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Keywords:

  • Arterial pressure;
  • graft survival;
  • proteinuria;
  • renal transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low-grade (<1 g/24 h) proteinuria earlier after transplantation and its short-term change affect long-term graft survival. The effects of proteinuria and its change on long-term graft survival were retrospectively assessed in 484 renal transplant recipients. One- and 3-month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One- and 3-month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p < 0.0001)—especially low-grade proteinuria (HR: 1.20 and 1.26, p < 0.0001)—were powerful, independent predictors of graft loss. Its short-term reduction correlated with arterial pressure (AP) (the lower the 3-month diastolic and 12-month systolic AP, the lower the risk of increasing proteinuria during 1–3 months and 3–12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p = 0.01 and 0.85, respectively, p = 0.02), and was associated with decreased long-term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p < 0.0001), independently of initial proteinuria. Early low-grade proteinuria due to pre-transplant renal lesions, ischemia-reperfusion and immunologic injuries is a potent predictor of graft loss. Short-term reduction in proteinuria is associated with improved long-term graft survival.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Proteinuria is an indicator of renal lesions and a risk factor for subsequent renal function decline in most nephropathies (1–3). However, recent in vitro and clinical studies in non-transplanted patients demonstrated that proteinuria is a modifiable parameter that plays an active role in the progression of renal disease (3,4), and that short-term reduction in proteinuria provides nephroprotection in many nephropathies (1,5,6). In effect, proteinuria is a trigger for the production of substances associated with the development of fibrogenesis and glomerulosclerosis (3,4). Moreover, short-term (1–3 months) change in proteinuria was a strong predictor of long-term renal outcome in diabetic (5) and non-diabetic (6–10) proteinuric patients.

Proteinuria (especially low-grade proteinuria defined as proteinuria <1 g/day) is observed in many patients within the first month following transplantation. Although proteinuria 1 year after transplantation was associated with poor renal outcome in renal transplantation in the few papers focused on this issue (10–14), it is generally believed that small amounts of proteinuria following transplantation are harmless. Low-grade proteinuria is often referred as ‘subclinical’ or ‘negligible,’ and only persistent proteinuria >0.5–1.0 g/day for at least 3–6 months is considered significant according to the American Society of Transplantation (15). The possible role of low-grade proteinuria seems to have been largely neglected despite the recent observation of its important role in diabetic and non-diabetic nephropathies (1,5,6).

In marked contrast, elevated serum creatinine at 1 year is considered as one of the major predictors of long-term graft survival in the transplant community (16,17). Nevertheless, elevated serum creatinine and proteinuria often coexist, so that it is possible that the effects of elevated creatinine on graft survival may be due, at least in part, to proteinuria. The respective effects of proteinuria and renal function on graft survival have not been elucidated (14,16,17).

Moreover, it is now acknowledged that histologic evidence of chronic allograft rejection may exist as early as 3 months after renal transplantation (18). Consequently, relevant prognostic markers should not be assessed 1 year after transplantation but much earlier. However, the roles of early low-grade proteinuria and its change as predictors of graft loss have not been specifically evaluated in renal transplantation.

In the present study, we assessed the influence of early (as early as 1 month after transplantation) low-grade proteinuria and its change within the first year on long-term (up to 15 years) renal graft survival.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Patient characteristics

Among 641 patients grafted in Tours between 1987 and 2001 and followed in Tours' University Hospitals, 484 were treated using the immunosuppressive protocol of our institution. All of them are included in the present study.

Our institution's immunosuppressive regimen included antithymocyte globulin (Thymoglobulin®, Sangstat, France) given for the first 10 days and monitored by blood T-lymphocyte counts; prednisone at 1 mg/kg/day for the first two weeks was then progressively decreased and finally withdrawn within the first year after transplantation; azathioprine from 1987 to 1996 (started at 2.5 mg/kg/day and adjusted subsequently according to white blood cells counts) or MMF thereafter (started at 2 g/day); anti-calcineurin drugs (mainly cyclosporine) were then added when serum creatinine was <250 μmol/L. The initial dose of cyclosporine was intended to obtain 150–250 ng/mL trough levels for the first 12 months and 100–150 ng/mL trough levels thereafter. Microemulsion cyclosporine was used from May 1996. No patient was treated with sirolimus in this cohort.

