Long-Term Outcomes and Prognostic Factors in Kidney ......Dec 04, 2020 · Polycystic kidney...

1

Long-Term Outcomes and Prognostic Factors in Kidney Transplant Recipients

with Polycystic Kidney Disease

Gauri Bhutani1*, Brad C. Astor

1, 2, Didier A. Mandelbrot

1, Lori Mankowski-Gettle

4,

Timothy Ziemlewicz4, Shane A. Wells

4, Leah Frater-Rubsam

6, Vanessa Horner

5,6,

Courtney Boyer1, Jennifer Laffin

7, Arjang Djamali

1, 3

1Divsion of Nephrology, University of Wisconsin School of Medicine and Public

Health, Madison, Wisconsin, USA; 2Department of Population Health Sciences,

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin,

USA; 3Division of Transplant Surgery, University of Wisconsin School of Medicine and

Public Health, Madison, Wisconsin, USA; 4Department of Radiology, University of

Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;

5Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison,

Wisconsin, USA; 6Wisconsin State Laboratory of Hygiene, University of Wisconsin,

Madison, Wisconsin, USA; 7Department of Pediatrics, University of Wisconsin,

Madison, USA.

Corresponding Author:

Gauri Bhutani, MBBS

University of Wisconsin School of Medicine and Public Health

1685 Highland Avenue, # 5135 MFCB, Madison, WI – 53705

Phone – 608-262-0331; Fax – 608-262-6734

Email - [email protected]

Kidney360 Publish Ahead of Print, published on December 4, 2020 as doi:10.34067/KID.0001182019

Copyright 2020 by American Society of Nephrology.

2

ABSTRACT

Background: Polycystic kidney disease (PKD) accounts for ~15% of kidney transplants

but long-term outcomes in PKD kidney recipients are not well understood.

Methods: In primary kidney recipients at our center (1994-2014), we compared

outcomes of underlying PKD (N=619) to other native diseases (non-PKD, N=4312).

Potential factors influencing outcomes in PKD were evaluated using Cox-proportional

hazards regression and a rigorous multi-variable model.

Results: PKD recipients were older, less likely to be sensitized, or experience delayed

graft function (DGF). Over a median follow up of 5.6 years, 1256 of all recipients

experienced death censored graft failure (DCGF; 115 PKD) and 1617 died (154 PKD).

After adjustment for demographic, dialysis, co-morbid disease, surgical and

immunologic variables, PKD recipients had a lower risk of DCGF (adjusted hazard ratio

[aHR]=0.73; 95% confidence interval [CI]: 0.57-0.93; p=0.01) and death (aHR=0.62;

95% CI: 0.51-0.75; p<0.001). In our multi-adjusted model, calcineurin inhibitor (CNI)

use was associated with lower risk of DCGF (aHR=0.45; 95% CI: 0.26-0.76, p=0.003),

while 5-6 HLA mismatch (aHR=2.1 95% CI: 1.2-3.64, p<0.01), was associated with

higher likelihood of DCGF. Notably, both pre-transplant coronary artery disease (CAD)

and higher BMI were associated with increased risk of death (aHR: 2.5 for CAD [95%

CI:1.69-3.71], p<0.001; aHR: 1.07 per 1 kg/m2 higher BMI [95% CI: 1.04-1.11;

p<0.001), as well as, of DCGF and acute rejection. Nephrectomy at time of transplant

and polycystic liver disease were not associated with DCGF/death. Incidence of post-

transplant diabetes mellitus was similar between PKD and “non-PKD” cohorts.

3

Conclusion: PKD recipients have better long-term graft and patient survival than non-

PKD. Standard practices of CNI use and promoting HLA match are beneficial in PKD

and should continue to be promoted. Further prospective studies investigating the

potential benefits of CNI use and medical/surgical interventions to address coronary

artery disease and the immunologic challenges of obesity are needed.

4

INTRODUCTION

Polycystic kidney diseases (PKD) refers to genetic tubulo-interstitial diseases which

result in the formation of multiple cysts in the renal parenchyma accompanied by

gradual loss of renal function1. Recent annual incidence rates of end-stage renal disease

(ESRD) from PKD in the United States range between 8-9 per million population,

making it the fourth most common cause of ESRD2. Although new disease-modifying

therapies for PKD are being developed3,4

, renal transplantation is the only alternative to

dialysis after reaching ESRD5,6

. While PKD is responsible for 2-3% of annual incident

ESRD in the US, it is the underlying disease for almost 12-14% of the annual renal

transplants performed2,7

.

Despite being a major primary renal disease leading to ESRD and renal transplantation,

many post-transplant outcomes specific to PKD remain unclear. Epidemiologic studies

have reported graft and patient survival in PKD kidney transplant recipients as equal8-15

,

better7,15-17

, as well as worse18

than non-PKD recipients. PKD recipients show better

graft and patient outcomes than non-PKD in unadjusted reports from large transplant

databases7. Specific transplant or PKD-linked factors that influence post-transplant

outcomes in PKD recipients19

are not known as prior epidemiologic studies have not

assessed these factors rigorously8-16,18,19

. There is also no consensus on the timing of

native nephrectomy and the risk of post-transplant diabetes mellitus (PTDM) in PKD

recipients17

. In order to optimize renal transplantation practices, protocols and patient

education in PKD, we analyzed data from our center for a better understanding of post-

renal transplant outcomes and the factors affecting these outcomes in PKD.

5

PATIENTS AND METHODS

The Wisconsin Allograft Recipient Database (WisARD) was initiated in 1984 to collect

information on all solid organ transplants performed at the University of Wisconsin. All

patients who received a primary kidney transplant at the University of Wisconsin

between January 1, 1994, and June 30, 2014, and were at least 18 years of age at the

time of transplantation were eligible for inclusion in this study. Patients had follow-up

through December 31, 2014. The University of Wisconsin Health Sciences Institutional

Review Board approved this study. The clinical and research activities reported are

consistent with the Principles of the Declaration of Istanbul as outlined in the

'Declaration of Istanbul on Organ Trafficking and Transplant Tourism.

