Clinical Nephrology – Epidemiology – Clinical Trials

Kidney International (2002) 62, 1385–1394; doi:10.1111/j.1523-1755.2002.kid581.x

Autosomal-dominant medullary cystic kidney disease type 1: Clinical and molecular findings in six large Cypriot families

Christoforos Stavrou, Michael Koptides1, Christos Tombazos, Evlalia Psara, Charalambos Patsias, Ioanna Zouvani, Kyriacos Kyriacou, Friedhelm Hildebrandt, Tasos Christofides, Alkis Pierides and C Constantinou Deltas

Department of Nephrology, Ministry of Health, and Department of Molecular Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Department of Radiology, Pafos General Hospital, Pafos, Department of Histopathology, Nicosia General Hospital, and Department of Electron Microscopy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; University Children’s Hospital, Freiburg, Germany; and Department of Mathematics and Statistics, University of Cyprus, Nicosia, Cyprus

Correspondence: C Constantinou Deltas, Pharm.R., Ph.D., The Cyprus Institute of Neurology, and Genetics Department, Molecular Genetics, P.O. Box 23462, 6 International Airport Avenue, Ayios Dhometios, 1683 Nicosia, Cyprus. E-mail:

1Present address: Department of Biomedical Sciences, Intercollege, Nicosia, Cyprus.

Received 12 June 2001; Revised 5 April 2002; Accepted 10 May 2002.

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Autosomal-dominant medullary cystic kidney disease type 1: Clinical and molecular findings in six large Cypriot families.

Background Autosomal-dominant medullary cystic kidney disease (ADMCKD), a hereditary chronic interstitial nephropathy, recently attracted attention because of the cloning or mapping of certain gene loci, namely NPHP1, NPHP2 and NPHP3 for familial juvenile nephronophthisis (NPH) and MCKD1 and MCKD2 for the adult form of medullary cystic kidney disease. Our aim was to present and discuss the clinical, biochemical, sonographic and histopathological findings in six large Cypriot families in whom molecular analysis has confirmed linkage to the MCKD1 locus on chromosome 1q21.
Methods The clinical, biochemical, sonographic and histopathological findings in 186 members of six large Cypriot families with ADMCKD-1 are presented. Creatinine clearance was calculated according to the Cockroft-Gault formula and was corrected to a body surface area (BSA) of 1.73 m2. DNA linkage analysis was performed with previously identified flanking polymorphic markers.
Results This disease is characterized by the absence of urinary findings in the vast majority of patients, leading to end-stage renal failure (ESRF) at a mean age of 53.7 years. Hypertension and hyperuricemia are common, especially in males, the former encountered more frequently in advanced chronic renal failure (CRF). Gout has been noted in a small percentage of male patients. Loss of urinary concentrating ability was not a prominent early feature of the disease, while severe natriuresis was observed in a few males toward ESRF. Renal cysts are mainly corticomedullary or medullary, and they are present in about 40.3% of patients and appear more frequently near ESRF.
Conclusion ADMCKD type 1 is a common cause of ESRF among our dialysis population. The disease is difficult to diagnose clinically, particularly in the early stage when renal cysts are not usually present, making them a weak diagnostic finding. A dominant pattern of inheritance and DNA linkage analysis are helpful in the diagnosis of this disease.
Keywords: medullary cystic kidney disease, nephronophthisis, hyperuricemia, gout, linkage analysis, ADMCKD, MCKD1 gene
More than half a century has elapsed since Thorn, Keorf and Clinton in 1944 presented a case of salt losing nephritis1 and Smith and Graham first described medullary cystic disease (MCD) in 19452. In 1951 Fanconi et al published their experience with familial juvenile nephronophthisis3 and Murphy et al reported a case of salt losing nephritis in 1952 that at autopsy showed bilateral small medullary and corticomedullary renal cysts4. The first report on the clinical aspects of MCD was from Strauss et al, who studied 18 young adults (mean age of 27 years) with renal failure and salt wasting5. Heredity was not evident except in two of their cases. Goldman et al reported the first large family with MCD showing that the disease was inherited with a dominant trait, either autosomal or X-linked6. Mongeau et al published their own experience, proposing that MCD and familial juvenile nephronophthisis (NPH) were subcategories of the same disease entity, representing probably a toxic nephropathy that was transmitted as an inherited metabolic error. They also mentioned that macroscopic renal cysts were not essential for the diagnosis. This latter statement is still true today7.

