Objectives: Reported graft and patient survival rates in amyloidosis after renal transplant differ considerably between studies.

Materials and Methods: Group 1 included 24 patients who had end-stage renal disease secondary to amyloidosis. Group 2 (the control group) included 24 consecutive patients who had kidney disease secondary to various causes other than amyloidosis. Comparisons between groups were made for kidney and patient survival rates and other complications following kidney transplant. We also compared survival rates of patients in group 1 versus another control group that included patients with amyloidosis who were treated with hemodialysis (group 3; n = 25).

Results: Mean follow-up was 109.5 ± 79.8 months. Biopsy-proven acute rejection and graft failure rates were not significantly different between groups. In group 1 versus group 2, the cumulative 10-year and 20-year patient survival rates were 68.2% versus 86.1% and 36.9% versus 60.3%, respectively (P = .041). Survival was not significantly different in group 1 compared with group 2 and group 3, although patients in group 3 had significantly shorter duration of time to death after the start of renal replacement therapy.

Conclusions: Patient survival may be lower in kidney transplant recipients with amyloidosis compared with patients with end-stage renal disease due to other causes. However, graft failure and acute rejection rates seem to be similar.

Key words : Familial Mediterranean fever, Hemodialysis, Renal transplant, Survival

Introduction

Amyloidosis is a systemic disease group that leads to major organ dysfunction due to deposition of insoluble fibrils in the extracellular space.¹ Kidney involvement is frequent, and it often manifests as proteinuria. When amyloid fibrils deposit in the extracellular space of kidneys, progressive damage is inevitable.

More than 30 different unrelated proteins are known to form amyloid fibrils. AL amyloidosis is the most common form, especially in Western countries. It is characterized by deposition of free light chains produced by clonal hematopoietic cells. Life expect-ancy is increased with autologous hematopoietic stem-cell transplant in AL amyloidosis. Organ trans-plant can also be considered in these patients, which can result in good partial response or better in those with irreversible end-stage organ function, or in situations to facilitate aggressive chemotherapy, which may not be otherwise feasible due to organ dysfunction.² Long-term control of the underlying clonal disorder is vital to prevent recurrence after organ transplant. Renal transplant in patients with AL amyloidosis is considered to improve long-term survival and quality of life. Favorable outcomes are possible with renal transplant in highly selected cases.

AA amyloidosis is associated with overproduction of acute-phase proteins from the liver secondary to long-lasting inflammation, as seen in rheumatoid arthritis, periodic fever syndromes, inflammatory bowel diseases, chronic osteomyelitis, bronchiectasis, and many other inflammatory diseases. Because familial Mediterranean fever (FMF) is prevalent among Eastern Mediterranean populations, kidney transplant due to end-stage renal disease (ESRD) secondary to AA amyloidosis is much more common than in Western countries. Suppression of chronic ongoing inflammation is essential before transplant in patients with AA amyloidosis.

Similar renal survival has been reported in patients with amyloidosis following kidney transplant compared with that shown in patients with other causes of ESRD.^3,4 Acute rejection rates are not increased in renal transplant recipients with amyloidosis. However, most reports have shown that, although graft survival is acceptable, patient survival is significantly lower, mostly because of severe infections.^5-10 In 2006, we presented outcomes of 13 patients with secondary amyloidosis, most of whom had FMF.¹¹ In this report, we compared the long-term outcomes and patient survival of kidney transplant patients with amyloidosis with a control group that included patients who had ESRD secondary to various causes other than amyloidosis. We also compared survival of amyloidotic patients in the transplant group with a group of patients with amyloidosis who were treated with hemodialysis.

Materials and Methods

Our study was approved by the ethics committee of our institution. Participants of our study gave written informed consent for the inclusion of clinical data belonging to them and that their data were fully anonymized and they could not be identified in study reports. For patients who were deceased, written consent was obtained from the family or guardian.

Follow-up charts of patients who had a kidney transplant between 1992 and 2016 in our facility were evaluated. All patients had a diagnosis of amyloidosis based on histopathologic examination. Patients who had missing follow-up data were excluded. Group 1 consisted of 24 patients with kidney transplant following ESRD due to amyloidosis. Group 2 was a control group composed of 24 patients who had kidney transplant procedures following ESRD secondary to various causes other than amyloidosis. Individuals within groups were matched for time of transplant and donor type (deceased or living-related). Demographic, clinical, and laboratory findings at baseline and at follow-up were gathered from medical records. Age, sex, date of transplant, cause of ESRD, duration of dialytic therapies, cause of amyloidosis in the amyloidosis group, donor type, donor sex, donor age, donor body mass index (BMI), number of HLA mismatches, cold ischemia time, and last serum creatinine level of donor were recorded. We also recorded the BMI of recipients before transplant and at last visit; serum creatinine levels at baseline, month 1, month 3, and month 6 and at end of year 1, year 3, year 5, and last visit; and systolic and diastolic blood pressure levels at baseline. Baseline serum creatinine was accepted as the lowest value within the first month posttransplant.