We categorized kidney transplant recipients by the cause of ESRD recorded in the database.

Patients with ESRD from cystic kidney disease were classified as “PKD” and the rest were

grouped as “non-PKD”. We further categorized non-PKD as ESRD due to glomerulonephritis,

diabetes mellitus, hypertension or “other”. Information on baseline characteristics, including

demographics, pre-transplant dialysis, donor characteristics, co-morbid diseases,

immunosuppression, immunologic markers (HLA mismatch and cPRA >10%), prior kidney

transplantation and native nephrectomy, and for immediate graft function were obtained from

the transplant database.

6

Post-transplant outcomes of death-censored graft failure (DCGF), death and acute rejection

were compared across the five causes of ESRD (PKD, glomerulonephritis, diabetes mellitus,

hypertension and “other”) by Kaplan-Meier curves and Cox proportional hazards regression

analyses. Acute rejection was defined as biopsy proven acute cellular and/or acute antibody

mediated rejection. The multi-variable Cox-proportional hazards model was adjusted for age,

gender, race, body mass index (BMI), pre-emptive kidney transplant, dialysis prior to

transplant, duration of dialysis, pre-transplant co-morbidities (coronary artery disease,

congestive heart failure and polycystic liver disease), deceased donor, donor age, prior

transplant, induction agent, calcineurin inhibitor (CNI) and mycophenolate use, the degree of

HLA mismatch (0-2, 3-4 and 5-6) and nephrectomy at time of transplant.

Potential prognostic factors for the outcomes of DCGF, death and acute rejection in PKD

patients post-kidney transplant were investigated using Cox-proportional hazards regression

analyses and the multivariable model described above within the PKD cohort. To get a

complete picture of outcomes in PKD recipients, the cause of graft failure and incidence rates

of PTDM and post-transplant native kidney nephrectomy were also evaluated and compared

with non-PKD recipients using the χ² test (for graft failure) and the above multivariable model

and Cox-proportional hazards regression analyses (for PTDM and post-transplant

nephrectomy). All statistical analyses were performed using Stata 13.1 (stata.com).

RESULTS

7

Baseline characteristics (Table 1): Our cohort included 619 patients with polycystic

kidney disease (PKD) and 4312 patients with other native kidney disease (non-PKD).

Baseline demographic, co-morbid disease, donor/dialysis/immunologic characteristics

and immunosuppression utilization are fully detailed in Table 1.

Incidence of Graft Failure, Death, and Acute Rejection (Table 2, Figures 1-3):

Delayed graft function (DGF) was less common in the PKD recipients (15% [91/617] vs

19% [824/4312] in non-PKD; p<0.01). The incidence rate of death censored graft failure

(DCGF) was also lower in PKD (2.72 per 100-person years in PKD recipients and 4.11

per 100-person years in non-PKD recipients [p<0.001]; adjusted hazard ratios (aHR)

0.73 [95% confidence interval [CI]: 0.57-0.93; P=0.01] for PKD vs non-PKD; Figure

1a). The incidence rate of death was lower in the PKD cohort (3.51 per 100-person years

for PKD recipients and 5.55 per 100-person years in non-PKD recipients [p<0.01];

adjusted hazard ratio (aHR) of 0.62 [95% CI: 0.51-0.75; p<0.001] for PKD vs non-PKD;

Figure 2a). The incidence of acute rejection was similar between PKD and non-PKD

recipients (Figure 3a). Detailed comparison of these outcomes in PKD and specific

causes of non-PKD ESRD is shown in Table 2 and Figures 1b, 2b and 3b.

Risk Factors for Graft Failure, Death, and Acute Rejection in PKD (Tables 3-5):

Graft loss in PKD was from acute rejection in 14% (16/114) and chronic rejection in

54% (62/114). The frequency of recurrent primary disease was significantly lower in

PKD recipients (0% [0/114] vs 5% [60/1156], p=0.01; Figure 4). Several factors were

expectedly associated with DCGF in the PKD cohort including deceased donor (aHR:

8

1.62 [95% CI:1.01-2.58]; p=0.045), donor age (aHR: 1.36 per decade [95% CI:1.16-

1.58]; p<0.001) and HLA mismatch (aHR: 2.1 for 5-6 antigen mismatch vs 0-2

mismatch [95% CI:1.20-3.64]; p=0.009) [Table 3].

Interestingly, the use of CNIs was associated with a strong protection from DCGF (aHR: 0.45

[95% CI:0.26-0.76]; p<0.01 for CNI vs no-CNI) and acute rejection (aHR: 0.52 [95% CI: 0.29-

0.92]; p=0.03) in PKD recipients. There was no significant difference between tacrolimus and

cyclosporine for both DCGF and acute rejection rates (Tables 3 and 5). A higher BMI, on the

other hand, was associated with increased DCGF (aHR: 1.04 per 1 kg/m2 higher BMI [95%

CI: 1.01-1.08]; p=0.028; Table 3) and acute rejection in PKD recipients (aHR: 1.04 per 1

kg/m2 higher BMI [95% CI: 1.01-1.08]; p=0.022; Table 5). Moreover, a higher BMI, also

associated with increased likelihood of death in PKD recipients (aHR: 1.07 per 1 kg/m2 higher

BMI [95% CI: 1.04-1.11; p<0.001; Table 4).

Pre-transplant coronary artery disease strongly associated with death as expected (aHR: 2.5

[95% CI:1.69-3.71]; p<0.001). Interestingly, it also associated with increased risk of both

DCGF (aHR: 1.68 [95% CI:1.03-2.76]; p=0.038) and acute rejection (aHR: 2.37 [95% CI:1.47-

3.84]; p<0.001) in the PKD cohort. Recipient age, on the other hand, strongly associated with

death (aHR: 1.8 per decade increase [95% CI:1.46-2.22]; p<0.001) which was expected but a

paradoxical protective effect for DCGF (aHR: 0.76 per decade increase [95% CI:0.6-0.96];

p=0.019) was noted.