Many authors shared the opinion that MCD and NPH are related, often describing them under the title, FJN-MCD complex7,8,9. Gardner initially shared the same view but later considered MCD to be a separate disease entity10, and recent reports support this latter concept11,12,13,14,15,16,17. Regarding MCD of dominant inheritance, the first locus, MCKD1, was mapped on 1q21 using two large Cypriot families12 and subsequently one large British family16. The clinical phenotype of MCD was described under the name autosomal-dominant medullary cystic kidney disease (ADMCKD) after the MCKD1 locus was mapped12. One Iraqi Jewish family with progressive renal failure and hypertension was mapped in the same MCKD1 region18. The authors left open the possibility of this disease being different than ADMCKD-1 or being allelic to it. A second ADMCKD locus, MCKD2, was mapped to 16p12 using an Italian family15 and further gene locus heterogeneity has been described, as there are families not linked to either of the two loci17. Interestingly, a locus for familial juvenile hyperuricemic nephropathy has recently been co-localized with MCKD2 at 16p11.2-12, and the hypothesis has been proposed that the two conditions might be allelic, despite phenotypic differences19,20.

According to the literature and to our experience described here, ADMCKD presents as an autosomal-dominant tubulointerstitial nephropathy. It is a chronic interstitial nephritis with a variable age of onset, is very difficult to pinpoint precisely, and leads eventually to ESRF with a great inter- and intra-familial variability. In contrast to prior reports, our patients had no extra-renal manifestations, like red and blonde hair21, spastic quadriparesis22 or ocular abnormalities23. We found no association with hypokalemia and aldosteronism24. Renal cysts were not essential for the diagnosis, but when present they were of great help. These cysts were often not discovered by ultrasound or computed tomography (CT) scan25 but were only found at autopsy. There is still great difficulty in diagnosing this disease clinically, especially in patients where heredity is either not evident or absent, and where cysts are either absent or atypical. Histopathology, though very helpful, is not pathognomonic; the main histological changes are tubular atrophy, interstitial lymphocytic infiltration, interstitial fibrosis, tubular dilation and most important, tubular basement membrane thickening, with splitting and lamellation. Glomeruli can appear normal, totally sclerosed or with a variable degree of periglomerular fibrosis. Glomerular basement membranes (GBMs) are of normal thickness and appearance. Vessels are normal and immunofluorescence is negative. The tubular basement membrane changes resemble those seen in the GBM of Alport syndrome and are best seen under electron microscopy.

Gout and hyperuricemia have been reported to occur in this disease, a finding also observed in some of our families11. Their significance and relationship to ADMCKD is still unknown. We found no cause–effect relationship between the two, but there was a high incidence of both in our families.

Our findings stem from the investigation of six large Cypriot families, where 186 individuals have been examined clinically and genetically. To our knowledge, this is the largest series of families with ADMCKD reported to date.

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Six large Cypriot families [4901 (A+B), 4902, 4903, 4904, 4905, 4906] extending up to five generations have been studied since 1992. Family trees were obtained by personal interview of the patients and their relatives, trying to extend the trees to as many generations as possible. An effort was made to connect family trees to each other. This proved successful in families CY4901A and CY4901B, originating from two sisters who were considered as obligatory carriers. Initial molecular analysis and establishment of linkage of MCKD1 to 1q21 was with parts of pedigrees CY4901 and CY490312. All cases have been studied by the Departments of Nephrology in Pafos, Nicosia and Limassol General Hospitals. Seventy-nine individuals were diagnosed with the disease at the time of the study, in different stages of renal failure, with 26 of them in end-stage renal failure (ESRF). Additionally 19 deceased people were reported to have had chronic renal failure when alive. Kidney biopsies were available from eight patients in five families, all of which were consistent with ADMCKD. The incidence of renal cysts was compared between both affected and non-affected and between affected and normal controls. Normal controls were a group of 72 individuals, age- and sex-matched with the affected population, who came to the hospital during the last five years and had a renal ultrasound (US) for different reasons, except of renal failure. No one belonged to any of these six families and no one had a first-degree relative suffering from renal failure.
Diagnostic criteria
The diagnosis of ADMCKD can be difficult in many instances, a problem that we also had to face. Our diagnosis was based on Gardner’s suggested clues; the presence of an autosomal dominant nephropathy in the patient’s family, the certain diagnosis of MCD in at least one close relative and the compatibility of clinical, laboratory and histological findings with MCD, when the latter are available10,26. All patients had a decreased creatinine clearance of less than 80 mL/min/1.73 m2. Creatinine clearance was calculated according to the Cockroft-Gault formula and was corrected for a body surface area (BSA) of 1.73 m2. Clearance studies were performed on at least three occasions. All patients had a strong family history of an autosomal-dominant nephropathy with minimal or absent urinary findings and they did not suffer from polycystic kidney disease, Alport syndrome or any other obvious cause of renal failure. A few patients gave a history of gouty attacks in the past, but this alone did not amount to gouty nephropathy27. At least one patient in each family had radiological evidence of bilateral medullary or corticomedullary renal cysts. Eight kidney biopsies indicative of tubulointerstitial disease and consistent with the diagnosis were available from the first five families. We have no tissue confirmation from family CY4905.
Living family members were considered normal if they had normal renal function, no urinary or sonographic findings, and their ages were well above the mean age for ESRF within their family. The presence of renal cysts as a sole finding was not considered evidence of the disease. Younger members fulfilling the same criteria were considered at risk and were given a 50% risk factor. Apart from the standard investigation special urinary studies were performed, including fractional excretion of sodium (FENa) and fractional excretion of urate (FEurate) in most individuals, after a 48-hour abstinence of sodium and a 12-hour overnight water deprivation. A part of the representative pedigree CY4902 is shown in Figure 1, along with the molecular markers used for establishing linkage. DNA linkage analysis was performed as described previously, separately for each family Table 1, using up to six flanking polymorphic markers12. Interestingly, despite the fact that no relationship could be traced between the six families (except between CY4901A and CY4901B), they all shared the same affected extended haplotype (unpublished results)12. Perhaps they all originated from one common founder and his/her descendants contributed to the populations of these three neighboring villages at Pafos district, located in the southwest portion of the Cyprus island. The three villages form a triangle with distances of less than 5 kilometers from each other.

