Curr Opin Nephrol Hypertens 2001 Jan;10(1):23-31
Current advances in molecular genetics of autosomal-dominant polycystic kidney disease.
Department of Internal Medicine, Yale University School of Medicine, New
Haven, Connecticut 06520-8029, USA. firstname.lastname@example.org
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
Arch Dis Child 2000 Nov;83(5):401-7
Imaging in cystic renal disease.
de Bruyn R, Gordon I
Department of Radiology, Great Ormond Street Hospital for Children NHS
Trust, Great Ormond Street, London WC1N 3JH, UK.
J Am Soc Nephrol 2000 Sep;11(9):1767-75
Liver involvement in autosomal-dominant polycystic kidney disease: therapeutic dilemma.
Chauveau D, Fakhouri F, Grunfeld JP
Department of Nephrology, Hopital Necker, Paris, France.
Curr Opin Nephrol Hypertens 2000 Jul;9(4):385-94
The pathogenesis of autosomal dominant polycystic kidney disease: an update.
Somlo S, Markowitz GS
Department of Internal Medicine (Nephrology), Yale University School of Medicine, USA.
The identification of PKD1 and PKD2, the two major genes responsible for autosomal dominant polycystic kidney disease, are the seminal discoveries upon which much of the current investigation into the pathogenesis of this common heritable disease is based. A major mechanistic insight was achieved with the discovery that autosomal dominant polycystic kidney disease occurs by a
two-hit mechanism requiring somatic inactivation of the normal allele in individual polarized epithelial cells. Most recent advances are focused on the function of the respective protein products, polycystin-1 and polycystin-2. Indirect
evidence supports an interaction between polycystin-1 and -2, albeit it is unlikely that they work in concert in all tissues and at all times. They associate in yeast two hybrid and cotransfection assays and there is a striking similarity in the renal and pancreatic cystic phenotypes of Pkd2-/- and Pkd1del34/del34 mice. Also, the respective homologues of both proteins are expressed in the same sensory neuronal cells in the nematode and the human disease phenotypes remain completely overlapping with the major difference being in relative severity. Mounting evidence supports the hypothesis that polycystin-1 is a cell surface receptor. A close homologue in the sea urchin sperm mediates the acrosome reaction in response to contact with egg-jelly, the nematode homologue functions in mechano- or chemosensation, and the solution structure of the repeated extracellular polycystic kidney disease domains reveals a beta-sandwich fold commonly found in surface receptor
molecules. Indirect evidence also supports the initial hypothesis that polycystin-2 is a calcium channel subunit. Several closely related homologues retain the calcium channel signature motif but differ in their predicted interaction domains, and one of these homologues has been shown to be a calcium regulated cation
channel. Several important distinctions in polcystin-1 and -2 function have also been discovered.
Polycystin-2 has a role in cardiac development that polcystin-1 does not. High level polycystin-2 expression in renal epithelial cells coincides with maturation and elongation of tubules and, unlike polycystin-1, persists into adulthood. In cells in tissue culture, polycystin-2 is expressed exclusively in the endoplasmic reticulum whilst the cellular expression of polycystin-1 remains unknown.
Overall, the difficult task of understanding the autosomal dominant polycystic disease process is proceeding apace.
Nephrol Dial Transplant 2000 Jun;15(6):747-50
Transepithelial chloride secretion and cystogenesis in autosomal dominant polycystic kidney disease.
Persu A, Devuyst O
Urol Int 2000;64(1):9-12
Renal cell carcinoma in cases of adult polycystic kidney disease: changing diagnostic and therapeutic implications.
Hemal AK, Khaitan A, Singh I, Kumar M
Department of Urology, All India Institute of Medical Sciences, New Delhi, India.
Renal cell carcinoma in adult polycystic kidney disease is of rare occurrence and poses a diagnostic and therapeutic challenge. We have treated three such patients in our department. One was male and two were females ranging in age from 20 to 60 years. All were diagnosed preoperatively with ultrasonography or contrast-enhanced CT. Radical nephrectomy was performed in all patients. During the follow-up no patient had recurrence in the contralateral kidney. One patient had local recurrence in the renal fossa and was treated with local radiotherapy and immunotherapy. In the past due to difficulty in diagnosis, invasive investigations like angiography were recommended and prophylactic contralateral
nephrectomy was often undertaken. With the availability of reliable noninvasive
investigations these patients can be diagnosed accurately and the contralateral kidney saved in most cases. Copyright 2000 S. Karger AG, Basel
Review of reported cases
J Nephrol 1999 Jul-Aug;12 Suppl 2:S42-6
Polycystic kidney disease: <<30 ans apres>>.
