- Email: [email protected]
Comparative Analysis of Outcomes of Kidney Transplantation in Patients With AA Amyloidosis and Chronic Glomerulonephritis
Comparative Analysis of Outcomes of Kidney Transplantation in Patients With AA Amyloidosis and Chronic Glomerulonephritis T. Sahutoglua,*, K. Ataya, Y. Caliskanb, E. Karac, H. Yazicib, and A. Turkmenb From the aDepartment of Internal Medicine and bDivision of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; and cDepartment of Internal Medicine, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
ABSTRACT Background. Amyloid A (AA) amyloidosis is a multisystemic, progressive, and severe disease. Renal involvement is a prominent feature of the disease, and the outcome of patients on dialysis is poor. We aimed to analyze the outcomes of kidney transplantation in patients with AA amyloidosis in comparison with chronic glomerulonephritis (CGN). Methods. Charts of patients who underwent kidney transplantation between 1988 and 2012 were reviewed; 41 patients with AA amyloidosis were identified, and 41 age- and sex-matched control patients with chronic CGN were included. Baseline characteristics, immunosuppressive regimens, and transplantation-related outcomes were retrieved using a standardized form. Results. The mean follow-up period was 70.9 44.9 months. The 10-year patient survival was found to be significantly worse in the AA amyloidosis group (62.5%) compared to CGN group (100%) (P ¼ .008). During the follow-up period, three of the 41 patients (9.7%) died of sepsis and one patient died of cardiac complications in the amyloidosis group, whereas there was no patients were lost in the CGN group. The first-year, fifthyear, and tenth-year mean graft survival rates, acute and chronic rejections, and mean creatinine levels at last visits were not significantly different between the groups. Proteinuria >1 g/d, cytomegalovirus and tuberculosis infections, and rhabdomyolysis were recorded at a significantly higher rate in patients with amyloidosis. Conclusion. As compared to patients with CGN, patients with AA amyloidosis had a lower patient survival; equal graft survival and rejection rates; and higher risks of developing proteinuria, cytomegalovirus and tuberculosis infections, and rhabdomyolysis.
S
ERUM amyloid A (SAA)eassociated amyloidosis is a systemic disease that can cause severe morbidity and high mortality if progression is not prevented [1]. As a common consequence of chronic inflammatory/infectious diseases, AA amyloidosis is characterized by widespread extracellular deposition of insoluble fibrils composed of SAA fragments and subsequent cellular dysfunction [2]. The frequency of underlying inflammatory diseases varies according to geographic and ethnic factors; chronic inflammatory arthritis is the most common cause in western countries, whereas familial Mediterranean fever (FMF) and tuberculosis are as the major causes in the Middle East [3,4]. Although amyloid deposition typically has a widespread extension, kidney involvement is one of the earliest manifestations, heralded by proteinuria, and it is the most
common cause of mortality [5]. Current treatment options are based mainly on suppression of the underlying systemic inflammation, which has been shown to be effective in preventing the development and progression of secondary amyloidosis [6,7]. However, like in many other forms of chronic kidney diseases, advanced stages of renal T.S. is currently with the Department of Nephrology, Sisli Hamidiye Etfal Education and Research Hospital; K.A. is currently with the Department of Gastroenterology, Cerrahpasa School of Medicine, Istanbul University. *Address correspondence to Tuncay Sahutoglu, MD, Department of Nephrology, Sisli Hamidiye Etfal Education and Research Hospital, Halaskargazi Cad. Etfal Sk., 34371 Istanbul, Turkey. E-mail: [email protected]
ª 2016 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.04.015
Transplantation Proceedings, 48, 2011e2016 (2016)
2011
2012
SAHUTOGLU, ATAY, CALISKAN ET AL Table 1. Baseline Characteristics of KT Patients With Amyloidosis and CGN
Patient age (y) Sex (M/F) Height (cm) Weight (kg) BMI (kg/m2) Donor age (y) Donor sex (M/F) Donor type (live/deceased) HLA mismatch Follow-up time (mo) Preemptive transplantation RRT before KT (HD/PD)
Table 3. Immunosuppressive Regimens Used to Maintain Graft Tolerance
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
42.1 12.1 23/18 165.1 8.0 54.0 10.5 19.7 3.1 44.7 11.7 15/26 33/8 3.5 1.1 65.2 45.4 0 37/4
37.8 9.3 23/18 166.4 8.2 61.1 12.4 21.9 3.3 47.3 12.7 18/23 38/3 3.3 1.4 76.6 44.2 2 35/4
.079 1 .459 .007 .003 .329 .499 .105 .612 .254 .193 .193
Abbreviations: KT, kidney transplantation; CGN, chronic glomerulonephritis; M, male; F, female; BMI, body mass index; HLA, human leukocyte antigen; RRT, renal replacement therapy; HD, hemodialysis; PD, peritoneal dialysis.