9

Additional prognostic factors that associated with death in PKD were donor age (aHR: 1.24

[95% CI:1.09-1.41]; p=0.001) and the use of “other” subgroup of induction

immunosuppression (aHR: 0.46 in comparison to basiliximab sub-group [95% CI:0.22-0.96];

p=0.038). The latter was only a small fraction of patients amongst the PKD cohort (34/619)

and mainly consisted of patients who received OKT-3 (N=31).

Other than as noted above (lack of CNI maintenance, higher BMI and pre-transplant coronary

artery disease), acute rejection also strongly associated with HLA mismatch, lack of

mycophenolate maintenance and female gender in the PKD cohort (Table 5).

It is noteworthy that two PKD-specific factors, native nephrectomy at time of transplant as well

as the presence of polycystic liver disease, were not associated with increased DCGF, death or

acute rejection in our PKD cohort.

Other post-transplant outcomes in PKD: Recipients with underlying PKD underwent

native nephrectomy more often than “non-PKD” cohort at the time of transplant (27% vs

0.9%; p<0.001; Table 1) and in the post-transplant period (18% vs 0.1%; p<0.001). The

incidence rate of nephrectomy post-transplant in PKD recipients was 2.09 per 100

person years (aHR: 4.57 vs “non-PKD” [95% CI:3.09-6.76]; p<0.001; Table 6). The

incidence of post-transplant diabetes mellitus (PTDM) in the PKD cohort (2.86 per 100

person years), on the other hand, was similar to “non-PKD” causes of ESRD (Table 6).

DISCUSSION

10

We present the largest published observational cohort study of patients with PKD

following kidney transplantation. Our findings confirm that kidney transplant recipients

with PKD have better graft and patient survival than non-PKD recipients. Our study also

reveals that that two potentially modifiable variables – 4 or less HLA mismatch and CNI

use, may be protective for graft failure in PKD patients. Recipient age, BMI and pre-

transplant coronary artery disease were associated with death in the PKD cohort and are

also potentially modifiable variables to some extent. Both native nephrectomy at the

time of transplant and prior polycystic liver disease did not predict graft or patient

survival.

Graft survival was better in the PKD cohort mostly due to significantly lower frequency

of recurrent native renal disease in the allograft whereas acute rejection and other causes

of graft failure were similar between the PKD cohort and non-PKD. Recurrent disease is

known to be significant contributor to allograft loss20

and although recurrent native renal

disease may be seen in most non-PKD causes of ESRD, PKD by its genetic

pathophysiology is inherently safe from this.

Higher HLA mismatch (especially 5-6 antigen mismatch) was associated with both

worse allograft survival and higher acute rejection in our PKD recipients. Although the

importance of HLA matching in current era of immunosuppression has been

questioned21

, it continues to be a standard practice at most transplant centers including

ours. Our findings confirm the importance of HLA matching in appropriate donor

selection for PKD recipients. Higher donor age, and deceased donor are well reported

11

risk factors for DCGF post-renal transplantation overall2,22

. The apparent protective

effect of higher recipient age for DCGF seen in our PKD cohort is likely due to

confounding from longer survival in younger recipients as described in other graft

survival reports23,24

. Our findings indicate that recipient-donor age matching and

promoting living donation are important for optimizing graft survival in PKD recipients

as well.

Calcineurin inhibitor-based therapy is still a cornerstone in renal transplantation

although long-term benefits of CNI to long-term allograft survival are questioned25

. CNI

use associated with better allograft survival within our PKD cohort. This is helpful to

know since both PKD and CNI have been individually linked to increased risk of post-

transplant diabetes19

. In addition, mTOR inhibitors may theoretically seem preferable

agents in PKD recipients as these have some efficacy in inhibiting both renal and liver

cyst growth5. CNI use was also associated with less acute rejection within our PKD

cohort (Table 5) which suggests that the observed benefit from CNI use in PKD group

could be from better immunologic performance of CNI. Given the retrospective nature

of our study and selection bias (only ~10% were on non-CNI regimens), conclusions

cannot be made. Prospective studies of CNI use in PKD recipients post-transplantation

are needed to understand the significance of this observation better, especially in the

current era when new agents like belatacept are also available26

.

Our study also shows superior survival of recipients with PKD compared to non-PKD

kidney transplant recipients. Most prior published studies show similar overall patient8-15

12

and graft survival8-14

in PKD versus non-PKD recipients. One study18

shows worse

survival in PKD patient compared to non-PKD. In this study, the PKD cohort was small

(N=80) and age at transplant was significantly higher for PKD patients (vs non-PKD). In

fact, most of these prior reports employ small numbers8,9,11-14,18

, lack of robust

multivariable adjustment8-15,18

and many include patients transplanted in the 1980s-

1990s when the current standard maintenance immunosuppressants were not in use8,9,12-

15. Our findings of better graft and recipient survival in PKD are consistent with large

transplant registry data7 and one larger case-control study

16. PKD patients were also

shown to have better survival rates compared to a demographic and dialysis vintage

matched non-diabetic control population in a retrospective study of hemodialysis

patient17

. It is possible that residual effect from a lower chronic illness burden in PKD

(as shown in Table 1) contributes to this improved survival despite statistical

adjustments.

The association of recipient and donor age with survival was expected and is well

reported in post-kidney transplant population27

. Pre-transplant coronary artery disease

was highly associated with death in PKD recipients which is not surprising since

cardiovascular disease contributes heavily to post-transplant mortality28

. Notably, pre-

transplant coronary artery disease was also associated with worse DCGF and acute

rejection in our PKD cohort. Coronary artery disease has not been linked with DCGF

and rejection previously to our knowledge although post-transplant hypertension29

and

denovo CHF30

have been. In addition, statin use has been linked with improved post-

transplant outcomes although not consistently for graft outcomes31-34

. Our findings

13

suggest that coronary artery disease is an important potentially modifiable risk factor to

improve multiple post-transplant outcomes in PKD.