We next identified patients in our database who had ESRD secondary to amyloidosis and were treated with hemodialysis to serve as a second control group. We conducted a survival analysis in which we compared amyloidosis patients who were treated with kidney transplant (group 1; n = 24) with amyloidosis patients who were treated with hemodialysis (group 3; n = 25).

Induction and maintenance immunosuppressive protocols were recorded. Complications related to drug toxicities and adverse effects, infectious diseases, metabolic diseases, and malignant diseases were noted. Number of patients who reached the renal end-point (complete, irreversible loss of graft function and/or doubling in serum creatinine levels), acute and chronic rejection rates, delayed graft function and primary nonfunction rates, and number of deaths were compared between amyloidosis and control groups.

Presence of acute rejection and chronic rejection was diagnosed with kidney biopsy. Delayed graft function was defined as the need for at least 1 dialysis session within the first week after kidney transplant.¹² BK virus nephropathy was diagnosed based on kidney biopsy findings.¹³ Blood polymerase chain reaction tests for BK virus and Cytomegalovirus were done routinely as a screening tool after transplant.

Statistical analyses
Variable distributions were assessed by the Kolmogorov-Smirnov test. Quantitative variables are expressed as mean and standard deviation if normally distributed or as median and interquartile range. Qualitative variables are expressed as proportions. Groups were compared for means using t test if variables were normally distributed or otherwise with Mann-Whitney U test. For comparisons between proportions, chi-square tests or Fisher exact tests were used as appropriate. Renal and patient survival rates and times were determined using Kaplan-Meier test. Log-rank test was used to compare survival times across groups. Statistical analysis was performed using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA). P values of .05 or less were considered to be statistically significant.

Results

Mean follow-up was 109.5 ± 79.8 months. In group 1, eighteen patients had FMF, 1 had ankylosing spondylitis, 1 had rheumatoid arthritis, 1 had Crohn’s disease, and 1 had bronchiectasis. Two patients had AL amyloidosis. Amyloidosis was diagnosed before FMF in 4 patients. In group 2, 6 patients had chronic glomerulonephritis, 5 had hypertensive glomerulosclerosis, 4 had autosomal dominant polycystic kidney disease, 3 had chronic pyelonephritis, 2 vesicoureteral reflux, 2 had Alport syndrome, 1 had obstructive uropathy, and 1 had lupus nephritis.

Basiliximab was used in 6 patients in group 1 and in 5 patients in group 2. Lymphocyte-depleting agents were used for the remaining patients. All patients were treated with corticosteroids for maintenance therapy. Two patients in group 1 were treated with a combination of corticosteroid plus cyclosporine and corticosteroids plus azathioprine. All remaining patients in both groups were treated with various triple combinations. Corticosteroid, mycophenolate mofetil, and tacrolimus were the most frequent combination used in maintenance therapy (in 8 and in 9 patients in group 1 and group 2, respectively). Mammalian target of rapamycin inhibitors were prescribed for 3 patients (1 in group 2).

Twelve patients in group 1 and 7 patients in group 2 died during follow-up. In group 1, causes of death were sepsis (n = 5), adrenal insufficiency plus acute necrotizing pancreatitis plus sepsis (n = 2), ileal perforation plus sepsis (n = 1), adrenal insufficiency plus sepsis plus intracranial hemorrhage (n = 1), adrenal insufficiency plus sepsis (n = 1), and unknown cause (n = 2). In group 2, causes of death were sepsis (n = 5) and unknown cause (n = 2).

The cumulative 10-year and 20-year patient survival rates were 68.2% versus 86.1% and 36.9% versus 60.3% in group 1 versus group 2, respectively (P = .041; Figure 1). Patients in group 1 and group 2 showed mean survival of 124.1 ± 21.0 and 187.5 ± 18.2 months, respectively.

