Objectives: The number of renal transplants in elderly patients is increasing as age per se does not constitute a contraindication to transplant. We compared renal transplant outcomes in elderly recipients versus a group of middle-aged patients.

Materials and Methods: Our retrospective case-controlled study compared elderly transplant recipients (n = 252; > 60 y old) with a matched cohort of younger adult recipients (n = 710; between 40 and 60 years old) who underwent renal transplant at the Hamed Al-Essa Organ Transplant Center of Kuwait between 2000 and 2014. Demographic characteristics, comorbidities, complications after transplant, and graft and patient outcomes were compared between groups.

Results: There were 252 elderly kidney transplant recipients (mean age of 65.5 ± 4.8 y; 59.52% males) and 710 younger adult patients (mean age of 49.3 ± 5.5 years; 61.4% males). Most donors were males in their thirties. Deceased donors predominated in the younger adult group, whereas living unrelated donors predominated in the elderly group (P < .05). Diabetes represented the most common cause of end-stage kidney disease. Younger patients tended to receive heavier induction therapy but comparable maint­enance immunosuppression. Posttransplant diabetes was higher in younger patients; however, there were more elderly patients with micro- and macroangiopathies (P < .05). No significant differences were shown between groups with regard to patient or graft survival (P > .05). This could be attributed to a significantly higher number of patients with cardiovascular risks, less rejection episodes, and higher number of malignancies in the elderly group (P < .05).

Conclusions: Due to relatively less potent immuno­suppression, elderly patients experienced lower rejection rates and better graft survival; however, patient survival was lower due to higher cardio­vascular risk factors. Older patients should not be discouraged from living-donor renal transplant. Targeted research studies on protocols for the elderly are needed.

Key words : Cardiovascular disease, Immunosuppression, Malignancy, Posttransplant diabetes, Survival

Introduction

Kidney transplantation is currently the best available treatment for end-stage kidney disease (ESKD). It is associated with a better quality of life, lower costs, and higher survival rates than other renal replace­ment therapies.^1,2 Such advantages can also be found among elderly renal transplant recipients.³ Untenable factors such as lower life expectancy, associated comorbidities, surgical risk, and potential for serious complications have kept elderly patients from having access to transplants. However, not enough data exist to justify this conservative attitude in elderly patients.³

The incidence and prevalence of older patients with ESKD have been increasing, with a median patient age of 64.9 years at time of diagnosis in the United Kingdom.¹ Half of patients with ESKD in the United States are > 65 years old, and one-third are > 70 years old when first diagnosed.⁴ In the past 3 years,5 the estimated number of dialysis patients reached 100 000 in 2013, with 30% over the age of 65 years. However, during this period, patients in the same age range enrolled for transplant remained below 15%.⁶

An awareness of the relative benefits and risks of treatment for older patients with ESKD is therefore increasingly important to the practicing gerontologist. The mean age of renal transplant recipients is rising, and advanced age is no longer considered a contraindication to transplant. Better survival and quality of life and economic advantages have been demonstrated after renal transplant in older patients, including those with comorbidities, compared with dialysis treatment.^7-9 However, access to renal transplant has continued to be limited for older people with ESKD, possibly due to organ allocation policies and lack of awareness.^10,11 In a Canadian study, 26.5% of patients > 65 years old had no contraindications to transplant.¹²

Clearer definitions of outcomes after renal transplant in patients at the extremes of age would be beneficial. In this study, our primary objective was to evaluate and compare graft and patient outcomes after renal transplant in older donors and recipients versus a younger group of middle-aged patients.

Materials and Methods

This single-center retrospective study included 252 elderly patients (≥ 60 years old) who underwent renal transplant at the Hamed Al-Essa Organ Transplant Center of Kuwait during the period between 2000 and 2014. We compared this group of patients with another group of 710 middle-aged patients (between 40 and 60 years old). Patient medical records were reviewed for demographic parameters, pretransplant comorbidities, type of immunosuppression (induction and maintenance), posttransplant complications (immunologic and nonimmunologic), and graft and patient outcomes.

This study was conducted in full accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and adhered to local and national regulatory requirements and laws.

Each patient was evaluated clinically with thorough history taking and physical examinations monthly in the outpatient clinic. Laboratory tests included complete blood count, creatinine concen­tration, creatinine clearance, liver function tests, and fasting blood sugar. Patients were also tested for urinary protein level (g/24 h), serum drug levels, and virology profile (cytomegalovirus, Epstein-Barr virus, and parvovirus). Patients received annual abdominal ultrasonography.

