The development of proteinuria, even in a small amount, after kidney transplantation is associated with a reduction in graft and patient survival, and so the control of proteinuria is of clinical relevance.1–3 Unfortunately, a large number of kidney transplant recipients develop proteinuria. In a study of 613 kidney transplants, up to 45% had proteinuria of more than 150mg/day, and in 65% of these patients proteinuria was below 500mg/day. Biopsies from patients with proteinuria showed mainly interstitial fibrosis and tubular atrophy, or non-specific findings, except in those with proteinuria above 1500mg/day, in which glomerular involvement was predominant.4 The factors inducing the onset of proteinuria include: transplant from a female donor to a male recipient; advanced donor age; kidney function; blood pressure; cell rejection and antibody-mediated rejection; recurrence of glomerulonephritis; prolonged warm and cold ischaemia; and delayed initiation of graft function.4–6

The measures currently used to reduce post-transplant proteinuria include strict control of blood pressure, renin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor II blockers (ARBs), lipid control, stop smoking and maintaining a healthy weight.7 Specifically, the KDIGO guidelines recommend using ACE inhibitors or ARBs in patients with recurrent glomerulonephritis and proteinuria and in hypertensive patients with proteinuria ≥1g/day.8

In the general population, RAAS blockade has been shown to be effective in reducing proteinuria, controlling hypertension and reducing the progression of chronic kidney disease (CKD) in patients with diabetic and non-diabetic nephropathy.9,10 Although some studies have demonstrated the efficacy of the antiproteinuric effect of RAAS blockade in kidney transplantation,11,12 there is no precise information on the efficacy of proteinuria reduction on preservation of renal function and improvement of graft and patient survival.12–16

In non-transplant CKD patients, several factors can reduce the antiproteinuric effect of RAAS blockade.17–22 Salt intake is one of these factors. One meta-analysis that included 11 studies was able to quantify that albuminuria was decreased by 32.1% for every reduction in sodium intake of 92mEq/day.22 None of the cohorts considered in the meta-analysis included kidney transplant patients. The aim of our study was to assess the relationship between sodium intake and the antiproteinuric effect of ACE inhibitors and ARBs in our population of kidney transplant patients.

Patient characteristics at baseline and at 6 months are shown in Table 1. In all, 55.4% of patients received ACE inhibitors and 44.6%, ARBs. Six months after starting the RAAS blockade, serum creatinine and potassium levels increased, systolic and diastolic BP decreased, and 24-h proteinuria was significantly reduced (Table 1). By contrast, there were no significant differences at 6 months in urinary sodium or creatinine elimination, nor in urinary sodium/creatinine ratio (Table 1). In 46 patients (44.7%) proteinuria was reduced below one gram after 6 months of RAAS blockade. We found no significant differences in the initial sodium/creatinine ratio amongst patients with and without diuretic treatment (p=0.083).

A high urinary sodium/creatinine ratio was associated with a smaller reduction in proteinuria at 6 months (r=−0.251; p=0.011) and a lower percentage of decreased proteinuria from baseline proteinuria (r=−0.211; p=0.033). Similarly, the percentage of reduction in proteinuria from baseline was significantly lower in patients in the highest tertile for the urinary sodium/creatinine ratio [63.9% (IQR 47.1%); 60.1% (IQR 55.4%); 38.9% (IQR 85.5%); p=0.047] (Fig. 1). The decrease in the absolute value for proteinuria at 6 months was lower for the highest tertile, but was not statistically significant [1161mg (IQR 2406mg); 978mg (IQR 1299mg); 696mg (IQR 1422mg); p=0.056].

Fig. 1.

Percentage decrease in proteinuria for each tertile of urinary sodium/creatinine ratio.

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Table 2 shows the factors that are in relation with a percent reduction of in proteinuria of less than 50% (52 patients). The use of mTOR inhibitors and a lower urinary sodium/creatinine ratio was significantly related to a reduction in proteinuria greater than 50%. Neither serum creatinine nor glomerular filtration rate were associated with the percent decreased in proteinuria (Table 2) or reduction of proteinuria in absolute values (data not shown). The doses of ACE inhibitors and ARBs standardised for enalapril were not associated with the decreased in proteinuria (p=0.149). Using a logistic regression analysis, including the significant variables (use of mTOR inhibitors and sodium/creatinine ratio), the urinary sodium/creatinine ratio was the only factor related independently (OR 2.406 by 100mEq/g, 95% CI: 1.008–5.745; p=0.048) to an inadequate antiproteinuric response after RAAS blockade in kidney transplant recipients.

