Az idült vesebetegség progressziójának

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1 Az idült vesebetegség progressziójának
csökkentése, szövődményeinek kezelése Dr. Schneider Károly főorvos Petz Aladár Megyei Kórház Immunnephrológiai és Hypertonia Osztály B. BRAUN AVITUM 11. sz. Dialízisközpont, Győr

2 Az idült vesebetegség progressziójának csökkentése, szövődményeinek kezelése
Schneider Károly dr. Petz Aladár Megyei Oktató Kórház Immunnephrológia-Hypertonia Osztály B.BRAUN 11. sz Dialízisközpont Győr

3 Idült vesebetegség okai
Diabetes mellitus (40%) 1.tip.DM % - ban alakul ki DNP 2.tip.DM % - ban alakul ki DNP Hypertensio + ischaemia (27%) Glomerulonephritisek (akut vagy krónikus) (13%) Postrenalis (ureter obstrukció, vesico-ureteralis reflux, vesekőbetegség, ismétlődő pyelonephritis…) (6%) Hereditaer vesebetegségek (elsősorban polycystás vese) (4%) Renovascularis (kétoldali a. renalis szűkület) Chr. tubulointerstitialis nephritis Egyéb: akut veseelégtelenség KVE, nephrectomia, trauma, amyloidosis, myeloma

4 Idült vesebetegség progressziójának rizikó faktorai kísérő- és társbetegségei, szövődményei
CKD progresszió rizikófaktorai: GFR Proteinuria Hypertonia Diabetes Hyperlipidaemia (?) Anaemia Hyperuricaemia Oxidativ stressz Metabolicus acidosis Ca-P Csontanyagcserezavar Gyulladás dohányzás CKD szövődmények, társbetegségek Hypertonia (90-95%) Coronaria és szívbetegség (50-90%) Diab.mell. (20-30%) Hyperlipidaemia Anaemia Hyperuricaemia Mozgásszervi betegségek / Ca-P csontanyagcserezavar Szemészeti szövődmények Endocrin zavarok Infectiok Malnutríció Gyomor-bélrendszer betegségei

5 A vesebetegség progresszióját okozó tényezők
PU RR aldosteron ET-1 AG II Renin húgysav Fehérje diéta Oxidáció Só diéta GFR Diabetes lipidek kontrasztanyag NSAID dohányzás D vitamin hiány

6 Krónikus veseelégtelenség pathogenezise
Kezdeti inzultus Glomerularis károsodás Sejtfunkció változás Proteinuria Intraglom. nyomás  csökkent perfúzió RAAS aktiváció  art. eff. vasoconstrictio Interstitialis fibrosis Kompenzáló hyperperfúzió/hypertrophia Intraglom. nyomás  Tubularis dysfunctio Tubulus sejt hypoxia Glomerulosclerosis Tubulus károsodás nephron szám csökkenés

7 Hypertonia incidenciája és a vesefunktio romlása
Natalia Ridao et al., NDT ( 2001) 16 Suppl

8 A kezeletlen hypertonia és a vesebetegség progressziójának egyenes összefüggése
95 98 101 104 107 110 113 116 119 r = 0,69; p < 0,05 MAP (Hgmm) ΔGFR (ml/min/év) 130/80 140/90 Kezeletlen HTN -2 -4 -6 -8 -10 -12 -14 Bakris GL, et al. Am J Kidney Dis. 2000;36(3): 8

9 Krónikus veseelégtelenség és balkamra hypertrophia összefüggése
Szisztoles diszfunkció 15 % Diasztoles diszfunkcó 15 % Balkamra dilatáció 20-30 % CKD progresszió Levin et al. Amer J Am Kidney Dis 1996;34:

10 A diabeteses nephropathia természetes lefolyása 2-es típusú diabetesben
Funkcionális változások* Proteinuria Végstádiumú vesebetegség 2-es típusú diabetes Strukturális változások† Vérnyomás-emelkedés Szérum kreatinin- szint emelkedés Kardiovaszkuláris halálozás Microalbuminuria A diabetes kezdete 2 5 10 15 20 Diabetic nephropathy can be divided into 4 phases: microalbuminuria (urinary albumin excretion mg/24 h), macroalbuminuria or proteinuria (>300 mg/24 h), the nephrotic syndrome, and chronic renal failure (Grundy et al, 1999). Microalbuminuria is the first clinical sign of diabetic damage to the kidney and is a harbinger of progressive kidney damage. Microalbuminuria also reflects a higher risk for cardiovascular disease. Once microalbuminuria is present, it progresses over 5-10 years to macroalbuminuria in 22%-50% of patients (Mogensen, 1984; Cooper et al, 1988; Haneda et al, 1992; Ravid et al, 1992; John et al, 1994; Lebovitz et al, 1994). Macroalbuminuria denotes significant diabetic nephropathy and will be followed by a decline in glomerular filtration rate (GFR). Once a patient with type 2 diabetes develops macroalbuminuria, further decline in renal function appears to be inevitable; GFR declines at a rate of 4-12 mL/min/year (Pugh et al, 1993; Gall et al, 1993; Hasslacher et al, 1993). Some patients develop the nephrotic syndrome, which usually heralds progressive renal insufficiency and end-stage renal disease. In diabetic nephropathy studies, where the time of onset of type 2 diabetes is known, these patients follow a time course similar to that seen in patients with type 1 diabetes. However, the date of onset of type 2 diabetes is often unknown and usually precedes the clinical diagnosis by several years (Grundy et al, 1999). By the time patients are diagnosed with type 2 diabetes, many have already developed hypertension, signs of nephropathy (including microalbuminuria or even macroalbuminuria) and cardiovascular disease (Mogensen et al, 1992; The Hypertension in Diabetes Study Group, 1993a; American Diabetes Association, 1998). Whereas patients with type 1 diabetes are usually normotensive until overt renal disease develops, hypertension commonly occurs in patients with type 2 diabetes before the onset of overt diabetic nephropathy, and about 40% of newly diagnosed patients with type 2 diabetes are already hypertensive (The Hypertension in Diabetes Study Group, 1993a). Both the onset of microalbuminuria and the progression of renal disease after the onset of macroalbuminuria are accelerated by hypertension (Epstein and Sowers, 1992). The majority of patients with type 2 diabetes who have macroalbuminuria also have hypertension (Grundy et al, 1999). In these patients, control of hypertension slows the decline in GFR. The main goal of any treatment for patients with type 2 diabetic nephropathy should be to prevent the natural progression from microalbuminuria to macroalbuminuria to end-stage renal disease. Effective antihypertensive treatment is the best inhibitor of diabetic nephropathy (Ravid et al, 1993). Since reducing albuminuria delays progression of diabetic nephropathy, this parameter can be used as a benchmark for measuring the efficacy of therapeutic interventions (Rossing et al, 1994). Note that the high risk of cardiovascular mortality in patients with type 2 diabetes, even early in their disease, may not allow for the development of nephropathy (Ismail et al, 1999). évek * Vese mérete , GFR  † GBM vastagodás , mesangialis expanzió , mikrovaszkuláris változások +/-

