Amelioration of Metabolic Acidosis and Progression of CKD (Journal Club)


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  • Normally, after a dietary acid load there is distal nephron acidification (increased H+ secretion & decreased HCO3 secretion in DCT, resulting in decreased HCO3 delivery to terminal distal nephron, -> increased titration of non-HCO3 buffers).
  • Amelioration of Metabolic Acidosis and Progression of CKD (Journal Club)

    1. 1. Raj Kiran Medapalli, MD, MPH. Nephrology Fellow July 28th, 2010 Mount Sinai School of Medicine Division of Nephrology Journal Club
    2. 3. <ul><li>Increased muscle protein catabolism by up-regulation of ubiquitin-proteasome system (Mitch el al JCI 1994) </li></ul><ul><li>Bone disease (Kraut et al Adv Ren Replace Ther 1995) </li></ul><ul><li>Insulin resistance (Reaich et al Am J Physiol 1995) </li></ul><ul><li>Decreased sensitivity of parathyroid glands to calcium (Graham et al JASN 1997) </li></ul><ul><li>Possible acceleration of CKD ???? </li></ul>
    3. 5. <ul><li>Animal model for CKD. </li></ul><ul><li>Left kidney of anesthetized animals exposed with a flank incision and left renal artery and vein temporarily occluded. </li></ul><ul><li>Both renal poles removed with scissors, leaving approx. 1/3 rd single-kidney mass. </li></ul><ul><li>Bleeding controlled by applying thrombin to the cut surface and then abdomen is closed. </li></ul><ul><li>Then right kidney is removed after 1 week. </li></ul><ul><li>Sham Rx controls undergo L kidney exteriorization, followed 1 wk later by exteriorization of R kidney. </li></ul>
    4. 6. <ul><ul><li>Nath KA et al. J Clin Invest 1985; 76:667–675 . </li></ul></ul><ul><ul><li>After 4-6 weeks treated rats demonstrated: </li></ul></ul><ul><ul><li>Less impairment of tubular function as measured by urinary excretion of protein and higher transport maximum for PAH per unit GFR </li></ul></ul><ul><ul><li>Less histological evidence of tubulo-interstitial damage. </li></ul></ul><ul><ul><li>Gadola L et al. Kid Int 2004; 65: 1224–1230 . </li></ul></ul><ul><ul><li>Treated groups showed: </li></ul></ul><ul><ul><li>Less glomerular/tubulointerstitial cellular proliferation at week 1 </li></ul></ul><ul><ul><li>Less glomerular cell transdifferentiation at 10 weeks </li></ul></ul><ul><ul><li>Lower histological glomerular and tubulointerstitial damage scores at 20 weeks </li></ul></ul><ul><ul><li>Phisitkul S et al. Kid Int 2008; 73: 192–199 . </li></ul></ul><ul><ul><li>Treated rats showed: </li></ul></ul><ul><ul><li>Slower rate of GFR decline, less urinary albumin excretion and lower urinary endothelin-1levels. </li></ul></ul>
    5. 7. <ul><ul><li>Lyon et al. Lancet 1931; 218: 1009-1013. </li></ul></ul><ul><ul><li>A case series of 17 patients with moderate CKD. </li></ul></ul><ul><ul><li>Given various types of diets & acidic or alkaline therapy. </li></ul></ul><ul><ul><li>GFR stable or improved with alkaline therapy. </li></ul></ul><ul><ul><li>Urinary albumin diminished in some. </li></ul></ul><ul><ul><li>Rustom et al. Renal Failure 1998; 20(2):371-382 . </li></ul></ul><ul><ul><li>11 patients with mild to mod CKD with proteinuria. </li></ul></ul><ul><ul><li>NaHCO3 (0.09 g/kg) was given for 6 weeks. </li></ul></ul><ul><ul><li>Renal tubular catabolism of Tc-labelled aprotinin was measured before and after NaHCO3 administration </li></ul></ul><ul><ul><li>There was reduction in tubular peptide catabolism and ammonia excretion accompanied by a reduction in tubular injury markers like NAG A2. </li></ul></ul><ul><ul><li>Proteinuria, blood pressure and GFR were unaffected. </li></ul></ul><ul><ul><li>lone de Bristo, et al. JASN 2009; 20:2075-2084 . </li></ul></ul>