Steroids were withdrawn during the first year following transplantation (3–12 months, median 7 months) in 223 patients who had functioning renal grafts during the first 3 months after transplantation, panel reactive antibody (PRA) less than 70%, no vasculitis or systemic lupus erythematosus, no history of steroid resistant rejection and no loss of a first graft due to an immunological cause.

All our patients had a thorough evaluation at 1, 3 and 12 months following transplantation. Creatinine clearance on a 24-h urine collection was measured at 12 months in 354 of 484 (73.1%) patients: Proteinuria was also expressed as urinary protein/creatinine ratio in these patients.

Proteinuria was measured using the pyrogallol method (19). Coefficients of variation for the method were 4.8%, 1.9% and 1.7% for low, medium and high concentrations, respectively. The lowest detectable level is 0.007 g/L.

Transplant renal artery stenosis was systematically ruled out by Doppler sonogram (20). Systolic and diastolic arterial pressures were measured after 15 min of rest in subjects in a supine position with a sphygmomanometer adapted for arm size. Hypertension was defined according to the JNC VII report (21).

Delayed graft function (DGF) was defined as the need for dialysis during the first week following transplantation.

The patients were followed up in our institution, and the median follow-up period was 7.2 years (range: 0.4–15.4 years).

Statistical analyses

Results were expressed in means, standard deviations and proportions. Medians were presented when the distribution of the parameter was not normal. Proportions were compared using chi square or exact Fischer's test as appropriate.

Linear regression analysis was performed to evaluate the association between proteinuria as a continuous variable and relevant parameters. Logistic regression was performed to estimate the association between proteinuria as a categorical variable (proteinuria defined as any levels of proteinuria >0 g/24h) and relevant parameters. Logistic regression was also performed to assess whether short-term proteinuria as a categorical variable (three categories according to the change in proteinuria during 1–3 months and 3–12 months periods: decrease ≥0.2 g/day, increase ≥0.2 g/day, stable defined as a change <0.2 g/day) was associated with arterial pressure. Kruskal-Wallis test was used to compare proteinuria levels according to the number of acute rejection episodes.

Graft survival rates were computed using the Kaplan-Meier method, and curves were compared using the Log-Rank test. Cox models were used to identify parameters associated with graft loss during follow-up; parameters entered into the multivariate models were the variables significantly associated with graft loss in the univariate analyses: proteinuria and the short-term change in proteinuria and serum creatinine >130 μmol/L (yes vs. no), systolic arterial pressure (model 1); parameters included in model 1 and the number of acute rejection episodes, number of graft, maximum PRA (model 2); parameters included in model 1 and model 2 and delayed graft function (yes vs. no), warm ischemia time as a continuous variable. Other relevant parameters such as cold ischemia time, total HLA mismatch, donor age >60 years, DR HLA mismatch, type and dose of calcineurin inhibitors and CMV disease were not significantly associated with graft loss in the univariate analyses.

The analyses regarding the association between the use of anti-hypertensive drugs and proteinuria, and the potential role of anti-hypertensive drugs on graft survival could not be adequately performed: too many drug modifications occurred during the first year, and there was an obvious indication bias (i.e. patients with proteinuria were more prone to receive ACEI/ARB than other patients; however, ACEI/ARB were also prescribed for other reasons).

Analyses were performed using SAS (SAS Institute, Inc., Cary, NC, USA). A p-value <0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Baseline characteristics

As shown in Table 1, recipient age was 44.4 ± 13.6, and 302 of 484 (62%) patients were male. Most patients were Caucasians (98.3%). It was a first graft in 87.2% patients, and diabetes mellitus was present in 8.1%.

Table 1.  Characteristics of the study population
Donor
Age, yr38.5 ±14.1
Gender, M/F300/184
Cause of death: cardiovascular disease,%54.8
Recipient
Age, yr44.4 ± 13.6
Sex, M/F302/182
First graft,%87.2
Second graft,%12.4
Third graft,%0.4
Panel reactive antibody >50%,%11%
HLA-mismatch4.0 ± 1.1
Delayed graft function,%24.3
Maintenance immunosuppression,%
 Cyclosporine + azathioprine56.6
 Cyclosporine + MMF23.4
 Tacrolimus + MMF5.8
 Others14.2
Diabetes mellitus,%8.1
Number of anti-hypertensive medications at 3 months following transplantation
 None21.8
 One39.8
 Two32.7
 Three5.7
Hypertension at 3 months following transplantation, %87.2
Anti-hypertensive medications at 3 months following transplantation, %
 Converting-enzyme inhibitors or ARB7.3
 Calcium-channel blockers64.5
 Beta-blockers47.4
 Diuretics4.1

At 3 months, cyclosporine combined with azathioprine was used in 56.6% whereas cyclosporine was combined with MMF in 23.4%. Serum creatinine was 136 ± 65 μmol/L, and elevated (>130 μmol/L) creatinine was present in 41.6%. The respective figures were 153 ± 103 μmol/L and 50.8% at 1 month.

Systolic, diastolic and mean arterial pressures at 3 months were 142.8 ± 17.1, 82.0 ± 11.3 and 102.3 ± 11.5 MmHg, respectively. The respective values were 140.4 ± 17.5, 82.6 ± 10.1 and 101.9 ± 11.0 MmHg at 1 month.

Risk factors for graft loss

During follow-up, 98 grafts were lost. The cause of graft loss was chronic allograft rejection in most patients (usually confirmed by biopsy); although it was sometimes difficult to differentiate it from calcineurin inhibitors toxicity; recurrence of disease was rare.

The results of the univariate analysis (Table 2) indicated that the number of acute rejection episodes, the number of previous grafts, maximum PRA, warm ischemia time, delayed graft function, serum creatinine at 1 and 3 months, systolic arterial pressure and pulse pressure at 3 months were significantly associated with long-term graft loss during follow-up.

Table 2.  Predictors of graft loss (univariate analysis)
 Hazard ratio95% CI p-value
Number of acute rejection episodes (vs. 0)1.811.39–2.340.0001
Number of graft (vs. first graft)1.590.99–2.570.06
Maximum PRA (per 10% rise)1.081.02–1.150.01
Delayed graft function (yes vs. no)1.741.14–2.660.01
Warm ischemia time (per 10 min)1.121.02–1.230.01
Cold ischemia time >24 h (yes vs. no)1.210.69–2.140.51
Total HLA mismatch (per unit)1.140.83–1.550.41
Donor age > 60 (yes vs. no)1.820.74–4.490.19
At 1 month
Serum creatinine (per 10 μmol/L)1.061.05–1.070.0001
Serum creatinine > 130 μmol/L1.991.28–3.120.002
Systolic arterial pressure (per 10 MmHg)1.030.91–1.180.62
Diastolic arterial pressure (per 10 MmHg)1.050.86–1.390.58
Mean arterial pressure (per 10 MmHg)1.000.99–1.010.90
Pulse pressure (per 10 MmHg)1.070.93–1.230.33
At 3 months
Serum creatinine (per 10 μmol/L)1.111.09–1.140.0001
Serum creatinine >130 μmol/L2.301.43–3.690.0006
Systolic arterial pressure (per 10 MmHg)1.151.01–1.310.03
Diastolic arterial pressure (per 10 MmHg)1.100.86–1.390.45
Mean arterial pressure (per 10 MmHg)1.190.96–1.480.11
Pulse pressure (per 10 MmHg)1.161.00–1.350.05

No association was found between the type or the number of anti-hypertensive medications used (either at 1 or 3 months) and the long-term risk of graft loss. However, as stated earlier, anti-hypertensive medications were changed many times within the first 12 months following transplantation, so that it was impossible to take all these modifications into account.

Proteinuria and graft survival (univariate analysis)

Determinants of proteinuria:  Overall, only 4, 1, 1 and 0 patients had missing proteinuria values at 1, 3, 6 and 12 months after transplantation, respectively. Proteinuria values are shown in Table 3. Overall, 36.4% and 35.2% patients had proteinuria 1 and 3 months after transplantation, respectively; most of these patients had low-grade (<1 g/day) proteinuria.

Table 3.  Proteinuria levels within the first year following transplantation
  Mean ± SD (g/day) Patients with proteinuria, n (%)Range (g/day) (in patients with proteinuria)Patients with proteinuria >1 g/day, n (%)
1 month0.22 ± 0.53168 (36.4)0.05–5.622 (13.1)
3 months0.19 ± 0.42159 (35.2)0.05–4.020 (12.6)
6 months0.31 ± 1.14161 (36.3)0.03–12.7220 (12.4)
12 months0.22 ± 0.53142 (32.6)0.05–16.0429 (20.4)