11 Proteinuria súlyossága vérnyomásfüggően fokozza a vesebetegség relativ rizikóját
Proteinuria < 1g/nap Proteinuria > 1 g/nap Relatív rizikó Systolés vérnyomás (Hgmm) Jafar TH et al: Ann Intern Med, 139: ; 2003. 11

12 A GFR tartománytól függetlenül a fehérje ürítés súlyosbodása növeli a vesebetegség progressziójának kockázatát Ninomiya et al, J Am Soc Nephrol 20: 1813–1821,

13 Dohányzás növeli a vesebetegség kialakulásának rizikóját
(CLUE vizsgálat) Nic+ Nic- Haroun MK et al. J Am Soc Nephrol 2003; 14:

14 RAS Stroke Hypertonia Szívelégtelenség Myocardialis inf.
Fibrinogen ↑ PAI-1↑ Atherosclerosis Vazokonstrikció Érfali hypertrophia Endothel diszfunkció Balkamra hypertrophia Interstitialis fibrosis Remodeling Fokozott oxidativ stressz Endothelialis diszfunkció GFR↓ Proteinuria ↑ Aldoszteron↑ Glomerulosclerosis Stroke Hypertonia Szívelégtelenség Myocardialis inf. Veseelégtelenség RAS

15 Aldoszteron vesekárosító hatása
Rafiq ík. Et al., J Pharmacol Sci 115, 1 – 7 (2011) 15

16 Húgysav kiváltotta káros hatások
RAAS aktiváció vasoconstrictio Endoth.dysf Si. proliferatio Mesang. prolif Interst. fibrosis Podocyta károsodás Adapted from Johnson; Hypertension. 2003;41:

17 Hyperuricaemia megnöveli a macroalbuminuria incidenciáját
Hovind et al; DIABETES, VOL. 58, JULY 2009

18 Endothelin-A receptor aktiváció okozta vesekárosodás
Mann J. et al.; J Am Soc Nephrol 21: , 2010

19 A lipidek okozta vesekárosodás mechanizmusa
Proteinuria Agarwal R., Mayo Clin Proc. 2007;82(11):1381-1

20 Ox-LDL dózisfüggően fokozza a podocyta apoptózist, valamint az albumin diffusiot (Human podocyta sejttenyészeten végzett kísérlet) of podocyta of albumin The injury of podocytes is associated with alterations of the glomerular size-selective barrier to proteins. In this study, oxidized LDL (oxLDL) but not native LDL induced apoptosis in human cultured podocytes and reduced Akt activity and P-Akt/Akt ratio. Moreover, oxLDL-induced redistribution and loss of nephrin, an adhesion molecule specific for the glomerular slit diaphragm. Nephrin reduction was preceded by inhibition of nephrin tyrosine phosphorylation and of its association with p85 phosphatidylinositol 3-kinase (PI3K). Moreover, three different statins, mevastatin, pravastatin, and simvastatin, inhibited in a dose-dependent manner apoptosis and loss of nephrin induced by oxLDL by stimulating Akt activity. In addition, simvastatin significantly increased the expression of nephrin protein and mRNA by podocytes. The protective effects of statins were blocked by treatment of podocytes with two unrelated pharmacologic inhibitors of PI3K, LY and wortmannin, suggesting a role for PI3K, and by mevalonate, indicating dependency on HMG-CoA reductase activity. Statins directly stimulated Akt phosphorylation ad activity. Finally, oxLDL induced a retraction of cultured podocytes and an increase in the albumin diffusion across their monolayer that was inhibited by treatment with statins. In conclusion, statins reduced the oxLDL-induced apoptosis and loss of nephrin in glomerular podocytes. The statin-induced Akt activation may protect from the loss of nephrin by an inhibition of its redistribution and shedding and by a stimulation of its synthesis. These data provide a rationale for the anti-proteinuric effect of statins. The rapid redistribution of nephrin was associated with changes in the cytoskeleton of podocytes, characterized by a reduction of stress fibers and by peripheral accumulation of F-actin in respect to control shown). Statins are known to activate the Akt/PI3K survival pathway (30). The treatment of podocytes with the three statins also prevented the reduction of P-Akt/Akt ratio induced by oxLDL (Figure 6, A and B). ox-LDL dózisfüggően fokozza a sejtek apoptozisát, nativ LDL mellett nincs fokozódás Albuminnal inkubálva dózisfüggően fokozódik ox-LDL hatására az albumin diffusiója – funkció károsodás Bussolati B, J Am Soc Nephrol 16: 1936–1947, 2005

21 A vesebetegség progressziójának csökkentésére irányuló kezelés
Oki kezelés: immunsuppressiv kezelés, a. renalis tágítás, stent behelyezés postrenalis okok megszüntetése Progresszió lassítása: Sószegény diéta (4-5 gr/die) dohányzás elhagyása Kellő hidráltság fehérje szegény diéta (0,6-0,8 gr/tskg) (0,4 gr/tskg + Ketosav) szoros és adekvát vérnyomáskontroll - RAAS blokád ( ACE, ARB, DRI, aldo-A) (vesefunkció kontrollja!) - Ca-antagonista ( NDCCB, DCCB + ACE) szoros és adekvát vércukorkontroll ( metformin <60 alatt NE!, Glurenorm, DPP4 gátlók, sz.sz inzulin) Statin Hyperuricaemia kezelése Erythropoetin, anaemia korrekciója Aktív D vitamin

22 Decline in GFR from baseline
Fehérje megszorítás szerepe a vesebetegség progresszió lassításában N= 585 GFR ml/min/1.73 m² fehérjebevitel: NP: 1,3 g/ttkg/nap LP: 0,58 g/ttkg/nap Decline in GFR from baseline (ml/min) MDRD study

23 Szigorú fehérje megszorítás + ketodiéta-al elért renoprotectio
± ml/min/monthb ± ml/min/montha ± ml/min/monthb This figure shows the pattern of GFR change from baseline in each diet group with the corresponding slopes of GFR decline – they were significantly different among the three groups (p=0.028): GFR declineLPD: ± ml/min/months GFR declineVLPD + KA/AA: ± ml/min/months GFR declineVLPD + AA: ± ml/min/months Subsequent pairwise comparisons showed that a slower mean GFR decline occurred in patients assigned to a VLPD + KA/AA. Calculated for one year – the mean loss of GFR for the VLPD + KA/AA was 53% slower than the rate of loss in VLPD + AA. The significantly different rates of GFR decline in those diets occurred despite 1) assignment to the same very low protein diet 2) comparable mean achieved protein intake during follow-up and 3) comparable changes in mean protein intake form baseline values. Thus the composition of the supplement appeared to influence GFR decline independently of the level of protein intake. Teschan et al. (1998): Effect of KA-AA-supplemented VLPD on the progression of advanced renal disease: a re-analysis of the MDRD feasibility study. Clin Nephrol, 50,

24 A vesebetegség progressziójának csökkentésére irányuló kezelés
Oki kezelés: immunsuppressiv kezelés, a. renalis tágítás, stent behelyezés postrenalis okok megszüntetése Progresszió lassítása: Sószegény diéta (4-5 gr/die) dohányzás elhagyása Kellő hidráltság fehérje szegény diéta (0,6-0,8 gr/tskg) (0,4 gr/tskg + Ketosav) szoros és adekvát vérnyomáskontroll - RAAS blokád ( ACE, ARB, DRI, aldo-A) (vesefunkció kontrollja!) - Ca-antagonista ( NDCCB, DCCB + ACE) szoros és adekvát vércukorkontroll ( metformin <60 alatt NE!, Glurenorm, DPP4 gátlók, sz.sz inzulin) Statin Hyperuricaemia kezelése Erythropoetin, anaemia korrekciója Aktív D vitamin

25 IDDM-ben ACE alapú kezelés bizonyított proteinuria csökkentő hatása
Placebo ACE - 2 éves ACE gátló vc. placebo kezelés mellett elért 53.6% (37.4% %) albumin extretios rata csökkenés The ACE Inhibitors in Diabetic Nephropathy Trialist Group, Ann Intern Med. 2001;134:

26 ACE-gátló csökkenti a proteinuria macroalbuminuriába progressziójának rizikóját
Placebo Átlagos odds ratio 0.38 (0.25 to 0.57; P , 0.001) The ACE Inhibitors in Diabetic Nephropathy Trialist Group, Ann Intern Med. 2001;134:

27 ACE-gátló javítja a nomoalbuminuria elérésének esélyét
Placebo ACE odds ratio, 3.07 [ 2.15 to 4.44]; P , 0.001). The ACE Inhibitors in Diabetic Nephropathy Trialist Group, Ann Intern Med. 2001;134:

28 ARB-k vesevégpontokra vagy PU-ra kifejtett hatása
losartan valsartan irbesartan telmisartan candesartan Study RENAAL MARVAL IDNT IRMA2 DETAIL INNOVATION AMADEO VIVALDI CALM dózis mg mg 300 mg 150 mg 80 mg 40 mg 16 mg Pts 1513 332 1715 590 250 527 1566 800 197 Vizsg. idő 3,4 év 24 hét 2,6 év 2 év 5 év 1,3 év 52 hét PU  ESRD -35 % -28 % -36 % -32 % -24 % VE progr.  -12 % -21 % -29 % -33 %