Figure 1.

Part of a representative pedigree of family CY4902, described in this study. Two members of the younger generation are predicted to develop disease symptoms.

Full figure and legend (19K)

Table 1 – Two-point maximum LOD scores obtained between the disease and three polymorphic markers spanning the MCKD1 region on chromosome 1q21, at recombination fraction max = 0.00.

Full table

Statistical analysis
The statistical analysis for each one of the patients’ measurements was based on the 2 test of independence and the classical procedures like the two-sample t test and the Wilcoxon two-sample test statistic. In addition, all of the patient characteristics like corrected creatinine clearance, blood pressure, serum uric acid, FENa, FEurate, sex and age were considered as components of a multivariate measurement for each individual. Using these measurements for a total of 102 individuals for whom all components were available, logistic regression was performed, to produce a model able to calculate the (classification) probability that an individual is a carrier or not Figure 2. The statistical analysis was performed on an IBM RS6000 running AIX OS using the S-plus statistical package Version 5 software program.
Figure 2.

Classification probabilities of 102 individuals participating in the study. The initial 49 observations represent classification probabilities for carriers and the remaining 53 are for non-carriers. The interpolating line clearly shows higher classification probabilities for carriers.

Full figure and legend (20K)

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DNA linkage analysis in 186 individuals at risk for ADMCKD with ESRF, mild or advanced CRF or normal renal function, belonging to six large families, identified the responsible haplotype in 86 individuals (46.2%). A representative pedigree is shown in Figure 1, and indicative two-point LOD scores with three polymorphic markers are tabulated in Table 1. Table 2 shows the main demographic, clinical, biochemical and imaging data among affected and non-affected individuals of the six families. Among the 72 affected individuals there were 17 (23.6%) with normal renal function, 29 (40.3%) with renal failure (creatinine clearance less than 80 mL/min) and 26 (36.1%) diagnosed with ESRF. Among non-affected individuals 63.3% had normal renal function, while 36.7% had impaired renal function, and no one was in advance renal failure or ESRF.

Table 2 – Clinical, biochemical and sonographic data in 72 affected and 60 non-affected individuals, among 186 at-risk individuals from six Cypriot families with ADMCKD1.

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Males and females were equally affected (P> 0.05). The disease led to ESRF at a mean age of 53.7 years (males 53.1- and females 55.1 years old), ranging from 36 to 80 years. There was some variation in the mean age of ESRF between families. Worth mentioning is the earlier occurrence of ESRF in successive generations in all families, raising the possibility of anticipation Table 3.

Table 3 – Mean age of ESRF in the different generations of ADMCKD1 Cypriot families.

Full table

Hypertension was defined as blood pressure (BP)> 140/90 mm Hg on multiple measurements. It was found in 51.4% among affected and in 26.7% among non-affected individuals, a difference which was statistically significant (P < 0.01). Male carriers were more frequently affected (64.3%) compared to females (33.3%; P < 0.05). Hypertension was present in only 17.6% of the gene carriers with normal renal function, in 48.3% of gene carriers with CRF before ESRF and in 76.9% of patients with ESRF Table 4. No relationship between hypertension and FENa was found.
Table 4 – Hypertension and hyperuricemia in 72 carriers in relation to renal function.