None of the patients had primary nonfunction. Seven patients in each of group 1 and group 2 had delayed graft function. Twelve patients in group 1 and 15 in group 2 had biopsy-proven acute rejection (P = .714). Most rejections were T-cell mediated. Three patients had acute antibody-mediated rejection, with 2 of these in group 2. Half of the acute rejections in group 1 were seen in the first 3 months posttransplant, whereas 3 of 15 acute rejection episodes in group 2 were early. One patient in group 1 and 7 patients in group 2 had chronic rejection (P = .02). Most patients responded to antirejection treatment, although 4 patients had progressive permanent damage leading to graft failure. All 4 of these patients were in group 2. Graft failure was identified in 6 patients, with 2 of these patients in group 1. Doubling in serum creatinine levels and/or graft failure were present in 3 patients in group 1 and in 8 patients in group 2 (P = .332). Mean serum creatinine levels at baseline were 1.28 ± 0.44 mg/dL and 1.31 ± 0.40 mg/dL in groups 1 and 2, respectively (P = .778). Estimated marginal means of serum creatinine of patient groups at different time periods are presented in Figure 2.

Patients in group 1 had significantly lower mean BMI (P = .02). Group 2 had higher systolic (mean of 135.0 ± 14.4 vs 120.2 ± 12.9 mm Hg; P = .002) and diastolic blood pressure levels (mean of 82.7 ± 8.3 vs 73.6 ± 8.5 mm Hg; P = .002). Number of HLA mismatches, cold ischemia time, donor sex, donor age, and donor serum creatinine level were comparable between groups. Dialysis vintage before transplant was also not significantly different. Clinical characteristics of patient groups at baseline and follow-up are presented in Table 1.

Bleeding complications were significantly higher in group 1 (1 vs 6 patients; P = .034). Two patients had intracranial hemorrhage, whereas 1 patient had spontaneous retroperitoneal hematoma, 1 had gastrointestinal bleeding, 1 had hemoptysis and gastrointestinal bleeding, and 1 had postoperative surgical site hemorrhage. Perirenal hematoma was identified in a patient following renal biopsy. Renal artery embolization was performed in this patient, but graft nephrectomy was inevitable afterward. Briefly, in 3 patients, bleeding caused patient death directly; however, bleeding contributed to mortality in 2 patients, with 1 patient having mortality that seemed to be independent of bleeding. Mortality was not reported in the patient who had postoperative surgical site hemorrhage. International normalized ratio (INR) in 3 patients was approximately 1.2 to 1.5, whereas platelet counts were normal or a bit higher than upper level of normal values. One of these patients had acute necrotizing pancreatitis and the other 2 had sepsis. International normalized ratio and platelet count of remaining patients were in the normal range. One of these 3 patients was being treated with low-molecular-weight heparin.

Posttransplant hypertension was more common in group 2 (P = .001). Cytomegalovirus (P = .057), BK virus (P = .018), and herpes simplex virus infections (P = .037) were also higher in group 2. Four patients had adrenal insufficiency during follow-up, with all of these patients in group 1 (P = .109). Complications during follow-up are presented in Table 2.

Twenty-five patients with ESRD secondary to amyloidosis were identified as receiving hemo-dialysis (group 3). Of these individuals, FMF was present in 7 patients, tuberculosis in 3, inflammatory bowel disease in 3, bronchiectasis in 2, primary amyloidosis in 2, Wegener granulomatosis in 1, and rheumatoid arthritis in 1. Cause of amyloidosis could not be identified in 6 patients. When this hemo-dialysis group with amyloidosis (group 3) was compared with the transplant group with amyloidosis (group 1), patients were older (P < .001) and more frequently had gastrointestinal involvement of amyloidosis (Table 3). Although patient survival was not significantly different between patients who had a kidney allograft and those who were treated with dialysis (P = .550; Figure 3), patients in the latter group had significantly shorter duration of time to death after start of renal replacement therapy. Causes of death in the hemodialysis group included septic shock in 3 patients, cardiac complications in 2 patients, gastrointestinal bleeding in 2 patients, gastric cancer in 1 patient, and unknown cause in 2 patients.

