimulated cAMP production in ADPKD and ARPKD cells, activated ERK(1/2), and increased cellular proliferation in ADPKD cells. CAF increased positive short circuit current (I(SC)) in polarized ADPKD and T-84 monolayers, indicating stimulation of net anion secretion. CONCLUSION: Endogenous adenylyl cyclase agonists promote cell proliferation and electrolyte secretion of human ADPKD and ARPKD cells in vitro. We suggest that increased levels of cAMP may accelerate cyst growth and overall renal enlargement in patients with PKD.     

From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease.