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linical Implications of Proteinuria in Renal Transplant Recipientswitching to Rapamycin for Chronic Allograft Dysfunction

.J. Gutiérrez, E. González, A. Andrés, and J.M. Morales

ABSTRACT

There is evidence that treatment with m-TOR inhibitors can be beneficial in cases of chronicrenal allograft dysfunction. However, some authors have reported poor outcomes of renalfunction if the switch to m-TOR inhibitors is made in the presence proteinuria � 0.8 g/d. Thepresent study sought to provide a retrospective analysis of the clinical outcome of 63 kidneyrecipients diagnosed with chronic allograft dysfunction whose therapy was converted torapamycin including 35 subjects with renal biopsy-proven chronic allograft nephropathy. At thetime of conversion, patients were divided into three groups: group I (negative proteinuria),group II (proteinuria between 0.3 and 0.8 g/d), and group III (proteinuria � 0.8 g/d). Onconversion, 21 recipients had no proteinuria (group I). After a follow-up of 24.6 � 12.8months, they showed a significant improvement in renal function (previous MDRD4 � 39.9 �11.5 mL/m/1.73 m2, current MDRD4 50.3 � 13.3 mL/m/1.73 m2, P � .05). Fifteen patients(71.4%) developed proteinuria, which was generally mild (0.8 � 0.7 g/d) and controlled withangiotensin-converting enzyme inhibitors (42.8%). In group II (n � 18), renal function clearlystabilized after a follow-up of 23.2 � 14.4 months (previous MDRD4 � 30 � 8.8 mL/m/1.73m2, current MDRD4 � 37 � 12.2 mL/m/1.73 m2, NS), although there was a progressivedeterioration of previous proteinuria levels (previous proteinuria 0.4 � 0.15 g/d, currentproteinuria 1.2 � 2 g/d, P � .05), which was more frequent and intense in patients whosetreatment with calcineurin inhibitors (CNIs) was suspended (with CNI 0.9 � 1.7 g/d, withoutCNI 1.6 � 2.2 g/d, P � .05). Group III (n � 24) had a greater degree of renal insufficiency anda worse outcome after 25.9 � 18 months of follow-up, with a frank and progressivedeterioration in renal function (previous MDRD4 � 38 � 17 mL/m/1.73 m2, currentMDRD4 � 32.5 � 19.2 mL/m/1.73 m2, P � .05) and proteinuria (previous proteinuria � 1.5 �0.7 g/d, current proteinuria � 2.5 � 2.2 g/d, P � .05) after conversion. Again, the deteriorationin proteinuria was more intense in the patients whose previous CNIs were suspended (withCNI � 1.1 � 0.9 g/d, without CNI � 4.2 � 2.3 g/d, P � .05). In conclusion, for patients withchronic allograft dysfunction who do not present with proteinuria or whose proteinuria isless than 0.8 mg/d, switching to rapamycin is useful, since it clearly improves or stabilizesrenal function, although there may be a discrete increase in proteinuria in the second case.However, among patients with proteinuria greater than 0.8 mg/d accompanied by a greaterdegree of renal insufficiency, conversion to rapamycin leads to deterioration of proteinurialevels and renal function. These data show that conversion to rapamycin in cases of chronicallograft dysfunction must be made early when there is no proteinuria or it is minimal, and

that proteinuria is a predictor of the outcome of allograft function.

From the Nephrology Department, Hospital 12 de Octubre,adrid, Spain.

pital 12 de Octubre, Unidad de Transplante Renal, Departa-mento de Nefrologı́a, Carretera de Andalucia, Km 5.4, 28041

Address reprint requests to José Maria Morales, MD, Hos- Madrid, Spain. E-mail: jmorales@h12o.es

041-1345/09/$–see front matter © 2009 Published by Elsevier Inc.oi:10.1016/j.transproceed.2009.06.163 360 Park Avenue South, New York, NY 10010-1710

348 Transplantation Proceedings, 41, 2348–2350 (2009)

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CLINICAL IMPLICATIONS OF PROTEINURIA 2349

HRONIC ALLOGRAFT NEPHROPATHY is themost frequent cause of graft loss during the first year

fter transplantation (not counting patient death with aunctioning graft).1 The development of chronic allograftephropathy is affected by immunologic and nonimmuno-

ogic factors including nephrotoxicity induced by cal-ineurin inhibitors (CNIs), such as cyclosporine and tacroli-us, which is the most important identifiable factor in the

athogenesis of chronic allograft nephropathy. Sirolimusas immunosuppressive and antiproliferative propertiesithout being nephrotoxic. Reducing or suspending treat-ent with CNIs after converting to sirolimus has been

eported to be a possible therapeutic alternative for pa-ients with chronic allograft nephropathy. Multicenter stud-es have shown beneficial effects of discontinuing cyclospor-ne or tacrolimus in terms of improved renal functionmong transplant recipients who de novo were adminis-ered cyclosporine � sirolimus � low doses of corticoste-oids.2–5 Various authors have shown beneficial effects,afety, and efficacy of discontinuing CNIs with introductionf sirolimus among patients with chronic allograft nephrop-thy.6 However, other workers have described poor out-omes in renal function after conversion to sirolimus in theedium term6 and long term7 among patients whose chronic

llograft nephropathy was accompanied by proteinuria-reater than 0.8 g/d. These findings suggested that protein-ria is a predictor of renal functional outcome after con-ersion with a positive predictive value of 90%.7,8

The objective of our study was to retrospectively evaluatehe outcome of renal function and graft survival among aopulation with chronic allograft dysfunction after startingreatment with sirolimus seeking to reduce or discontinueNI treatment. We also studied baseline levels of protein-ria as a predictor of favorable outcomes after a change in

mmunosuppressive therapy.

