Objectives: Autosomal dominant polycystic kidney disease is the most common hereditary disorder resulting in end-stage renal disease that can affect other organs besides kidneys. Extrarenal involvement may increase mortality and morbidity. Approximately 50% of patients with this disorder require renal transplant. Posttransplant complications have been reported to be equal in these patients versus other recipients. We conducted this study to determine and compare characteristics and outcomes of transplanted patients with this disease versus other recipients at the only transplant center in southern Iran.
Materials and Methods: Detailed data of patients with autosomal dominant polycystic kidney disease were collected from medical records from the Shiraz Organ Transplantation Center. We also gathered data on a matched control group of transplant recipients who had end-stage renal disease due to other reasons, including other congenital kidney diseases and type 2 diabetes mellitus. Medical records of patients before and after transplant were reviewed. Statistical analyses were performed with SPSS software version 19 (Chicago, IL, USA).
Results: We collected data from 2002 to 2012 on 101 patients with autosomal dominant polycystic kidney disease and 100 control patients, including 74 female (36.8%) and 127 male patients (63.2%). Average duration of pretransplant dialysis was 14.9 ± 10.3 months in study patients and 12.8 ± 8.1 months in control patients. Rejection rate was statistically greater in recipients with this disease (30 patients; 68%) versus controls (14 patients; 32%) (P = .010).
Conclusions: Short- and long-term survival rates of patients with autosomal dominant polycystic kidney disease were not statistically different from control patients. However, graft survival was significantly lower. In short- and long-term follow-up of autosomal dominant polycystic kidney disease patients, hemoglobin and hematocrit levels were slightly higher than those of the control group. Autosomal dominant polycystic kidney disease is not a risk factor for posttransplant diabetes mellitus.
Key words : End-stage renal disease, Hereditary disorder, Kidney transplant, Southern Iran, Transplant recipients
Autosomal dominant polycystic kidney disease (ADPKD) is a late-onset hereditary multisystem disorder that leads to end-stage renal disease.1-3 It is characterized by bilateral renal cysts diagnosed by positive family history.4-10 Its global prevalence ranges from 0.1% to 0.3% in the normal population and accounts for 5% to 10% of end-stage renal disease cases.1,11-14 Autosomal dominant polycystic kidney disease is divided into 3 groups. Mutation PKD1, located on chromosome 16, is the most common type and is responsible for 85% of cases; it presents more aggressive at younger ages versus the disease course in those with mutation PKD2, which accounts for most of the remaining cases (10%-15%), with the related gene located on chromosome 4. Some previous studies1,11-23 have mentioned the possibility of a third type, named PKD3.
After patients present with signs and symptoms of ADPKD, such as abdominal or flank pain, hematuria, hypertension, and recurrent urinary tract infection (UTI), imaging studies follow. Extrarenal manifestations lead to mortality and morbidity in ADPKD patients. In addition, cysts in other organs can also occur, with liver cysts being the most common.24-28 Cardiac and vascular abnormalities and infertility in men due to seminal vesicle cysts have also been shown in patients with ADPKD.8,26,29-34
Previous studies have reported equal or insignificantly better transplant outcomes in patients with ADPKD versus other disorders leading to transplant.8,35-40 However, data on this observation are not clear regarding our center. Therefore, we conducted this study to determine and compare the characteristics and outcomes of transplanted ADPKD patients with other recipients at the Shiraz Organ Transplantation Center, the only transplant center in southern Iran.
Materials and Methods
Setting and sampling
This study included patients seen at a transplant ward in Shiraz Namazi Hospital (Shiraz University of Medical Sciences). All patients in this study underwent kidney transplant at the Shiraz Organ Transplantation Center (Shiraz, Iran) between 2004 and 2014. Their medical records were assessed, and patients with ADPKD were selected.
For each patient, a control case was chosen among transplant recipients from other causes. Patients with diabetes mellitus before transplant were excluded. Our study group of ADPKD patients comprised 101 kidney recipients, and our control group comprised 100 patients who received a transplant because of other causes during the study period (2004 to 2014).