    6. 8. <ul><li>Only RCT; single center study from UK. </li></ul><ul><li>134 incident adult CKD4 pts with HCO3 btwn 16-20. </li></ul><ul><li>Heterogeneous pt population: 36% pts with DKD, 26% with HTN related CKD, 13% with GN, 4% with obstructive uropathy, 21% unknown or other dz. </li></ul><ul><li>Pts with poorly controlled BP (>150/09 on 4 agents) & CHF were excluded. </li></ul><ul><li>Average of 1.75g proteinuria (24 hr). </li></ul><ul><li>Randomized to NaHCO3 (started at 600mg TID and titrated to achieve HCO3 of >=23) or standard care. </li></ul><ul><li>Followed for 2 years. </li></ul><ul><ul><li>lone de Bristo, et al. JASN 2009; 20:2075-2084. </li></ul></ul>
    7. 9. <ul><li>Compared to controls, pts on HCO3 supp showed: </li></ul><ul><ul><li>Slower decline in CrCl over 2 yrs </li></ul></ul><ul><ul><ul><li>(5.93 vs 1.88 ml/min; P<0.0001) </li></ul></ul></ul><ul><ul><li>Lower risk of rapid progression (>3ml/min fall in CrCl/yr) </li></ul></ul><ul><ul><ul><li>(9% vs 45%; RR 0.15; 95% CI: 0.06 to 0.40). </li></ul></ul></ul><ul><ul><li>Lower risk of developing ESRD </li></ul></ul><ul><ul><ul><li>(6.5% vs 33%; RR 0.13; 95% CI: 0.04 to 0.40). </li></ul></ul></ul><ul><ul><li>Protein intake, lean body mass, serum albumin improved. </li></ul></ul><ul><ul><li>No significant reduction in proteinuria. </li></ul></ul><ul><ul><li>No significant worsening of BP, edema or CHF. </li></ul></ul><ul><ul><li>Only increasing age, male gender and HCO3 supp. were significant predictors of rate of decline. </li></ul></ul><ul><li>But mechanisms involved in renal protection with HCO3 not elucidated. </li></ul><ul><li>lone de Bristo, et al. JASN 2009; 20:2075-2084 </li></ul>
    8. 11. <ul><li>Munich-Wistar rats given (NH4)SO4 soln for 7 days had higher endothelin-1 levels in renal interstitium (measured in renal cortex using micro-dialysis technique) than those given distilled H2O. </li></ul><ul><li>(NH4)SO4 ingesting animals given Bosentan (inhibits both endothelin receptors A & B ) had higher HCO3 secretion than controls . </li></ul><ul><li>Animals given a specific ET-A inhibitor (BQ-123) had statistically similar levels of HCO3 secretion as control NH4SO4 rats. </li></ul><ul><li>No effect of Bosentan on control animals. </li></ul><ul><li>ET-1 seems to play a role in distal nephron acidification in response to dietary acid load through ET-B receptors . </li></ul><ul><li>Wesson DE. JCI 1997; 99(9): 2203-2211. </li></ul>
    9. 12. <ul><li>Human RMVECs were exposed to serum free media for 24 hrs and then incubated in either control (7.2), acid (7.0) or alkaline (7.4) media for 12 hours. </li></ul><ul><li>ET-1 levels were measured by RIA : </li></ul><ul><ul><li>Acid vs control: ET-1 significantly high in acid grp. </li></ul></ul><ul><ul><li>Alkali vs control: no significant difference in ET-1 levels. </li></ul></ul><ul><li>Similar experiments performed on Human aortic endothelial cells: all 3 cell culture subgroups had similar levels. </li></ul><ul><li>Wesson DE et al. JCI 1998; 101 (3): 578-583 </li></ul>
    10. 13. <ul><li>Munich-Wistar Rats had 5/6 th nephrectomy. </li></ul><ul><li>And, a micro-dialysis apparatus was inserted into the remnant kidney and the left kidney for sham-treated control animals. </li></ul><ul><li>After 4 weeks, Nx rats had: </li></ul><ul><ul><li>Higher creatinine, but no significant difference in blood pH, PCO2 or HCO3 (21.4 vs. 23.2). </li></ul></ul><ul><ul><li>Higher ET-1 levels in dialysate </li></ul></ul><ul><ul><li>Higher urinary ET-1 excretion </li></ul></ul><ul><ul><li>Greater absorption of HCO3 in PCT and DCT </li></ul></ul><ul><li>Bosentan (ET A/B receptor antagonist) decreased urinary net acid excretion (NAE) 2/2 decreased HCO3 reabsorbtion in PCT and DCT. </li></ul><ul><li>Wesson DE. JASN 2001;12:1826-1835. </li></ul>