amyloidosis appear to be irreversible. In addition, patients with renal AA amyloidosis associated end-stage renal disease (ESRD) have been shown to have higher rates of mortality than those in the general dialysis population [6]. Peritoneal dialysis and hemodialysis have been used as renal replacement treatments for renal AA amyloidosise associated ESRD; however, data regarding outcomes of these treatments come from retrospective analyses [4,7]. Kidney transplantation is an eminent treatment of ESRD for most etiologies, and recent studies suggest that transplantation has favorable graft and patient outcomes in secondary amyloidosis [8,9]. In this single-center study, we aimed to analyze the outcomes of kidney transplantation in patients with secondary amyloidosis in comparison to patients with chronic glomerulonephritis (CGN). METHODS Patients Follow up charts of patients who underwent kidney transplantation between 1988 and 2012 at the Istanbul Faculty of Medicine were Table 2. Graft- and Patient-Related Outcomes
Last BMI Change in weight Last systolic BP Last diastolic BP Last eGFR (MDRD) Last creatinine eGFR change Post KT proteinuria (<1g /1e3 g />3 g) Acute rejection (n) Chronic rejection (n) Graft loss (n) Death (n)
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
22.1 2.9 þ6.6 3.4 116.8 16.2 74.1 8.4 65.3 32.7 1.5 0.5 0.06 1.0 17/19/5
24.1 3.3 þ5.9 4.2 129.2 13.6 82.9 10.5 64.2 29.5 1.8 1.5 0.008 1.2 27/8/6
.007 .436 <.001 <.001 .868 .160 .548 .027
10 0 1 4
11 2 4 0
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
5 12 8 6 5 5
13 4 0 12 8 4
.003
FKþMMFþsteroid FKþMPSþsteroid FKþAZAþsteroid CsAþMMFþsteroid CsAþMPSþsteroid CsAþAZAþsteroid
Abbreviations: CGN, chronic glomerulonephritis; FK, tacrolimus; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; AZA, azathioprine; CsA, cyclosporine A.
screened retrospectively, and patients whose primary renal disease was biopsy-confirmed AA amyloidosis (Congo redepositive staining in the kidney, rectum, duodenum, subcutaneous fat or bone marrow) were identified. Patients with lost follow-up data were excluded from the analysis. Patients matched for sex, transplantation time, and age were included as the control group. A total of 41 patients with AA amyloidosis and 41 patients with chronic glomerulonephritis (CGN) were included in this retrospective study (all transplantations were performed between 1988 and 2011 in patients with amyloidosis, and 1993 to 2011 in patients with CGN). Baseline characteristics, immunosuppressive regimens, and transplantation related outcomes were recorded using a standardized form. Glomerular filtration rates were estimated using the Modification of Diet in Renal Disease (MDRD) equation [10].
Statistical Analyses Statistical analysis were performed using SPSS version 20 (SPSS Inc, Chicago, IL). All data were presented as median and standard deviation [SD]. Parametric and nonparametric tests were compared using the Student t test and Yates correction c2 test, respectively. The Pearson test was used for correlation analysis. Multivariate Cox proportional hazard model analysis was performed to determine independent risk factors for patient mortality. Survival was estimated by the Kaplan-Meier and log-rank test. A P value of less than 0.05 was considered significant. The study was approved by the Ethics Committee of Istanbul Faculty of Medicine.
RESULTS Baseline Characteristics
There were 41 patients with AA amyloidosis and 41 patients with CGN included in this retrospective analysis (Table 1). The underlying etiologies of amyloidosis were FMF (n ¼ 35), tuberculosis (n ¼ 3), bronchiectasis (n ¼ 2), and inflammatory bowel disease (n ¼ 1). Mean follow-up times were 65.2 45.4 and 76.6 44.2 months (P ¼ .254) in Table 4. Graft and Patient Outcomes
.800 .152 .166 .040
Abbreviations: CGN, chronic glomerulonephritis; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation; KT, kidney transplantation.
Under follow-up Lost to follow-up Graft loss Death
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
36 0 1 4
36 1 4 0
NS NS .166 .019
Abbreviations: CGN, chronic glomerulonephritis; NS, not significant.
KIDNEY TRANSPLANT OUTCOMES IN AMYLOIDOSIS
2013
Table 5. Patient Survival 95% Confidence Interval Group
n
Death (n)
Mean Patient Survival (mo)
Lower
Upper
1-Year Survival
5-Year Survival
10-Year Survival
P Value
Amyloidosis CGN Overall
41 41 82
4 0 4
185.5 29.5 e 222.7 10.9
127.5 e 201.1
243.5 e 244.2
100 100 100
100 100 100
61.5 100 87.9
.008
Abbreviation: CGN, chronic glomerulonephritis.
amyloidosis and CGN patients, respectively. Patient age, donor age, sex, and type (live/deceased), human leukocyte antigen (HLA) mismatch, and renal replacement therapies preceding the transplantation were similar in the two groups (Table 1). Weights and body mass indexes (BMI) of patients with amyloidosis were significantly lower than patients with CGN at the first and last visits (Tables 1 and 2); however, patients in both groups similarly gained weight, and their BMIs increased between the first and last visits (Table 2). Immunosuppressive Agents
A triple immunosuppressive regimen was used for all patients (Table 3). Tacrolimus was more frequently used in amyloidosis patients, and cyclosporine A was more commonly used in CGN patients, but the differences were not statistically significant (Table 3). More patients in the amyloidosis group used azathioprine, whereas more patients in the CGN group used mycophenolate mofetil (MMF). Graft and Patient-Related Outcomes
The mean follow-up period was 70.9 44.9 months. Four deaths were recorded, all from the amyloidosis group (P ¼ .019); the causes of death were sepsis in three patients (two pneumonia and one urinary tract infection), and congestive heart failure in one patient (Table 4). The 10-year patient survival was found to be significantly worse in the AA amyloidosis group (62.5%) compared to the CGN group (100%) (P ¼ .008) (Table 5 and Fig 1). Serum creatinine levels and estimated glomerular filtration rates (eGFR, MDRD equation) early after transplantation and at the last visits did not differ between the groups (Table 2). eGFR changes throughout the follow-up period were also similar in the two groups. Graft loss occurred in five patients: one in amyloidosis group and four in the CGN group (P ¼ .166) (Table 4). Although more patients in the CGN group experienced acute rejection, chronic rejection, and graft loss, the differences were not statistical significant (Table 3). The 1-year deathcensored graft survival rates were similar in the two groups, whereas the mean death-censored graft survival time and 10-year graft survival rates were insignificantly lower in the CGN patients (144.7 6.3 vs 232.2 7.5 months and 66.1% vs 96%, respectively) (Table 6 and Fig 2). Posttransplantation proteinuria in excess of 1 g per day developed in a significantly greater number of patients (58%) with amyloidosis (Table 2). Colchicine treatment was
offered to all patients with AA amyloidosis; and 11 patients (26.8%) experienced colchicine-related adverse effects. Complications After Kidney Transplantation
Approximately one-half of the patients in each group developed urinary tract infections and pneumonia, but the differences in infection rates were not significant (Table 7). The rates of CMV and tuberculosis infections, osteoporosis, cataracts, and rhabdomyolysis were significantly higher in patients with amyloidosis (Table 7). All patients who developed rhabdomyolysis were in the amyloidosis group (12.1% vs 0%, P ¼ .021), and were receiving colchicine in combination with either cyclosporine A (three patients) or tacrolimus (two patients). DISCUSSION
Although some recent studies have provided evidence that attaining lower levels of SAA could improve the prognosis, the natural history of AA amyloidosis in the case of renal disease follows a progressive increase in proteinuria, worsening of renal function, and finally, if death has not yet occurred, development of ESRD [3,11]. Mortality is particularly higher in patients who developed significant renal dysfunction, hypoalbuminemia, or ESRD [4,6,7,12]. In this retrospective comparison of outcomes of patients with amyloidosis and CGN, like in other reports, we found that the
Fig 1. Kaplan-Meier patient survival curves for AA amyloidosis patients compared with chronic glomerulonephritis (CGN) patients.
2014
SAHUTOGLU, ATAY, CALISKAN ET AL Table 6. Graft Survival Outcomes (Death Censored) 95% Confidence Interval
Groups
n
Graft Loss (n)
Mean Graft Survival (mo)
Lower
Upper
1-Year Survival
5-Year Survival
10-Year Survival
P Value
Amyloidosis CGN Overall
41 41 82
1 4 5
232.2 7.5 144.7 6.3 206.1 13.7
217.5 132.4 179.3
247.0 157.1 233.0
100% 100% 100%
96.0% 100% 98.2%
96.0% 66.1% 73.9 %
.551
Abbreviation: CGN, chronic glomerulonephritis.
overall survival of amyloidotic patients after transplantation has improved, as the mean patient survival was 15.4 years [8,13]. The comparison of posttransplantation survival rates of patients with and without amyloidosis is not uniform across the literature, but, like in some other reports, in this study amyloidotic patients had a lower survival than CGN patients [14,15]. It should be emphasized that AA amyloidosis is a systemic disease that is inherently expected to be associated with higher disease burden than other renal-limited diseases. Therefore, it may be more important to focus on having improved patient survival after kidney transplantation in AA amyloidosis, rather than discussing whether survival of patients with AA amyloidosis after kidney transplantation is better than in patients with other primary renal disorders [16]. However, the retrospective nature of the studies, inhomogeneity of patients and control groups, different time periods, different ethnicities and medical practices, and different policies of excluding amyloidotic patients from transplantation could all account for the variable survival rates that have been reported. All deaths occurred in amyloidosis group after 5 years of postekidney transplantation follow-up. In this study, three of four deaths were due to sepsis. Infections with fatal consequences were also reported as the major cause of mortality in patients with AA amyloidosis, both under dialysis and after kidney transplantation [4,8,9,15e17]. These findings suggest that secondary amyloidosis confers a predilection to severe infections.
Fig 2. Kaplan-Meier graft survival curve of amyloidosis patients and chronic glomerulonephritis (CGN) patients (death censored).
We found that graft survival was better in amyloidosis patients as compared to CGN, with 1-year, 5-year, and 10-year graft survival rates of 100%, 96%, and 96%, respectively. As in the case of patient survival, reports on graft survival are not uniform. However, in most of the recent reports, graft survival was good in patients with AA amyloidosis and similar to patients with other primary renal diseases [9,13,18,19]. Rejection rates and serum creatinine levels at the last visits were not significantly different in amyloidotic and CGN patients in this study. In an earlier report, Sherif et al also reported that creatinine levels were similar in patients with amyloidosis and nonamyloidosis throughout the follow-up period after transplantation, whereas rejection rates were lower in patients with amyloidosis [18]. Proteinuria greater than 1 g per day developed in 58% of patients with amyloidosis, which was significantly higher than in patients with CGN. Data regarding graft biopsy were not available to review in this study; therefore, the causes of proteinuria could not be determined. However, it could be speculated that the recurrence of AA amyloidosis in allografts is an important cause of proteinuria in these patients.