Grunfeld JP, Chauveau D, Joly D, Fonck C, Oualim Z
Service de Nephrologie, Hopital Necker, Paris, France.
Major progress has been achieved in autosomal dominant polycystic kidney disease in the last 30
years; Progress in imaging procedures has been decisive for diagnosis (by
ultasonography), management of kidney and liver complications (by CT
scan), and investigation and sometimes management of intracranial aneurysms (by
MRI-angiography and endovascular treatment procedures). On the other hand, progress in molecular genetics has led to the identification of PKD1 and PDK2 genes, and their respective gene
products, polycystin 1 and 2. A two-hit model for cyst formation has recently been put
forward. The link between the gene defects and cyst fluid formation and progression is still
unknown. In addition, cystic and non-cystic lesions coexist in the
disease, underlining that the primary molecular defect is located upstream of the mechanism of cyst
Nephron 2000 Jan;84(1):6-12
Obstructive nephropathy: lessons from cystic kidney disease.
Department of Pediatrics, University of Virginia, School of Medicine, Charlottesville, VA, USA.
Obstructive nephropathy is one of the most important causes of renal failure in infants and
children, while polycystic kidney disease (PKD) is a major cause of renal failure in the adult
population. This review summarizes the evidence that there may be a number of mechanisms common to the pathophysiology of both conditions. In animal models of obstructive nephropathy and
PKD, the renal tubular expression of epidermal growth factor is
suppressed, and expression of clusterin is increased, both of which suggest arrested maturation or dedifferentiation of the tubular
cell. There is a marked increase in apoptosis of epithelial cells in dilated
tubules, associated with an increase in apoptotic stimuli. The renin-angiotensin system is activated in both obstructive nephropathy and
PKD, which may contribute to tubular atrophy and interstitial fibrosis, which characterize the progression of both
conditions. Focal cystic dilatation of the tubule is found in obstructive
nephropathy, while tubular obstruction is present in cystic kidney
disease. It is therefore likely that elucidation of the effects of mechanical stretch on renal tubular epithelial cells will contribute to our understanding of both
conditions. Copyright 2000 S.
Karger AG, Basel
BMJ 2000 Jan 8;320(7227):98-101 [Texto
Recent advances: nephrology.
North Bristol NHS Trust, Richard Bright Renal Unit, Southmead Hospital, Westbury on
Trym, Bristol BS10 5NB. email@example.com
Nephrol Dial Transplant 1999 Oct;14(10):2319-22
Cerebral aneurysms in patients with autosomal dominant polycystic kidney disease--to
screen, to clip, to coil?
Mariani L, Bianchetti MG, Schroth G, Seiler RW
Department of Neurosurgery, University Hospital, Inselspital, Bern,
Am J Kidney Dis 1999 Oct;34(4):639-45
Renal asymmetry in children with autosomal dominant polycystic kidney disease.
Fick-Brosnahan G, Johnson AM, Strain JD, Gabow PA
University of Colorado Health Sciences Center, Denver Health and The Children's
Hospital, Denver, CO 80262, USA. Godela.Fick-Brosnahan@UCHSC.edu
Although for decades autosomal dominant polycystic kidney disease (ADPKD) was
considered a disease of adults, our recent longitudinal studies on children from ADPKD families have shown that the disease is evident by ultrasound imaging in approximately 75% of children who are carriers of the ADPKD1 gene, the most common form of ADPKD. Here we report that, in contrast to adults, the disease appears to be unilateral initially in approximately 17% of children. Asymmetric enlargement of the kidneys is also frequently observed. This renal asymmetry can be extreme and lead to diagnostic confusion. We present 2 unusual cases of asymmetric renal involvement that we have observed during the last 10 years. The first is a 14-year-old boy who was scheduled for a nephrectomy to relieve pain and whose family requested a second opinion. The second is a 10-year-old girl
who was diagnosed with ADPKD in utero by prenatal ultrasound. After birth, 1 kidney progressively developed cysts and enlarged, whereas the other had only a few tiny cysts and remained normal in size. A review of the literature shows that presentations like these often lead to a nephrectomy or surgical biopsy. A carefully obtained family history and examination of both parents with ultrasound can help to avoid unnecessary invasive procedures. If pain is a prominent symptom, it can be treated by cyst aspiration if there are only a few cysts or a single dominant cyst. The molecular mechanism for extremely
asymmetric renal disease remains to be elucidated.