    11. 14. <ul><li>Munich-Wistar Rats with 5/6 th nephrectomy given casein diet (acid load) and followed for 12 weeks. </li></ul><ul><li>Casein fed rats developed acidosis, decreased GFR and had higher urine ET levels (compared to sham). </li></ul><ul><li>Dietary NaHCO3 but not NaCl improved acidosis, reduced albuminuria, reduced ET levels and ameliorated decrease in GFR , but only after NaHCO3 induced increase in BP was treated (with methyl dopa+hydrallazine+HCTZ). </li></ul><ul><li>NaHCO3 rx (but not Nacl Rx) rats had lower NAE, NH4 & titratable acid excretion than control rats. </li></ul><ul><li>Decline in GFR was prevented by ET-A (Darusentan) but not ET-A&B receptor (Bosentan) antagonism suggesting involvement ET-A receptors in progression of CKD 2/2 acidosis. </li></ul><ul><li>Consistent results also in NaHCO3 vs. CaHCO3 (± BP control), CaHCO3 vs. CaGluc, NH4SO4 vs. NaSO4 and soy diet experiments. </li></ul><ul><li>Phisitkul S, Wesson DE, et al. KI 2008; 73:192-199. </li></ul>
    12. 15. <ul><li>21-AA peptide 1st described in 1988. </li></ul><ul><li>Synthesized mainly by endothelial cells across the body. </li></ul><ul><li>Synthesis stimulated by TGF-ß, ROS, PDGF, TNF- α , IL-1, angiotensin-2, vasopressin, LDL, CNI, among others. </li></ul><ul><li>In kidney, main sites of synthesis: </li></ul><ul><ul><li>Intra-renal blood vessel endothelium </li></ul></ul><ul><ul><li>Intra-glomerular endothelial cells </li></ul></ul><ul><li>Also produced in lower quantities by </li></ul><ul><ul><li>Mesangial cells </li></ul></ul><ul><ul><li>Podocytes. </li></ul></ul><ul><ul><li>Thick ascending loops </li></ul></ul><ul><ul><li>Intra-medullary CT (10X more than other tubular seg) </li></ul></ul><ul><li>Renal medullary ET-1 synthesis is higher than in any other body tissue. </li></ul><ul><li>Neuhofer W & Pittrow D. Eur JCI 2009;39(S2):50-67 </li></ul>
    13. 16. <ul><li>In Renal Cortex : </li></ul><ul><li>ET-A receptors : Abundant in vascular smooth muscle cells of large arteries, afferent & efferent arterioles, mesangial cells. </li></ul><ul><ul><li>Cause vasoconstriction (eff>aff), increase glomerular hydrostatic pressure (but filtration fraction constant 2/2 MC contraction also). </li></ul></ul><ul><li>ET-B receptors : vascular and glomerular endothelial cells. </li></ul><ul><ul><li>Cause vasodilatation through NO & Prostacyclin. </li></ul></ul><ul><li>In Renal Medulla : </li></ul><ul><li>Contains highest density of ET-1 Receptors in the body. </li></ul><ul><li>70-90% ET-B receptors – primarily localized to the intra-medullary collecting duct. </li></ul><ul><li>Ratio of ET-B to ET-A in tubular epithelium is 5-10:1 ratio. </li></ul><ul><ul><li>Causes increased medullary blood flow, natriuresis, diuresis (inhibits vasopressin also) & distal nephron acidification. </li></ul></ul><ul><li>Neuhofer W & Pittrow D. Eur JCI 2009;39(S2):50-67 </li></ul>
    14. 18. <ul><li>Amelioration of metabolic acidosis by oral alkali: </li></ul><ul><ul><li>Reduces kidney ET-1 production </li></ul></ul><ul><ul><li>Reduces urine parameters of tubulointerstitial injury, and </li></ul></ul><ul><ul><li>Slows GFR decline </li></ul></ul>
    15. 19. <ul><li>Population pool: All (? incident) patients referred for management of “resistant hypertension” to the IM clinic at Texas Tech University HSC. </li></ul><ul><li>Pts with hypertensive nephropathy and eGFR ≥20 but <60ml/min & VTCO2 <22 were offered Sodium Citrate. </li></ul><ul><li>Those who refused or could not tolerate (bloating and bad taste) or could not afford were then offered NaHCO3. Those who accepted NaHCO3 were excluded. </li></ul><ul><li>Total 59 pts included in the study. </li></ul><ul><li>30 pts on Na Citrate arm vs. 29 on standard care arm. </li></ul>