ATERIALS AND METHODS

rom February 1999 to June 2008, 78 stable transplant recipientsncluding 79.5% men with an overall mean age of 49.5 � 15 yearsisplayed chronic allograft dysfunction as evidenced by renaliopsy on 35 patients (44.8%) showing chronic allograft nephrop-thy and 22 (28.2%), CNI-induced nephrotoxicity. The mean timerom transplantation to initiation of sirolimus was 76.5 � 64.7onths. The dose of CNI was reduced to 50% when sirolimus was

nitiated with doses adjusted according to levels. We divided theatients into three groups at the time of conversion: group I, with

Table 1. Proteinuria and R

PreviousCreatinine(mg/dL)

CurrentCreatinine(mg/dL) P

roup I, negative proteinuria (n � 21) 2.1 � 1.3 1.9 � 0.8 .05roup II, proteinuria 0.3–0.8 g/d(n � 18)

2.5 � 1 2.4 � 1.6 NS

roup III, proteinuria � 0.8 g/d(n � 24)

2.3 � 0.7 3.4 � 1.7 .05

MDRD, modification of diet in renal disease.

egative proteinuria; group II, with proteinuria 0.3 to 0.8 g/d; androup III, with proteinuria � 0.8 g/d.

ESULTS

e discontinued sirolimus in 15 (19.2%) patients forarious reasons: 8 (10.3%) patients showed acute deterio-ation of renal function including acute rejection, biopsyroven in 3; 3 (3.8%) patients with diarrhea; 3 (3.8%),evere edema; 3 (3.8%), severe pancytopenia; 2 (2.6%),ever; and 1 (1.3%), serositis.

The remaining 63 transplant recipients continued siroli-us for a mean follow-up of 24.7 � 15.2 months; they were

ncluded in the analysis. CNIs were discontinued in 3149.2%) subjects.

At the time of conversion, 21 patients who star-ed sirolimus had negative proteinuria (group I). After aollow-up of 24.6 � 12.8 months, their renal function wasxcellent and the improvement significant. However, 1571.4%) patients developed proteinuria, which was gener-lly mild and well controlled with angiotensin-convertingnzyme (ACE) inhibitors (42.8%). Despite the favorableutcome, two patients lost their allografts due to chronicephropathy and three patients with functioning grafts diedf cardiovascular causes. If patient deaths with functioningrafts are excluded, the survival was 90.4% (Table 1).

Eighteen patients started sirolimus with proteinuria at 0.3o 0.8 g/d (group II). After conversion, renal functionlearly stabilized even the renal function was numericallyigher in the sirolimus group. After a follow-up of 23.2 �4.4 months, they were stable despite the presence ofdvanced renal insufficiency before the change. However,roteinuria did not significantly increase and when thereas a change it was controlled with ACE inhibitors (44.4%).hree patients lost their renal allografts due to chronicephropathy; one died of cardiovascular causes. If patienteaths with functioning grafts are excluded, graft survivalas 83.3% (Table 1).Twenty-four patients started sirolimus in the presence of

roteinuria � 0.8 g/d before conversion (group III). After aollow-up of 25.9 � 18 months, we observed poor renalunction (with significant deterioration) with gradual wors-ning of baseline levels of proteinuria, despite treatmentith ACE inhibitors in 54.2% of patients. Five patients lost

heir grafts due to chronic allograft nephropathy. Thereere three deaths: two cardiovascular and one infection. If

Function With Sirolimus

vious MDRD4L/m/1.73 m2)

Current MDRD4(mL/m/1.73 m2) P

PreviousProteinuria

(g/d)

CurrentProteinuria

(g/d) P

9.9 � 11.5 50.3 � 13.3 .05 0.13 � 0.08 0.8 � 0.7 .0530 � 8.8 37 � 12.2 NS 0.4 � 1.5 1.2 � 2 .05

38 � 17 32.5 � 19.8 .05 1.5 � 0.74 2.5 � 2.2 .05

enal

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2350 GUTIÉRREZ, GONZÁLEZ, ANDRÉS ET AL

he patient deaths with functioning grafts are excluded, theurvival was 79.1% (Table 1).

In the three groups, we observed significant worsening ofaseline proteinuria values in patients whose CNIs wereuspended compared with those who maintained low doses ofNIs, irrespective of baseline proteinuria. Only 50% of pa-

ients with negative proteinuria values on starting sirolimusgroup I) and maintained on low doses of CNIs developedroteinuria compared with 85% of those whose CNI had beenuspended (P � .05). The increase in proteinuria was generallyreater when the baseline values were higher. We observed noifferences in the outcomes of renal function among the threeroups between patients who maintained CNIs at low dosesersus those who suspended CNIs. Logically, there wereifferences in the drug levels (Table 2).