Full table

It is defined as serum uric acid more than 7.0 mg/dL in males and more than 6.0 mg/dL in females. It was found in 36 out of 72 gene carriers (50%) and in only two among 60 non-carriers (3.3%), a difference that was statistically highly significant (P < 0.005). Male carriers were more frequently affected (64.1%) than female carriers (34.5%; P < 0.10). Hyperuricemia was found in two carriers with normal renal function (11.8%), in 13 carriers with CRF (44.8%) and in 21 carriers with ESRF (80.8%; Table 4). Among 19 hyperuricemic carriers 14 had a decreased FEurate (73.7%) and 5 had normal values (26.3%), a difference which was statistically significant at the 10% level (P 1.0), in the former group (P < 0.005). FENa also was more frequently increased in male compared to female carriers (P 0.05). However, comparison of the incidence of cysts between affected individuals and normal controls (16.7%) gave a statistically significant difference (P < 0.01)

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It is now clear that ADMCKD and NPH are two separate genetic diseases with similar clinicopathological findings but a different age of involvement and mode of inheritance. Several genetic loci have been mapped or cloned, emphasizing the genetic heterogeneity even within the same disease entity. At least three genes are known to be mutated in NPH (NPHP1, NPHP2 and NPHP313) and another three are responsible for ADMCKD. Two of them, MCKD1 and MCKD2, have been mapped to chromosomes 1q2112,16 and 16p12, respectively15. A third one is suspected based on the information that certain families link to neither of the previous two chromosomes17.

This disease, almost unknown in our region until recently, proved to be the most common cause of ESRF among our patients, accounting for up to 40% of all cases with ESRF treated at Pafos General Hospital Dialysis Unit. The vast majority of the patients originate from three nearby villages. Previous clinical and molecular work on two of these families led to the mapping of the first gene, MCKD1, mutations of which can cause the disease11,12. Symptoms were essentially absent, except in very advanced CRF, with severe anemia or uremia, or in some cases of severe sodium loss, before ESRF. This made the estimation of the age of onset very difficult. Thus, we concentrated on determining the age of ESRF, the mean age of which was 53.7 years with great inter- and intra-familial variability. This late appearance of ESRF has been reported by others28,29. As it is shown in Table 3, the disease leads to ESRF earlier in succeeding generations, with a difference of more than 20 years in some instances [Table 3, Family 4901(B)]. Whether this is a result of a higher protein consumption by younger generations or an anticipation phenomenon aiming at disease control remains an interesting question to investigate. One pitfall of the possible false appearance of anticipation could be the small number of individuals in each generation. Another pitfall may be the different criteria of ESRF definition in different chronic periods or even a misdiagnosis. It is true that in previous years, especially before 1972, substitution of renal function by transplantation or dialysis was not possible in Cyprus, and ESRF was considered as the physical death of an individual suffering from chronic renal failure. However, this would falsely increase the age of ESRF only minimally and not affect on our results substantially. The possibility of a misdiagnosis cannot be excluded theoretically, but the collected information about patients of previous generations was only accepted if it matched on the family trees. These patients were then considered as obligatory carriers. Therefore, we strongly believe that anticipation really does exist.

Hypertension is a frequent feature affecting both sexes equally. It is not an early finding, affecting 17.6% of gene carriers with normal renal function and 76.9% of the gene carriers with ESRF Table 4. No correlation between hypertension and sodium loss was found in our cases. However, three male patients who were treated with antihypertensive medications (but not diuretics) during the course of their disease presented with severe sodium loss, hyponatremia and hypotension just before ESRF. They required hospital admission, intravenous saline, oral sodium and discontinuation of antihypertensive drugs. This is known to happen in MCD, but according to Gardner, when it happens in uremic patients, it should raise the suspicion for ADMCKD10. Natriuresis, expressed as FENa, was found to be a significant component among the carriers of this disease in the performed multivariate analysis. However, increased natriuresis toward ESRD is not unique to ADMCKD, probably in a lesser degree. Among carriers, males presented with sodium loss more frequently than females (P < 0.05; Table 4), which explains why our patients with hyponatremia were all males.

