Autosomal dominant polycystic kidney diseasetype 2. Ultrasound, genetic and clinical correlations
Kyproulla Demetriou1,
Chrysa Tziakouri2,
Kristiana Anninou3,
Andri Eleftheriou3,
Michalis Koptides3,
Alexia Nicolaou3,
C. Constantinou Deltas3 and
Alkis Pierides1
1 Departments of Nephrology and
2 Diagnostic Radiology, Nicosia General Hospital and
3 The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Correspondence and offprint requests to:
Dr Alkis M. Pierides FRCP, FACP, PO Box 25638, 1311 Nicosia, Cyprus.
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Abstract
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Background. Ultrasound, genetic and clinical correlations are available for ADPKD-1, but lacking for ADPKD-2. The present study was carried out to address: (i) the age-related diagnostic usefulness of ultrasound compared with genetic linkage studies; (ii) the age-related incidence and prevalence of relevant symptoms and complications; and (iii) the age and causes of death in patients with ADPKD-2.
Methods. Two hundred and eleven alive subjects, from three ADPKD-2 families at 50% risk, were evaluated by physical examination, consultation of hospital records, biochemical parameters, ultrasound and with genetic linkage and DNA mutation analyses. Nineteen deceased and affected family members were also included in the study.
Results. Of the 211 alive members, DNA linkage studies and direct mutation analyses showed that 106 were affected and 105 were not. Ultrasound indicated 94 affected, 108 not affected and nine equivocal results in nine children under the age of 15. For all ages, the false-positive diagnostic rate for ultrasound was 7.5% and the false-negative rate was 12.9%. The difference between ultrasound and DNA findings was most evident in children aged 514 years where the ultrasound was correct in only 50% and wrong or inconclusive in the remaining 50%. The mean age of the 106 alive, ADPKD-2 genetically affected patients was 37.9 years (range: 666 years). Among them, 23.5% had experienced episodes of renal pain, 22.6% were treated for hypertension, 22.6% had experienced at least one urinary tract infection, 19.8% had nephrolithiasis, 11.3% had at least one episode of haematuria, 9.4% had asymptomatic liver cysts, 7.5% had developed chronic renal failure and 0.9% had reached end-stage renal failure. Of the 19 deceased members, nine died before reaching end-stage renal failure at a mean age of 58.7 years (range: 4068 years), mainly due to vascular complications, while the remaining 10 died on haemodialysis at a mean age of 71.4 years (range: 6682 years).
Conclusions. DNA analysis is the gold standard for the diagnosis of ADPKD-2, especially in young people. Ultrasound diagnosis is highly dependent on age. Under the age of 14, ultrasound is not recommended as a routine diagnostic procedure, but ultrasound becomes 100% reliable in excluding ADPKD-2 in family members at 50% risk, over the age of 30. ADPKD-2 represents a mild variant of polycystic kidney disease with a low prevalence of symptoms and a late onset of end-stage renal failure.
Keywords: autosomal dominant polycystic kidney disease type 2; end-stage renal failure; genetic linkage analysis; renal ultrasonography
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Introduction
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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder [13]. Clinically, it is characterized by the formation and progressive enlargement of renal cysts which often lead to end-stage renal failure (ESRF) in late middle life. Although the name portrays a renal disorder, the disease is systemic and it includes both cystic and non-cystic extrarenal abnormalities, including liver and pancreatic cysts [4,5], intracranial [68] and coronary aneurysms [9], mitral valve prolapse [1012] and possibly spontaneous arterial dissections [13]. The main causes of death in ADPKD are uraemia, atherosclerosis affecting coronary, intracranial and peripheral arteries, sudden rupture of intracranial aneurysms and sepsis [13,14,15]. ADPKD is phenotypically heterogeneous both between and also within affected families [3,1618]. The inter-familial variability is explained by the well-known genetic heterogeneity with at least two major genes responsible for ADPKD, and another third putative gene [19,20]. For both major genes, different mutations are observed in different families and to this day no single common mutation has been identified [21,22]. The available data indicate that ADPKD-2 may run a milder course with slower progression to end-stage renal failure (ESRF) and longer renal survival [2327]. The mean age of onset of ESRF in non-ADPKD-1 (presumably ADPKD-2) or proven ADPKD-2 families varies from 66.9 to 72.7 years [17,2325,27,28]. As yet not much is known about the age-related incidence and prevalence of hypertension, episodes of renal pain, presence of liver and pancreatic cysts, nephrolithiasis and urinary tract infections (UTI) in ADPKD-2 [10,2531]. The detailed ultrasound and genetic linkage studies by Ravine et al. [32] analysed the findings in ADPKD-1 but no similar studies have been published for ADPKD-2. We present the clinical, ultrasound and laboratory data in 211 members of three large Cypriot families with known PKD-2 mutations [3335] at 50% risk of the disease with the following goals. (i) To define the age-related ultrasound diagnostic criteria for ADPKD-2; (ii) to correlate ultrasound findings with genetic studies; (iii) to determine the age-related incidence and prevalence of the classical symptoms and complications of the disease; and (iv) to define the mean age of onset of hypertension and ESRF in these patients. Nineteen, deceased and affected members from these three families provide useful data on age at death, causes of death and length of survival on haemodialysis.