29 RAAS blokád tartós proteinuria csökkentő hatása
34% RR↓ 38% RR↓ Background: Reduction of proteinuria is associated with delayed progression of chronic kidney disease. Reports suggest that angiotensin-receptor blockers (ARBs) reduce proteinuria, but results are variable. The relative effect of ARBs and angiotensin-converting enzyme (ACE) inhibitors, and their combined administration, remains uncertain. Purpose: To establish the effect of ARBs versus placebo and alternative treatments, and the effect of combined treatment with ARBs and ACE inhibitors, on proteinuria. Data Sources: English-language studies in MEDLINE and the Cochrane Library Central Register of Controlled Trials (January 1990 to September 2006), reference lists, and expert contacts. Study Selection: Randomized trials of ARBs versus placebo, ACE inhibitors, calcium-channel blockers, or the combination of ARBs and ACE inhibitors in patients with or without diabetes and with microalbuminuria or proteinuria for whom data were available on urinary protein excretion at baseline and at 1 to 12 months. Data Extraction: Two investigators independently searched and abstracted studies. Data Synthesis: Forty-nine studies involving 6181 participants reported results of 72 comparisons with 1 to 4 months of follow-up and 38 comparisons with 5 to 12 months of follow-up. The ARBs reduced proteinuria compared with placebo or calcium-channel blockers over 1 to 4 months (ratio of means, 0.57 [95% CI, 0.47 to 0.68] and 0.69 [CI, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [CI, 0.63 to 0.69] and 0.62 [CI, 0.55 to 0.70], respectively). The ARBs and ACE inhibitors reduced proteinuria to a similar degree. The combination of ARBs and ACE inhibitors further reduced proteinuria more than either agent alone: The ratio of means for combination therapy versus ARBs was 0.76 (CI, 0.68 to 0.85) over 1 to 4 months and 0.75 (CI, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (CI, 0.72 to 0.84) over 1 to 4 months and 0.82 (CI, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups. Limitations: Most studies were small, varied in quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure. Conclusion: The ARBs reduce proteinuria, independent of the degree of proteinuria and of underlying disease. The magnitude of effect is similar regardless of whether the comparator is placebo or calcium-channel blocker. Reduction in proteinuria from ARBs and ACE inhibitors is similar, but their combination is more effective than either drug alone. Uncertainty concerning adverse effects and outcomes that are important to patients limits applicability of findings to clinical practice. Ann Intern Med. 2008;148:30-48. 49 diab. nephropatia vizsgálat metaanalízise Kunz R., Ann Intern Med. 2008;148:30-48.

30 A kettős RAAS blokád kifejezettebb PU csökkentő hatékonysága a monoterápiával szemben
25 %-os RR↓ 18 %-os RR↓ Kunz R., Ann Intern Med. 2008;148:30-48.

31 Az intenzív vérnyomáskontroll NIIDM-ben csökkenti a nephropathia kialakulásának kockázatát és progresszióját standard BP control (140 mm Hg) Intensive BP control (135 mm Hg) For the outcome of new-onset microalbuminuria, intensive control was associated with a 17% reduction in the odds compared with the standard control group (OR, 0.83; 95% CI, 0.77 to 0.89). Similarly, for the outcome of overt nephropathy, intensive control was associated with a 27% reduction in the odds compared with the standard control group, with greater benefit with more intensive BP control (130 mm Hg) in which there was a 36% reduction compared with standard control (Pinteraction0.06; Figure 5). - 17 %-os újkeletű microalbuminuria kialakulás rizikó csökkenés - 27%-os nephropathia progresszió rizikó csökkenés Az intensiv kezelés 2,6x-ra növelte a súlyos mellékhatások kockázatát - 17X hypotensio rizikó - 10x hyperkalaemia rizikó növekedés Bangalore S. et al., Circulation. 2011;123:

32 Sóterhelés okozta MR aktiváció hatása a vérnyomásra és a proteinuriára
Background. Excessive prepubertal salt intake permanently increases blood pressure (BP). We examined the role that the mineralocorticoid receptor (MR) plays in the salt-induced hypertension and renal damage of prepubertal Dahl salt-sensitive (SS) rats. Methods. Prepubertal (6 weeks old) and adult (10 weeks old) Dahl SS rats fed a high (8.0%) salt (HS) diet for 10 weeks were compared in terms of BP and renal function. The effect of treatment between the ages of 4 and 10 weeks with the MR antagonist eplerenone (0.125% in chow), the vasodilator hydralazine (50 mg/kg/day in drinking water) or the superoxide dismutase mimetic 4- hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (tempol) (0.6 mmol/kg/day in drinking water) on the BP and renal function of prepubertal rats fed a HS diet for 10 weeks was also examined. Results. Excessive salt intake starting in prepuberty was associated with a higher BP increase and greater proteinuria than if it started in adulthood. Eplerenone moderately reduced BP and markedly improved renal injury during its administration in prepubertal rats. These effects continued after drug discontinuation. Hydralazine greatly decreased BP and reduced proteinuria, but these effects were completely lost after drug discontinuation. Excessive salt increased urinary 8-hydroxy-2′-deoxyguanosine levels, intrarenal macrophage infiltration and renal plasminogen activator inhibitor-1 and transforming growth factor-beta mRNA expression. Eplerenone, but not hydralazine, attenuated these salt-induced inflammatory reactions. Tempol improved salt-induced hypertension and renal injury, even after its discontinuation. Conclusions. Dahl SS rats exposed to excessive salt in prepubescence show a permanent increase in susceptibility to salt-induced hypertension and proteinuria. MR activation may promote these effects at least in part by inducing oxidation and inflammation. Kawarazaki H. et al. NDT (2010) 1 of 11

33 Sóterhelésének okozta MR aktiváció szelektív gátlásával kivédhető a proteinuria növekedés és kreatinin szint emelkedés MR gátlás – eplerenone-al (MR antagonista) RR csökkentés – hydralazin (direkt asodilatator) Antioxidans – tempol (superoxid dismutase mimeticum) Kawarazaki H. et al. NDT (2010) 1 of 11