After transplant, patients with functioning graft were seen in the transplant unit at regular follow-up visits, with patient assessments and laboratory tests as documented in their medical records. A questionnaire was prepared based on the pre- and posttransplant data, which included age at time of diagnosis and transplant, duration of dialysis before transplant, age of donor, sensitization (expressed as percentage of antibodies reactive to a lymphocyte panel [panel reactive antibody]), cause of graft loss and death, source of graft, and posttransplant complications such as type 2 diabetes mellitus, defined as fasting plasma glucose > 126 mg/dL or a requirement for hypoglycemic agents or insulin after transplant, according to the American Diabetes Association, and posttransplant erythrocytosis, defined as hemoglobin level > 17 g/dL.8 Medical records of the control group were also reviewed by the same investigator gathering the same data. We also reviewed the biopsy results of donated kidneys in patients who developed graft rejection.
At the Shiraz Transplant Unit, the immunosuppressive protocol consists of cyclosporine, mycophenolate mofetil (CellCept, Roche Pharmaceuticals, Basel, Switzerland), azathioprine (Imuran, San Diego, CA, USA), and prednisolone. The surgical technique includes placing the graft in the iliac fossa extraperitoneally.
This study was approved by the ethics committee of Shiraz University of Medical Sciences. The study protocol was in accordance with the Declaration of Helsinki.
Data were presented as means and standard deviations for continuous variables or number and percentage for categorical variables. Data were analyzed by the chi-squared and t tests. For data analyses, we use SPSS version 19 (Chicago, IL, USA), with P values < .05 considered as statistically significant.
Our study group included 101 patients with ADPKD who underwent kidney transplant and 100 control patients who also underwent kidney transplant but as a result of other causes during the same period. Patient characteristics of the study groups are presented in Table 1. In the ADPKD group, the mean age at time of transplant was 44.5 ± 11.3 years, with 61 male patients (60.4%). In the control group, the mean age was 36.7 ± 12.7 years, with 66 male patients (66.5%). These results revealed a significantly higher age in the ADPKD patients (P < .001).
Dialysis duration before transplant was 14.9 ± 10.3 months in the ADPKD group versus 12.8 ± 8.1 months in the control group (P = .111). Duration of hospital admission posttransplant was significantly longer in ADPKD patients (16.7 ± 11.1 d vs. 10.4 ± 4.3 d; P < .001).
Glomerulonephritis was the most frequent cause of kidney failure in the control group, consisting of 66 patients (66.0%), followed by hypertensive nephropathy in 29 patients (29.0%). Living unrelated kidney was the common type of transplanted kidney in both group, with a higher rate in the ADPKD group (70 patients [69.3%] vs 46 patients [46.0%]; P = .002).
We found that rejection rate was higher in ADPKD patients (odds ratio: 2.6, 95% confidence interval, 1.3-5.3). In the ADPKD group, 30 patients (29.7%) experienced rejection versus 14 patients (14.0%) experiencing rejection in the control group (P = .01).
In the ADPKD group, 21 patients (20.8%) died during the course of study, whereas 16 patients (16.0%) in the control group died during our study period (P = .46). The most common cause of death was cardiovascular accident (with 8 patients [38.0%] in the ADPKD group and 8 patients [50.0%] in the control group), followed by infection (5 patients [23.80%] in the ADPKD group and 6 patients [37.5%] in the control group).
Patients were treated with conventional immunosuppressive agents posttransplant. Table 2 shows the prescribed medications. The most common drug regimen in both groups was a combination of prednisolone, mycophenolate mofetil, and cyclosporine, with 68 patients (67.3%) in the ADPKD group and 62 patients (62.0%) in the control group.
The patients’ laboratory test results during follow-up are shown in Table 3. There were no significant differences in creatinine levels and blood urea nitrogen between the ADPKD and control groups during the 10-year follow-up, except in year 5 regarding creatinine levels, which were significantly higher in ADPKD patients (1.5 ± 0.9 vs 1.3 ± 0.3; P = .013). Hemoglobin concentrations at short- and long-term follow-up of ADPKD patients were slightly higher than in the control group. However, these results were only statistically significant after year 1 and year 3 of follow-up, at 14.3 ± 1.6 versus 13.8 ± 1.7 g/dL (P = .057) for year 1 and 14.6 ± 2.0 versus 14.0 ± 1.5 g/dL (P = .022) for year 3. Type 2 diabetes mellitus developed in 5% of ADPKD patients (5 patients) versus 6% of control patients (6 patients) after transplant (P = .767). In addition, all of the patients with positive reactive antibody were in the control group (2 patients [2.0%] vs 0 in the ADPKD group; P = .509).
