Outcome of kidney transplantation in autosomal dominant medullary cystic kidney disease type 1
Christoforos Stavrou1,
C. Constantinou Deltas2,
Tasos C. Christophides3 and
Alkis Pierides4
1Royal Artemis Medical Centre, Pafos, 2Cyprus Institute of Neurology and Genetics and Department of Biological Sciences, University of Cyprus, Nicosia, 3Department of Mathematics and Statistics, University of Cyprus, Nicosia and 4Nicosia General Hospital, Nicosia, Cyprus
Correspondence and offprint requests to: Dr Christoforos Stavrou, 8 Solon Street, 8577 Tala, Pafos, Cyprus. Email: royaldial{at}cytanet.com.cy
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Abstract
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Background. Autosomal dominant medullary cystic kidney disease (ADMCKD) is an inherited, distinct, chronic, tubulointerstitial, cystic-type nephropathy, often described together with juvenile nephronophthisis as a single disease complex (NPHMCD). However, since the recent localization of two genes responsible for ADMCKD, namely MCKD1 and MCKD2, ADMCKD has gained independent status. Unfortunately, there appears to be a distinct lack of up-to-date information in the currently available medical literature concerning worldwide patient and graft survival after renal transplantation in ADMCKD. This report is based on all 41 transplanted patients [19 suffering from autosomal dominant medullary cystic kidney disease type 1 (ADMCKD1) and 22 from other causes] who were referred for kidney transplantation from our centre in Pafos, Cyprus between 1976 and 2000. All patients had regular follow-up examinations. This report aims to present the results of kidney transplantation of the 19 ADMCKD1 patients and to compare them with those for the 22 non-ADMCKD patients.
Methods. Patient and graft survival times in both groups were recorded, analysed and compared 1 and 5 years post-transplant. Patient and graft survival times were calculated according to the KaplanMeier method and some descriptive statistical comparisons were based on the
2-test.
Results. The 1 year patient and graft survival rates for ADMCKD1 (group A) were 100%, while the 5 year figures were 100% and 90%, respectively. For non-ADMCKD1 patients (group B) the 1 year figures were 95% for both parameters, while the 5 year figures were 93.3% for both parameters. There were no statistically significant differences in patient and graft survival times between the two groups.
Conclusions. Kidney transplantation is the treatment of choice for patients suffering from ADMCKD, with an excellent outcome and no specific complications.
Keywords: autosomal dominant medullary cystic kidney disease; kidney transplantation; nephronophthisis
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Introduction
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Autosomal dominant medullary cystic kidney disease (ADMCKD) and familial juvenile nephronophthisis (NPH) have for many years been described together under the title of the NPHMCD complex [13]. However, ADMCKD mainly affects adults and is inherited with an autosomal dominant mode [4], while NPH affects mainly children or young adults and is inherited with an autosomal recessive mode [5]. ADMCKD and NPH are also genetically different.
Clinically they are mostly quiescent, except for early polyuria, polydipsia and some extrarenal manifestations associated with NPH. Their histopathology is characterized by the triad of tubular basement membrane thickening with splitting and lamellation, tubular atrophy with dilatation and non-specific cellular interstitial infiltration with fibrosis [6]. Renal cysts, especially at the corticomedullary region, appear in most of the patients in advanced stages and towards end-stage renal failure (ESRF). However, renal cysts are absent in almost half of the patients on ultrasonography, in the early stages of the disease.
There is evidence for at least four genes for NPH, namely NPHP1, NPHP2, NPHP3 and NPHP4 [7,8], and at least another three for ADMCKD, two of which, MCKD1 and MCKD2, have already been localized [911]. These new observations have provided opportunities for more accurate diagnosis and further in-depth study of these conditions.
However, while some reports on kidney transplantation exist for children with NPH [1217], such reports are very rare for ADMCKD [1820]. In Pafos, Cyprus, autosomal dominant medullary cystic kidney disease type 1 (ADMCKD1) has been proved to be the leading cause of ESRF, amounting to 40% of all cases. This report, based on all transplanted individuals from our centre over the years 19762000, aims to present the results of kidney transplantation for its 19 patients with ADMCKD1 and to compare them with those for the 22 patients with non-ADMCKD.