34 Különböző korú prepubertas patkányok sóterhelésének hatása a glomerulus, tubulointerstitium és vasculatura szerkezetére Kawarazaki H. et al. NDT (2010) 1 of 11

35 A vesebetegség progressziójának csökkentésére irányuló kezelés
Oki kezelés: immunsuppressiv kezelés, a. renalis tágítás, stent behelyezés postrenalis okok megszüntetése Progresszió lassítása: Sószegény diéta (4-5 gr/die) dohányzás elhagyása Kellő hidráltság fehérje szegény diéta (0,6-0,8 gr/tskg) (0,4 gr/tskg + Ketosav) szoros és adekvát vérnyomáskontroll - RAAS blokád ( ACE, ARB, DRI, aldo-A) (vesefunkció kontrollja!) - Ca-antagonista ( NDCCB, DCCB + ACE) szoros és adekvát vércukorkontroll ( metformin <60 alatt NE!, Glurenorm, DPP4 gátlók, sz.sz inzulin) Statin Hyperuricaemia kezelése Erythropoetin, anaemia korrekciója Aktív D vitamin

36 A statinok csökkentik a vesebetegség progresszióját
A statinok direkt és indirekt (pleiotrop) hatása Csökkentik az öcho, LDL, TG, emelik a HDL-t intra-renalis atherosclerosis gátlás lipidek mesangialis accumulatiójának csökkentése Mesangialis scavanger receptorok down-regulatioja Gyulladásos, migratiot indukáló cytokinek, növekedési faktorok mennyiségének csökkentése - Csökkent gyulladás Monocyta/macrophag glomerularis migratiojanak csökkentése Habos sejt kialakulásának csökkentése Mesangialis sejt proliferatio gátlás Extracellularis matrix szaporulat és fibrosis csökkentése lipidek okozta direkt renalis sejt toxicus károsodás gátlás eNOS aktivitás  – endoth.dysfunk.  Podocyta károsodás csökkentése – csökkenti a proteinuriat The benefit of statins may derive from their lipid lowering effects. More recently, data suggest that the benefit of statins is greater than lipid lowering alone. The pleiotropic effects of statins may derive from inhibition of other downstream targets (isoprenoids) of the mevalonic acid pathway that are separate from cholesterol synthesis. Statins inhibits isoprenylation of Ras and Rho GTPases. These effects may lead to decreased monocyte/macrophage infiltration in the glomerulus, decreased mesangial proliferation and decreased accumulation of extracellular matrix and fibrosis. In addition, inhibition of RhoA and Ras may decrease inflammation and increase eNOS activity. These effects could lead to improvement in the progression of kidney disease. Kidney International advance online publication, 4 June 2008; Moorhead JF, Lancet 1982; 2: 1309–1311 Abrass CK, Am J Nephrol 2004; 24: 46–53 Ozsoy RC, Clin Nephrol 2005; 63: 245–249 Kidn. Int. Adv. online publication, 4 June 2008

37 Statinok dózisfüggően kivédik az ox-LDL okozta apoptozist és albumin diffusio fokozását (Human podocyta sejttenyészeten végzett kísérlet) of podocyta mevastatin pravastatin simvastatin of albumin Statinok kivédik az ox-LDL indukálta podocyta károsodást a Phosphatidylinositol 3- Kinase (PI3K)/AKT - jelátvitel aktiválása révén Statinok a podocyta károsodás kivédése révén antiproteinurias hatással bírnak Bussolati B, J Am Soc Nephrol 16: 1936–1947, 2005

38 Az atorvastatin renoprotectiv hatása dózis és vesefunkció függő (TNT study )
(GFR<60 ml/min) (GFR>60 ml/min) Background and objectives: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. Design, setting, participants, & measurements: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. Results: Mean estimated GFR at baseline was ml/min per 1.73 m2 in the 10-mg group and ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of ml/min per 1.73 m2 with 10 mg and ml/min per 1.73 m2 with 80 mg (P < for treatment difference). In the 80-mg arm, estimated GFR improved to >60 ml/min per 1.73 m2 in significantly more patients and declined to <60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. Conclusions: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related. Shepherd J., Clin J Am Soc Nephrol 2: 1131–1139, 2007

39 Statinok különbözősége proteinuria csökkentésben
Atorva 15 %↓, Rosuva Ø Atorva 20 %↓, Rosuva Ø ☝ AGARWAL R, Mayo Clin Proc. 2007;82(11):

40 SHARP: Vese kimenetel Diabetes mellitus 23%
Risk ratio & 95% CI Event Placebo Eze/simv better (n=3130) (n=3117) Main renal outcome End-stage renal disease (ESRD) 1057 (33.9%) 1084 (34.6%) 0.97 ( ) Tertiary renal outcomes ESRD or death 1477 (47.4%) 1513 (48.3%) 0.97 ( ) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 ( ) 0.6 0.8 1.0 1.2 1.4 Diabetes mellitus 23% Nem-dializált betegek (n=6247) eGFR (ml/min/1.73m2) 27 (13) Albuminuria 80% 40

41 Allopurinol kezelés lassítja a vesebetegség progresszióját
113 Pts eGFR<60 ml/min Clin J Am Soc Nephrol Aug;5(8): Epub 2010 Jun 10. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, Arroyo D, Luño J. Source Servicio de Nefrología, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Abstract BACKGROUND AND OBJECTIVES: Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. RESULTS: Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of /- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. CONCLUSIONS: Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects. Comment in Eredmények: Allopurinol kortol, nemtől, diabetesetől, CRP-től, RAAS blokádtól függetlenül javította a GFR-t, csökkentette az albuminuriat Goicoechea M, Clin J Am Soc Nephrol Aug;5(8):