Other than coronary artery disease, higher BMI was the only other risk factor that

associated with all 3 outcomes of death, DCGF, and acute rejection. A higher BMI is

well reported to associate with these outcomes in post-kidney transplant setting likely

due to influence of increased cardiovascular risk, changes in pharmacokinetics/dynamics

of immunosuppressive medications as well as the inflammatory state linked with

obesity35,36

. Although obesity by itself should not discourage transplantation in PKD or

otherwise, as outcomes on dialysis are likely to be worse than with transplantation37,38

but prospective studies to understand the best interventions to address the cardiovascular

as well immunologic challenges in obesity are needed, as consistent improvements in

BMI are not straightforward or easy to achieve35,36

. In addition, the contribution of the

increased weight of the native kidneys and/or liver to the BMI in PKD recipients in our

study is not known but can be considerable39

, and how this factor contributes to

outcomes certainly needs investigating as well.

Finally, we also found lack of mycophenolate agent and female gender as risk factors for

acute rejection but not for DCGF. Similar findings have also been reported in post-

kidney transplant setting overall40,41

. Further studies of mycophenolate use and role of

gender in PKD recipients are needed to better inform us about the significance of these

findings. The apparently protective effect on rejection and survival with use of “other”

induction agent (OKT-3 mainly), on the other hand, was likely highly subject to

14

selection bias and error due to the small number who received this form of induction

(N=34) and therefore, this is likely not a reliable finding.

Based on our study findings, we recommend that general nephrologists educate their

PKD patients who have moderate-severe chronic kidney disease (stages 3-4) about

excellent post-transplant outcomes to help encourage timely kidney donation by

family/friends. Given the excellent post-transplant outcomes, it may also be worthwhile

for transplant centers to investigate a GFR cut off >20 ml/min/1.73 m2 for deceased

donor listing for high risk PKD (in whom GFR decline can be as high as 5-7

ml/min/year)42

, who are otherwise healthy but do not have potential donors.

The timing of native nephrectomy (at or post-transplantation) did not significantly affect

allograft or survival outcomes in our study. This is consistent with findings in some

other prior smaller reports43-45

and another recent report46

. Pre-transplant nephrectomy is

well established as undesirable due to increased surgical complications and the risk of

losing native renal function19,47

. Nephrectomy at time of transplant, however, is still not

a universally adopted practice due to concern of potential insults to the new allograft, the

benefit of preserving residual renal function and avoidance of unnecessary surgical

procedure if possible47

. These are important considerations; however, our findings do

strongly suggest safety of a simultaneous nephrectomy. An individualized approach to

timing and need for nephrectomy based on patient’s needs, preference, and surgical risk,

would likely be the most optimal clinical practice48

.

15

Some studies11,15,49,50

and meta-analyses51,52

have showed increased risk of PTDM in

PKD recipients, but this has not been a consistent finding53,54

and most of these studies

have small number of PKD patients. Amongst the 2 largest cohorts, however, one study

has minimally increased risk of PTDM with PKD in an unadjusted analysis15

while the

other has none54

. Our findings (from the largest reported post-transplant PKD cohort to

date) show no increase in risk of PTDM in PKD recipients.

Limitations of our study include the observational nature, single center population,

residual confounding due to differences in baseline characteristics which may not have

been completely accounted for by the statistical adjustments made. A potential era effect

due to the long observation period and immortal time bias may affect outcomes in both

PKD/non-PKD groups. There is also likely heterogeneity of the PKD group with regards

to the underlying genetic mutation. Assessment of underlying genetic disease in PKD is

not advocated as a routine clinical practice5. This practice may change in the near future

as disease specific therapies become available. Assessing outcomes based on genotype

may provide novel genotype specific information about post-renal transplantation

outcomes and complications.

In conclusion, renal allograft and patient survival is better in PKD than in other native

kidney diseases post-kidney transplant. Our study confirms that many currently used

standard transplant practices are associated with better post-transplant outcomes in PKD

recipients. A better HLA match, living donor, recipient-donor age matching and

cardiovascular health should continue to be encouraged during pre-transplant

16

evaluations in this group. For maintenance immunosuppression, both CNI and

mycophenolate appear to be associated with better allograft outcomes. Further

prospective studies are needed to better inform about potential benefits of specific

immunosuppressive agents as well as of potential medical/surgical interventions to

address coronary artery disease and the immunologic challenges in obesity in PKD

recipients. Our findings also strongly suggest that native nephrectomy at time of

transplant is safe and the risk of PTDM is not increased in PKD recipients.

17

DISCLOSURES

All authors have nothing to disclose.

FUNDING

None.

ACKNOWLEDGEMENTS

We acknowledge Dana Clark, MA, for her significant editorial assistance.

AUTHOR CONTRIBUTIONS

G Bhutani: Data curation; Formal analysis; Writing - original draft; Writing - review and

editing

B Astor: Data curation; Formal analysis; Methodology; Writing - review and editing

D Mandelbrot: Writing - review and editing

L Mankowski Gettle: Writing - review and editing

T Ziemlewicz: Writing - review and editing

S Wells: Writing - review and editing

L Frater-Rubsam: Writing - review and editing

V Horner: Writing - review and editing

C Boyer: Writing - review and editing

J Laffin: Writing - review and editing

A Djamali: Conceptualization; Methodology; Resources; Supervision; Writing - review

and editing

Each author takes responsibility that this study has been reported honestly, accurately

and transparently; that no important aspects of the study have been omitted. Each author

accepts accountability for the overall work and will ensure that questions pertaining to

the accuracy or integrity of any portion of the work are appropriately investigated and

resolved.

18

REFERENCES

1. Wilson, P.D. Polycystic kidney disease. The New England journal of medicine 350,

151-164 (2004).

2. https://www.usrds.org/reference.aspx. United States Renal Data System Annual Data

Report 2017. (2015).

3. Torres, V.E., et al. Tolvaptan in patients with autosomal dominant polycystic kidney

disease. The New England journal of medicine 367, 2407-2418 (2012).

4. Torres, V.E., et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney

Disease. The New England journal of medicine 377, 1930-1942 (2017).

5. Chapman, A.B., et al. Autosomal-dominant polycystic kidney disease (ADPKD):

executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO)

Controversies Conference. Kidney international 88, 17-27 (2015).

6. Eckardt, K.U., et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis,

classification, and management--A KDIGO consensus report. Kidney international 88,

676-683 (2015).