As in previous studies in transplant and non-transplant patients,9,26 we have observed that RAAS blockers significantly reduce proteinuria. After 6 months of treatment, mean proteinuria was reduced from 3.6 to 2.2g/day, and in almost half of patients (44.7%) proteinuria fell below 1g/day. The advantages of the use of ACE inhibitors/ARBs in kidney transplants remain controversial, with studies where there is no histological improvement, and no change in graft or patient survival, or in the cardiovascular risk15,16,27; others studies show an increase in patient survival, but not in the graft survival28; and there are also studies showing an improvement in both graft and patient survival.29 In this latter study, the greatest benefit on graft outcome was observed in patients with higher proteinuria.29 Whether due to a specific effect of RAAS blockade, or not, what is clear is that the reduction of short-term albuminuria has a long-term nephroprotective effect.

In a meta-analysis of 21 clinical trials that included 78,342 patients, Heerspink et al. observed that for every 30% reduction in albuminuria achieved with RAAS blockade, the risk to reach stage 5 CKD was reduced by 32% in the long term analysis.30 The reduction of approximately 39% in proteinuria observed in our study with RAAS blockers may lead to a reduction in the loss of long-term renal grafts of more than 30%, although this effect should be evaluated in long-term studies. In contrast to the general population, in the kidney transplant population the reduction of proteinuria with ACE inhibitors/ARBs has not been demonstrated to be reduce the progression of renal disease. This may be due to the characteristics of the transplant patients (i.e. immunosuppressive therapy, especially with calcineurin inhibitors and alloimmune damage) as well as to methodological problems. For example, in the meta-analysis by Heerspink et al., a sample size of less than 1250 patient or the cause of the nephropathy affected the ability of the studies to show any benefit from RAAS blockade.30 In kidney transplantation it is difficult to conduct long-term studies with large numbers of patients enough to demonstrate the long-term benefit of ACE inhibitors and ARBs.

The effect of low-salt diet on BP is recognised both in the transplant population as well as in the general population.31 However, many patients with CKD have a salt intake above the WHO recommendations (below 5g/day).32 Amongst kidney transplant recipients, up to 87% have a urinary sodium excretion that reflects a salt intake above 5g. In addition, salt intake is maintained over time in each patient and in the overall population, despite the recommendations made.31,33,34 This suggests that, despite some difficulties, we have an opportunity to improve outcomes in kidney transplant recipients by intensifying dietary measures without requiring drug.

The main finding of our study is that a high-salt diet limits the antiproteinuric effect of ACE inhibitors and ARBs in the kidney transplant population, similar to previously published studies of CKD patients. In a prospective study of 500 non-diabetic patients with CKD, Vegter et al. showed that patients in the highest tertile of urinary sodium/creatinine ratio showed a minor decrease in proteinuria with ramipril (20%) compared with patients with lower salt intake (25% and 31%), leading to an increased risk of developing stage 5 CKD.17 In our kidney transplant patients the percent reduction in proteinuria in the different tertiles of sodium/creatinine ratio (from to the highest to the lowest) was 16%, 41% and 43%, respectively. The antiproteinuric effect of low-salt diet has been proven to be more effective even than double RAAS blockade, or as effective as diuretic therapy.18,20 Thus, in a randomised study of 52 patients with non-diabetic nephropathy, the reduction in proteinuria caused by adding a low-salt diet to treatment with ACE inhibitors was significantly greater than the reduction of proteinuria by adding ARBs to ACE inhibitors (51% vs. 21%; p<0.001).18 Also in 34 patients with proteinuria without diabetes, in whom treatment with losartan decreased proteinuria by 30%, the addition of hydrochlorothiazide achieved a reduction of 56%, and of 55% by adding a low-salt diet.20

Therefore, it seems advisable to insist that the transplant patients also must follow a diet low in salt, especially in those with proteinuria who have not responded, or responded only partially, with RAAS blockade. Given the differences between the highest tertile for salt intake and the middle and lower tertiles in our study, we recommend at least a moderate decrease in sodium intake to improve the antiproteinuric response to treatment with ACE inhibitors/ARBs, without requiring a severe restriction. It is foreseeable that, in parallel to that observed in the non-transplant CKD population, a greater reduction in proteinuria will contribute to improving renal graft survival.