42 Erythropoesis stimuláló ágens hatásai
EPO hatásai: Vvt szám emelése – szöveti oxigénellátottság javulása – hypoxia csökkentése – csökkent profibroticus aktivítás Oxidativ stress elleni védelem – vvt a természetes antioxidans rendszer része enzimaticus: superoxide dismutase, catalase, and glutathione peroxidase, sejtfehérjéhez kötött: vvt. membrán alacsony molekulasúlyú fehérjéi, E vitamin,C-vitamin, Q coenzyme Apoptosis gátlás (EPO non-hematopoietic sejtek EPO receptorához kötődése – idegsejtek, cardiomyocytak, vascular sejtek, vese tubulus sejtek) Angiogenesis stimulatio Rossert et al; Kidney International, Vol. 68, Supplement 99 (2005), pp. S76–S81

43 Bizonyítékok az EPO kezelés residualis veseműködésre kifejtett előnyös hatásáról
Prospectiv vizsgálatok: 83 beteg (43 EPO kezelt / 40 kontroll) 48 hetes vizsgálata GFR csökkenés 3x lassúbb az EPO kezelt csoportban (-0,13±0,35ml/min/hó vs. -0,39 ±0,65ml/min/hó ) 73 beteg (42 EPO kezelt / 31 kontroll) 36 hetes vizsgálata Kreatinin duplázódás szign. kisebb az EPO csoportban (52% vs 90% Pts) Dialísis indítási igény kisebb az EPO csoportban (33% vs. 64% Pts) 88 nem diabeseses CVE beteg korai (Hb:9 g/l felett) vs. késői (Hb:9 g/l alatt) indítású EPO kezelése Végpont: Kreatinin duplázódás, ESRD kialakulása, halál Korai EPO indítás szignifikáns előnye (13 vs. 22 Pts) Következtetés: Korai EPO kezelés lassítja a veseelégtelenség progresszióját Roth D. at al.; Am J Kidney Dis 24:777–784, 1994 Kuriyama S.at al.; Nephron 77:176–185, 1997 Gouva C.at al.; Kidney Int 66:753–760, 2004

44 D vitamin kezelés nephroprotectiv hatása
281 diab.nephropathias beteg Feltételezett renalis hatásmechanizmus: - haemodynamikai hatás - renin transciptio gátlás - antifibroticus hatás antiproliferativ hatás TGF ß gátlás antiinflammatoricus hatás DVR aktiváció  Nephrin upregulatio csökkent NFκB activitás - Szignifikáns albuminuria csökkenés - Szisztolés vérnyomáscsökkenéssel szinkron szignifikáns eGFR csökkenés Background Despite treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy. Methods In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks’ treatment with placebo, 1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT Findings Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo (n=93), 1 μg paricalcitol (n=93), or 2 μg paricalcitol (n=95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on 2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: –3% (from 61 to 60 mg/mmol; 95% CI –16 to 13) in the placebo group; –16% (from 62 to 51 mg/mmol; –24 to –9) in the combined paricalcitol groups, with a between-group diff erence versus placebo of –15% (95% CI –28 to 1; p=0ｷ071); –14% (from 63 to 54 mg/mmol; –24 to –1) in the 1 μg paricalcitol group, with a between-group diff erence versus placebo of –11% (95% CI –27 to 8; p=0ｷ23); and –20% (from 61 to 49 mg/mmol; –30 to –8) in the 2 μg paricalcitol group, with a between-group diff erence versus placebo of –18% (95% CI –32 to 0; p=0ｷ053). Patients on 2 μg paricalcitol showed an early, sustained reduction in UACR, ranging from –18% to –28% (p=0ｷ014 vs placebo). Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo. Interpretation Addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes. Zeeuw D. et al., Lancet 2010; 376: 1543–51

45 A vesebetegség progressziójának csökkentésére irányuló kezelés
Egyéb: Endothelin antagonista Antioxidans Károsító hatások kerülése Diureticumot csak hyperhydratio esetén (intravascularis volumendepletio a GFR-t ronthatja) Kontrasztanyag (kellő hidráltság, ACC) Nephrotoxicus antibioticumok Aminoglycosid, vancomycin… (indikáció, megfelelő dózis, gyakoriság, elimináció útja) NSAID

46 Avosentan (Endothelin antagonista) hatására csökkenő albuminuria (diab NP)
Mann, J Am Soc Nephrol 21: 527–535, 2010.

47 Avosentan (Endothelin antagonista) nem befolyásolta a vesebetegség progresszióját T2DM-ban
N=1392, T2DM 25-50 mg/d vs placebo sekreat 2x, ESRD, halál ABSTRACT In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebocontrolled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P ), 17 (3.6%; P ), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure. J Am Soc Nephrol 21: 527–535, doi: /ASN Data from animal studies and observational data from humans suggest that proteinuria is not simply a biomarker of renal disease but also contributes to progressive renal damage, ultimately leading to ESRD.1 Proteinuric nephropathies are a leading cause of ESRD, and, despite current available treatments, most patients still exhibit residual proteinuria and disease progression.1–4 In controlled trials, 15 to 20% of patients who had type 2 diabetes and overt diabetic nephropathy and had been intensively treated still reached ESRD after only 2.5 to 3.5 years.2,3 Clearly, there is a need for the development of new strategies to reduce further and perhaps arrest the rate Mann, J Am Soc Nephrol 21: 527–535, 2010.