Discussion

In countries where FMF is prevalent, amyloidosis is shown in a considerable number of patients who progress to ESRD. Hence, it is essential to determine the best option for renal replacement therapy for each individual. In this retrospective study, we evaluated a cohort of patients who had mean follow-up of almost 10 years. Similar to previous studies, graft survival and acute rejection rates were similar in patients with amyloidosis versus those with other causes of ESRD. However, patient survival was markedly reduced. Interestingly, chronic rejection was more frequent in our control group (group 2) than in our amyloidosis group (group 1), and serum creatinine levels tended to increase in the control group. Reduced patient survival may have been an important cause of higher chronic rejection rates in the control group. A previous report showed that patients with amyloidosis secondary to FMF did not have a higher tendency for acute rejection and graft loss.⁷ Death with a functioning graft was increased in patients with amyloidosis. Besides this phenotype with acceptable immunologic risk, patients with amyloidosis may have shorter patient survival because of higher infection rates.⁵ However, it has been shown that patient survival is more favorable after transplant, even in those with amyloid recurrence, than in individuals with amyloidosis who remain on hemodialysis.⁵ Clinicians should evaluate patients carefully prior to transplant and follow patients diligently after the procedure for possible infectious complications that may consi-derably shorten survival.

Increased bleeding is a well-described entity in amyloidosis. However, to our knowledge, our paper is the first to report several cases of serious bleeding that led to mortality in kidney transplant recipients. Major bleeding complications require great attention because bleeding contributes to a considerable number of deaths. Reduced activity of factor X, vascular fibril deposition, disruption in the conversion of fibrinogen to fibrin, circulating heparin-like anticoagulants, factor V deficiency, and decreased synthesis of coagulation factors may be responsible for bleeding diathesis.^14-17

In our patient cohort, INR and platelet count of most patients were shown to be within normal ranges. One patient had acute necrotizing pancreatitis and 2 had sepsis. These 3 patients showed INR of around 1.2 to 1.5, whereas platelet counts were normal or a bit higher than upper level of normal values. One of these patients received low-molecular-weight heparin. Irrespective of laboratory results, these situations may pose patients at high risk for bleeding. However, these events do not always cause major bleeding complications and amyloidosis itself is a well-known risk factor for bleeding. Many patients in our control group had sepsis or were exposed to anticoagulants and showed no bleeding. Patients with amyloidosis usually receive supportive treatment for bleeding. Splenectomy,^18,19 plasma exchange,¹⁵ fresh-frozen plasma, and recombinant factor concentrates²⁰ have been shown to be effective treatment options. It should be noted that the benefits of all options are temporary.

Amelioration of amyloid-related factor X deficiency in primary amyloidosis after high-dose chemotherapy followed by autologous stem cell transplant has been demonstrated.²¹ However, data are not yet clear on whether particular interventions may reduce bleeding risk following amyloid formation in FMF. Regression of bilateral surrenal hematoma was observed in 1 case report.²² Interestingly, the patient was asymptomatic, and the authors stated that hematoma regressed and the disease was controlled over a 6-month observation period after colistin administration. Because the pathophysiology of this disorder in these patients is multifactorial, bleeding tests may not adequately represent the risk and thrombosis may be observed after treatment.²⁰ Factor X activity was not evaluated in our patients, and only fresh-frozen plasma and red blood cell suspensions were used for treatment.

The use of conventional tests to show risk of bleeding in patients with amyloidosis secondary to FMF should be evaluated in studies with larger sample sizes. Efficient preventive measures and permanent treatment options should also be investigated.

We observed no significant differences in infection rates between groups. Sepsis was more common in our amyloidosis plus transplant group, although this was not statistically significant. Interestingly, viral infections were also more commonly seen in the amyloidosis group. Cai and associates reported that serum amyloid A functions as part of the host innate immune defense mechanism against hepatitis C virus infection in humans.²³ Bourgade and associates also established that amyloid beta 42 was produced by H4 neuroglioma cells in response to herpes simplex 1 virus infection, leading to inhibition of secondary replication.²⁴ Cytomegalovirus infections were more frequently seen in patients with amyloidosis in the study of Sahutoglu and associates.⁹

Malnutrition is a prominent clinical feature of patients with AL amyloidosis. This is probably also the case for AA amyloidosis.²⁵ Patients in our amyloidosis group had significantly lower mean BMI values. Although other manifestations of mal-nutrition were not presented in detail, lower BMI levels in the amyloidosis group possibly signifies malnutrition.