Nephrol Dial Transplant 1999 Aug;14(8):1999-2003
Unilateral renal cystic disease in adults.
Hwang DY, Ahn C, Lee JG, Kim SH, Oh HY, Kim YY, Lee ES, Han JS, Kim S, Lee JS
Division of Nephrology, College of Medicine, Seoul National University Hospital, Korea.
Unilateral renal cystic disease (URCD) is morphologically indistinguishable from autosomal dominant polycystic kidney disease (ADPKD) except for its unilaterality. Unlike ADPKD, URCD patients show neither a genetic background nor progressive deterioration in renal function; thus, the differential diagnosis of URCD from ADPKD is important. Only a few cases of URCD have been reported. This study reports two cases of URCD in adults together with a literature review. We identified these two cases using abdominal computerized tomography and family screening with renal ultrasonography.
Review of reported cases
Urology 1999 Jun;53(6):1227-8 [Texto
Unilateral renal cystic disease.
Division of Pediatric Urology, SUNY Health Science Center at Brooklyn, New
Review of reported cases
Am Surg 1999 May;65(5):464-6
Traumatic hematuria in patients with polycystic kidney disease.
Klein AJ, Kozar RA, Kaplan LJ
Department of Surgery, MCP Hahnemann University, Philadelphia,
Autosomal dominant polycystic kidney disease (PKD) is the most prevalent hereditary disorder in this country and a common cause of chronic renal
failure. Patients frequently present with hematuria as the initial manifestation of
PKD. We describe a patient with gross hematuria after blunt trauma who was found to have previously undiagnosed PKD. We review present diagnostic and treatment modalities and suggest potential management strategies for surgeons caring for patients presenting with traumatic hematuria and PKD.
Review of reported cases
J Urol 1998 Sep;160(3 Pt 2):1207-11; discussion 1216
Outcome and cost analysis of operative versus nonoperative management of neonatal multicystic dysplastic kidneys.
Perez LM, Naidu SI, Joseph DB
Department of Surgery, University of Alabama at Birmingham, USA.
PURPOSE: We determine whether nephrectomy or observation is the more appropriate
treatment of neonates with multicystic dysplastic kidney in terms of medical care and cost-effectiveness. MATERIALS AND METHODS: We retrospectively reviewed our 10-year clinical experience with 17 female and 32 male neonates presenting with multicystic dysplastic kidney who were followed with serial renal ultrasound. The literature also was reviewed. RESULTS: Nephrectomy was performed in 12 patients (24%) for various reasons, of which family request at concomitant surgery was the most common (7). No kidney was removed due to hypertension or tumor. In the remaining 37 patients followup continues (mean 42 months) with involution developing in 9 multicystic dysplastic kidneys (24%) and 9 patients (24%) lost to followup. The total cost of 1-hour outpatient simple nephrectomy was estimated at $5,000 to $7,000 and, when performed as a concomitant procedure, it cost $2,000 to $5,000, the equivalent charges incurred for 17 to 28 serial ultrasound studies performed by a radiologist. Our review of the literature revealed that children with multicystic dysplastic kidney are at minimal risk for hypertension, pain and infection. The most important reason to perform screening renal ultrasound in this condition is to detect earlier stage Wilms tumor (3 to 10-fold the general pediatric population risk of 1/10,000 cases). With a maximum risk of 0.1% for Wilms tumor controversy exists as to whether any screening program is necessary. When screening is
instituted, options include monthly parental abdominal palpation versus serial renal
ultrasound. Because Wilms tumor has a rapid growth rate, when screening renal ultrasound is instituted, it must be performed no less than every 3 months until age 8 years (total of 32 studies) to screen effectively for early stage
tumors. CONCLUSIONS: The risks associated with multicystic dysplastic kidney are
slight. Early nephrectomy is more cost-effective than observation in neonates with multicystic dysplastic kidney only when observation involves screening with ultrasonography every 3 months until age 8 years. Extensive parental counseling should be provided on the slight but definite risks of this condition.
Kidney Int Suppl 1997 Dec;63:S93-7
Mechanisms of progression in autosomal dominant polycystic kidney disease.
Department of Medicine, Kansas University Medical Center, Kansas City, USA.