Proteinuria and serum creatinine were significantly associated at 1 month (r2= 0.12, p < 0.0001), 3 months (r2= 0.18, p < 0.0001) and 12 months (r2= 0.09, p < 0.0001). Proteinuria at 3 months tended to be more abundant in patients who experienced 1 or more acute rejection episodes (for 0, 1, 2 and 3 acute rejection episodes: 0.19 ± 0.42, 0.15 ± 0.35, 0.42 ± 0.70 and 0.47 ± 0.70 g/day, respectively, p = 0.06), and this was more evident in those with two or more rejection episodes at 3 months (0.42 ± 0.68 vs. 0.18 ± 0.39 g/day, p = 0.02) and 6 months (0.44 ± 0.90 vs. 0.23 ± 0.84 g/day, p = 0.03).

As shown in Table 4, significant parameters associated with proteinuria (as a categorical variable) were donor age >60 years, prolonged warm and cold ischemia times and cardiovascular origin of donor death; the relationship was weaker with DGF. There was no association with the cause of renal disease.

Table 4.  Determinants of proteinuria (univariate analysis)
 At 1 monthAt 3 months
OR95% CIp-valuesOR95% CIp-values
Donor age >60 (yes vs. no)4.431.61–14.130.0034.702.10–14.650.002
Donor cardiovascular death (yes vs. no)1.981.20–3.140.0021.721.39–3.670.01
Warm ischemia time >60 min (yes vs. no)2.231.39–3.660.0011.660.99–2.620.04
Cold ischemia time >24 h (yes vs. no)1.771.17–2.730.0061.771.16–2.750.008
Delayed graft function (yes vs. no)1.210.97–1.510.091.200.96–1.510.11

No relationship was found between cyclosporine levels and proteinuria at 1, 3 and 12 months. The agreement between 24-h proteinuria and protein/creatinine ratio at 12 months was very high (r2= 0.81, p < 0.0001).

Effect of proteinuria on graft survival:  Patients with 3-month proteinuria had a significantly lower 15-year actuarial death-censored graft survival rate than the others (51.0% vs. 80.5%, p < 0.0001). The results were similar when 1-month proteinuria (59.9% vs. 82.2%, p < 0.0001) was considered.

As shown in Table 5, proteinuria as a continuous variable at 1, 3, 6 and 12 months was a powerful predictor of renal outcome. Similar results were found when urinary protein/creatinine ratio (HR per 1 g/g: 1.57 [95%CI: 1.37–1.81], p < 0.0001) was considered. Moreover, the risk of graft loss associated with proteinuria seemed as strong or even stronger in patients with low-grade (<1g/24h) proteinuria than in the whole population: each 0.1 g/24h difference in proteinuria increased the risk of graft loss by 25% in patients with low-grade proteinuria and by 15% in the whole population; however, the difference between these two hazard ratios was not significant.

Table 5.  Proteinuria and the risk of graft loss (univariate analysis)
 All subjectsSubjects with proteinuria < 1 g/day
Hazard ratio95% CI p-valuesHazard ratio95% CI p-values
  1. Hazard ratios were calculated per 0.1 g(24 h of proteinuria.

Proteinuria at 1 month1.071.05–1.090.00011.201.10–1.310.0001
Proteinuria at 3 months1.151.11–1.180.00011.261.15–1.380.0001
Proteinuria at 6 months1.031.01–1.040.00031.221.09–1.370.0004
Proteinuria at 12 months1.021.01–1.030.00011.251.11–1.410.0002

This was true in patients with proteinuria <0.5 g/day (HR per 0.1 g/day at 1 and 3 months after transplantation: 1.24 [1.05–1.45], p = 0.01 and 1.31 [1.08–1.60], p = 0.006, respectively, as compared to HR: 1.04 [1.01–1.07], p = 0.005 and 1.10 [1.04–1.17], p = 0.0002, respectively, in patients with proteinuria ≥0.50 g/day). Similar results were found when patients with proteinuria <0.15 g/day were excluded from the analysis: HR per 0.1 g/day: 1.05 [1.03–1.08], p < 0.0001 and 1.12 [1.08–1.17], p < 0.0001 at 1 and 3 months after transplantation, respectively (Figure 1).

image

Figure 1. Effect of early low-grade proteinuria on long-term death-censored graft survival.