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Subjects and methods
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Among 12 large, ADPKD families with informative linkage studies, followed-up in the Department of Nephrology at the Nicosia General Hospital, three were classified as type 2 based solely on genetic linkage studies [16,30,3335]. A total of 230 individuals are included in this study. This number includes 211 alive members at 50% risk of the disease and 19 affected, deceased members. All 19 deceased patients had chronic renal failure (CRF) of varying degrees and information on their progress was obtained from their hospital medical records. After informed consent and a personal interview, all 211 alive members were examined prospectively with a physical examination during which blood was drawn for biochemical and haematological tests and molecular investigations including direct mutation and/or DNA linkage analysis. These genetic studies were carried out using techniques described previously [16,3335]. The 211 alive members underwent a thorough abdominal ultrasound examination by a single radiologist using the HDI 3000 ultrasound system and the 3.55 MHz sector probe. Initially, the ultrasound diagnostic criteria were modelled on those by Ravine et al. [32] for adults with ADPKD-1, and also on those by Gabow et al. [36] particularly as they relate to children with ADPKD-1. Our working ultrasound diagnostic criteria for members with a family history of ADPKD-2 and at 50% risk were: (i) 514 years of age, at least one cyst in one kidney; (ii) 1519 years of age, at least two unilateral cysts or one in each kidney; (iii) 2029 years of age, at least three cysts with bilateral involvement; (iv) 3059 years of age, bilateral disease with at least two cysts in each kidney; and (v) over 60 years of age, bilateral disease, with at least four cysts in each kidney. No routine computed tomographic examinations were carried out in these patients. Attention was also paid to the size of the kidneys, the presence of hepatic cysts and also the presence of any pancreatic and ovarian pathology.
The physical examination focused on the presence of any palpable abdominal masses and the measurement of arterial blood pressure (BP). An adult patient was considered to be hypertensive if the untreated BP was
150/90 mmHg or if he/she had been previously diagnosed and treated for hypertension. Haematology and biochemical tests included measurements of serum creatinine, urea and lipids. The presence of a serum creatinine >1.5 mg% (or 135 µmol/l) was taken to indicate the presence of definite CRF.
During the clinical check-up and from the patient's medical records, a careful record was made of: (i) all episodes of renal pain with or without haematuria; (ii) all episodes of upper/lower UTIs with positive urine cultures; and (iii) all episodes of renal calculi indicated by either the passage of a stone or the presence of a stone on a plain kidney, ureter and bladder film (KUB) or ultrasound. The patient's age when ADPKD-2 was first diagnosed, age at the time of onset of hypertension and age when ESRF was reached were also recorded. For the purpose of this publication all relevant events up to August 1998 are included.