Autosomal dominant polycystic kidney disease (ADPKD) progresses to end-stage renal insufficiency before the age of 73 in approximately 48% of affected individuals. Why the disease, characterized by innumerable cysts arising in proximal and distal tubules, eliminates functioning non-cystic parenchyma in some patients and spares other is a mystery. The cysts initiate in early childhood in fewer than 1% of renal tubules as a consequence of the focal
expression of mutated DNA. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of extracellular matrix proteins. Most of the cysts separate from the parent tubules and fill with fluid by cAMP-mediated chloride secretion. Risk factors associated with accelerated loss of renal function include: genotype (PKD Type 1 progresses more rapidly than PKD Type 2); gender (males progress more rapidly than females); race (black patients progress more rapidly than whites); hypertension; proteinuria. The relation between kidney size and progression to renal failure is debated. Progressive PKD is associated with the cellular expression of proto-oncogenes (fos, myc, ras, erb), growth factors (EGF, HGF, acid and basic FGF), chemokines (MCP-1. osteopontin), metalloproteinases, and apoptotic markers, and the interstitial accumulation of Types I and IV collagen, laminin, fibronectin, macrophages and fibroblasts, the magnitudes of which increase with age. Cyst activating factor (CAF), a neutral lipid identified in cyst fluid that stimulates fluid secretion and proliferation of renal epithelial cells and monocyte chemotaxis, has recently been identified as a potential progression factor. In those patients destined to develop renal failure there is loss of non-cystic parenchyma in association with mass replacement by fluid-filled cysts in a network of interstitial fibrosis. The decline in renal function is probably the consequence of processes leading to interstitial fibrosis, as in other nephropathies, rather than due to simple mechanical displacement of parenchyma by cysts.
Kidney Int 1997 Jun;51(6):2022-36
Extrarenal manifestations of ADPKD.
New England Medical Center, Boston, Massachusetts, USA.
Curr Opin Nephrol Hypertens 1997 May;6(3):276-83
Cystic kidney diseases.
Griffin MD, Torres VE, Kumar R
Nephrology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
The goal of understanding the primary defects that lead to renal cystic diseases has proved to be an elusive one, despite 3 decades of physiologic and genetic investigation. Within the past 2 years the genes responsible for type 1 and type 2 autosomal dominant polycystic kidney disease have been identified. The process of defining the normal distribution and functions of the proteins encoded by these genes as well as the precise pathophysiology of cystogenesis is underway. For other major hereditary cystic kidney diseases, chromosomal localization or gene identification has also been achieved in recent years. Mouse and rat models of renal cystic disease continue to be a rich source of new data on the effect of genetic and environmental modifying factors on disease progression as well as serving as a preliminary testing ground for novel approaches to management such as gene therapy and early dietary modification. Ongoing clinical research continues to better define the renal and extra-renal manifestations of autosomal dominant polycystic and other renal cystic diseases. It is likely that a clearer understanding of the pathophysiology of these diseases will provide important insights into the processes that control tissue development and growth, and
Emerg Infect Dis 1997 Apr-Jun;3(2):113-27 [Texto
Polycystic kidney disease: an unrecognized emerging infectious disease?
Miller-Hjelle MA, Hjelle JT, Jones M, Mayberry WR, Dombrink-Kurtzman MA, Peterson SW, Nowak DM, Darras FS
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria 61656, USA. Marcia.A.Miller@uic.edu
Polycystic kidney disease (PKD) is one of the most common genetic diseases in humans. We contend that it may be an emerging infectious disease and/or microbial toxicosis in a vulnerable human subpopulation. Use of a differential activation protocol for the Limulus amebocyte lysate (LAL) assay showed bacterial endotoxin and fungal (1-->3)-beta-D-glucans in cyst fluids from human kidneys with PKD. Fatty acid analysis of cyst fluid confirmed the presence of 3-hydroxy fatty acids characteristic of endotoxin. Tissue and cyst fluid from three PKD patients were examined for fungal components. Serologic tests showed Fusarium, Aspergillus, and Candida antigens. IgE, but not IgG, reactive with Fusarium and Candida were also detected in cyst fluid. Fungal DNA was detected in kidney tissue and cyst fluid from these three PKD patients, but not in healthy human kidney tissue. We examine the intertwined nature of the actions of endotoxin and fungal components, sphingolipid biology in PKD, the structure of PKD gene products, infections, and integrity of gut function to establish a mechanistic hypothesis for microbial provocation of human cystic disease. Proof of this hypothesis will require identification of the microbes and microbial components involved and multifaceted studies of PKD cell biology.