    16. 20. <ul><li>Initial 6-month BP reduction protocol </li></ul><ul><ul><li>All 59 patients (both groups) were subject to a BP reduction protocol, including ACE inhibition for 6 months. </li></ul></ul><ul><ul><li>Doppler US & Renin/Aldo ratio WNL for all. </li></ul></ul><ul><ul><li>All subjects received ACEI. </li></ul></ul><ul><ul><li>“ No diff in the distribution of non-ACE drugs or diuretics” in the 2 groups. No other details provided. </li></ul></ul><ul><ul><li>Maintained throughout study period (30 months). </li></ul></ul><ul><li>Followed by 24-month Na Citrate vs Std Rx . </li></ul><ul><ul><li>After BP was controlled, the 30 pts who chose to receive Na Citrate were started on it (1 meq/kg HCO3 equivalent daily in 3 divided doses; no titration). </li></ul></ul><ul><ul><li>Remaining 29 pts continued standard care. </li></ul></ul><ul><li>Total f/u for 30 months . </li></ul>
    17. 21. <ul><li>Inclusion criteria </li></ul><ul><ul><li>Age ≥ 18 + ≥ 2 visits with their PCPs. </li></ul></ul><ul><ul><li>eGFR ≥20 and <60. </li></ul></ul><ul><li>Exclusion criteria </li></ul><ul><ul><li>Known primary kidney disease. </li></ul></ul><ul><ul><li>≥ 3 RBCs per HPF or urine cellular casts. </li></ul></ul><ul><ul><li>History of DM or fasting BG ≥ 110. </li></ul></ul><ul><ul><li>Hx of malignancies, chronic infections, pregnancy. </li></ul></ul><ul><ul><li>Clinical evidence of “cardio-vascular disease”. </li></ul></ul><ul><ul><li>Peripheral edema or diagnosis associated with edema (CHD, ESLD, Nephrotic Syndrome). </li></ul></ul><ul><ul><li>Doppler studies and/or serum aldo/renin ratios consistent with RAS and/or primary hyperaldo. </li></ul></ul><ul><ul><li>Hx of taking aluminum containing products. </li></ul></ul><ul><ul><li>Hx of medication non-compliance. </li></ul></ul>
    18. 22. <ul><li>Primary end-point </li></ul><ul><ul><li>Urine ET-1 levels. </li></ul></ul><ul><li>Secondary end-points </li></ul><ul><ul><li>eGFR by MDRD. </li></ul></ul><ul><ul><li>eGFRcystatin-C by CKD-EPI. </li></ul></ul><ul><ul><li>Urine albumin excretion. </li></ul></ul><ul><ul><li>Urine N-Acetyl-ß-D-Glucosaminidase (NAG) excretion (marker of TI injury). </li></ul></ul><ul><ul><li>Urine TGF-ß excretion (reflected kidney injury by dietary acid in an experimental model of CKD and also possible mediator of HTN nephropathy) . </li></ul></ul><ul><ul><li>Urine net titratable acid excretion. </li></ul></ul>
    19. 28. At 30 months: NaCit vs. No-NaCit: 107.1±48.7 vs 146.9 ±44.6 mg/g Cr; p=0.002
    20. 30. <ul><li>eGFR using creatinine (NaCit vs No Citrate) : </li></ul><ul><ul><li>-1.60 ± 0.13 vs. -3.79 ± 0.30 ml/min/yr </li></ul></ul><ul><ul><li>P<0.0001 </li></ul></ul><ul><li>eGFR using cystatic-C (NaCit vs No Citrate) : </li></ul><ul><ul><li>-1.82 ± 0.08 vs. -4.38 ± 0.98 ml/min/yr </li></ul></ul><ul><ul><li>P<0.0001 </li></ul></ul><ul><li>Calculated using a linear mixed-effects model with terms for treatment (yes or no), time (6months vs 30 months) and interaction between the two. </li></ul>
    21. 31. <ul><li>First and only study to evaluate possible biological mechanisms at the population level. </li></ul><ul><li>Relatively long follow-up (30 months). </li></ul><ul><li>Limiting the study population to only hypertensive nephropathy pts means less heterogeneity in pt population and less confounding. </li></ul><ul><li>Having the 6-month BP reduction protocol enables evaluation of possible treatment effects separately from effects of HTN control and ACEI inhibition. </li></ul><ul><li>Despite lack of randomization, both groups similar at baseline with respect to the parameters reported. </li></ul><ul><li>Achieved Rx goal of HCO3 >22 in Rx grp. </li></ul><ul><li>Results consistent across the board (improvement in acidosis, ET-1, TI markers, albuminuria, rate of eGFR decline with Rx+ worsening of all without Rx). </li></ul>