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Results
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Table 1
analyses the 230 members in the three ADPKD-2 Cypriot pedigrees. Pedigree 1 contributed 39 members, pedigree 2 contributed 13 members and pedigree 3 with many smaller families contributed 178 members. Members of one family of pedigree 1 feature additional autoimmune hypothyroidism, early-onset hypertension and mixed hyperlipidaemia requiring treatment. Some families within pedigree 3 feature mixed severe hyperlipidaemia requiring treatment and a ß-thalassemia trait, while another family has some members with diabetes mellitus and polycythaemia requiring venesection. Nineteen affected relatives died between 1963 and 1998. One female died at age 57 from a metastatic carcinoma of the cervix while the remaining 18 died from CRF and its complications. Eight died from CRF and vascular episodes before reaching ESRF at a mean age of 58.7 years (range: 4068). Five of these eight relatives who died before reaching ESRF, died from a myocardial infarct at 40, 49, 56, 62 and 66 years of age and three from cerebrovascular accidents at 63, 66 and 68 years of age respectively. The remaining 10 patients reached ESRF at a mean age of 66.3 years (range: 6074) and survived on haemodialysis for an additional 5.1 years (range: 5 months11 years). Their mean age at death while on haemodialysis was 71.4 years (range: 6682). Their death, while on haemodialysis was the result of generalized atherosclerosis with cardiac and peripheral vascular disease, associated in several cases with the development of limb gangrene.
Table 2
compares the ultrasound and DNA findings in the 211 alive members. Family members are divided into four age groups and the ultrasound results are compared with those from genetic linkage or mutation analyses. There were 32 children aged 514, 31 members aged 1519, 54 members aged 2029 and 94 members aged 30 to 59. Using our ultrasound diagnostic criteria, 94 members fulfilled the ultrasound criteria for ADPKD-2, nine aged 514 had equivocal, inconclusive results and 108 were described as negative. The equivocal findings in nine children were related to the difficulty in separating the usual sonolucency of the normal pyramids from true cysts. These pseudocystic changes were invariably <0.7 cm in diameter, often symmetrical and usually multiple. Five of these nine children were genetic positive and four genetic negative for a PKD-2 mutation.
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Table 2. Comparison of ultrasound and genetic findings in 211 members at 50% risk for ADPKD-2. Ultrasound diagnosis is age dependent. Under the age of 14 ultrasound is only correct in 50% of cases and either equivocal or frankly wrong in the remaining 50%. Ultrasound is reliable in excluding ADPKD-2 in people over the age of 30. Of the patients between 30 and 59 with more than four cysts in both kidneys 3.9% represent non-affected people with simple renal cysts
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Of the 94 members positive by ultrasound, 87 were confirmed positive by genetic analysis giving a correct positive ultrasound rate of 92.5% for all ages. There were seven members with positive ultrasound, but negative genetic results. Four cases occurred in people aged 2059 and they must represent healthy members without polycystic kidney disease, but with multiple simple renal cysts. Their progress and follow-up over the next 510 years will be of interest. Three children under the age of 20 with a positive ultrasound examination also had a negative genetic study. These children are 12, 13 and 15 years old, respectively and again their long-term follow-up will be of interest and importance. Of the 108 members with negative ultrasound studies, 14 had positive genetic findings giving an ultrasound false-negative rate of 12.9%. These discrepancies were most evident in young people. In the 32 children aged 514, ultrasound was OK in only 50% and equivocal or frankly wrong in the remaining 50%. Over the age of 30, all members with negative ultrasound studies also proved to have negative genetic results and ultrasound appeared 100% reliable in excluding ADPKD-2 in these people. However, the opposite was not always true. Forty-nine of 51 (96.1%) patients over the age of 30 with positive ultrasound scans also had positive DNA studies, but two patients (3.9%) turned out to have negative DNA studies. It is likely that these two people represent non-polycystic patients with idiopathic simple renal cysts.
Table 3
shows the prevalence of all relevant symptoms in the 106 alive genetically affected patients with ADPKD-2 up to August 1998. Their mean age at the time was 37.9 years (range: 666). The most frequent symptom in these 106 patients with ADPKD-2 was the development of acute renal pain, observed in 25 patients (23.5%). These episodes of renal pain usually lasted 110 days and the aetiology was variable, e.g. rupture of a renal cyst, haemorrhage into a cyst with or without extension into the calyceal system and non-specific. The prevalence of renal pain in the 105 genetic negative at risk members was significantly less at only 2.8% (Figure 1
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Table 3. Prevalence of symptoms and signs according to age in 106 alive, genetic positive, patients with ADPKD-2. Some patients had more than one symptom
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Fig. 1. Comparison of prevalence of symptoms between the 106 genetically affected and the 105 genetically non-affected alive members in the study.
