EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Recurrent glomerulonephritis can nega-tively affect kidney allograft survival. However, how primary renal disease affects transplant outcomes in the new era of immunosuppression remains unclear.

Materials and Methods: We categorized 426 kidney transplant recipients (performed from 1996 to 2007) into 4 disease groups: (1) 99 recipients with biopsy-proven immunologically mediated kidney disease, (2) 40 recipients with urologic disease, (3) 67 recipients with polycystic kidney disease, and (4) 220 recipients with other causes of terminal renal failure/uncertain kidney disease. Long-term transplant outcomes were compared between groups at 1, 5, and 10 years of follow-up.

Results: Compared with the urologic, polycystic, and other diseases groups, the immunologic group showed significantly lower time of graft survival (9.5 ± 4 vs 8 ± 4 vs 8.5 ± 4 vs 7 ± 4 years, respectively) and estimated glomerular filtration rate (52.5 ± 32 vs 49 ± 22 vs 50 ± 32 vs 35.5 ± 30 mL/min; P < .05). Relative risk of 10-year graft loss for the immunologic group was 2.8 (95% confidence interval, 1.6-4.9). Recurrence rate was 12% in the immunologic group versus 1% and 0% in the other diseases and remaining groups (P < .05). The relative risk of 10-year graft loss for patients with recurrence was 2.7 (95% confidence interval, 1.2-6.3). Ten-year graft loss rates for patients with biopsy-proven acute rejection, chronic allograft nephropathy, and recurrent glomerulonephritis were 30%, 23%, and 42% (P < .05). For those with biopsy-proven recurrent glomerulonephritis, 10-year estimated glomerular filtration rate was significantly lower than for those with biopsy-proven acute rejection or chronic allograft nephropathy (14 ± 6 vs 18 ± 7 vs 30 ± 10 mL/min; P < .05).

Conclusions: Kidney transplant recipients with immunologically mediated kidney diseases have inferior long-term allograft survival and function versus patients with other causes of renal failure. Recurrence represents the strongest risk factor for premature loss of function and transplant failure.

Key words : Glomerulonephritis, Graft survival, Recurrence, Renal function, Renal transplant

Kidney transplantation is the treatment of choice for end-stage renal disease.¹ However, long-term results have not yet been optimized as organs are still lost mainly due to the death of a patient with a functioning graft, chronic allograft dysfunction, and recurrent primary kidney disease.² Several studies have investigated how the cause of terminal renal failure might actually affect outcomes after transplant, but most of these were performed more than 10 years ago, used third-party databases, or only focused on primary and secondary glomerulonephritis.^3-6

It is well known that primary and secondary glomerulonephritis often recurs after transplant and can negatively affect graft survival.^3-6 Nevertheless, many other diseases can virtually recur after transplant, but their long-term effects on transplant outcomes remain unclear.^7,8 The main reason is that clinical studies evaluating recurrent primary kidney diseases in renal transplant recipients generally include only a limited number of cases. Patients with chronic renal failure who eventually become trans-plant candidates are often referred to the nephrologist in an advanced stage of their kidney disease, when renal biopsy is routinely not performed or when biopsy cannot show specific findings. After transplant, the scenario remains quite similar, as most recipients receive biopsies when clinically symptomatic and when renal damage is already nonspecific or irreversible.^6-8 With kidney allografts now having longer survival, more recurrences will be diagnosed in the future. Therefore, it is a primary issue for the transplant community to better define the risk of poor outcomes for recipients affected by potentially recurrent renal diseases.

The aim of this single-center retrospective cohort study was to evaluate the effects of primary renal disease on long-term graft survival among a series of 426 kidney transplants performed at our Institution between 1997 and 2007.

Materials and Methods

All adult patients who underwent living-donor or deceased-donor kidney transplant at the Catholic University of Rome, Italy between January 1, 1997 and December 31, 2007 were included in the study. The study was conducted on patients who signed an informed consent, was approved by the Università Cattolica del Sacro Cuore Ethical Committee, and was performed according to the Declaration of Helsinki. Donor data, organ details, recipient characteristics, and transplant outcomes were prospectively recorded from a central database by dedicated staff and retrospectively reviewed by the authors.

According to their primary renal disease, trans-plant recipients were categorized into 4 groups: (1) immunologic group, which included patients with biopsy-proven immunologically mediated kidney disease; (2) urologic group, which included patients with well-documented urologic disease; (3) polycystic group, which included patients with polycystic kidney disease; and (4) other diseases group, which included patients with other causes of terminal renal failure or with uncertain kidney disease.