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Subjects and methods
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Forty-one patients were referred for kidney transplantation, from our unit, over the years 19762000. They were organized into two groups, A and B.
Group A includes 19 transplanted patients suffering from ADMCKD1. They belonged to six large Cypriot families. Molecular studies and DNA linkage analysis established that all these families map to the MCKD1 locus [9,21] on chromosome 1q21.
Group B includes the 22 other transplanted patients who had developed ESRF from causes other than ADMCKD1. Two of them (patients 2 and 12) suffer from an undetermined familial nephritis (Table 1).
Kidney donors to both groups were mainly living related or cadaver. In group A, to prevent the possibility of a carrier of MCKD1 becoming a donor, all siblings were excluded. Only a clinically not-affected parent was accepted as a donor, subject to all other pre-transplant tests being satisfactory. Five patients from group A and two from group B received living, non-related transplants. In four cases, the donor was the spouse and in three cases the father-in-law. The clinical data for the 19 patients in group A are presented in Table 2 and for the 22 patients in group B, in Table 1. Resultant comparative numerical data between the two groups are shown in Table 3.
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Results
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Nineteen patients (15 males, 4 females) with ESRF due to ADMCKD1, aged 3863 years at the time of transplantation (mean age: 48.3 years), underwent successful kidney transplantation between 1976 and 1999 (Table 2). Four patients received a parent kidney (living related donor) (21.1%), 10 received a cadaveric kidney (52.6%) and five received a living, not blood related, family kidney from the spouse or father-in-law (26.3%). One patient (patient 3, Table 2) died during the study period from liver failure and non-Hodgkin's lymphoma with a functioning renal graft (serum creatinine 3.3 mg/dl). Three patients lost their grafts and are currently back on haemodialysis (patients 2, 7 and 11, Table 2). Two of them, patients 2 and 11, lost their grafts due to chronic rejection, while patient 7 lost his graft due to a haematoma and thrombosis after a transplant kidney biopsy. At the time his serum creatinine was 3.2 mg/dl. At the end of the study period, from the original 19 patients of group A, 15 patients (78.9%) were alive and well with functioning grafts and a mean serum creatinine of 1.8 mg/dl, a mean 84.6 months post-transplantation (Table 3).
Those 22 patients with ESRF due to non-ADMCKD1 type renal disease (13 males, 9 females), aged between 23 and 66 years (mean age: 40.8 years), received transplants in Cyprus between 1984 and 2000 (Table 1). Thirteen of these patients (59.1%) received a living related kidney transplant, seven (31.8%) a cadaver transplant and two (9.1%) a living, not blood related, kidney transplant.
Nineteen of these patients in group B are currently alive and well with a functioning graft (86.4%). Two of the transplant recipients lost their grafts due to chronic rejection (patients 2 and 7, Table 1) and one patient (patient 13, Table 1) died 2 months after transplantation from septicaemia and extended cavernous sinus thrombosis.
The patient and graft survival rates for group A were 100% for the first year, while at 5 years they were 100% and 90%, respectively. For group B the 1 year patient and graft survival rates were 95% for both parameters, while the 5 year figures for both parameters were 93.3%. Comparison of patient and graft survival rates between groups A and B revealed no significant differences (P > 0.05). More precisely, for patient survival, the P-value was 0.88 while for graft survival it was 0.36.
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Discussion
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ADMCKD is a hereditary, chronic tubulointerstitial nephropathy, which can ultimately lead to ESRF. It affects adults at different ages and although occasionally considered a disease of the elderly, it affects younger adults as well. It is often misdiagnosed as nephrosclerosis.