While hyperuricemia and gout have been reported in families with MCD15,26, their pathophysiologic significance remains unclear. Hyperuricemia alone is not considered sufficient to lead to chronic renal failure30,31. There are reports about familial nephropathies associated with hyperuricemia and gout that probably constitute MCD cases, too27,32. FEurate was not increased among affected hyperuricemic patients and this excludes it from being secondary to renal failure33. The possibility that hyperuricemia is the cause of the patient's renal failure is remote and very unlikely. The spectrum of clinical findings, the characteristic cysts seen in some cases, the absence of specific gouty signs clinically, radiologically or histopathologically, as well as the absence of gout in most patients and of hyperuricemia in some, strongly argues against it27. However, hyperuricemia was found to be one of the factors in calculating the classification probability of an individual among these families as a carrier, and thus for the disease diagnosis. Gout was reported only by 6.7% of our gene carriers, all males. There was no difference on FEurate between carriers and non-carriers, so that hypo-excretion of uric acid found in a number of patients and normal subjects could not be etiologically related to the development of this disease. We share the view of Scolari et al for two independently inherited diseases15.

Histology, although not considered pathognomonic for this disease, is very helpful. All of the kidney biopsies showed very similar findings. Some glomeruli were globally sclerosed, while the remaining were normal, except for a variable degree of periglomerular fibrosis. GBMs were of normal thickness and appearance. The vessels also appeared normal. Bowman's capsule appeared thick in some cases. The most interesting and informative changes were seen on the tubules and the interstitium, with tubular atrophy, interstitial lymphocytic infiltration, interstitial fibrosis, tubular basement membrane thickening and tubular dilation at the sites. The last finding was seen in only one case. All biopsies were examined by electron microscopy, which confirmed the light microscopic findings. Most important was the confirmation of tubular basement membrane thickening, with splitting and lamellation Figure 4, and in some cases, there was an abrupt change from thick to thin. These changes have been reported in NPH34,35, in MCD6, and can be considered analogous to the changes of GBM in Alport syndrome.

Renal cysts were found in 40.3% of gene carriers and were of variable size, location and numbers. Only 12.5% of the carriers had small, multiple, bilateral cysts. It is now generally accepted that renal cysts are not essential for the diagnosis7 and, furthermore, they can appear late in the course of the disease36. The majority of cysts are corticomedullary or medullary, but cortical cysts also are reported. It is possible that some of these cortical cysts are in fact corticomedullary, appearing as cortical, due to the coexisting cortical atrophy and thinning. Detection of renal cysts can be achieved by ultrasonography, CT scan or MRI. Although enhanced CT scan is more sensitive to ultrasonography for detecting cysts less than 0.5 cm25,37, it is expensive, not always available, exposes the patient to a significant amount of radiation and must be avoided in individuals with impaired renal function. Ultrasonography is a less expensive, safer and readily available technique, which is in practice the method of choice for cyst detection, although it is less sensitive than the other two methods. Enhanced CT can be used in individuals with normal renal function either in complicated cysts, or in cases where the disease is suspected and where ultrasonography has failed to detect cysts. MRI can offer a great help in the case of an individual with impaired renal function, in whom the disease is suspected but ultrasonography has failed to detect any cysts38.

Polydipsia and polyuria were not reported as problems among our patients. These symptoms denoting a severe loss of concentrating ability are often reported in NPH3,7,8,9,10,39,40,41,42,43 and very rarely in MCD. The results on specific gravity measurements Figure 5 and on FENaTable 5 explain why our patients lacked these symptoms, at least at the initial stages of the disease. The concentrating ability seems to remain intact until moderate renal insufficiency. Proteinuria was absent in the majority (68.7%) of the examined carriers, while in the others it was mild or minimal, never exceeding 1 g/24 h. This is in full accordance with the literature, where only one case has been reported with massive proteinuria and the nephrotic syndrome and that was in a patient with NPH44.

The data indicate that ADMCKD is not as rare as has been previously thought, at least in Cyprus, where in the Pafos area it constitutes the most common cause leading to ESRF. Familial nephritis is generally underestimated as a cause of ESRF45 and is often reported as "unknown etiology." ADMCKD now has been proven to be a genetically distinct disease entity, with clinical and histopathological similarities to NPH. It is characterized by inter- and intra-familial variability and a mean age of onset of ESRF at 53.7 years. Although strong diagnostic criteria have not been suggested for this disease, in our families the corrected creatinine clearance, hyperuricemia and a decreased FENa proved to be influential factors. It is hoped that the recent reports on the mapping of responsible genes for Cypriot and other families will help toward the better understanding of this disease and clarify its pathogenesis in the near future. These genetic breakthroughs should help in more accurate and earlier diagnosis, with short and long-term benefits for all affected families and individuals.
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We thank our families for their understanding during this study, the Cyprus Kidney Association and the Cyprus Ministry of Health for their financial support, and last but not least, the people who so willingly have participated.

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