Immunosuppression
Our immunosuppression protocol consisted of 5 doses of antithymocyte globulin (Sanofi US, Bridgewater, NJ, USA) for high-risk patients (as retransplants, prior pregnancy, blood transfusion, HLA-antibody positive, and/or > 4 HLA mismatches) or 2 doses of interleukin 2 receptor blocker (basiliximab; Novartis, Inc., Basel, Switzerland) for low-risk patients. Maintenance therapy consisted of prednisolone, mycophenolate mofetil, and a calcineurin inhibitor. The dose of calcineurin inhibitor was gradually decreased until it reached the lowest dose by the end of year 1, as guided by 12-hour trough level. We kept the cyclosporine level between 200 and 250 ng/mL during month 1, then between 150 and 200 ng/mL for 2 months, between 125 and 150 ng/mL for up to 6 months, and from 75 to 125 ng/mL until the end of year 1. Similarly, we kept tacrolimus trough levels between 8 and 10 ng/mL during the first 3 months and then from 5 to 8 ng/mL thereafter. Maintenance immunosuppression with a sirolimus-based regimen was used for rejection-free patients with low immunologic risk at 3 months after transplant. All patients received valganciclovir and sulfamethoxazole trimethoprim prophylaxis for 6 months.

Acute cellular rejection was treated with intra­venous methylprednisolone sodium succinate (1 g daily for 3 d) and/or with thymoglobulin (1 mg/kg for 5-7 d) for steroid-resistant rejection. Antibody-mediated rejection was treated with plasma exchange, intravenous immunoglobulin (2 g/kg), and rituximab. All rejection episodes were biopsy proven according to Banff criteria. Patients who received thymoglobulin as antirejection were managed by secondary anticytomegalovirus prophylaxis for 1 month, whereas those who developed viremia were treated with therapeutic valganciclovir for 3 weeks followed by prophylaxis for 3 months.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 24.0, IBM Corporation, Armonk, NY, USA). Variables and means were compared using paired sample t test, independent sample t test, chi-square test, Fisher exact test, and analysis of variance as appropriate. Results are expressed as means and standard deviation, and differences were considered significant at P ≤ .05.

Results

Of 3600 renal transplant recipients, 932 patients were included in this retrospective analysis. There were 252 elderly kidney transplant recipients with mean age of 65.5 ± 4.8 years (range, 60-81 y; 59.52% males), and 710 middle-aged patients with mean age of 49.3 ± 5.5 years (range, 19-59 y; 61.4% males) (P > .05).

Most donors were males (78.5% and 70.14% in the 2 groups), and most were in their thirties. Deceased donors significantly predominated in the younger group of patients, whereas living donors signi­ficantly predominated in the elderly group (P = .007).

Diabetes represented the most common cause of ESKD among elderly patients (49.5%), with a signi­ficantly higher incidence versus the younger group, whereas glomerulonephritis represented the second most common cause among younger patients after diabetes (28.5%), with a significantly higher inci­dence versus the older group (Table 1; P < .001). The 2 groups were comparable regarding virology profile and type of pretransplant dialysis modality (Table 1, P > .05).

In the elderly group, we observed a significantly higher percentage of patients with hypertension, diabetes, dyslipidemia, chronic anemia, reactive T-spot test for tuberculosis, and ischemic heart disease (Table 1; P < .05). However, the percentage of patients with hyperlipidemia and bone disease was com­parable between groups (P > .05). The percentage of elderly patients who received interleukin 2 receptor blockers as induction was significantly higher (P < .001). However, the 2 groups were comparable regarding heavy induction using antilymphocytic agents and maintenance immunosuppressive regi­mens (despite the tendency toward steroid-free regimens in elderly patients; P = .07). In addition, we observed that the groups were comparable regarding immediate-term outcomes of graft function post­transplant (P > .05).

We observed more patients with posttransplant diabetes mellitus (PTDM) in the younger group (24% vs 17%; P = .053); however, the total percentage of patients with diabetes was significantly higher in the elderly group (P = .01, Table 2). In addition, there were significantly more patients with micro- and macroangiopathies in the elderly group (P = .01).

Bacterial infections that necessitated hospitalization (as represented by chest and urinary infections) were comparable between groups (P > .05). The percentage of patients with both BK viremia and BK nephropathy was also comparable between groups (P > .05).

Graft survival was significantly better in the elderly group, whereas patient survival was significantly better in the younger group of patients (P < .05; Table 2). We observed a significant increase in the percentage of patients with early acute rejection (T-cell mediated, antibody mediated, or mixed) among the younger patients (P = .024), but the 2 groups were comparable regarding percentage of patients with late acute rejection (P = .09; Table 2).