ISCUSSION

e showed that conversion to sirolimus for patients withhronic allograft dysfunction and no or minimal proteinuriat the time of conversion significantly improved or stabi-ized renal function, although it did not stop the deteriora-ion of graft function when proteinuria levels were high�0.8 g/d). In other words, the risk of graft loss was greatern patients with higher levels of proteinuria before conver-ion; therefore, proteinuria was a prognostic marker oforsening of renal function.CNI withdrawal after sirolimus conversion among pa-

Table 2. Proteinuria With and Without CNIs After SirolimusTherapy

PreviousProteinuria (g/d)

CurrentProteinuria (g/d) P

roup I (n � 21)With CNI (n � 8)

Tac: 6 � 3.3 ng/mL 0.14 � 0.1 0.7 � 0.8 NSSirolimus: 5.3 � 2.5 ng/mL

Suspension CNI (n � 13)Sirolimus: 9.1 � 3.3 ng/mL 0.13 � 0.1 0.8 � 0.6 .02

roup II (n � 18)With CNI (n � 10)

Tac: 4.2 � 1.3 ng/mL 0.4 � 0.1 0.9 � 1.7 NSSirolimus: 5.1 � 2 ng/mL

Suspension CNI (n � 8)Sirolimus: 6.4 � 1.2 ng/mL 0.5 � 0.1 1.6 � 2.2 .05

roup III (n � 24)With CNI (n � 14)

Tac: 4.3 � 1.6 ng/mL 1.2 � 0.3 1.1 � 0.9 NSSirolimus: 5.5 � 2.5 ng/mL

Suspension CNI (n � 10)Sirolimus: 7.4 � 3.5 ng/mL 1.9 � 0.9 4.2 � 2.3 .01

CNI, calcineurin inhibitors; NS, not significant; SRL, sirolimus; Tac, tacroli-us.

ients with chronic allograft nephropathy was accompanied by fi

nset of proteinuria or increased proteinuria levels. Theseata suggested that previous renal structural damage wasxacerbated by loss of the vasoconstrictive effects of CNIs.

Our study confirmed previous findings by Bumbea et al4

nd by Diekmann et al,7,8 the absence of proteinuria thatas associated with good outcomes after conversion from a

egimen based on CNI to sirolimus. They identified pro-einuria values as predictive of outcomes after conversion.

The main limitations of our study were its retrospectiveharacter, the small sample size, and the absence of a controlroup. Nevertheless, this study may identify patients whoould benefit in the short or medium term from suspension oreduction of CNI doses after conversion to sirolimus.

In conclusion, patients with chronic allograft nephropa-hy who do not present with proteinuria, or display protein-ria less than 0.8 mg/d, may benefit from a switch toapamycin, since it clearly improves/stabilizes renal func-ion, although there may be a discrete, nonsignificantncrease in proteinuria among the latter group. Neverthe-ess, if baseline proteinuria is greater than 0.8 g/d conver-ion to rapamycin is accompanied by deterioration ofroteinuria and of renal function. These data showed thatonversion to rapamycin in cases of chronic allograft ne-hropathy must be made early, when there is no proteinuriar when it is minimal, and that proteinuria is a predictor ofutcomes of graft function.

EFERENCES

1. Pascual M, Theruvath T, Kawai T, et al: Strategies to improveong-term outcomes after renal transplantation. N Engl J Med46:580, 20022. Johnson RWG, Kreis H, Oberbauer R, et al: Sirolimus allows

arly cyclosporine withdrawal in renal transplantation resulting inmproved renal function and lower blood pressure. Transplantation2:777, 20013. Watson CJE, Firth J, Williams PF, et al: A randomized

ontrolled trial of late conversion from CNI-based to sirolimus-ased immunosuppression following renal transplantation. Am Jransplant 5:2496, 20054. Bumbea V, Kamar N, Ribes D, et al: Long-term results in

enal transplant patients with allograft dysfunction after switchingrom calcineurin inhibitors to sirolimus. Nephrol Dial Transplant0:2517, 20055. Morales JM, Grinyó JM, Campistol JM, et al: Improve renal

unction, with similar proteinuria, after three years of early tacróli-us withdrawal from a regimen of sirolimus plus tacrolimus.ransplantation 86:620, 20086. Citterlo F, Scatà MC, Violi P, et al: Rapid conversion to

irolimus for chronic progressive deterioration of the renal func-ion in kidney allograft recipients. Transplant Proc 35:1292, 2003

7. Diekmann F, Budde K, Oppenheimer F, et al: Predictors ofuccess in conversion from calcineurin inhibitor to sirolimus inhronic allograft dysfunction. Am J Transplant 4:1869, 2004

8. Diekmann F, Budde K, Slowinski T, et al: Conversion toirolimus for chronic allograft dysfunction: long-term results con-

rm predictive value of proteinuria. Transpl Int 21:152, 2008