Table 7. Complications After Kidney Transplantation
HSV VZV CMV UTI Pneumonia Hirsutism BKV PCP (PJP) TB primary TB total NODAT Avascular necrosis Cataracts Gingival hypertrophy Hypercholesterolemia Erythrocytosis Rhabdomyolysis Hyperuricemia Cancer CNI toxicity
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
4 3 6 18 23 2 1 1 7 9 4 1 8 2 14 10 5 7 3 2
2 6 1 17 17 5 0 0 2 2 3 2 2 6 21 12 0 7 1 0
.396 .289 .048 .823 .185 .236 .314 .320 .077 .023 .693 .556 .043 .137 .118 .618 .021 1 .305 .152
Abbreviations: HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; UTI, urinary tract infection; BKV, BK virus; PCP, Pneumocystis carinii (jirovecii) pneumonia; TB, tuberculosis; NODAT, new-onset diabetes after transplantation; CNI, calcineurin inhibitor.
KIDNEY TRANSPLANT OUTCOMES IN AMYLOIDOSIS
In a previous study, Livneh et al reported that colchicine dose was important in preventing amyloidosis recurrence and that AA amyloidosis recurred in 11 of 21 FMF patients (52%) who received inadequate colchicine within 3 years after kidney transplantation [20]. However, recurrence rates of AA amyloidosis can be different across various etiologies. In a recent study by Kofman et al, patients with heterogeneous etiologies of AA amyloidosis were retrospectively analyzed; the authors reported that the recurrence rates of AA amyloidosis were 8.7% for chronic inflammatory diseases, 20% for hereditary periodic fever syndromes, 11% for chronic infections, and 33.3% for unknown etiologies [9]. In this study, colchicine was offered to all patients with AA amyloidosis, but colchicine-related adverse effects, poor patient compliance, or underdosing may have caused proteinuria in a large number of patients. In addition, in a nationwide multicenter study, the complete response rate in Turkish FMF patients who take colchicine regularly was about 50% [21]. These data suggest that, besides colchicine therapy, other preventive measures may be needed in FMF patients to avoid amyloidosis recurrence. Urinary tract infections and pneumonia developed in nearly half of the patients in each group. Kofman et al also reported a similarly high rate of infections (73.2% of all amyloidosis cases) after transplantation in patients with AA amyloidosis [9]. Cytomegalovirus (CMV) and tuberculosis infections occurred in a significantly higher rate in patients with AA amyloidosis as compared to patients with CGN. The rates of CMV infections were not reported in most other cohort studies, but a smaller study by Celik et al did not find an increased rate of CMV infection (1/13 in amyloidotic and 4/13 in nonamyloidotic patients) in AA amyloidosis patients [19]. In addition, donor and recipient CMV serostatus as well as induction and maintenance immunosuppressive regimens can affect the rate of CMV infection; therefore, evidence is insufficient to draw a conclusion regarding CMV infections in AA amyloidosis [22]. Cyclosporine A and colchicine combination are known to interact, whereby cyclosporine A inhibits P-glycoprotein and decreases the elimination of colchicine [23]. In this study, only three of five patients who developed rhabdomyolysis were taking cyclosporine A in combination with colchicine. There are multiple causes of rhabdomyolysis such as statins, alcohol, toxins, and serotonin reuptake inhibitors, and we conclude that there could be other drug combinations or metabolic factors that could cause rhabdomyolysis in patients taking colchicine [24]. Mammalian target of rapamycin (m-TOR) inhibitors and MMF combinations without calcineurin inhibitors may be the alternative treatment regimens in patients with rhabdomyolysis. Limitations of this study were its retrospective nature, the lack of biopsy data, lack of induction immunosuppression data, small number of patients, and relatively short followup time. In conclusion, as compared to patients with CGN, kidney transplantation in patients with AA amyloidosis results in at least equal graft survival, slightly higher mortality, greater
2015
risk of developing proteinuria greater than 1 g per day, and increased risk of rhabdomyolysis. Infectious and noninfectious complications may occur more frequently in patients with AA amyloidosis after kidney transplantation.
REFERENCES [1] Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol 2006;17:3458e71. [2] Sungur CI. Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:1872e3. [3] Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007;356:2361e71. [4] Ahbap E, Kara E, Sahutoglu T, Basturk T, Koc Y, Sakaci T, et al. Outcome of 121 patients with renal amyloid a amyloidosis. J Res Med Sci 2014;19:644e9. 5 Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997-2012. Mt Sinai J Med 2012;79:749e56. [6] Tang W, McDonald SP, Hawley CM, Badve SV, Boudville N, Brown FG, et al. End-stage renal failure due to amyloidosis: outcomes in 490 ANZDATA registry cases. Nephrol Dial Transplant 2013;28:455e61. [7] Moroni G, Banfi G, Montoli A, Bucci A, Bertani T, Ravelli M, et al. Chronic dialysis in patients with systemic amyloidosis: the experience in northern Italy. Clin Nephrol 1992;38:81e5. [8] Ozdemir BH, Ozdemir FN, Sezer S, Sar A, Haberal M. Among therapy modalities of end-stage renal disease, renal transplantation improves survival in patients with amyloidosis. Transplant Proc 2006;38:432e4. [9] Kofman TI, Grimbert P, Canouï-Poitrine F, Zuber J, Garrigue V, Mousson C, et al. Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study. Am J Transplant 2011;11:2423e31. [10] K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2001;39:81e100. [11] Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24e9. [12] Martinez-Vea A, García C, Carreras M, Revert L, Oliver JA. End-stage renal disease in systemic amyloidosis: clinical course and outcome on dialysis. Am J Nephrol 1990;10:283e9. [13] Abedi AS, Nakhjavani JM, Etemadi J. Long-term outcome of renal transplantation in patients with familial Mediterranean fever amyloidosis: a single-center experience. Transplant Proc 2013;45:3502e4. [14] Türkmen A, Yildiz A, Erkoç R, Ecder T, Görçin B, Türk S, et al. Transplantation in renal amyloidosis. Clin Transplant 1998;12: 375e8. [15] Pasternack A, Ahonen J, Kuhlbäck B. Renal transplantation in 45 patients with amyloidosis. Transplantation 1986;42:598e601. [16] Sever MS, Turkmen A, Sahin S, Yildiz A, Ecder T, Kayacan MS, et al. Renal transplantation in amyloidosis secondary to familial Mediterranean fever. Transplant Proc 2001;33:3392e3. [17] Haq A, Hussain S, Meskat B, Mohan P, Conlon P, Hickey DP. Complications of renal transplantation in patients with amyloidosis. Transplant Proc 2007;39:120e4. [18] Sherif AM, Refaie AF, Sobh MA, Mohamed NA, Sheashaa HA, Ghoneim MA. Long-term outcome of live donor kidney transplantation for renal amyloidosis. Am J Kidney Dis 2003;42:370e5. [19] Celik A, Saglam F, Dolek D, Sifil A, Soylu A, Cavdar C, et al. Outcome of kidney transplantation for renal amyloidosis: a single-center experience. Transplant Proc 2006;38:435e9.