48 ACE gátló mellé adott Avosentan additív nephroprotectiv hatása
Uninephrectomisalt patkány kísérlet Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L, Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal Physiol 297: F1448–F1456, First published August 12, 2009; doi: /ajprenal —In the present study, we evaluated the effect of simultaneously blocking angiotensin II synthesis and endothelin (ET)-1 activity as a multimodal intervention to implement renoprotection in overt diabetic nephropathy. Mechanisms underlying combined therapy effectiveness were addressed by investigating podocyte structure and function and glomerular barrier size-selective properties. Uninephrectomized rats made diabetic by streptozotocin received orally placebo, lisinopril (12.5 mg/l), the ETA receptor antagonist avosentan (30 mg/kg), or their combination from 4 (when animals had proteinuria) to 8 mo. Proteinuria, renal damage, podocyte number, nephrin expression, and glomerular size selectivity by graded-size Ficoll molecule fractional clearance were assessed. Combined therapy normalized proteinuria, provided complete protection from tubulointerstitial damage, and induced regression of glomerular lesions, while only a partial renoprotection was achieved by each drug alone. Lisinopril plus avosentan restored to normal values the number of podocytes. Single therapies only limited podocyte depletion. Defective nephrin expression of diabetes was prevented by each drug. Altered glomerular size selectivity to large macromolecules of diabetic rats was remarkably improved by lisinopril and the combined treatment. Avosentan ameliorated peritubular capillary architecture and reduced interstitial inflammation and fibrosis. The ACE inhibitor and ETA receptor antagonist induced regression of glomerular lesions in overt diabetic nephropathy. Regression of renal disease was conceivably the result of the synergistic effect of the ACE inhibitor of preserving glomerular permselective properties and the ETA antagonist in improving tubulointerstitial changes. These findings provide mechanistic insights to explain the antiproteinuric effect of this combined therapy in diabetes.

49 Az pro-oxidans/anti-oxidans és pro-inflammatoricus/anti-inflammatoricus szabályozás
Bardoxolon methyl Nrf-2 aktivátor anti-oxidans Nrf-2 (NF-E2-related factor 2): anti-inflammatoricus szabályozó detoxificatios

50 Bardoxolon methyl (antioxidans) hatására javult veseműködés (CKD - T2DM)
Week Background Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined. Methods In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m2 of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. Results Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m2 of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m2 of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl. Conclusions Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT ) 227 NIDDM Pts Induló GFR: ml/min/1,73 m2 Mh: Mg↓, GI, izomspazmus, transaminase↑ Pergola; N Engl J Med 2011;365:

51 Változatlanul megválaszolásra váró kérdés:
Pontos hatásmechanizmusa még nem tisztázott. Feltétetelezett hatásmechanizmusa zömében haemodynamicai: Tubuloglomerularis feedback megváltoztatása? TGF- ß gátlás okozta afferens arteriola csökkent vasoconstrictiója? Csökkent oxidativ stressz miatti anti-fibroticus hatás vagy egyéb folyamatok megváltozása? Nrf-2 aktiváció okozta TGF-β1 gátlás – csökkent növekedése faktor The mechanism(s) by which bardoxolone achieves this improvement remains to be established. It is unlikely that there is reversal of structural damage, as advanced glomerulosclerosis, tubular atrophy and nephron dropout are essentially irreversible. However, activation of tubuloglomerular feedback (TGF) may also functionally down-regulate renal function in failing kidneys. It is possible to speculate that bardoxolone increases GFR in patients with CKD by inhibiting TGF, leading to a reduced afferent arteriolar vasoconstriction. While such data suggest that the actions of bardoxolone on eGFR are most likely haemodynamic, this does not preclude other activities in diabetic kidney disease. Indeed, the antioxidant actions that lead to restoration of heme oxygenase may also affect many other pathways rendered dysfunctional by oxidative stress in diabetes. Clearly, reduced levels of superoxide and other ROS would be expected to be anti-fibrotic. Indeed, experimental studies have suggested that activation of Nrf-2 is also able to inhibit the promoter activity of TGF-β1,1 a key growth factor implicated in the development and progression of diabetic nephropathy. Változatlanul megválaszolásra váró kérdés: Mi lesz a veseműködéssel a szer abbahagyását követően?

52 A vesebetegség progressziójának csökkentésére irányuló kezelés
Egyéb: Endothelin antagonista Antioxidans Károsító hatások kerülése Diureticumot csak hyperhydratio esetén (intravascularis volumendepletio a GFR-t ronthatja) Kontrasztanyag (sze. a legkisebb dózisban, kellő hidráltság, ACC) Nephrotoxicus antibioticumok Aminoglycosid, vancomycin… (indikáció, megfelelő dózis, gyakoriság, elimináció útja) NSAID

53 endothel-dep. vasodilat vascularis permeabilitas
Renalis RAAS - kallikrein-kinin - prosztaglandin rendszer által fenntartott vese autoregulatio Renalis kallikrein – kinin rendszer Bradikinin RAAS (Renin – AGII – Aldoszteron) fájdalom mediátora endothel-dep. vasodilat vascularis permeabilitas natriuresis Prosztaglandin E2 (PGE2) Prosztaciklin (PGI2) Gyulladás fájdalom gyomor nyh. védelem vese keringés só és vízreabsorptio Nephrológia; Rosivall L, Kiss I.;2003