Download figure to PowerPoint

Proteinuria was a similar risk factor in patients who stopped steroids during follow-up and in those who did not (HR per 0.1 g/day: 1.12 [1.09–1.13], p < 0.0001 and 1.19 [1.10–1.30], respectively, both p < 0.0001). The effect of proteinuria on graft survival was not influenced by the immunosuppression regimen used (cyclosporine, tacrolimus, MMF or azathioprine).

Short-term change in proteinuria and graft survival

Determinants of short-term change in proteinuria:  Among patients with proteinuria at 1 month, 72.5% had proteinuria at 3 months whereas among those without, 14.3% developed proteinuria at 3 months. For the 3- to 12-month period, the respective figures were 66.2% and 9.7%.

ARB or ACEI were increasingly prescribed with time: 1.7% at 1 month, 6.5% at 3 months and 20.9% at 12 months. As stated earlier, the relationship between the use of anti-hypertensive drugs and proteinuria could not be adequately assessed.

Univariate analysis indicated that achieved arterial pressure values at 3 and 12 months influenced the short-term change in proteinuria: the lower the diastolic arterial pressure at 3 months, the lower the risk of increasing proteinuria during 1–3 month period (as a categorical variable: three categories: increase ≥0.2 g/day, stable as defined as a change <0.2 g/day, decrease ≥0.2 g/day): OR per 10 MmHg: 0.78 [0.63–0.95], p = 0.01. Similarly, the lower the systolic arterial pressure at 12 months and the greater the decrease in systolic arterial pressure from 3 to 12 months, the lower the risk of increasing proteinuria during 3–12 month period (as a categorical variable): OR per 10 MmHg: 0.85 [0.75–0.96], p = 0.009 and 0.87 [0.78–0.98], p = 0.02, respectively. Of note, serum creatinine >130 μmol/L at 1 and 3 months were not associated with the short-term changes in proteinuria (OR: 1.45 [0.96–2.18], p = 0.08 and 1.13 [0.73–1.76], p = 0.56 at 1 and 3 months, respectively).

After adjustment for initial proteinuria, we found that increase in proteinuria from 1 to 3 months was associated to donor cardiovascular death (F = 4.22, p = 0.04, serum creatinine (+0.008 ± 0.002 g/day/μmol, p = 0.003) and donor age (+0.02 ± 0.01 g/day/year, p = 0.06); parameters associated with increase in proteinuria from 3 to 12 months were hypertension at 3 months (F = 2.97, p = 0.08) and delayed graft function (F = 8.80, p = 0.003).

Effect of short-term change in proteinuria on graft survival:  The univariate analysis indicated that short-term changes in proteinuria modulated long-term graft survival: the greater the short-term decrease in proteinuria the lower the long-term risk of graft loss (for each 0.1 g/24h proteinuria reduction during 1–3 and the 3–12 months period: HR: 0.88 [0.71–0.99], p = 0.04 and HR: 0.98 [0.97–0.99], p < 0.0001, respectively). The short-term reduction in proteinuria led to a similar lowering in the risk of graft loss in patients with low-grade (<1 g/24h) proteinuria (for each 0.1 g/24h reduction in proteinuria during 1–3 and 3–12 months periods: HR: 0.87 [0.84–0.91] and 0.92 [0.90–0.95], respectively, both p < 0.0001).

Inversely, the greater the short-term increase in proteinuria the higher the long-term risk of graft loss (for each 0.1 g/24h proteinuria increment during 1–3 and the 3–12 months periods) (HR: 1.02 [1.01–1.03], p < 0.0001 and 1.07 [1.01–1.14], p = 0.04, respectively).

As shown in Table 6, several models were computed for the multivariate analyses, both at 1 and 3 months following transplantation. Proteinuria and short-term reduction in proteinuria were strong independent predictors of graft loss, regardless of the models used and covariables entered into the models. Moreover, point estimates of the hazard ratios associated with proteinuria and its change were unaffected by multiple adjustments.

Table 6.  Proteinuria and short-term decrease in proteinuria as predictors of graft loss
 At 1 monthAt 3 months
Hazard ratio95% CIp-valueHazard ratio95% CIp-value
  1. *Denotes decrease in proteinuria during 1–3 month period when proteinuria at 1 month was considered, and during 3–12 month period when proteinuria at 3 months was considered.