2016 [20] Livneh A, Zemer D, Siegal B, Laor A, Sohar E, Pras M. Colchicine prevents kidney transplant amyloidosis in familial Mediterranean fever. Nephron 1992;60:418e22. [21] Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005;84:1e11. [22] Jassal SV, Roscoe JM, Zaltzman JS, Mazzulli T, Krajden M, Gadawski M, et al. Clinical practice guidelines: prevention of
SAHUTOGLU, ATAY, CALISKAN ET AL cytomegalovirus disease after renal transplantation. J Am Soc Nephrol 1998;9:1697e708. [23] Garrouste C, Philipponnet C, Kaysi S, Enache I, Tiple A, Heng AE. Severe colchicine intoxication in a renal transplant recipient on cyclosporine. Transplant Proc 2012;44: 2851e2. [24] Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore) 2005;84:377e85.
ABSTRACT Background. Amyloid A (AA) amyloidosis is a multisystemic, progressive, and severe disease. Renal involvement is a prominent feature of the disease, and the outcome of patients on dialysis is poor. We aimed to analyze the outcomes of kidney transplantation in patients with AA amyloidosis in comparison with chronic glomerulonephritis (CGN). Methods. Charts of patients who underwent kidney transplantation between 1988 and 2012 were reviewed; 41 patients with AA amyloidosis were identified, and 41 age- and sex-matched control patients with chronic CGN were included. Baseline characteristics, immunosuppressive regimens, and transplantation-related outcomes were retrieved using a standardized form. Results. The mean follow-up period was 70.9 44.9 months. The 10-year patient survival was found to be significantly worse in the AA amyloidosis group (62.5%) compared to CGN group (100%) (P ¼ .008). During the follow-up period, three of the 41 patients (9.7%) died of sepsis and one patient died of cardiac complications in the amyloidosis group, whereas there was no patients were lost in the CGN group. The first-year, fifthyear, and tenth-year mean graft survival rates, acute and chronic rejections, and mean creatinine levels at last visits were not significantly different between the groups. Proteinuria >1 g/d, cytomegalovirus and tuberculosis infections, and rhabdomyolysis were recorded at a significantly higher rate in patients with amyloidosis. Conclusion. As compared to patients with CGN, patients with AA amyloidosis had a lower patient survival; equal graft survival and rejection rates; and higher risks of developing proteinuria, cytomegalovirus and tuberculosis infections, and rhabdomyolysis.
S
ERUM amyloid A (SAA)eassociated amyloidosis is a systemic disease that can cause severe morbidity and high mortality if progression is not prevented [1]. As a common consequence of chronic inflammatory/infectious diseases, AA amyloidosis is characterized by widespread extracellular deposition of insoluble fibrils composed of SAA fragments and subsequent cellular dysfunction [2]. The frequency of underlying inflammatory diseases varies according to geographic and ethnic factors; chronic inflammatory arthritis is the most common cause in western countries, whereas familial Mediterranean fever (FMF) and tuberculosis are as the major causes in the Middle East [3,4]. Although amyloid deposition typically has a widespread extension, kidney involvement is one of the earliest manifestations, heralded by proteinuria, and it is the most
common cause of mortality [5]. Current treatment options are based mainly on suppression of the underlying systemic inflammation, which has been shown to be effective in preventing the development and progression of secondary amyloidosis [6,7]. However, like in many other forms of chronic kidney diseases, advanced stages of renal T.S. is currently with the Department of Nephrology, Sisli Hamidiye Etfal Education and Research Hospital; K.A. is currently with the Department of Gastroenterology, Cerrahpasa School of Medicine, Istanbul University. *Address correspondence to Tuncay Sahutoglu, MD, Department of Nephrology, Sisli Hamidiye Etfal Education and Research Hospital, Halaskargazi Cad. Etfal Sk., 34371 Istanbul, Turkey. E-mail: [email protected]
ª 2016 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.04.015
Transplantation Proceedings, 48, 2011e2016 (2016)
2011
2012
SAHUTOGLU, ATAY, CALISKAN ET AL Table 1. Baseline Characteristics of KT Patients With Amyloidosis and CGN
Patient age (y) Sex (M/F) Height (cm) Weight (kg) BMI (kg/m2) Donor age (y) Donor sex (M/F) Donor type (live/deceased) HLA mismatch Follow-up time (mo) Preemptive transplantation RRT before KT (HD/PD)
Table 3. Immunosuppressive Regimens Used to Maintain Graft Tolerance
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
42.1 12.1 23/18 165.1 8.0 54.0 10.5 19.7 3.1 44.7 11.7 15/26 33/8 3.5 1.1 65.2 45.4 0 37/4
37.8 9.3 23/18 166.4 8.2 61.1 12.4 21.9 3.3 47.3 12.7 18/23 38/3 3.3 1.4 76.6 44.2 2 35/4
.079 1 .459 .007 .003 .329 .499 .105 .612 .254 .193 .193
Abbreviations: KT, kidney transplantation; CGN, chronic glomerulonephritis; M, male; F, female; BMI, body mass index; HLA, human leukocyte antigen; RRT, renal replacement therapy; HD, hemodialysis; PD, peritoneal dialysis.