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Twenty-four patients (22.6%), 11 males and 13 females, were treated for hypertension. Their mean age at the time of diagnosis of their hypertension was 41.5 years (range: 3259). Six of these affected hypertensives also had a family history of essential hypertension. Four of the 105 genetically unaffected members (3.8%) also had hypertension, presumably resulting from essential hypertension (Figure 1
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UTIs in 24 patients were confirmed by positive urine culture and were mostly due to cystitis. Attacks of clinical pyelonephritis were by far the exception, occurring in only three patients. Twelve of the 105 genetically unaffected members also had episodes of UTI (11.4%). Nephrolithiasis was diagnosed with a plain KUB and/or ultrasound. The most commonly diagnosed kidney stone was made of uric acid. This was diagnosed either from stone analysis or from the demonstration of a stone on a renal ultrasound in the absence of a visible radiopaque kidney stone on a KUB. The prevalence of renal stones in the 105 genetically unaffected members was significantly less at 3.8%. Twelve patients (11.3%) have had at least one episode of gross haematuria with or without pain. Some patients had repeated episodes of haematuria associated with pain usually affecting the same polycystic kidney. Only one non-affected control had haematuria associated with lithiasis. Liver cysts were found by ultrasound in only 10 of the 106 affected patients (9.4%). These liver cysts were mostly <1 cm in diameter and caused no symptoms. The mean age of these 10 patients at the time of diagnosis of their liver cysts was 46.6 years, much higher than the mean age of 31.2 years for all 106 ADPKD-2 patients. None of the non-affected members had liver cysts. No pancreatic cysts were encountered.
CRF developed in nine of the 106 alive patients (8.4%). Their age at the time of diagnosis of CRF ranged from 4865 and there were five males and four females. All were hypertensive. No patient is currently on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). One of the patients underwent successful transplantation with a kidney from a living donor in 1990 and her serum creatinine is currently 0.9 mg%. The remaining eight patients have serum creatinines between 1.6 and 5.2 mg%. The cumulative prevalence of CRF in the 106 alive and 19 dead affected patients with ADPKD-2 in the 35 years of follow-up between 1963 and 1998 was estimated to be 21.6% (27 patients in a sample of 125 affected patients).
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Discussion
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Genetic and ultrasound findings
The gold standard for confirming the diagnosis of ADPKD-2 in members of affected families is currently genetic linkage and/or mutation analysis [25,34,37]. However, when the specific mutation is unknown, these molecular genetic studies are costly, time consuming and demand the availability of a highly specialized laboratory, knowledge of the family tree and, at least initially, blood samples from affected and non-affected members of the family. In our population of 211 alive members at 50% risk of ADPKD-2, 106 (50.2%) were found by genetic linkage studies and/or direct mutation analysis to be affected while 105 (49.8%) were unaffected, which is in keeping with the known dominant transmission of the disease.
Ultrasound offers a much simpler, cheaper, more convenient and non-invasive way of diagnosing ADPKD-2. Detailed ultrasound studies in large ADPKD-2 populations are lacking. Reference to some documented ADPKD-2 families is, however, found in some published reports [27,38]. Bear et al. [28] studied two small families with non-PKD-1 disease and remarked that only 11% of members under age 30 had renal cysts. Coto et al. [39] studied 36 carriers in five families with ADPKD-2 and remarked that 83.3% of carriers under age 20 had no renal cysts. They stressed that renal cysts were invariably found in patients over 30. They concluded that DNA analysis was essential for diagnosing ADPKD-2 in subjects less than 30 years of age. Torra et al. [25] agreed with the above. Renal cysts were present in all their 14 patients with ADPKD-2 over the age of 30 but in only two out of their six patients under the age of 30.