Model 1
Proteinuria (per 0.1 g/day)1.151.11–1.190.00011.161.11–1.210.0001
Short-term decrease in proteinuria* (per 0.1g/day)0.880.84–0.910.00010.990.97–0.990.01
Serum creatinine >130 μmol/L (yes vs. no)1.620.98–2.690.061.490.87–2.550.14
Systolic arterial pressure (per 10 MmHg)1.080.91–1.240.281.060.91–1.240.47
Model 2
Proteinuria (per 0.1 g/day)1.141.10–1.190.00011.161.10–1.210.0001
Short-term decrease in proteinuria* (per 0.1 g/day)0.880.84–0.910.00010.980.97–0.990.006
Serum creatinine >130 μmol/L (yes vs. no)1.570.88–2.810.131.380.74–2.570.31
Systolic arterial pressure (per 10 MmHg)1.060.90–1.240.471.000.84–1.210.97
Number of acute rejection episodes (vs. 0)1.981.44–2.710.00011.811.39–2.340.0001
Number of graft (vs. first graft)0.890.38–2.120.790.530.28–1.910.74
Maximum PRA (per 10% rise)1.040.94–1.160.451.050.94–1.170.39
 0.84–0.91 
Model 3
Proteinuria (per 0.1 g/day)1.151.10–1.200.00011.151.10–1.210.0001
Short-term decrease in proteinuria* (per 0.1 g/day)0.880.84–0.930.00010.980.96–0.990.004
Serum creatinine >130 μmol/L (yes vs. no)1.570.84–2.920.161.400.72–2.730.32
Systolic arterial pressure (per 10 MmHg)1.060.89–1.270.491.020.84–1.240.83
Number of acute rejection episodes (vs. 0)2.151.52–3.030.00012.521.74–2.640.0001
Number of graft (vs. first graft)0.770.29–2.040.590.560.19–1.670.30
Maximum PRA (per 10% rise)1.060.93–1.190.421.060.93–1.210.36
Delayed graft function (yes vs. no)0.890.42–1.880.751.000.44–2.290.99
Warm ischemia time (per 10 min)1.000.99–1.020.710.990.82–1.210.95

Although patients with higher baseline proteinuria had a greater short-term decrease in proteinuria, the results were unchanged when both parameters and the interaction between proteinuria and short-change in proteinuria were entered into the models. At 1 month, for proteinuria, short-term increase in proteinuria and interaction the HR were 1.19 ([1.12–1.25], p < 0.0001), 1.13 ([1.08–1.17], p < 0.0001) and 1.01 ([0.99–1.04], p = 0.24), respectively. The HR values at 3 months were 1.14 ([1.09–1.19], p < 0.0001), 1.04 ([1.01–1.07], p = 0.02) and 0.75 ([0.51–1.11], p = 0.15), respectively.

In contrast, high serum creatinine was no longer significantly associated with graft loss when proteinuria and short-term change in proteinuria were entered into the model (Table 6).

In all models used, the number of acute rejection episodes remained a powerful predictor of graft loss.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The results of the present study indicate that early low-grade proteinuria and short-term reduction in proteinuria are independent powerful predictors of graft loss in renal transplantation, even after multiple adjustments. This was true as early as 1-month after transplantation.

Proteinuria was associated with donor age, cardiovascular cause of donor death, prolonged cold and warm ischemia times and acute rejection episodes. These findings suggest that proteinuria is the consequence of many factors including pre-transplant renal lesions, ischemia-reperfusion injury and immunologic aggression. Accordingly, we previously reported that microalbuminuria was more frequent (22), and others found that proteinuria was more abundant (14) in patients with a history of acute rejection. Moreover, proteinuria was indeed more frequent when donor age was 60 or more in two recent papers (14,23).