amyloidosis appear to be irreversible. In addition, patients with renal AA amyloidosis associated end-stage renal disease (ESRD) have been shown to have higher rates of mortality than those in the general dialysis population [6]. Peritoneal dialysis and hemodialysis have been used as renal replacement treatments for renal AA amyloidosise associated ESRD; however, data regarding outcomes of these treatments come from retrospective analyses [4,7]. Kidney transplantation is an eminent treatment of ESRD for most etiologies, and recent studies suggest that transplantation has favorable graft and patient outcomes in secondary amyloidosis [8,9]. In this single-center study, we aimed to analyze the outcomes of kidney transplantation in patients with secondary amyloidosis in comparison to patients with chronic glomerulonephritis (CGN). METHODS Patients Follow up charts of patients who underwent kidney transplantation between 1988 and 2012 at the Istanbul Faculty of Medicine were Table 2. Graft- and Patient-Related Outcomes
Last BMI Change in weight Last systolic BP Last diastolic BP Last eGFR (MDRD) Last creatinine eGFR change Post KT proteinuria (<1g /1e3 g />3 g) Acute rejection (n) Chronic rejection (n) Graft loss (n) Death (n)
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
22.1 2.9 þ6.6 3.4 116.8 16.2 74.1 8.4 65.3 32.7 1.5 0.5 0.06 1.0 17/19/5
24.1 3.3 þ5.9 4.2 129.2 13.6 82.9 10.5 64.2 29.5 1.8 1.5 0.008 1.2 27/8/6
.007 .436 <.001 <.001 .868 .160 .548 .027
10 0 1 4
11 2 4 0
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
5 12 8 6 5 5
13 4 0 12 8 4
.003
FKþMMFþsteroid FKþMPSþsteroid FKþAZAþsteroid CsAþMMFþsteroid CsAþMPSþsteroid CsAþAZAþsteroid
Abbreviations: CGN, chronic glomerulonephritis; FK, tacrolimus; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; AZA, azathioprine; CsA, cyclosporine A.
screened retrospectively, and patients whose primary renal disease was biopsy-confirmed AA amyloidosis (Congo redepositive staining in the kidney, rectum, duodenum, subcutaneous fat or bone marrow) were identified. Patients with lost follow-up data were excluded from the analysis. Patients matched for sex, transplantation time, and age were included as the control group. A total of 41 patients with AA amyloidosis and 41 patients with chronic glomerulonephritis (CGN) were included in this retrospective study (all transplantations were performed between 1988 and 2011 in patients with amyloidosis, and 1993 to 2011 in patients with CGN). Baseline characteristics, immunosuppressive regimens, and transplantation related outcomes were recorded using a standardized form. Glomerular filtration rates were estimated using the Modification of Diet in Renal Disease (MDRD) equation [10].
Statistical Analyses Statistical analysis were performed using SPSS version 20 (SPSS Inc, Chicago, IL). All data were presented as median and standard deviation [SD]. Parametric and nonparametric tests were compared using the Student t test and Yates correction c2 test, respectively. The Pearson test was used for correlation analysis. Multivariate Cox proportional hazard model analysis was performed to determine independent risk factors for patient mortality. Survival was estimated by the Kaplan-Meier and log-rank test. A P value of less than 0.05 was considered significant. The study was approved by the Ethics Committee of Istanbul Faculty of Medicine.
RESULTS Baseline Characteristics
There were 41 patients with AA amyloidosis and 41 patients with CGN included in this retrospective analysis (Table 1). The underlying etiologies of amyloidosis were FMF (n ¼ 35), tuberculosis (n ¼ 3), bronchiectasis (n ¼ 2), and inflammatory bowel disease (n ¼ 1). Mean follow-up times were 65.2 45.4 and 76.6 44.2 months (P ¼ .254) in Table 4. Graft and Patient Outcomes
.800 .152 .166 .040
Abbreviations: CGN, chronic glomerulonephritis; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation; KT, kidney transplantation.
Under follow-up Lost to follow-up Graft loss Death
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
36 0 1 4
36 1 4 0
NS NS .166 .019
Abbreviations: CGN, chronic glomerulonephritis; NS, not significant.