54 A vese kompenzatórikus mechanizmusát gátló NSAID hatás
Csökkent renalis perfusiojú beteg Renin-Ang-Aldosteron  AGII ↑ Szimpatikus Idegrendszer  Katekolaminok ↑  Renalis vasoconstictio Vesefunktio ↓ Renalis prostaglangin szintézis okozta kompenzatórikus vasodilatatio „normalizált” Vesefunktio NSAID

55 NSAID okozta funkcionális és strukturális vesekárosodás
Acut veseelégtelenség (reversibilis haemodynamikai hatás) Interstitialis nephritis (allergias, nephrosissal vagy anélkül) Acut tubularis necrosis (ischemias, reversibilis) Glomerulitis/vasculitis „Minimalis change” nephropathia Mesangioproliferatív glomerulonephritis Membranosus glomerulonephritis Thromboticus és nem thromboticus purpurák Analgeticum nephropathia (Papilla necrosis) Hyperkalaemia (hyporerinaemias hypoaldosteronismus) Volumen és sóretenció (vesék hypoperfusiója esetén) Hyponatraemia (ha a vízretenció aránytalanul nagyobb mint a sóvisszatartás; diureticum súlyosbíthatja )

56 De!!! A vesebetegség progressziójának lassítása nem csak predialízisben, hanem dialízis kezelés mellett is kiemelt fontosságú

57 A maradék veseműködés szerepének felértékelődése dializáltakban
Hatékonyabb só és folyadékegyensúly Hatékonyabb vérnyomáskontroll Kisebb LVH Jobb tápláltság Kisebb EPO igény Hatékonyabb Sav-bázis egyensúly Hatékonyabb középmolekulasúlyú clearance Hatékonyabb gyulladás gátlás

58 A maradék veseműködés szerepének felértékelődése PD betegeken
CANUSA reanalízis (2001) szoros összefüggés a beteg túlélés és a RRF közt. Bargman JM, at al;. J Am Soc Nephrol 2001; 12: 2158–2162. ADEMEX (2002) A total oldott anyag elvonás nem mutat összefüggést a túléléssel. RRF független markere a túlélésnek. Paniagua R. at al.; J Am Soc Nephrol 2002; 13:1307–1320. NECOSAD study (2003) A szolgáltatott dialízis dózisnak nincs hatása a klinikai kimenetelre. Termorshuizen F. at al.; Am J Kidney Dis 2003; 41: 1293–1302. renalis clearance ǂ dialízis clearance

59 Residualis veseműködés előnye a túlélésben HD kezelt betegeken
650 induló HD pts. – 15 éves követése >1 ml/min vs. <1 ml/min RRF Total KT/V (HD + renal) megegyezett >1 ml/min RRF - kisebb szolgáltatott dialízis dózis halálozási rizikó csökkenés (>1 ml/min vs. <1 ml/min RRF) - 12 hó HD után 39 % - 24 hó HD után 40 % Abstract Background and Methods. The importance of residual renal function is well recognized in peritoneal dialysis but its role in haemodialysis (HD) has received much less attention. We studied 650 incident patients in our incremental high-fluxHDprogramme over a 15-year period. Target total Kt/V urea (dialysis plus residual renal) was 1.2 per session and monitored monthly. Renal urea clearance (KRU) was estimated 1–3 monthly. Results. KRU declined during the first 5 years of HD from 3.1±1.9 at 3months to 0.9±1.2ml/min/1.73m2 at 5 years. The percentage of patients with KRU≥1 ml/min at these time points was 85% and 31%, respectively. Patients with KRU≥1 ml/min had a significantly lower mean creatinine (all time points), ultrafiltration requirement (all time points) and serumpotassium (6, 12, 36 and 48 months). Nutritional parameterswere also significantly better in respect to nPCR and serum albumin (6, 12, 24 and 36 months). Patients with KRU≥1 ml/min had significantly lower erythropoietin requirements and erythropoietin resistance indices (12, 24, 36 and 48 months). Mortality was significantly lower in patients with a KRU≥1 at 6, 12 and 24 months after HD initiation, this benefit being maintained after correcting for albumin, age, comorbidities, HDF use and renal diagnosis. Our unique finding was that these benefits occurred despite those with KRU≥1 ml/min having a significantly lower dialysis Kt/V at all time points. Conclusion. The associations demonstrated suggest that residual renal function contributes significantly to outcome in HD patients and that efforts to preserve it are warranted. Comparative outcome studies should be controlled for residual renal function.

60 Dializáltak residualis veseműködést befolyásoló faktorok
Negativ: Szívelégtelenség (hypotonia) Diabetes Nagy BMI (inadequate small solute clearance) Gyakori peritonitis (infectio, nephrotoxicus agensek) Gyakori sepsis (infectio, nephrotoxicus agensek) Diastoles/malignus hypertonia Hypotensios epizódok (dehydratio, CHF, sepsis) Súlyos proteinuria Interstitialis nephritis női nem, fehér bőr Pozitiv: ACE-inhibitor ARB Ca-antagonista Icodextrin Biocompatibilis oldatok (?) Sómegszorítás Fehérjeszegény diéta (?)

61 Fehérje megszorítás ketosavval kiegészítve dializáltakban is segít megőrizni a maradék veseműködést
LP: 0,6-0,8 gr/tskg fehérje sLP: 0,6-0,8 gr/tskg fehérje + ketosav kiegészítés HP: 1,0-1,2 gr/tskg fehérje Jiang et al., NDT (2009) 1-8

62 Összefoglalás A vesebetegség progressziója több tényezős, ezért csak az összes rizikófaktor együttes befolyásolása révén lehet sikeres a progresszió lassítás, vagy regresszió elérése Az residualis veseműködés megőrzése dializált betegeken is elsődleges szempont kell legyen

63