    22. 32. <ul><li>Selection bias: no randomization, single center, no info if all incident pts were screened, how many pts were screened overall and how many pts were excluded because they opted for NaHCO3. </li></ul><ul><li>Small sample size. </li></ul><ul><li>No clear explanation as to why NaCitrate and not NaHCO3. </li></ul><ul><li>It would have been nice to have f/u on pts on NaHCO3 also. </li></ul><ul><li>No info on adverse events (higher need for BP meds, edema, etc) </li></ul><ul><li>Pcr and eGFRcr (with MDRD) outcomes not statistically significant, but outcomes significant with cystatin-C (with CKD-EPI). Predefined analysis or subsequent quest for significant results? </li></ul><ul><li>Diagnosis of hypertensive nephropathy was assumed, not tissue diagnosis. Some pts may have idiopathic FSGS, etc. </li></ul><ul><li>Truly resistant HTN at baseline? 100% success rate in lowering BP in 6 months. </li></ul><ul><li>>50% AA pts and >25% Hipanics. </li></ul>
    23. 33. Shah, Hostetter et al. AJKD 2009 Aug; 54(2): 270-277 Low serum bicarbonate levels have been shown to be associated with progression of kidney disease independent of baseline eGFR and other clinical, demographic, and socioeconomic factors.
    24. 34. <ul><li>There is at least one study where in rats with CKD produced by 5/6 th nephrectomy failed to demonstrate a beneficial effect of dietary NaHCO3 on renal function (Throssell et al. Clin Sci 1995) . </li></ul><ul><li>There are also animal studies (in rats with CKD on high phos diet) that suggest that acidosis prevents progression of CKD presumably 2/2 inhibition of CaPO4 deposition in the kidney (Jara et al. KI 2000 and NDT 2004). </li></ul><ul><li>The animal data available on distal nephron acidification by ET-1 is all from one lab (Wesson, DE who is one of the primary authors on this study . </li></ul>
    25. 35. <ul><li>We now have 2 single centers studies with at least 2 year f/u (1RCT and 1 prospective study) which suggest that correction of metabolic acidosis slows down CKD progression with the mentioned caveats. </li></ul><ul><li>RCT also shows improvement in nutrition parameters. </li></ul><ul><li>No significant worsening of BP & CHF (in RCT). </li></ul><ul><li>We have a plausible ET-1 mediated biological mechanism with the mentioned caveats. </li></ul><ul><li>We have evidence HCO3<22 is associated with greater risk of progression of CKD than HCO3 ≥22 </li></ul><ul><li>KDOQI guidelines (2000) recommend oral HCO3 supplementation to CKD pts with HCO3<22. </li></ul>
    26. 36. <ul><li>Follow KDOQI guideline - but after BP control is achieved. </li></ul><ul><li>Avoid in CHF, edema & uncontrolled HTN. </li></ul><ul><li>Need more animal & cell culture studies to elucidate specific roles of ET-A and ET-B receptors in the kidney. (Using newer inhibitors like Atrasentan & Sitaxentan which are 10 times more selective for ET-A receptors than Darusentan). </li></ul><ul><li>Need larger prospective studies to evaluate role of ET-1pathway more thoroughly at population level using RCTs (especially in diff pt populations such as diabetics, etc). </li></ul><ul><li>Another potential area of study is to examine if addition of ET-1 receptor inhibitors to HCO3 supplementation results in additional benefit? </li></ul><ul><li>s </li></ul>
    27. 37. <ul><li>Thank You. </li></ul>