Kidney Int 1997 Jan;51(1):353-65
Complications of polycystic kidney disease.
Royal Infirmary of Edinburgh, Scotland.
Am J Kidney Dis 1996 Dec;28(6):788-803
The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances.
Department of Medicine, University of Kansas Medical Center, Kansas City 66160, USA.
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52 kb gene with a 14 kb mRNA. The PKD2 protein is also large (110 kd) and is thought to interact with polycystin. ADPKD1 is caused by mutated DNA that encodes an abnormal form of polycystin. Polycystin appears to have a normal role in the differentiation of
epithelial cells, and when defective, these cells fail to maturate fully. These incompletely differentiated cells proliferate abnormally and express altered amounts of otherwise normal electrolyte transport proteins that result in excessive secretion of solute and fluid into the cysts. The proliferation of the cells and the associated apoptosis, and the secretion of the fluid into the cysts created by the enlarging tubule segments appear to be regulated by growth factors, hormones, and cytokines that can alter the extent to which the disease is clinically expressed among individuals. The formation of the cysts is associated with complex changes in the extracellular matrix of the kidneys and other organs that may be directly or indirectly tied to mutated polycystin. The summation of these pathogenetic elements leads to renal interstitial infiltration, with monocytes, macrophages, and fibroblasts culminating in fibrosis and progressive loss of renal function. The modem understanding of cyst pathogenesis opens opportunities to develop treatments that may diminish or halt
altogether the progression of this disease.
Radiol Clin North Am 1996 Sep;34(5):947-64
Acquired cystic kidney disease.
Department of Radiology, University of Kansas Medical Center, Kansas City, USA.
ACKD is characterized by the development of many fluid-filled renal cysts and sometimes neoplasms in the kidneys of individuals with chronic renal failure but without a history of hereditary cystic disease. The condition is seen mainly in dialysis patients, but often begins in patients with ESRD before dialysis is started. Most patients with ACKD are asymptomatic, but the disorder may be associated with such serious complications as retroperitoneal hemorrhage and metastatic renal cell carcinoma. The diagnosis of ACKD and its complications is best achieved by CT scanning, although US and MR imaging may be useful in evaluation, particularly in patients not treated with dialysis. Cyst hemorrhage is common in ACKD and may cause flank pain and hematuria. Hemorrhagic cysts may be recognized by their CT scan, sonographic, or MR imaging features. Hemorrhagic cysts may rupture into the perinephric space causing large perinephric hematomas. These can usually be treated-conservatively. Patients with ACKD, particularly those treated with dialysis, have an increased risk of renal cell carcinoma. Renal cell carcinoma may also develop in the native kidneys of renal transplant recipients with good graft function many years after transplantation. Annual imaging of the native kidneys of all dialysis patients or of transplant
recipients for the development of carcinoma is not justified, however, because it has not been shown to have a significant effect on patient outcome. Screening may, however, be useful in selected dialysis patients with good general medical condition and who have known risk factors for renal cell carcinoma including prolonged dialysis, large kidneys, ACKD, and male gender. Screening of the native kidneys of transplant recipients may be performed when they are referred for US evaluation of the renal allograft.
Radiol Clin North Am 1996 Sep;34(5):925-46
Inherited cystic diseases of the kidney.
Department of Radiology, National Institutes of Health, Bethesda, Maryland, USA.
The inherited cystic diseases of the kidney represent a diverse group of diseases. Recent advantages in molecular medicine have greatly enhanced the presymptomatic detection of these entities. To data, however, genetic tests cannot determine the severity of the disease or prevent complications. Therefore, imaging will continue to play a major role in the screening and management of these complex diseases.
Am Fam Physician 1996 Feb 15;53(3):925-31
Autosomal dominant polycystic kidney disease.
University of Mississippi Medical Center, Jackson, Mississippi, USA.
Autosomal dominant polycystic kidney disease is one of the most commonly inherited diseases in the United States. It affects nearly 500,000 Americans and accounts for 5 to 10 percent of patients with end-stage renal disease. Diagnosis is usually made in middle age, when complications such as hypertension, pain and hematuria develop. Renal complications include hypertension, cyst infection and hemorrhage, hematuria and flank pain. Other manifestations and related conditions include polycystic liver disease, cerebral aneurysm, cardiac valve abnormalities and diverticulosis. The severity and course of the disease vary in individual patients. Management involves the control of hypertension and treatment of complications. Genetic counseling is important. Dialysis and renal transplantation often are successful treatments in patients who develop renal failure.