As shown in Figure 1, we found no significant differences between the groups with regard to baseline graft function, as represented by estimated glomerular filtration rate (P > .05). Although graft function was significantly better in the elderly group at 6 months, 1 year, and 3 years during follow-up

(P < .05), long-term graft function showed no significant difference between the groups at 5 and 10 years of follow-up (P > .05).

Discussion

Elderly patients represent a considerable and increasing fraction of adults with ESKD. In the absence of contraindications, they have better outcomes after renal transplant than with other forms of renal replacement therapies.^4,13 Stevens and associates¹¹ reported a much lower probability of older patients receiving transplant procedures than younger patients, with only 8% of listed patients from 65 to 74.9 years old receiving transplant procedures within 5 years. Moreover, Segev and associates¹⁴ reported a 30% decrease in access to transplant for each decade increase in age. When compared with comorbidity-matched male coun­terparts, access to transplant was 29% lower for women aged 65 to 75 years and 59% lower for women older than age 75 years.3 Here, our work is one of the few Arab world studies comparing the evolution of renal transplant in elderly versus middle-aged recipients with long-term follow-up.

We aimed to compare renal transplant outcomes in elderly recipients versus a more commonly transplanted group of kidney recipients (middle-aged patients). In our center, the percentage of elderly kidney transplants represented 15% of annual total transplants. This percentage is nearly similar to a population enrolled for transplant in the same age group (below 15%)¹⁵ and slightly more than that reported in a retrospective study by Dempster and associates,¹⁶ who showed that elderly transplant recipients represented 4% of living donor and 9.1% of deceased donor transplants.

Similarly, it was reported that only 12.5% of kidney transplants, performed in a Brazilian kidney hospital that was responsible for 20% of all kidney transplants, were above 60 years old.¹⁷ Although 30% of dialysis patients are elderly (above 65 years old), those who were listed for transplant remained below 15%.⁶ Moreover, the US Renal Data System (USRDS) observed a slower increase in kidney transplant procedures in patients older than 65 years when compared over time, such that, by 2006, patients older than age 65 years only accounted for 13.3% of all kidney transplant recipients.¹⁸

Furthermore, a previous study emphasized that one-half of dialysis patients referred to a transplant unit are greater than 65 years old.¹¹ In fact, they represented only 4% and 9.1% of living-donor and deceased-donor renal transplants, respectively. In our study, we did not find any significant difference between our age groups regarding sex distribution, which was not in agreement with that reported by Segev and associates.¹⁴ They showed that the prob­ability of transplant is 29% lower among older women (> 65 y). This difference could be due to cultural and religious factors with regard to elderly mothers.

In our study, deceased-donor procedures signi­ficantly predominated in the younger group of patients, whereas living-donor procedures signifi­cantly predominated in the elderly group (P = .007; Table 1). This difference from other studies could be explained by differences in transplant awareness and other cultural factors. In addition, it could be explained by our adopted policy of assigning organs from younger deceased donors to younger recipients and vice versa.

Many studies have reported that older age represents the strongest and most consistent risk factor for PTDM in kidney transplantation.^19-27 Data from the US Renal Data System showed that recipients of a first kidney transplant who were between 45 and 59 year had a relative risk for PTDM of 1.9 (95% confidence interval [CI], 1.73 to 2.09; P < .0001), whereas patients older than 60 years had a risk of 2.6 (95% CI, 2.32 to 2.92; P < .0001).¹⁹ Even with increasing age, the risk for development of diabetes mellitus increased by 1.5-fold for every 10-year increase in age.²⁵ In our cohort, we observed a trend toward more patients with PTDM among the younger group of patients (24% vs 17%; P = .022), but the total percentage of patients with diabetes was significantly higher in the elderly group (68.2% vs 50.8%; P = .01). This might be explained by the significantly higher number of elderly patients with type 2 diabetes as a cause of ESKD. Although this finding was matched with that reported by Orlandi and colleagues,²⁸ in which diabetes mellitus has a frequency twice as high among elderly patients, it was not in accordance with other studies. The difference in such an observation might be due to genetic factors predisposing to type 2 diabetes mellitus. The higher prevalence of PTDM among younger recipients could be explained by the heavier immuno­suppression, especially with steroid-based regimens, which were used to control the significantly higher rate of early acute rejection episodes recorded in our younger patients. This observation was in accordance with Cosio and associates²⁹ who showed that patients who were older than 45 years were 2.9 times more likely to develop PTDM. They added that the rate of increase in PTDM after the first 6 months posttransplant was significantly faster in older than in younger individuals. However, we did not observe this finding in our cohort, which was possibly due to faster reduction of maintenance steroid therapy in our protocol.