7. https://optn.transplant.hrsa.gov/data/view-data-reports/annual-report/. OPTN/SRTR

Annual Report 2012.

8. Hadimeri, H., Norden, G., Friman, S. & Nyberg, G. Autosomal dominant polycystic

kidney disease in a kidney transplant population. Nephrology, dialysis, transplantation

: official publication of the European Dialysis and Transplant Association - European

Renal Association 12, 1431-1436 (1997).

9. Stiasny, B., Ziebell, D., Graf, S., Hauser, I.A. & Schulze, B.D. Clinical aspects of renal

transplantation in polycystic kidney disease. Clinical nephrology 58, 16-24 (2002).

10. Roozbeh, J., et al. Outcome of kidney transplantation in patients with polycystic kidney

disease: a single center study. Saudi journal of kidney diseases and transplantation : an

official publication of the Saudi Center for Organ Transplantation, Saudi Arabia 19,

72-75 (2008).

11. Goncalves, S., et al. Autosomal-dominant polycystic kidney disease and kidney

transplantation: experience of a single center. Transplantation proceedings 41, 887-890

(2009).

12. Florijn, K.W., Chang, P.C., van der Woude, F.J., van Bockel, J.H. & van Saase, J.L.

Long-term cardiovascular morbidity and mortality in autosomal dominant polycystic

kidney disease patients after renal transplantation. Transplantation 57, 73-81 (1994).

13. Shiroyanagi, Y., et al. Kidney transplantation in the recipient with autosomal-dominant

polycystic kidney disease: a single center experience. Transplantation proceedings 32,

1841-1843 (2000).

14. Sanfilippo, F.P., Vaughn, W.K., Peters, T.G., Bollinger, R.R. & Spees, E.K.

Transplantation for polycystic kidney disease. Transplantation 36, 54-59 (1983).

15. Jacquet, A., et al. Outcomes of renal transplantation in patients with autosomal

dominant polycystic kidney disease: a nationwide longitudinal study. Transpl Int 24,

582-587 (2011).

16. Johnston, O., et al. Favorable graft survival in renal transplant recipients with

polycystic kidney disease. Renal failure 27, 309-314 (2005).

17. Perrone, R.D., Ruthazer, R. & Terrin, N.C. Survival after end-stage renal disease in

autosomal dominant polycystic kidney disease: contribution of extrarenal complications

https://www.usrds.org/reference.aspx

https://optn.transplant.hrsa.gov/data/view-data-reports/annual-report/

19

to mortality. American journal of kidney diseases : the official journal of the National

Kidney Foundation 38, 777-784 (2001).

18. Illesy, L., Kovacs, D.A., Szabo, R.P., Asztalos, A.B.L. & Nemes, B. Autosomal

Dominant Polycystic Kidney Disease Transplant Recipients After Kidney

Transplantation: A Single-center Experience. Transplantation proceedings 49, 1522-

1525 (2017).

19. Kanaan, N., Devuyst, O. & Pirson, Y. Renal transplantation in autosomal dominant

polycystic kidney disease. Nature reviews. Nephrology 10, 455-465 (2014).

20. El-Zoghby, Z.M., et al. Identifying specific causes of kidney allograft loss. American

journal of transplantation : official journal of the American Society of Transplantation

and the American Society of Transplant Surgeons 9, 527-535 (2009).

21. Su, X., Zenios, S.A., Chakkera, H., Milford, E.L. & Chertow, G.M. Diminishing

significance of HLA matching in kidney transplantation. American journal of

transplantation : official journal of the American Society of Transplantation and the

American Society of Transplant Surgeons 4, 1501-1508 (2004).

22. Snoeijs, M.G., et al. Kidney transplantation using elderly non-heart-beating donors: a

single-center experience. Am J Transplant 6, 1066-1071 (2006).

23. Ferrari, P., Lim, W., Dent, H. & McDonald, S.P. Effect of donor-recipient age

difference on graft function and survival in live-donor kidney transplantation.

Nephrology, dialysis, transplantation : official publication of the European Dialysis

and Transplant Association - European Renal Association 26, 702-708 (2011).

24. Foley, D.P., et al. Long-term outcomes of kidney transplantation in recipients 60 years

of age and older at the University of Florida. Clin Transpl, 101-109 (2005).

25. Stegall, M.D., Gaston, R.S., Cosio, F.G. & Matas, A. Through a glass darkly: seeking

clarity in preventing late kidney transplant failure. Journal of the American Society of

Nephrology : JASN 26, 20-29 (2015).

26. Ferguson, R., et al. Immunosuppression with belatacept-based, corticosteroid-avoiding

regimens in de novo kidney transplant recipients. Am J Transplant 11, 66-76 (2011).

27. Keith, D.S., Demattos, A., Golconda, M., Prather, J. & Norman, D. Effect of donor

recipient age match on survival after first deceased donor renal transplantation. Journal

of the American Society of Nephrology : JASN 15, 1086-1091 (2004).

28. Cosio, F.G., Hickson, L.J., Griffin, M.D., Stegall, M.D. & Kudva, Y. Patient survival

and cardiovascular risk after kidney transplantation: the challenge of diabetes. Am J

Transplant 8, 593-599 (2008).

29. Kasiske, B.L., et al. Hypertension after kidney transplantation. American journal of

kidney diseases : the official journal of the National Kidney Foundation 43, 1071-1081

(2004).

30. Lentine, K.L., et al. De novo congestive heart failure after kidney transplantation: a

common condition with poor prognostic implications. American journal of kidney

diseases : the official journal of the National Kidney Foundation 46, 720-733 (2005).

31. Masterson, R., et al. Impact of statin treatment on 1-year functional and histologic renal

allograft outcome. Transplantation 80, 332-338 (2005).

32. Fellström, B., et al. Effect of fluvastatin on renal end points in the Assessment of

Lescol in Renal Transplant (ALERT) trial. Kidney international 66, 1549-1555 (2004).

33. Katznelson, S., et al. The effect of pravastatin on acute rejection after kidney

transplantation--a pilot study. Transplantation 61, 1469-1474 (1996).