Patient and graft survival rate, patient and graft time of survival, renal function, acute rejection rate, prevalence of chronic allograft nephropathy, and incidence of recurrent primary kidney disease were analyzed and compared between groups at 1, 5, and 10 years of follow-up. Graft survival rates in recipients with or without recurrence of their primary renal disease were assessed. Transplant loss rates for patients with biopsy-proven acute rejection, chronic allograft nephropathy, or recurrent primary renal disease were also evaluated.

Transplant loss was defined as death of patient with a functioning graft or need for permanent dialysis or retransplant. All allograft losses that were due to recurrent primary renal disease, acute rejection, or chronic allograft nephropathy were proven by biopsy. Acute rejection and chronic allograft nephropathy were diagnosed and scored according to Banff 1997 criteria.⁹ Renal function was assessed by calculated creatinine clearance (Cockcroft-Gault formula).

Data were reported using percentages, mean (± standard deviation), or median values. Categorical and numerical variables were compared using chi-square test, t test, analysis of variance (post hoc analysis), or Tukey range test as appropriate. A P value ≤ .05 was considered statistically significant. To estimate the effects of primary renal disease and recurrent primary renal disease on graft survival, a Cox proportional hazard regression analysis was performed. As covariates, the model considered primary renal disease, donor type (deceased or living), recipient sex, recipient body mass index, biopsy-proven acute rejection, biopsy-proven chronic allograft nephropathy, and biopsy-proven recurrent primary renal disease. Statistical analysis was carried out using PASW Statistics for Windows, version 18.0 (SPSS Inc., Chicago, IL, USA).

From January 1, 1997 to December 31, 2007, we performed 426 consecutive adult kidney transplants. All transplants were included in the analysis. The mean follow-up of the study was 9.2 ± 3.4 years. Main characteristics of this cohort of patients are detailed in Table 1.

According to their primary renal disease, transplant recipients were selectively categorized into 4 different groups: immunologic (n = 99, 23%), urologic (n = 40, 9%), polycystic (n = 67, 16%), and other diseases (n = 220, 52%). Main characteristics of these groups are summarized in Table 2. Patient survival rate and mean time of survival were similar between groups. As depicted in Figure 1, patients in the immunologic group showed consistently lower graft survival rates than recipients in the other groups (P < .001). Accordingly, mean time of survival for grafts in the immunologic group was significantly shorter at 7 ± 4 years versus 9.5 ± 4 years for the urologic, 8 ± 4 years for the polycystic, and 8.5 ± 4 years for the other diseases group (P < .05). The relative risk of 10-year graft loss for patients in the immunologic group was 2.8 (95% confidence interval, 1.6-4.9). Ten-year graft function (calculated glomerular filtration rate) was significantly lower for recipients with immunologically mediated diseases than for patients with other primary kidney diseases (35.5 ± 30 mL/min for the immunologic group versus 52.5 ± 32 mL/min for the urologic, 49 ± 22 mL/min for the polycystic group, and 50 ± 32 mL/min for the other diseases group; P < .05).

One-year, 5-year, and 10-year cumulative recur-rence rates for the entire patient cohort were 0.9%, 1.4%, and 2.8%, respectively. More specifically, we observed 12 recurrences (12%) in the immunologic group, 2 recurrences (1%) in the other diseases group, and 0 recurrences in the remaining groups (P < .05). Recurrent diseases included primary membrano-proliferative glomerulonephritis (4 cases), immuno-globulin A nephropathy (3 cases), primary focal segmental glomerulosclerosis (2 cases), primary membranous glomerulonephritis (1 case), lupus nephritis (1 case), rapidly progressive glomerulo-nephritis (1 case), and diabetic nephropathy (2 cases). As depicted in Figure 2, patients with biopsy-proven recurrence of their primary renal disease showed significantly lower graft survival rates than those without recurrence (P < .01). The relative risk of 10-year graft loss for patients with recurrence was 2.7 (95% confidence interval, 1.2-6.3).