The pathophysiological mechanisms that contribute to the antiproteinuric effect of salt restriction are not fully known. In normal conditions, salt intake is associated with an increase in serum sodium that triggers the thirst centre and stimulates the secretion of antidiuretic hormone. All this leads to increased blood volume, blood pressure and glomerular filtration rate. This decreases the activating stimulus of renin, which makes RAAS blockade less effective for hypertension and proteinuria. If serum sodium decreases, blood volume and blood pressure are also reduced; the RAAS blockade is activated and becomes more effective.22 Furthermore, sodium appears to play a role through the endothelium. Verhave et al. showed that salt intake increases albuminuria independently of blood pressure,35 a fact that reflects the specific endothelial damage. We also found a relationship between changes in blood pressure and antiproteinuric response, a finding previously described by some authors and which suggests that the reduction in proteinuria induced by salt restriction is influenced both by intraglomerular pressure and systemic BP.17 This endothelial damage could also be mediated by inflammatory mechanisms: it has even been observed that high salt intake is associated with higher albuminuria and with elevated CRP in hypertensive patients.22,36

Analysing the factors that could be related to the antiproteinuric response, we noted that the use of mTOR inhibitors is associated with a greater antiproteinuric response to ACE inhibitors/ARBs, although this finding was not confirmed in the multivariate analysis. The use of ACE inhibitors/ARBs has been shown to be effective in the literature in treating and even preventing proteinuria that develops after conversion from calcineurin inhibitors to mTOR inhibitors.37 Several mechanisms have been described that contribute to the onset of proteinuria with mTOR inhibitors. Most times proteinuria develops after discontinuation of calcineurin inhibitors, probably related to the interruption of their vasoconstrictor effect.38,39 There are some assumptions that point to possible direct glomerular and tubular damage and there have been reported cases of focal and segmental glomerulosclerosis.39,40 There are no specific studies demonstrating a better antiproteinuric response with ACE inhibitors/ARBs in patients treated with mTOR inhibitors. To explain our findings, we can speculate with 2 potential mechanisms: (1) ACE inhibitors and ARBs reduce glomerular capillary pressure that would increase after the withdrawal of calcineurin inhibitors and beginning the mTOR inhibitor; and 92) both ACE inhibitors and ARBs reverse the damage mediated by angiotensin II, specifically induced by mTOR on albumin uptake in the proximal tubule.40

The main limitation of our study is that it is an observational study in which patients are on different drugs and different ACE inhibitors and ARBs. However, it does reflect routine clinical practice in that the doses are adjusted according to potassium, creatinine and BP. There were no different antiproteinuric responses seen when normalising to a standard dose of enalapril, which can be explained because most patients were on 5mg of enalapril and the same dose was maintained throughout the study period (Table 2). As discussed above, the absence of a relationship between changes in BP and the antiproteinuric effect of salt restriction indicates that low-salt diet exerts its additional antiproteinuric effect through partially independent mechanisms of lower BP and doses of ACE inhibitors/ARBs. A second limitation is that this is a single-centre study, with a limited sample size. However, the significant relationship between urinary sodium/creatinine ratio and antiproteinuric response indicates that there is an association between them. There need to be larger, multicentre, prospective studies to confirm the role of sodium intake in the antiproteinuric response to RAAS blockade in renal transplant patients.

In conclusion, our study indicates that, in renal transplant patients with proteinuria treated with ACE inhibitors/ARBs, high salt intake is associated with a smaller decrease in proteinuria and possibly with lower graft survival. Avoiding excessive salt intake is a necessary and effective measure that should be combined with RAAS blockade.

The authors have no conflicts of interest.