20

34. Co, M.L.F., Agdamag, A.C., Co, M.Z., Hertl, M. & Mohamedali, B. Intensity-

Dependent Benefit of Statins in Survival Among Prospective Kidney Transplant

Patients. Am J Cardiol 123, 254-259 (2019).

35. Potluri, K. & Hou, S. Obesity in kidney transplant recipients and candidates. American

journal of kidney diseases : the official journal of the National Kidney Foundation 56,

143-156 (2010).

36. Lentine, K.L., et al. Obesity and kidney transplant candidates: how big is too big for

transplantation? American journal of nephrology 36, 575-586 (2012).

37. Khwaja, A. & El-Nahas, M. Transplantation in the obese: separating myth from reality.

Nephrology, dialysis, transplantation : official publication of the European Dialysis

and Transplant Association - European Renal Association 27, 3732-3735 (2012).

38. Glanton, C.W., Kao, T.C., Cruess, D., Agodoa, L.Y. & Abbott, K.C. Impact of renal

transplantation on survival in end-stage renal disease patients with elevated body mass

index. Kidney international 63, 647-653 (2003).

39. Freise, J., et al. The Effect of Enlarged Kidneys on Calculated Body Mass Index

Categorization in Transplant Recipients With ADPKD. Kidney Int Rep 4, 606-609

(2019).

40. Clayton, P.A., McDonald, S.P., Chapman, J.R. & Chadban, S.J. Mycophenolate versus

azathioprine for kidney transplantation: a 15-year follow-up of a randomized trial.

Transplantation 94, 152-158 (2012).

41. Meier-Kriesche, H.U., et al. Gender differences in the risk for chronic renal allograft

failure. Transplantation 71, 429-432 (2001).

42. Irazabal, M.V., et al. Imaging classification of autosomal dominant polycystic kidney

disease: a simple model for selecting patients for clinical trials. Journal of the American

Society of Nephrology : JASN 26, 160-172 (2015).

43. Glassman, D.T., Nipkow, L., Bartlett, S.T. & Jacobs, S.C. Bilateral nephrectomy with

concomitant renal graft transplantation for autosomal dominant polycystic kidney

disease. The Journal of urology 164, 661-664 (2000).

44. Fuller, T.F., et al. End stage polycystic kidney disease: indications and timing of native

nephrectomy relative to kidney transplantation. The Journal of urology 174, 2284-2288

(2005).

45. Veroux, M., et al. Simultaneous Native Nephrectomy and Kidney Transplantation in

Patients With Autosomal Dominant Polycystic Kidney Disease. PloS one 11, e0155481

(2016).

46. Abrol, N., Bentall, A., Torres, V.E. & Prieto, M. Simultaneous bilateral laparoscopic

nephrectomy with kidney transplantation in patients with ESRD due to ADPKD: A

single-center experience. Am J Transplant (2020).

47. Chebib, F.T., et al. Native Nephrectomy in Renal Transplant Recipients with

Autosomal Dominant Polycystic Kidney Disease. Transplantation direct 1, e43 (2015).

48. Argyrou, C., Moris, D. & Vernadakis, S. Tailoring the 'Perfect Fit' for Renal Transplant

Recipients with End-stage Polycystic Kidney Disease: Indications and Timing of

Native Nephrectomy. In Vivo 31, 307-312 (2017).

49. Hamer, R.A., Chow, C.L., Ong, A.C. & McKane, W.S. Polycystic kidney disease is a

risk factor for new-onset diabetes after transplantation. Transplantation 83, 36-40

(2007).

21

50. Ducloux, D., et al. Polycystic kidney disease as a risk factor for post-transplant diabetes

mellitus. Nephrology, dialysis, transplantation : official publication of the European

Dialysis and Transplant Association - European Renal Association 14, 1244-1246

(1999).

51. Culliford, A., Phagura, N. & Sharif, A. Autosomal Dominant Polycystic Kidney

Disease Is a Risk Factor for Posttransplantation Diabetes Mellitus: An Updated

Systematic Review and Meta-analysis. Transplant Direct 6, e553 (2020).

52. Cheungpasitporn, W., Thongprayoon, C., Vijayvargiya, P., Anthanont, P. & Erickson,

S.B. The Risk for New-Onset Diabetes Mellitus after Kidney Transplantation in

Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review

and Meta-Analysis. Can J Diabetes 40, 521-528 (2016).

53. Ruderman, I., et al. New onset diabetes after kidney transplantation in autosomal

dominant polycystic kidney disease: a retrospective cohort study. Nephrology (Carlton)

17, 89-96 (2012).

54. Courivaud, C., et al. Impact of pre-transplant dialysis modality on post-transplant

diabetes mellitus after kidney transplantation. Clin Transplant 25, 794-799 (2011).

22

TABLES

Table 1: Baseline characteristics of recipients with polycystic kidney disease (PKD) and

other native kidney disease (Non-PKD).

Variable (units) PKD^ Non-PKD^ P-Value

N=619 N=4312

Age (years) 52.9 (9.13) 48.7 (13.4) <0.001

Female (%) 45.7 39.3 0.002

Non-White Race (%) 6.6 17.2 <0.001

BMI (kg/m2) 27.8 (5.04) 27.2 (5.43) <0.001

Any dialysis prior to transplantation (%) 60.1 78.3 <0.001

Dialysis duration (months) 14.1 (24) 22 (27.24) <0.001

Deceased donor (%) 57.5 60.9 0.107

Co-morbid diseases:

- Diabetes

- Hypertension

- Coronary artery disease

- Congestive heart failure

- Polycystic liver disease

0.3

97.5

21.8

7.4

32.1

16.6

97.6

35.2

11.8

0

<0.001

0.88

<0.001

0.001

<0.001

Induction treatment (%)

• Alemtuzumab

• Basiliximab

• Thymoglobulin

• Other

• None

14.1

61.0

17.6

5.5

10.8

16.4

49.2

22.4

8.2

15.9

<0.001

Calcineurin inhibitor maintenance (%)

Tacrolimus

Cyclosporine

No CNI

52.02

38.77

9.21

52.97

37.71

9.32

0.877

Mycophenolate maintenance (%) 93.1 90.1 0.020

HLA MM

0-2

3-4

5-6

23.6

42.3

34.1

28.8

41.0

30.2

0.02

cPRA > 10% (%) 23.3* 30.8* 0.009

23

Prior kidney transplantation (%) 10.0 22.7 <0.001

Native nephrectomy at transplantation (%) 26.8 0.9 <0.001

Donor age (%) 43.3 (14.2) 42.2 (14.8) 0.0372

^All values are expressed in means (+ standard deviation) or in % as noted in the variable

column. *N=296 for PKD and 2088 for non-PKD; Thymoglobulin denotes rabbit

antithymocyte globulin.