In 10 years of follow-up, 185 graft biopsies in 127 recipients were performed. Most of the procedures (98%) were carried out for clinical reasons (ie, worsening graft function). Prevalent findings included acute rejection (74 cases; 40%), chronic allograft nephropathy (80 cases; 43%), and recurrent glomerulonephritis (12 cases; 6.5%). Among patients who had a kidney biopsy during the follow-up, 37 patients (29%) were diagnosed with acute rejection, 66 patients (52%) had chronic allograft nephropathy, and 12 patients (9%) had recurrent glomerulonephritis. Ten-year graft loss rates for patients with biopsy-proven acute rejection, chronic allograft nephropathy, and recurrent glomerulonephritis were 30% (11/37), 23% (15/66), and 42% (5/12), respectively (P < .05). Recipients with biopsy-proven recurrent glomer-ulonephritis also showed significantly lower 10-year calculated glomerular filtration rate at 14 ± 6 mL/min compared with those with biopsy-proven acute rejection (18 ± 7 mL/min) or chronic allograft nephropathy (30 ± 10 mL/min) (P < .05).

In this retrospective cohort study with 10 years of follow-up, we evaluated the effects of primary renal disease on long-term allograft outcomes in 426 conse-cutive kidney transplants performed in adult recipients at a single institution between 1997 and 2007.

Glomerulonephritis was the most common cause of terminal renal failure observed in our series. This finding confirms previous reports3,4 and highlights the need for aggressive diagnostic protocols in the pretransplant phase. Still, too many patients proceed to transplant without a formal diagnosis of their kidney disease, thus limiting the opportunity to improve our knowledge about potentially recurrent diseases and the chance to better treat recipients at risk of recurrence.^5,10,11 Early referral to a nephrol-ogist and prompt histologic evaluation of the kidney are key factors and should be strongly promoted by the transplant community.

We showed that recipients with immunologically mediated renal diseases have inferior graft survival and worse graft function than patients with other primary kidney diseases. We also demonstrated that recurrent glomerulonephritis is an independent risk factor for early transplant failure and premature loss of function.

Posttransplant recurrence of primary kidney disease usually refers to recurrent glomerulonephritis. However, almost any primary cause of renal failure can recur after transplant. To decrease the risk of recurrence and optimize results, preemptive strategies should be developed as soon as the patient is included on a transplant wait list. Polycystic kidney disease does not recur after transplant. Urologic diseases can be addressed at the time of enlistment and generally do not recur after surgery. Diabetic nephropathy is extremely common and often difficult to manage. Aggressive glycemic control combined with tailored immunosuppression (early steroid withdrawal, calcineurin-inhibitor minimization, and avoidance of mammalian target of rapamycin inhibitors) can reduce the risk of recurrence and slow disease progression.

Immunologically mediated kidney diseases represent the leading cause of end-stage renal disease in Western countries. Posttransplant recurrence rates of primary and secondary glomerulonephritis have been reported to be between 6% and 19% and generally increase over time after transplant.^3,4,12 Moreover, glomerulonephritis is the cause of graft loss in 1% to 4% of all transplant recipients.^3,4 Our data are similar to those reported by Briganti and associates who analyzed 1505 patients with biopsy-proven glomerulonephritis. The authors showed recurrent glomerulonephritis in up to 8% of their recipients and concluded that immunologic primary kidney diseases significantly impaired long-term graft function and survival.¹³

Presently, patients with glomerulonephritis are treated with the same immunosuppressive agents routinely used to prevent rejection. Patients who do not respond to treatment develop terminal renal failure and become transplant candidates. As a consequence, we are conducting an increased number of transplant procedures for recipients with a primary kidney disease that is resistant to standard immuno-suppressive protocols.^5,6,13-15 If such an aggressive disease recurs after transplant, a poor prognosis should be expected and alternative treatments considered as soon as a formal diagnosis is available.^5,6,10,13-18

Our study was retrospective in nature and had a relatively small sample size. However, the cohort of patients was overall homogeneous, data were prospectively collected by qualified personnel, and the follow-up was extended enough to allow proper evaluation of long-term outcomes.

Recipients with primary and secondary glomer-ulonephritis have inferior long-term renal function and transplant survival versus patients with other renal diseases. Having recurrent primary kidney disease represents the strongest risk factor for premature loss of function and transplant failure. Patients with immunologically mediated and poten-tially recurrent kidney diseases should receive special counselling and should be clearly advised about the need for tailored immunosuppression and protocol allograft biopsies after transplant. Well-powered pro-spective studies on this topic are strongly encouraged.

Volume: 16 Issue: 5 October 2018

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