The lack of early symptoms and the absence of clear diagnostic criteria for this disease make the selection of candidate kidney donors among family members very difficult or almost impossible on clinical grounds. This has resulted in exclusion of all brothers and sisters of the patients in our families so far and acceptance of only one of the parents (the one without the disease). This problem had a major impact on the families of our ADMCKD patients and is reflected on the much lower incidence of living related transplants amongst them. Living related donors in the ADMCKD group (group A) amounted to only 21.1%, while in group B it was 59.1% (Table 3) (P < 0.05). The localization of two genes, namely MCKD1 and MCKD2, for this entity will certainly ameliorate the problem, since DNA linkage analysis, if applied, will separate the affected from the non-affected family members, thus increasing the potential number of living related donor candidates. Despite some hesitation by a few centres, there is a growing acceptance for living unrelated kidney donors, provided that they are emotionally related, they express their willingness to donate and they are carefully selected and thoroughly informed. Under these conditions the results are very satisfactory and better than in cadaver transplantation [2226].
The world experience is very limited with regards to kidney transplantation in ADMCKD. Only a very few patients with ADMCKD receiving kidney transplants have been reported [1820]. Most reports refer to young patients with familial juvenile NPH [1217,2729]. The report of Zevin et al. [30] is of great interest, since it is the only published study of massive anti-glomerular and anti-tubular deposits leading to a rejection-related nephritic syndrome in a transplanted patient with NPH. This is probably similar to the appearance of anti-glomerular basement membrane in some patients with Alports syndrome after transplantation. We have not encountered a similar problem in our ADMCKD patients.
There was one death and three graft losses in group A, while in group B there were one death and two graft losses (Tables 1 and 2). The patient who died and the two patients who lost their grafts from group A had received parent kidneys, which were normal on clinical grounds. Although not expected to be carriers of MCKD, two of them, cases 2 and 7 (Table 2), were alive in 1998 and they were included in the linkage analysis study. They were found not to carry the responsible MCKD1 locus.
Although in group A the majority of transplants were cadaveric (52.6%), compared with 31.8% in group B (P = 0.30), the 1 and 5 year patient and graft survival rates in group A were as good as in group B (P > 0.05) (Table 3). We encountered no case of recurrence of the disease and no recurrence of renal cysts. The relatively small number of 19 patients is a limiting factor for the very reliable statistical results.
Kidney transplantation is a safe and highly recommended method of renal replacement treatment in ADMCKD. Recurrence of the disease and/or of the renal cysts has not been observed among the 19 transplanted patients in Pafos. The current difficult problem of identifying suitable living related donors in the context of this disease should improve dramatically in the near future as DNA linkage analysis becomes more widely known for the help it offers in the study of families with ADMCKD. This will ultimately lead to an increased availability of living related donors.
Thus, the practical importance of these breakthroughs in the genetics of ADMCKD should be made more widely known among nephrologists, anticipating that the expected cloning of the involved MCKD genes may facilitate further family studies in these patients.
Conflict of interest statement. None declared.
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References
|
---|
- Gardner KD, Jr. Juvenile nephronophthisis and renal medullary cystic disease. In: Gardner KD, Jr, ed. Cystic Diseases of the Kidney. John Wiley & Sons, New York: 1976;173185
- Strauss MB, Sommers SC. Medullary cystic disease and familial juvenile nephronophthisis: clinical and pathological identity. N Engl J Med 1967; 277: 863864[ISI][Medline]
- Burke JR, Inglis JA, Craswell PW, Mitchell KR, Emmerson BT. Juvenile nephronophthisis and medullary cystic disease: the same disease (report of a large family with medullary cystic disease associated with gout and epilepsy). Clin Nephrol 1982; 18: 18[ISI][Medline]