KIDNEY TRANSPLANT OUTCOMES IN AMYLOIDOSIS
2013
Table 5. Patient Survival 95% Confidence Interval Group
n
Death (n)
Mean Patient Survival (mo)
Lower
Upper
1-Year Survival
5-Year Survival
10-Year Survival
P Value
Amyloidosis CGN Overall
41 41 82
4 0 4
185.5 29.5 e 222.7 10.9
127.5 e 201.1
243.5 e 244.2
100 100 100
100 100 100
61.5 100 87.9
.008
Abbreviation: CGN, chronic glomerulonephritis.
amyloidosis and CGN patients, respectively. Patient age, donor age, sex, and type (live/deceased), human leukocyte antigen (HLA) mismatch, and renal replacement therapies preceding the transplantation were similar in the two groups (Table 1). Weights and body mass indexes (BMI) of patients with amyloidosis were significantly lower than patients with CGN at the first and last visits (Tables 1 and 2); however, patients in both groups similarly gained weight, and their BMIs increased between the first and last visits (Table 2). Immunosuppressive Agents
A triple immunosuppressive regimen was used for all patients (Table 3). Tacrolimus was more frequently used in amyloidosis patients, and cyclosporine A was more commonly used in CGN patients, but the differences were not statistically significant (Table 3). More patients in the amyloidosis group used azathioprine, whereas more patients in the CGN group used mycophenolate mofetil (MMF). Graft and Patient-Related Outcomes
The mean follow-up period was 70.9 44.9 months. Four deaths were recorded, all from the amyloidosis group (P ¼ .019); the causes of death were sepsis in three patients (two pneumonia and one urinary tract infection), and congestive heart failure in one patient (Table 4). The 10-year patient survival was found to be significantly worse in the AA amyloidosis group (62.5%) compared to the CGN group (100%) (P ¼ .008) (Table 5 and Fig 1). Serum creatinine levels and estimated glomerular filtration rates (eGFR, MDRD equation) early after transplantation and at the last visits did not differ between the groups (Table 2). eGFR changes throughout the follow-up period were also similar in the two groups. Graft loss occurred in five patients: one in amyloidosis group and four in the CGN group (P ¼ .166) (Table 4). Although more patients in the CGN group experienced acute rejection, chronic rejection, and graft loss, the differences were not statistical significant (Table 3). The 1-year deathcensored graft survival rates were similar in the two groups, whereas the mean death-censored graft survival time and 10-year graft survival rates were insignificantly lower in the CGN patients (144.7 6.3 vs 232.2 7.5 months and 66.1% vs 96%, respectively) (Table 6 and Fig 2). Posttransplantation proteinuria in excess of 1 g per day developed in a significantly greater number of patients (58%) with amyloidosis (Table 2). Colchicine treatment was
offered to all patients with AA amyloidosis; and 11 patients (26.8%) experienced colchicine-related adverse effects. Complications After Kidney Transplantation
Approximately one-half of the patients in each group developed urinary tract infections and pneumonia, but the differences in infection rates were not significant (Table 7). The rates of CMV and tuberculosis infections, osteoporosis, cataracts, and rhabdomyolysis were significantly higher in patients with amyloidosis (Table 7). All patients who developed rhabdomyolysis were in the amyloidosis group (12.1% vs 0%, P ¼ .021), and were receiving colchicine in combination with either cyclosporine A (three patients) or tacrolimus (two patients). DISCUSSION
Although some recent studies have provided evidence that attaining lower levels of SAA could improve the prognosis, the natural history of AA amyloidosis in the case of renal disease follows a progressive increase in proteinuria, worsening of renal function, and finally, if death has not yet occurred, development of ESRD [3,11]. Mortality is particularly higher in patients who developed significant renal dysfunction, hypoalbuminemia, or ESRD [4,6,7,12]. In this retrospective comparison of outcomes of patients with amyloidosis and CGN, like in other reports, we found that the
Fig 1. Kaplan-Meier patient survival curves for AA amyloidosis patients compared with chronic glomerulonephritis (CGN) patients.
2014
SAHUTOGLU, ATAY, CALISKAN ET AL Table 6. Graft Survival Outcomes (Death Censored) 95% Confidence Interval
Groups
n
Graft Loss (n)
Mean Graft Survival (mo)
Lower
Upper
1-Year Survival
5-Year Survival
10-Year Survival
P Value
Amyloidosis CGN Overall
41 41 82
1 4 5
232.2 7.5 144.7 6.3 206.1 13.7
217.5 132.4 179.3
247.0 157.1 233.0
100% 100% 100%
96.0% 100% 98.2%
96.0% 66.1% 73.9 %
.551
Abbreviation: CGN, chronic glomerulonephritis.
overall survival of amyloidotic patients after transplantation has improved, as the mean patient survival was 15.4 years [8,13]. The comparison of posttransplantation survival rates of patients with and without amyloidosis is not uniform across the literature, but, like in some other reports, in this study amyloidotic patients had a lower survival than CGN patients [14,15]. It should be emphasized that AA amyloidosis is a systemic disease that is inherently expected to be associated with higher disease burden than other renal-limited diseases. Therefore, it may be more important to focus on having improved patient survival after kidney transplantation in AA amyloidosis, rather than discussing whether survival of patients with AA amyloidosis after kidney transplantation is better than in patients with other primary renal disorders [16]. However, the retrospective nature of the studies, inhomogeneity of patients and control groups, different time periods, different ethnicities and medical practices, and different policies of excluding amyloidotic patients from transplantation could all account for the variable survival rates that have been reported. All deaths occurred in amyloidosis group after 5 years of postekidney transplantation follow-up. In this study, three of four deaths were due to sepsis. Infections with fatal consequences were also reported as the major cause of mortality in patients with AA amyloidosis, both under dialysis and after kidney transplantation [4,8,9,15e17]. These findings suggest that secondary amyloidosis confers a predilection to severe infections.