Patients in the amyloidosis group had signi-ficantly lower blood pressure levels. Lower blood pressure levels in patients with amyloidosis are not unexpected. Actually, amyloidosis is also a cause of orthostatic hypotension. Deposition of fibrils in vessels, heart, and kidney may alter physiologic responses to blood pressure changes.²⁶

Few patients with amyloidosis had adrenal insufficiency, bleeding, and bowel perforation. These complications draw attention for possible amyloid recurrence. However, it is not clear whether amyloid deposition in organs before transplant resolves with the treatment of underlying disorders and with kidney transplant. Regression of amyloidosis was shown in AL amyloid deposition in fat tissue,²⁷ liver,²⁸ and heart²⁹ after normalization of serum free light chain. Marked regression of amyloid deposits was also demonstrated in abdominal fat tissue³⁰ and gastric mucosa³¹ of patients with familial amyloid polyneuropathy who were treated with liver transplant. Familial amyloid polyneuropathy is a fatal autosomal dominant disorder that leads to progressive peripheral and autonomic neuropathy. Orthotopic liver transplant causes prompt replacement of variant transthyretin by donor wild-type mutation in the plasma.³² After transplant, neurologic declines in the patient are halted and amyloid deposits can be mobilized.

In a case report, AA amyloidosis was defined as secondary to primary sclerosing cholangitis, and secondary amyloidosis-induced nephrotic syndrome was reversed as a result of liver transplant.³³ In another study that included patients with familial amyloid polyneuropathy, serum amyloid P component scintigraphy was used to monitor amyloid deposits.³⁴ The authors noted substantial regression of the visceral amyloid deposits in 2 patients and modest improvements in 3 patients after liver transplant. In addition to these studies, Zeier and associates investigated renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplant in 2 patients.³⁵ Although both patients were in complete remission without detectable serum and urinary monoclonal immunoglobulin A-lambda and a normal percentage of plasma cells in the bone marrow at the time of the second renal biopsy, glomerular amyloid deposits persisted. Higher bleeding rates in the amyloidosis group may have been related to amyloid deposition.

Amyloid recurrence is a considerable concern after transplant,^6,8 and colchicine is essential for its prevention.^3,36,37 All patients with FMF were prescribed colchicine within days after transplant. Amyloidosis recurrence was confirmed with kidney biopsy in 1 patient. However, recurrence may have been missed in some patients who did not receive a biopsy. Interleukin-1 antagonists are used to treat FMF patients who have resistant disease despite colchicine treatment. In our patient group, interleukin-1 antagonists were not used to treat FMF in any patient before or after transplant.

Differences in patient survival rates between our study and others may be attributed to differences in the control groups. Our control group included patients with various causes of ESRD. We also presented outcomes of 2 patients with primary amyloidosis. Both were female. One died of septic shock and intracerebral hemorrhage at 102 days after transplant. She did not have cardiac involvement before transplant. The other patient died of ileocecal perforation and septic shock 20 months after transplant. She had complete remission before transplant, and no cardiac involvement was noted.

Although transplant is not contraindicated as a treatment for ESRD in patients with renal amyloidosis, it carries high risk of cardiac complications in the postoperative period.^38,39 Three patients with AA amyloidosis had documented heart involvement before transplant. Two patients died at 54 and 146 months after transplant, whereas the other patient completed 175 months posttransplant without mortality or graft loss.

Mortality rates were not significantly different between patients who received a kidney allograft and those who were treated with hemodialysis. However, clinical profiles of patients may considerably differ between groups. Patients in the hemodialysis group were significantly older in our sample. There may be particular contraindications for kidney transplant in few patients, but this could not be identified except for one patient who had a diagnosis of gastric cancer shortly after identification of amyloidosis.

There are several limitations of our study, including its retrospective design and the small sample size. However, amyloidosis is a relatively rare disease and our follow-up time was enough to determine patient and graft survival. Our data may be especially valuable for clinicians who care for patients in particular regions where FMF is prevalent. We note that it would be difficult to perform a randomized controlled study in this specific group of patients. Mutations in patients with FMF were not routinely analyzed, which may have further illuminated effects of various mutations on outcomes. Serum amyloid-associated protein was also not studied. Recurrence of amyloid deposition after transplant cannot be determined because biopsy was not routinely performed. Serum amyloid-associated protein levels would reflect ongoing inflammation and indicate recurrence. However, biopsy, which was performed in certain clinical conditions, suggested several differential diagnoses including amyloid recurrence. Although a comparison was made with a patient group treated with hemodialysis, the groups had age differences and differences in causes of amyloidosis. However, an absolute comparison does not seem possible because hemodialysis is possible to prescribe to almost every patient and transplant is performed in only highly selected patients who have a more favorable clinical profile.

Conclusions

Although renal allograft survival is not worse than other causes of ESRD, amyloidosis is clearly associated with markedly reduced patient survival.

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