Interestingly, the estimate of the relative risk (expressed by the HR) of graft loss associated with proteinuria was similar in univariate and multivariate analyses, and seemed unmodified when the change in proteinuria was entered into the model, regardless of the period considered (1, 3, 6 or 12 months). Altogether, these findings suggest that early proteinuria may thus reflect the existence of renal lesions fixed to a great extent. However, short-term reduction in proteinuria was associated with improved long-term graft survival, probably because it blocks the proteinuria-induced progression of renal function decline. Proteinuria may reflect tubular or glomerular lesions, and it may indicate irreversible damage due to ischemia-reperfusion injury or donor renal lesions; in this view, proteinuria would thus be a marker of damage, but it would have an active role. However, it was demonstrated that proteinuria probably play a key role in the degradation of renal function. Some of the mechanisms that lead to the intrinsic toxicity of proteinuria were recently identified. Proximal tubular cells exposed to high plasma protein concentrations up-regulate NFκB, endothelin 1, MCP-1, RANTES and IL-8, which promote monocyte and lymphocyte recruitment into the renal interstitium (3,4). The activation and up-regulation of these very same substances (transcription factors, chemokines and hormones) may constitute the basis for chronic allograft rejection (CAN) (24). Recently, it was emphasized that chronic interstitial fibrosis plays a major role in the long-term deterioration of renal function in renal transplantation (25). The correlation between massive or significant (>1 g/day) proteinuria and renal histology has been the subject of several reports (26,27). In contrast, histopathology of low-grade proteinuria has not been specifically studied (17,25–27). Finally, it is presently unclear whether low-grade proteinuria represents an early presentation of chronic interstitial fibrosis or reflects the presence of CAN (25,28). It is unclear whether the origin of proteinuria in our study was tubular or glomerular. Analysis of correlation between proteinuria and histopathology findings in protocol renal biopsies should shed light on this issue (18).

Proteinuria is a potent risk factor for ESRD in non-transplanted patients (1,5,6,29), as it was in renal transplant recipients from our cohort. In a recent paper, proteinuria, both as categorical variable and a continuous variable, was a risk factor for graft loss (10). The risk of graft loss associated with proteinuria seemed linearly dependent upon its quantity, so it was thought that the risk associated with small amounts of proteinuria was quantitatively similar to that found with significant proteinuria. In contrast, we found that proteinuria was a risk for graft loss even for low-grade proteinuria, even in patients with proteinuria <0.5 g/day. In marked contrast, massive proteinuria was proportionally a stronger risk for further renal function decline than low-grade proteinuria in non-transplanted proteinuric patients (6). The present results indicate that it is crucial to reduce low-grade proteinuria in renal transplant recipients even more than it is in non-transplanted patients. It is also possible that even smaller amounts of protein excretion such as microalbuminuria constitute a risk in renal transplantation, as it is in diabetes mellitus (30). In addition, we found that urinary protein/creatinine ratio was as good as 24-h proteinuria to predict long-term graft loss. This practical information may be valuable for many physicians who progressively gave up the use of 24-h urine collections, notably difficult to obtain in some patients. Our results thus confirm the recently published recommendations of the American Society of Transplantation on the use of urinary protein/creatinine ratio in renal transplantation (15).

In the present study, it was not possible to assess the specific effect of ACEI and ARB on graft survival. However, we observed that ACEI and ARB were increasingly prescribed with time (1.7%, 6.5% and 20.9% at 1, 3 and 12 months following transplantation, respectively). In addition, the lower arterial pressure values at 3 and 12 months, the greater reductions in proteinuria from 1 to 3 months and from 3 to 12 months. Admittedly, our observational study does not allow us to draw firm conclusions on this issue. However, it is possible that the change in proteinuria within the first year may be the consequence of both better arterial pressure control and more frequent use of ACEI/ARB. It is tempting to speculate that ACEI and ARB may preserve renal function in renal transplant recipients with significant proteinuria. In effect, it was shown that ACEI effectively decrease proteinuria, and maintain renal function in patients with advanced CAN (31,32). However, whether the use of AECI or ARB is beneficial in patients with early low-grade proteinuria and no evidence of chronic rejection remains to be demonstrated.

In our analysis, initial serum creatinine was indeed a risk for graft loss. However, the point estimate of the relative risk (expressed by the HR) of graft loss associated with serum creatinine decreased from 2.30 (in univariate analysis) to 1.49 (in multivariate analysis) when proteinuria was entered into the model, and was no longer significant. It is thus possible that some of the deleterious effects of elevated serum creatinine on graft survival may be mediated by proteinuria. Nevertheless, analyses from a recent paper indicated that both 1-year proteinuria >0.5 g/day and serum creatinine affected graft survival in a multivariate model, but the results were not adjusted on short-term change in proteinuria (14).

In conclusion, our results suggest that early proteinuria may be an integrator of pre-transplant renal lesions, ischemia-reperfusion injury and immunologic aggression. It is not harmless and should not be neglected, especially in the low-grade range, since it constitutes a potent predictor of graft loss. Short-term reduction in proteinuria as a consequence of better arterial pressure control is associated with improved renal outcome, independently of initial proteinuria and renal function. Altogether, these findings support an appropriate management of early proteinuria.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References
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