24

Table 2: Outcomes in polycystic kidney disease (PKD) and other native kidney disease groups.

Outcomes

Polycystic kidney

disease

(N=619)

Glomerulonephritis

(N=1331)

Diabetes (N=1209) Hypertension

(N=520)

Other (N=1252)

Death censored graft failure

All events=1256

# Events

Incidence Rate (per 100

person-years)

Adjusted Hazard Ratio#

(95% CI)

115

2.72

1.0

Reference

371

2.98*

1.28 (0.98, 1.66)

P=0.065

304

4.27*

1.51 (1.15, 1.98)

P=0.003

143

4.82*

1.47 (1.09, 1.97)

P=0.011

323

3.87*

1.32 (1.02, 1.72)

P=0.038

Death

All events=1617

# Events


person-years)


(95% CI)

154

3.21

1.0

Reference

363

3.74

1.28 (1.02, 1.59)

P=0.029

656

8.68*

2.23 (1.80, 2.76)

P<0.001

199

6.21*

1.50 (1.18, 1.91)

P=0.001

399

4.59*

1.61 (1.29, 1.99)

P<0.001

Acute Rejection

All events=937

# Events


person-years)


(95% CI)

107

2.76

1.0

Reference

274

3.23

1.16 (0.86, 1.54)

P=0.328

189

2.84

0.99 (0.73, 1.35)

P=0.953

106

3.9^

1.29 (0.92, 1.79)

P=0.135

261

3.51^

1.18 (0.88, 1.57)

P=0.272

#The model was adjusted for all variables noted in Methods: age, gender, race, body mass index (BMI), pre-emptive kidney transplant, dialysis

duration, comorbid disease (coronary artery disease, congestive heart failure, polycystic liver disease), deceased donor, prior transplant, induction,

calcineurin inhibitor use, mycophenolate use, HLA mismatch and nephrectomy at time of transplant. *P<0.01 vs PKD, ^P<0.05 vs PKD; CI

denotes confidence intervals.

25

Table 3: Risk factors for death-censored graft failure in recipients with polycystic kidney

disease

Variable Hazard

Ratio

95% CI P value

Age (per decade) 0.76 0.6-0.96 0.019

Female gender 1.22 0.82-1.81 0.329

Non-white Race 1.14 0.51- 2.55 0.756

Body mass index (per 1 kg/m2 higher

BMI)

1.04 1.01- 1.08 0.028

Dialysis prior to transplantation 1.26 0.77-2.06 0.354

Dialysis duration 1.00 0.99-1.01 0.422

Coronary artery disease 1.68 1.03-2.76 0.038

Congestive heart failure 1.3 0.61-2.74 0.499

Polycystic liver disease 1.12 0.72-1.74 0.609

Deceased donor 1.62 1.01-2.58 0.045

Donor age 1.36 1.16-1.58 <0.001

Prior kidney transplantation 1.15 0.58-2.26 0.689


Basiliximab

Thymoglobulin

Alemtuzumab

Other

None

Reference

0.81

1.12

1.32

0.67

0.46- 1.43

0.66-1.92

0.60-2.90

0.22-2.03

0.472

0.654

0.497

0.481

Calcineurin inhibitor maintenance

agent

Tacrolimus

Cyclosporine

None

Reference

0.69

1.80

0.42-1.11

0.99-3.27

0.124

0.055

Mycophenolate maintenance 1.05 0.49-2.28 0.892

HLA mismatch

0-2

3-4

5-6

Reference

1.32

2.1

0.77-2.27

1.20-3.64

0.313

0.009

Nephrectomy at transplantation 1.00 0.64- 1.54 0.990

26

CI denotes confidence intervals; HLA: human leukocyte antigen; Thymoglobulin: rabbit


27

Table 4: Risk factors for death post-kidney transplant in recipients with polycystic

kidney disease

Variable Hazard Ratio 95% CI P value

Age (per decade) 1.80 1.46-2.22 <0.001

Female gender 0.85 0.60-1.21 0.370

Non-White Race 1.54 0.73-3.27 0.261

Body mass index (per 1 kg/m2

higher BMI)

1.07 1.04- 1.11 <0.001

Dialysis prior to transplantation 1.36 0.88-2.12 0.171


Coronary artery disease 2.50 1.69-3.71 <0.001


Polycystic liver diseasePolycystic

liver disease

1.02 0.66- 1.56 0.942

Deceased donor 1.35 0.89-2.03 0.156

Donor age 1.24 1.09-1.41 0.001

Prior kidney transplantation 1.40 0.78- 2.48 0.255


Basiliximab

Thymoglobulin

Alemtuzumab

Other

None

Reference

0.80

0.86

0.46

0.41

0.50-1.27

0.49-1.54

0.22-0.96

0.15-1.12

0.342

0.623

0.038

0.084


Tacrolimus

Cyclosporine

None

Reference

0.83

1.30

0.54-1.27

0.70-2.40

0.392

0.414


HLA mismatch

0-2 (reference)

3-4

5-6

Reference

1.23

1.10

0.81-1.86

0.69-1.76

0.335

0.693

Nephrectomy at transplantation 0.83 0.54-1.28 0.401

CI denotes confidence intervals; HLA: human leukocyte antigen and Thymoglobulin: rabbit