In this study, we also analyzed the biopsy results of the rejected donor kidney posttransplant. The most common histologic type in the ADPKD group with rejected kidney was acute cellular rejection (19 patients; 63.3%), with antibody-mediated rejection being the most common in control patients (8 patients; 57%).
Autosomal dominant polycystic kidney disease is the most common hereditary disease leading to end-stage renal disease. The condition may be accompanied by multiple extrarenal manifestations, which increase patient mortality and morbidity.10,41,42 Transplant is the best treatment for these patients.35 Excluding type 2 diabetes mellitus, which is increased in ADPKD patients, other posttransplant complications have been described with equal frequency in these patients and others with end-stage renal disease.36,43,44 In this retrospective study, we compared characteristics of ADPKD patients after transplant with transplant patients with other diagnoses.
In our study, the mean age of ADPKD patients was significantly greater than in our control group. Other studies have shown the same pattern in age,8,39 which may imply the late initiation and slow progression of this disease.13,14,18 This observation may also be due to the better control of signs and symptoms (such as blood pressure), which can prevent or slow down the development of end-stage renal disease.8
In the present study, despite the pattern of autosomal dominant inheritance of ADPKD, sex distribution trended to male dominancy (nearly 60%). In addition, another study showed the older age of women at the time of end-stage renal disease.8 This observation may indicate the modulatory role of sex hormone in women.8
Similar to our previous study, most ADPKD patients received living unrelated donations followed by deceased donor kidneys due to the inheritable pattern of the disease.36
Posttransplant hospital admission was significantly longer in the ADPKD group, demonstrating greater number of postoperative complications. To our knowledge, no study has documented posttransplant admission days. However, some studies have shown no evidence of more postoperative complications in ADPKD patients.36
In our study, hemoglobin levels measured at short- and long-term follow-up of ADPKD patients was slightly greater than those shown in our control group, perhaps due to overproduction of erythropoietin in the involved kidney. As a result, some studies have recommended nephrectomy to solve this complication.8
One of the posttransplant complications is type 2 diabetes mellitus, which some previous studies have revealed to be more prevalent in ADPKD patients after transplant.43 Hamer and associates reported that ADPKD patients are at the risk of type 2 diabetes mellitus 2.4 times more than non-ADPKD patients.44 These studies mentioned increased age of ADPKD patients as a cause of the increase in type 2 diabetes mellitus incidence. However, in this study, we did not find the same relation, perhaps due to the different definition of type 2 diabetes mellitus and considering just 1 criterion of the definition.
Rejection was significantly (2.6 times) greater in our ADPKD group. Previous studies have revealed no significant difference between rejection rates in ADPKD patients versus other patients.8,38,39
Cardiovascular disease was the most common cause of death among both groups in our study. Other studies have shown more cardiovascular events in ADPKD patients due to involved vessels and perhaps due to the increased age of ADPKD patients.39,40 However, Errasti and associates mentioned malignancy as the most common cause of death.38 Infections were the second cause of death in our study, whereas previously studies have reported it as the most common posttransplant complication among ADPKD patients. The use of immunosuppressant drugs can result in infection.36,37
There were no significant differences in patient death between the ADPKD and control groups, although we found a significant increase in rejection rate. In addition, we found a significantly greater number of admission days in ADPKD patients, implying more short-term postoperative complications. Long-term posttransplant complications were not found to occur more frequently in ADPKD patients, including development of type 2 diabetes mellitus. Because of the results shown here, more studies should be performed to assess these patients for a longer period of time.
Volume : 16
Issue : 6
Pages : 676 - 681
DOI : 10.6002/ect.2016.0163
From the 1Department of Internal Medicine, Shiraz Nephro-Urology
Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; the 2Department
of Community Medicine, Shiraz Nephro-Urology Research Center, Shiraz University
of Medical Sciences, Shiraz, Iran; and the 3Shiraz Nephro-Urology
Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Acknowledgements: The Vice-Chancellery of Research and Technology of Shiraz University of Medical Sciences financially supported this study that derived from a student’s thesis (Mohammad Mostafa Harifi, number 5263). The authors declare that they have no conflicts of interest.
Corresponding author: Leila Malekmakan, Department of Community Medicine, Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Phone/Fax: +98 711 212 7300
Table 1. Recipient Characteristics of the Study Groups
Table 2. Distribution of Different Regimens in the Study Groups
Table 3. Laboratory Results of the Study Groups