Indomethacin reduces glomerular and tubular damage markers but not renal inflammation in chronic kidney disease patients: a post-hoc analysis.
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.
Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. m.h.de.borst@umcg.nl
Martin H
MH
de Borst
Ferdau L
FL
Nauta
Liffert
L
Vogt
Gozewijn D
GD
Laverman
Ron T
RT
Gansevoort
Gerjan
G
Navis
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers / Q000652:urine; D018932:Chemokine CCL2 / Q000652:urine; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy* / Q000652:urine*; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000150:complications / Q000188:drug therapy* / Q000652:urine*; D011446:Prospective Studies; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003404:Creatinine; D007213:Indomethacin