Abstract
Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38–513] vs NSAID 38[17–218] mg/24 h, p<0.01; IgG4: 50[16–68] vs 10[1–38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55–404] vs 50[28–110] ug/24 h, p = 0.03; KIM-1: 9[5]–[14] vs 5[2]–[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term.
Highlights
Reduction of proteinuria is a major therapy target to achieve long-term renoprotection in chronic kidney disease
In chronic kidney disease (CKD) patients, proteinuria was reduced by non-steroidal anti-inflammatory drugs (NSAIDs) treatment with a median of 51% (IQR 33–73%) compared with the study period without antiproteinuric treatment (‘‘untreated UP’’; Figure 1A)
*p,0.05, **p,0.01 CKD untreated vs healthy controls. #p,0.05, ## p,0.01 CKD NSAID vs CKD untreated. $Antihypertensive use remained stable during the study protocol. doi:10.1371/journal.pone.0037957.t001
Summary
Reduction of proteinuria is a major therapy target to achieve long-term renoprotection in chronic kidney disease. To this end, blockade of the renin-angiotensin-aldosterone system (RAAS) ideally combined with a diuretic or dietary sodium restriction [1] is the cornerstone of current renoprotective therapy in chronic kidney disease [2,3]. Chronic kidney disease (CKD) progression persists in a considerable proportion of patients. Before the era of RAAS inhibitors, NSAIDs were well known for a distinct antiproteinuric effect. Their use in nephrotic syndrome was supported by retrospective data suggesting that
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