Our large prospective study of 211 alive members from three well-documented ADPKD-2 families representing all age groups proves that ultrasound diagnosis of ADPKD-2 is clearly age dependent. In 32 children under the age of 14, ultrasound by an experienced radiologist, under research conditions, gave correct diagnoses, either positive or negative in only 50%. These results question the usefulness of routine ultrasound diagnostic studies in very young asymptomatic people at risk for ADPKD-2. Our study and other publications [25,28,39] are also in complete agreement that over the age of 30, a negative, good quality ultrasound, not fulfilling the diagnostic criteria of at least four renal cysts bilaterally is 100% reliable in excluding ADPKD-2. No patient over the age of 30 with a negative kidney ultrasound had positive DNA findings in our study or in that by Torra et al. [25]. The opposite, however, is not 100% true. There is a small, but definite chance of simple renal cysts mimicking ADPKD-2 in older patients. In our series this occurred in 3.9% of patients over 30. There is a transitional zone between the ages of 1529 where the diagnostic usefulness of ultrasound increases steadily with age and one should always be aware of the age limitations of ultrasound examinations in ADPKD-2. Strongly positive results may be helpful but equivocal and negative results should be interpreted with caution. Hepatic cysts were found in only 9.4% of the 106 genetic positive ADPKD-2 patients, but none were found in the 16 genetic positive children under 14. These findings confirm previous reports that hepatic cysts, like renal cysts, are also age dependent and that they tend to appear later than renal cysts [4,25]. They tend to grow slowly with advancing age. In agreement with Torra et al. [25] pancreatic cysts were not encountered on ultrasound in any of our ADPKD-2 patients.
Symptoms in ADPKD-2
Beginning with the observations by Parfrey et al. [23] and with the exeption of Bogdanova et al. [40], most other investigators [1,3,17,25,27,28] have found that ADPKD-2 represents a milder form of polycystic disease than ADPKD-1. ADPKD-2 has fewer symptoms, which appear at a significantly later age, and patients also appear to reach ESRF much later [1,14,17,25,27,28,41]. In a good comparative study between ADPKD-1 and ADPKD-2, Torra et al. [25] showed that ADPKD-2 is a milder disease as manifested by a much later age of onset of ESRF (53.4 years for ADPKD-1 vs. 72.7 years for ADPKD-2). Hateboer et al. [27] found the mean age for the onset of ESRF in their ADPKD-2 patients to be 69.1 years. The present study shows the mean age of all 11 patients with ADPKD-2 who reached ESRF to be 66.3 years (range: 6074), confirming a late onset of ESRF and a milder disease. Patients on haemodialysis died at a mean age of 71.4 years (range: 6682) which is 5.1 years later.
The presentation in Table 3
of all observed symptoms in the 106 alive and affected individuals with ADPKD-2 reveals that at any given time, essentially 75% of all patients are symptom-free and only 7.5% have progressive CRF which is expected to change their lives significantly. It is possible that for symptoms like mild episodes of renal pain and cystitis, some incidents may not be recorded. However, there is only one renal service on the island and most patients with ADPKD consult this service for anything that appears significant. The recorded cumulative prevalence of symptoms in the 106 alive patients ranged from 7.5% for renal failure to 23.5% for attacks of renal pain and 22.6% for hypertension and UTI. Though the prevalence of these symptoms is relatively low, they occur more frequently in the affected than the non-affected members of these families indicating that they are indeed the result of the polycystic disease. However, the early development of symptoms, such as hypertension in these ADPKD-2 patients, justifies early diagnosis of the disease. Hopefully, education, correct treatment and better supervision will significantly reduce the long-term morbidity from these symptoms and also delay the loss of renal function. Early development of hypertension seems to be the most important factor in the progression of the disease and the eventual development of CRF [15,26,42,43]. A striking finding in our study was the observation that nine of the observed deaths (47.3%) occurred before these patients reached ESRF; the most common cause of death being hypertension and atherosclerosis-related myocardial infarction and cerebrovascular accidents. Fick et al. [15] found that 27% of their polycystic patients died before reaching ESRF. They also commented that after 1975, cardiac disease with hypertrophy and CAD became the most common cause of death. It is of interest that some of our families showed significant hyperlipidaemia, diabetes and hypertension, which may increase the risks of premature atherosclerosis. These factors may modulate the progression of polycystic kidney disease. Hyperlipidaemia is now amenable to effective treatment with dietary advice and HMG CoA-reductase inhibitors and effective treatment may improve survival and quality of life. Equally well, prompt and effective treatment of hypertension may prolong overall survival and renal function. The aim of early diagnosis, appropriate treatment and good follow-up must be to minimize vascular pathology, eliminate all premature deaths due to vascular accidents when possible and preserve renal function, delaying as far as possible the onset of ESRF. With these goals in mind, programmes for early diagnosis of ADPKD-2 with molecular DNA analyses and ultrasound studies are fully justified because they lay the foundation for good preventive medicine.
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Received for publication: 4.12.98
Accepted in revised form: 4.10.99