Fig 2. Kaplan-Meier graft survival curve of amyloidosis patients and chronic glomerulonephritis (CGN) patients (death censored).
We found that graft survival was better in amyloidosis patients as compared to CGN, with 1-year, 5-year, and 10-year graft survival rates of 100%, 96%, and 96%, respectively. As in the case of patient survival, reports on graft survival are not uniform. However, in most of the recent reports, graft survival was good in patients with AA amyloidosis and similar to patients with other primary renal diseases [9,13,18,19]. Rejection rates and serum creatinine levels at the last visits were not significantly different in amyloidotic and CGN patients in this study. In an earlier report, Sherif et al also reported that creatinine levels were similar in patients with amyloidosis and nonamyloidosis throughout the follow-up period after transplantation, whereas rejection rates were lower in patients with amyloidosis [18]. Proteinuria greater than 1 g per day developed in 58% of patients with amyloidosis, which was significantly higher than in patients with CGN. Data regarding graft biopsy were not available to review in this study; therefore, the causes of proteinuria could not be determined. However, it could be speculated that the recurrence of AA amyloidosis in allografts is an important cause of proteinuria in these patients.
Table 7. Complications After Kidney Transplantation
HSV VZV CMV UTI Pneumonia Hirsutism BKV PCP (PJP) TB primary TB total NODAT Avascular necrosis Cataracts Gingival hypertrophy Hypercholesterolemia Erythrocytosis Rhabdomyolysis Hyperuricemia Cancer CNI toxicity
Amyloidosis (n ¼ 41)
CGN (n ¼ 41)
P Value
4 3 6 18 23 2 1 1 7 9 4 1 8 2 14 10 5 7 3 2
2 6 1 17 17 5 0 0 2 2 3 2 2 6 21 12 0 7 1 0
.396 .289 .048 .823 .185 .236 .314 .320 .077 .023 .693 .556 .043 .137 .118 .618 .021 1 .305 .152
Abbreviations: HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; UTI, urinary tract infection; BKV, BK virus; PCP, Pneumocystis carinii (jirovecii) pneumonia; TB, tuberculosis; NODAT, new-onset diabetes after transplantation; CNI, calcineurin inhibitor.
KIDNEY TRANSPLANT OUTCOMES IN AMYLOIDOSIS
In a previous study, Livneh et al reported that colchicine dose was important in preventing amyloidosis recurrence and that AA amyloidosis recurred in 11 of 21 FMF patients (52%) who received inadequate colchicine within 3 years after kidney transplantation [20]. However, recurrence rates of AA amyloidosis can be different across various etiologies. In a recent study by Kofman et al, patients with heterogeneous etiologies of AA amyloidosis were retrospectively analyzed; the authors reported that the recurrence rates of AA amyloidosis were 8.7% for chronic inflammatory diseases, 20% for hereditary periodic fever syndromes, 11% for chronic infections, and 33.3% for unknown etiologies [9]. In this study, colchicine was offered to all patients with AA amyloidosis, but colchicine-related adverse effects, poor patient compliance, or underdosing may have caused proteinuria in a large number of patients. In addition, in a nationwide multicenter study, the complete response rate in Turkish FMF patients who take colchicine regularly was about 50% [21]. These data suggest that, besides colchicine therapy, other preventive measures may be needed in FMF patients to avoid amyloidosis recurrence. Urinary tract infections and pneumonia developed in nearly half of the patients in each group. Kofman et al also reported a similarly high rate of infections (73.2% of all amyloidosis cases) after transplantation in patients with AA amyloidosis [9]. Cytomegalovirus (CMV) and tuberculosis infections occurred in a significantly higher rate in patients with AA amyloidosis as compared to patients with CGN. The rates of CMV infections were not reported in most other cohort studies, but a smaller study by Celik et al did not find an increased rate of CMV infection (1/13 in amyloidotic and 4/13 in nonamyloidotic patients) in AA amyloidosis patients [19]. In addition, donor and recipient CMV serostatus as well as induction and maintenance immunosuppressive regimens can affect the rate of CMV infection; therefore, evidence is insufficient to draw a conclusion regarding CMV infections in AA amyloidosis [22]. Cyclosporine A and colchicine combination are known to interact, whereby cyclosporine A inhibits P-glycoprotein and decreases the elimination of colchicine [23]. In this study, only three of five patients who developed rhabdomyolysis were taking cyclosporine A in combination with colchicine. There are multiple causes of rhabdomyolysis such as statins, alcohol, toxins, and serotonin reuptake inhibitors, and we conclude that there could be other drug combinations or metabolic factors that could cause rhabdomyolysis in patients taking colchicine [24]. Mammalian target of rapamycin (m-TOR) inhibitors and MMF combinations without calcineurin inhibitors may be the alternative treatment regimens in patients with rhabdomyolysis. Limitations of this study were its retrospective nature, the lack of biopsy data, lack of induction immunosuppression data, small number of patients, and relatively short followup time. In conclusion, as compared to patients with CGN, kidney transplantation in patients with AA amyloidosis results in at least equal graft survival, slightly higher mortality, greater
2015
risk of developing proteinuria greater than 1 g per day, and increased risk of rhabdomyolysis. Infectious and noninfectious complications may occur more frequently in patients with AA amyloidosis after kidney transplantation.
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