The lower prevalence of biopsy-proven acute rejection episodes among our elderly patients was also highlighted previously by Panda and associates.³⁰ The group explained this issue by the fact that prevention of rejection is generally easier in older patients due to natural immunosenescence,³⁰ which allows use of less potent immunosuppressant regimens. Moreover, Friedman and colleagues added that immuno­suppressant dose reduction in older renal transplant recipients has been associated with improved recipient and graft survival, reduction in cardio­vascular risk, reduced drug side effects, and even cost.³¹

We found that the percentages of patients with micro- and macroangiopathies were significantly higher in elderly patients (P = .01; Table 2). This could be explained by the significantly higher percentage of patients with hypertension, diabetes, anemia, and ischemic heart disease in our elderly cohort (P < .05; Table 1). Neale and colleagues32 also stated that conventional cardiovascular risk factors such as diabetes mellitus, hypertension, and renal dysfunction remain major influences on cardiovascular disease among renal transplant recipients. Jeloka and associates33 added that these variables represented major risk factors responsible for the development of micro- and macroangiopathies significantly encountered in elderly patients. Posttransplant survival of patients with high cardiovascular risk (with known coronary artery disease) was lower than for low-risk recipients but remained acceptable, and cardiac interventions could reduce perioperative risk without reduction of posttransplant cardiac events compared with low-risk patients.

Renal transplant recipients continued to be at higher cardiovascular risk compared with those who remain on dialysis or even to the general population. Traditional risk factors and other influential factors will need to be considered when attempting to improve morbidity and mortality in this complex population. Immunosuppression played a vital role in preserving the graft; medications should be optimized to prevent toxicity causing a worsening of cardiovascular disease.²⁸

Infection-related mortality is considered the second most common cause of death in ESKD and transplant populations.¹⁸ In general, older trans­plants are more susceptible to infectious deaths than younger patients.³⁴ This finding might be due to the susceptibility of the elderly to the effects of immunosuppression, in addition to age-related immunosenescence. In our cohort, we found that bacterial infections that necessitated hospitalization (as represented by chest and urinary infections) were comparable between groups (P > .05). The relatively low prevalence of bacterial infections in our elderly patients could be explained by the earlier and more aggressive antibiotic management protocol adopted in our center, which was associated with better patient outcomes. Similarly, the percentages of patients with BK viremia and BK-associated neph­ropathy were comparable between groups (P > .05).

Significantly better graft outcomes were observed among elderly patients, which may be explained by the significantly higher number of younger living donors, less acute rejection episodes, and relatively more potent immunosuppression given to this group of patients. The worse patient survival could be due to the significantly higher number of patients with cardiovascular risks (hypertension, diabetes, cardiac ischemia, and anemia) and higher number of malignancies in our elderly group (P < .05). This outcome was in accordance with that concluded by Neri and associates,³⁵ who included deceased donor transplant and reported that optimization of both organ allocation and immunosuppression protocols could be vital factors to validate improvements.

Our elderly patients received mainly kidneys from living donors, which resulted in better graft outcomes than shown in our younger age group, who received more grafts from deceased donors. These results are unlike the inferior outcomes shown when patients receive grafts from extended-criteria deceased donors in other studies.^36,37 Use of living donors, even older living donors, provides signifi­cantly better outcomes for elderly recipients than use of deceased donors. However, in the absence of a living donor, survival is improved significantly by accepting an extended-criteria donor organ rather than remaining on a wait list for a standard criteria deceased donor.^36-38

Similarly, Gencoglu and associates³⁹ concluded in a pilot study of 16 patients older than 55 years that renal transplant was an effective therapy for elderly ESKD patients, with results similar to young kidney transplant recipients. They found no relevant adverse effects of recipient age on immunologic reactivity.

Despite the augmented effects of age on infectious death with transplant, kidney transplant is asso­ciated with a lower risk of infection-related mortality in all age groups compared with dialysis.⁴⁰

Conclusions

Because of relatively less potent immunosup­pression, elderly patients experienced lower rejection rates with better graft but lower patient survival due to higher cardiovascular risk factors. Older indi­viduals should therefore not be discouraged from living-donor renal transplant. Targeted research studies on protocols are needed for elderly patients.

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