- Berstein J, Gardner KD, Jr. Hereditary tubulo-interstitial nephropathies. In: Brenner BM, Star JH, eds. Contemporary Issues of Nephrology. Churchill Livingstone, New York, Edinburgh, London, Melbourne: 1983; 10: 335357
- Kleinknecht C. The inheritance of nephronophthisis. In: Spitzer A, Avner ED, eds. Inheritance of Kidney and Urinary Tract Diseases. Kluwer Academic Publishers, Boston, 1990; 278292
- Hildebrandt F, Omram H. New insights: nephronophthisis-medullary cystic kidney disease. Pediatr Nephrol 2001; 16: 168176[CrossRef][ISI][Medline]
- Hildebrandt F. Identification of a gene for nephronophthisis. Nephrol Dial Transplant 1998; 13: 13341336[Free Full Text]
- Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol 2000; 11: 17531761[Abstract/Free Full Text]
- Christodoulou K, Tsingis M, Stavrou C et al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease (ADMCKD). Hum Molec Genet 1998; 7: 905911[Abstract/Free Full Text]
- Scolari F, Puzzer D, Amoroso A et al. Identification of a new locus for medullary cystic disease on chromosome 16p12. Am J Hum Genet 1999; 64: 16551660[CrossRef][ISI][Medline]
- Fuchshuber A, Deltas C, Berthold S et al. Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity. Nephrol Dial Transplant 1998; 13: 19551957[Abstract]
- King SY, Buttimore A, Lynn KL, Bailey RR. Active treatment of children with end-stage renal failure. N Z Med J 1982; 95: 763766[ISI][Medline]
- Henriksson C, Andersen HJ, Gustaffson A, Gelin LE. Renal transplantation in children. Acta Pediatr Scand 1975; 64: 833838[ISI][Medline]
- Balfe JW. Transplantation of a 14-year-old girl with nephronophthisis. Pediatr Nephrol 1997; 11: 132[ISI][Medline]
- Nyberg G, Friman S, Svalander C, Norden G. Spectrum of hereditary renal disease in a kidney transplant population. Nephrol Dial Transplant 1995; 10: 859865[Abstract]
- Yoshida A, Morozumi K, Koyama K et al. Familial juvenile nephronophthisis and renal transplantation in two siblings. Nippon Jinzo Gakkai Shi 1992; 34: 10351039[Medline]
- Valadez RA, Firlit CF. Renal transplantation in children with oculorenal syndrome. Urology 1987; 30: 130132[ISI][Medline]
- Rahnsen F, Munda R, Haraharan S, First MR, Demmy A. Combined kidneypancreas and parathyroid transplantation: a case report. Clin Transplant 1997; 11: 341343[ISI][Medline]
- Lim EC, Terasaki PI. Outcome of kidney transplantation in different diseases. Clin Transplant 1990;461469
- Chagnac A, Zevin D, Weinstein T, Hirsh J, Levi J. Combined tubular dysfunction in medullary cystic disease. Arch Intern Med 1986; 146: 10071009[Abstract]
- Stavrou C, Koptides M, Tombazos C et al. Autosomal dominant medullary cystic kidney disease type 1. Clinical and molecular findings in six large Cypriot families. Kidney Int 2002; 62: 13851394[CrossRef][ISI][Medline]
- Cortesini R, Pretagostini R, Bruzzone P, Alfani D. Living unrelated kidney transplantation. World J Surg 2002; 26: 238242[CrossRef][ISI][Medline]
- Binet I, Bock AH, Vogelbach P et al. Outcome in emotionally related living kidney donor transplantation. Nephrol Dial Transplant 1997; 12: 19401948[Abstract]
- Gjertson DW, Cecka JM. Living unrelated donor kidney transplantation. Kidney Int 2000; 58: 491499[CrossRef][ISI][Medline]
- Foss A, Leivestat T, Brekke IB et al. Unrelated living donors in 141 kidney transplantations: an ongoing centre study. Transplantation 1998; 66: 4952[ISI][Medline]
- Hillebrandt GF, Theodorakis J, Illner WD et al. [Living donors in kidney transplantation. Renaissance by non-related donors?] Fortschr Med Orig 2001; 118: 135139[Medline]
- Chantler C, Scharer K, Gilli G et al. Dialysis and renal transplantation of children in Europe, 1975. Acta Pediatr Scand 1978; 67: 510[ISI][Medline]
- Gomez-Campdera FJ. Renal transplantation from a living donor in nephronophthisis. Ann Intern Med 1989; 6: 106
- Galan A, Robles NR, Rengel M, Valderrabano F. Nephronophthisis and kidney transplantation from a kindred living donor. Ann Intern Med 1989; 6: 105
- Zevin D, Ben Bassat M, Weinstein T, Shapira Z, Levi J. Rejection-related nephritic syndrome associated with massive antiglomerular and antitubular basement membrane deposits. Isr J Med Sci 1985; 21: 915918[ISI][Medline]
Received for publication: 5. 6.02
Accepted in revised form: 21. 2.03