Acute obstructive nephropathy: A pathophysiological view

Transcription

1 Acute obstructive nephropathy: A pathophysiological view Jean-Philippe Haymann, Christophe Vinsonneau, Alexis Girshovich, Héloise Bilbault, Emmanuel Letavernier, Vincent Frochot, Michel Daudon Service d Explorations Fonctionnelles Multidisciplinaires. Hôpital Tenon (APHP) Sorbonne Universités Paris 6

2 Case report Mr. B, 30 years old. left back pain since 2 days with nausea and anuria (treatment by ibuprofene initiated 1 day ago)

3 N-acetylsulfadiazine stones

4 Outcome Bilateral JJ stenting Diuresis 3900mL/24h at day 4 Plasma Creatinine :133 µmol/l at day 4 At Day 28: ureteral stents withdrawal No residual stones. Bilateral ureteral obstruction Obstruction by crystals within tubular lumen?

5 Vincent Estrade

6 Localization of crystals & proteins and drug casts?

7 Crystal Nephropathy Localization of crystals & proteins and drug casts? 1. Tubular flow /Transit time & ph * ph 7,4 ph 6,9 ph 6,7 ph 5,8

8 Crystal Nephropathy Localization of crystals & proteins and drug casts? 2. Tubular fluid osmolality * *

9 Crystal Nephropathy Localization of crystals Renal Medulla Experimental Model: lithium carbonate & monourate Renal Medulla +++ Conger 1976

10 Crystal Nephropathy Localization of casts mtal & IMCD & Papilla Experimental Model: myoglobine mtal IMCD Casts mtal Dilatation CD Papilla Heyman 1996

11 Crystal Nephropathy Localization of casts mtal & IMCD & Papilla Experimental Model: myoglobine Heyman 1996

12 Crystal Nephropathy Localization of casts Proximal Tubules Human oxalate nephropathy Proximal tubule +++ Lefaucheur 2006

13 Mechanisms of crystal retention?

14 Sursaturation Crystal Germination < 0,1 µm Crystal growth 0,5-100 µm Crystal Aggregation µm Crystal Retention

15 Crystal Nephropathy Mechanisms of crystal retention Influence of number & shape & size C 2 O 4 2- Ca 2+ D=100 µm W=100µm L=5cm Laffite 2016

16 Crystal Nephropathy Mechanisms of crystal retention Influence of number & shape & size

17 Crystal Nephropathy Mechanisms of crystal retention Influence of lumen diameter & tubular adhesion

18 Crystal Nephropathy Mechanisms of crystal retention Importance of tubular adhesion? Vervaet 2009

19 RUTEC Urothelium Modèle UUO Crystal Nephropathy Mechanisms of crystal retention Importance of tubular proliferation? UUO Day 2 Collagen IV UUO Day 2 BrdU UUO Day 14 A. Girshovich

20 Crystal Nephropathy Mechanisms of crystal retention Importance of tubular proliferation? A. Girshovich

21 Crystal Nephropathy Mecanismes of crystal retention Formation of protein gels UMOD Schaeffer 2012

22 Crystal Nephropathy Mechanisms of crystal retention Formation of protein gels UMOD/Ig light chains? Casts localization: Distal tubules Sanders 1992

23 Renal Hemodynamic modification?

24 Renal Hemodynamic: RBF = 20% Qc RPF = RBF x (1-Ht ) 1000 ml/min 600 ml/min RPF Renal artery Renal vein FF = % GFR GFR = FPR x FF 99% Water reabsorption Qc RR DP Kf DQ

25 Obstructive ARF: renal hemodynamics Mechanisms of GFR - Arterial Pressure - Renal arterial resistance? Hydrostatic Pressure Urinary space - [Protides] - RPF Net. flow Starling Law Q H20 = Kf. [ DP- D ] = 0 Kf

26 Obstructive ARF: renal hemodynamics Experimental model : «tubular oil bockade» DFG = FPR? x FF Qc RR? DP Kf Arendhorst 1974

27 Obstructive ARF: renal hemodynamics Kinetics in lysine model Racusen 1985

28 Obstructive ARF: Increased tubular diameter Kinetics in lysine model Lysine Racusen 1985

29 Mechanisms involved in Ureteral Obstruction

30 Renal hemodynamic in UUO model DFG = FPR x FF Qc RR DP = Kf Arendhorst 1974 Chaabane 2013

31 Renal hemodynamic in UUO model Kinetics Pelaez 2005

32 Renal hemodynamic in UUO versus BUO model (UUO) or loss (BUO) of Tubulo Glomerular reflex Siegel 1977 Wahberg 1984

33 Renal hemodynamic in UUO versus BUO model Peritubular capillaries and vasa recta? UUO & BUO Racusen 1985 Wahlberg 1984

34 Renal hemodynamic in UUO versus BUO model Peritubular capillaries and vasa recta? Roman1988

35 Ischemic ARF : A tubular obstruction?

36 Ischemic ARF : a tubular obstruction? Sutter et coll. 2002

37 Ischemic ARF: renal hemodynamics A tubular pressure increase Arendhorst 1975

38 Dilated proximal tubules (% ) urea mmol/l Ischemic ARF : a tubular obstruction? a Control Control FGF7 24h URAi URAi IRAi IRAi 24h h 48h h 24 24h h 48 48h h FGF7 D-1 and D0 IRAi 24h FGF7 D-1 and D0 IRAi 48h FGF7 D0 FG IRAi 24h IRA b Control Control FGF7 24h UIR 24h UIR 48h IARF 24h IARF 48h FGF7 FGF7 D-1 and D-1 and D0 IARF 24h D0 IARF 48h FGF7 D0 FGF7 D0 IARF 24h IARF 48h Girshovich submitted

39 Mechanism of clearance and tubular patency?

40 Mechanism of recovery Tubular Patency Tubular proliferation & inflammation Vervaet B 2009

41 Mechanism of recovery Tubular Patency Tubular proliferation Atubular Glomeruli Forbes 2011

42 Conclusion (1) Obstructive ARF is also a vascular/ischemic ARF 1) Intratubular obstruction: intrinsic compression ( Crystal formation & Gels Polymerisation) - High intratubular pressure ( Tubular Dilatation) - Progressive RPF decrease & Peritubular capillaries occlusion 2) Ureteral obstruction : extrinsic compression (Gels Polymerisation delayed?) - Mild tubular pressure increase UUO: RPF decrease (TGF sensitization) occurs shortly +++ BUO: Increased interstitial pressure in medulla +++

43 Conclusion (2) Ischemic ARF is also an Obstructive ARF Early tubular obstruction - Intrinsic compression: Cellular desquamation Polymerization and gels formation (uromoduline.) - Extrinsic compression: Interstitial oedema

44 Conclusion (3) Factors involved in tubular patency: Renal plasma flow +++ Macromolecular Inhibitors and Solubilizing factors (citrates) Proteases, ph proliferation & inflammation Crystal clearance Open Question: Role of tubular obstruction in: - Acute Tubular and Tubulo-interstitial lesions? - CKD progression? Microscope FTIR

45 Illustration (1) Lionet A 2016

46 Illustration (2) Lionet A 2016