28

Table 5: Risk factors for biopsy-proven acute rejection post-kidney transplant in recipients

with polycystic kidney disease

Variable Hazard Ratio 95% CI P value

Age (per decade) 0.79 0.62-1.01 0.062

Female gender 1.64 1.07-2.50 0.022

Non-White Race 1.26 0.65-2.47 0.493

Body mass index (per 1 kg/m2

higher BMI)

1.04 1.01-1.08 0.022

Dialysis prior to transplantation 1.27 0.7 9- 2.10 0.325


Coronary artery disease 2.37 1.47 -3.84 <0.001


Polycystic liver disease 1.25 0.79-1.84 0.392

Deceased donor 0.92 0.59-1.44 0.716

Donor age 1.00 0.85-1.16 0.956

Prior kidney transplantation 2.59 1.38-4.87 0.003


Simulect

Thymoglobulin

Campath

Other

None

Reference

0.82

1.38

0.13

0.64

0.45-1.49

0.81-2.33

0.03-0.62

0.19-2.14

0.501

0.233

0.010

0.464


Tacrolimus

Cyclosporine

None

Reference

0.86

1.79

0.53-1.37

0.97-3.32

0.518

0.063


HLA mismatch

0-2

3-4

5-6

Reference

2.30

4.07

1.21-4.37

2.10-7.92

0.011

<0.001

Nephrectomy at transplantation 1.17 0.74-1.84 0.493

CI denotes confidence intervals; HLA: human leukocyte antigen and Thymoglobulin: rabbit


29

Table 6: Incidence of post-transplant events in PKD vs non-PKD

PKD Diabetes Hypertension Glomerulonephritis Other

Post-transplant diabetes

# Events

Incidence Rate (per

100 person-years)

Adjusted Hazard

Ratio# (95% CI; p-

value)

103

2.86

1.0 (Reference)

NA

110

4.55

1.12 (0.82, 1.54)

P=0.480

187

2.27

0.82 (0.62, 1.10)

P=0.187

186

2.54

0.94 (0.7, 1.25)

P=0.656

Post-transplant nephrectomy

# Events

Incidence Rate (per

100 person-years)

Adjusted Hazard

Ratio# (95% CI; p-

value)

59

2.09

1.0 (Reference)

20

0.28

0.14 (0.08, 0.25)

P<0.001

11

0.38

0.22 (0.11, 0.43)

P<0.001

31

0.34

0.18 (0.11, 0.29)

P<0.001

48

0.61

0.33 (0.21, 0.51)

P<0.001

#The model was adjusted for all variables noted in Methods: age, gender, race, body mass index (BMI), pre-emptive kidney transplant,

dialysis duration, comorbid disease (coronary artery disease, congestive heart failure, polycystic liver disease), deceased donor, prior

transplant, induction, calcineurin inhibitor use, mycophenolate use, HLA mismatch and nephrectomy at time of transplant. CI denotes

confidence intervals

Patient and Graft Survival in PKD

30

FIGURE LEGENDS

Figure 1: Death censored graft failure in PKD and non-PKD kidney transplant

recipients.

(a) PKD vs all non-PKD (N=619 [black solid line] and 4312 [black small dashed line],

respectively; p<0.001); (b) PKD (N=619) vs glomerulonephritis (N=1331; grey long dashed

line; p<0.01), diabetes (N=1209; light grey solid line; p<0.01), hypertension (N=520; grey

dotted line; p<0.01) and other (N=1252; black small dashed line; p<0.01) causes of ESRD. The

model was adjusted for all variables noted in Methods: age, gender, race, body mass index

(BMI), pre-emptive kidney transplant, dialysis duration, comorbid disease (coronary artery

disease, congestive heart failure, polycystic liver disease), deceased donor, prior transplant,

induction, calcineurin inhibitor use, mycophenolate use, HLA mismatch and nephrectomy at

time of transplant.

Figure 2: Death in PKD and non-PKD kidney transplant recipients.


respectively; p<0.001); (b) PKD (N=619) vs glomerulonephritis (N=1331; grey long dashed

line; p=NS), diabetes (N=1209; light grey solid line; p<0.01), hypertension (N=520; grey

dotted line; p<0.01) and other (N=1252; black small dashed line; p<0.01) causes of ESRD. The

model was adjusted for all variables noted in Methods: age, gender, race, body mass index

(BMI), pre-emptive kidney transplant, dialysis duration, comorbid disease (coronary artery

disease, congestive heart failure, polycystic liver disease), deceased donor, prior transplant,

induction, calcineurin inhibitor use, mycophenolate use, HLA mismatch and nephrectomy at

time of transplant. *NS denotes not significant

Figure 3: Acute rejection in PKD and non-PKD kidney transplant recipients.


respectively; P=NS); (b) PKD (N=619) vs glomerulonephritis (N=1331; grey long dashed line;

p=NS), diabetes (N=1209; light grey solid line; p=NS), hypertension (N=520; grey dotted line;

p<0.05) and other (N=1252; black small dashed line; p<0.05) causes of ESRD. The model was

adjusted for all variables noted in Methods: age, gender, race, body mass index (BMI), pre-

emptive kidney transplant, dialysis duration, comorbid disease (coronary artery disease,

congestive heart failure, polycystic liver disease), deceased donor, prior transplant, induction,

calcineurin inhibitor use, mycophenolate use, HLA mismatch and nephrectomy at time of

transplant. *NS denotes not significant

Figure 4 (a) Causes of graft loss in PKD cohort. (b) Causes of graft loss in “non-PKD” cohort.

*There was significantly lower frequency of recurrent native renal disease in the allograft in

PKD recipients (p=0.01) whereas acute rejection and other causes of graft failure were similar

between the PKD cohort and non-PKD (N = 114 for PKD and 1156 for non-PKD).

Figure 1a

Figure 1b

Figure 2a

Figure 2b

Figure 3a

Figure 3b

Figure 4a

Figure 4b

Long-Term Outcomes and Prognostic Factors in Kidney ......Dec 04, 2020 · Polycystic kidney...

Documents

Transcript of Long-Term Outcomes and Prognostic Factors in Kidney ......Dec 04, 2020 · Polycystic kidney...