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  1. Special Thanks to… For sponsorship of LMEF programs This activity supported in part by an educational grant from Genzyme Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org

  2. Chronic Kidney Disease and CKD-MBD Akram Al-Makki, MD, FACP, FASNNephrology Department

  3. Chronic Kidney Disease (CKD) • A CKD diagnosis is made when • Kidney damage is present for ≥3 months, with or without decreased glomerular filtration rate (GFR), manifested by either • Pathologic abnormalities, or • Markers of kidney damage, including abnormalities in blood, urine, or imaging tests • A GFR level <60 mL/min/1.73m2 persists for ≥3 months, with or without kidney damage National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and diseasein chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

  4. Staging of CKD National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and diseasein chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

  5. Prevalence of CKD • In 2000, approximately 26 million adults in the US had chronic kidney disease and most were unaware of their condition1 • Contributors to the growing prevalence2,3: • Aging population • Increasing prevalence of diabetes mellitus • Increasing prevalence of hypertension • Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. Nov. 7, 2007;298:17. • U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Diseasein the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007. • National Kidney Foundation. Part 4. Definition and classification of stages of chronic kidney disease.American Journal of Kidney Diseases. 2002;39(Suppl 1):S46-S75.

  6. US Prevalence:Breakdown Based on CKD Stage 1 1 * 1 1 2 1995-1999 estimates Year 2000 estimates * >20 years old • Coresh J, Selvin E, Stevens LA, et al. JAMA. 2007;298:2038-2047. • Coresh J, et al. Am J Kidney Dis. 2003 Jan;41(1):1-12.

  7. Risk Factors for CKD • Diabetes (type 1 and type 2) • Hypertension • Advancing age • Proteinuria • Family history of kidney disease • Environmental nephrotoxins • Race Healthy People 2010; Nelson NA et al, Am J Nephrol, 1999; US Renal Data System. 2001 Atlas of ESRD in the United States.

  8. Prevalence of CKD Contributors* Urologic disease2.8% Other known cause10.2% Unknown cause3.9% Cystic kidney disease4.6% Missing cause1.2% Glomerulonephritis16.2% Diabetes36.9% Hypertension24.2% *Based on 2005 data United States Renal Data System 2007 Atlas. Bethesda, MD: National Institutes of Health National, National Institute of Diabetes & Digestive & Kidney Diseases, 2007.

  9. Consequences of CKD DeathFrom Any Cause Hospitalization CV Events eGFR (mL/min/1.73 m2) eGFR (mL/min/1.73 m2) eGFR (mL/min/1.73 m2) eGFR = estimated glomerular filtration rate *Age-standardized rates per 100 person-years N=1,120,295 ambulatory adults Adapted from Go AS et al. N Engl J Med. 2004;351:1296-1305.

  10. ABC of CKD management • Appropriate screen and diagnose early CKD. • Be aware of complications and comorbidities: • Anemia • Bone and mineral abnormalities • Cardiovascular and renal. • Consult nephrologist in a timely manner

  11. Definition of CKD-MBD And Renal Osteodystrophy • Definition of CKD-MBD • A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or the combination of the following: • Abnormalities of calcium, Phosphorus, PTH, or Vitamin D metabolism • Abnormalities in bone turnover, mineralization, volume, linear growth, or strength. • Vascular or other soft-tissue calcification • Definition of Renal Osteodystrophy • Renal osteodystrophy is an alteration of bone morphology in patiens with CKD. • It is one measure of the skeletal Component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy. • Uhlig et al, AJKD Vol 55, No 5, May 2010.

  12. Consequences of Phosphorus Dysregulation

  13. CKD-MBD: Dysregulation and Clinical Manifestations of an Increasingly Compromised System

  14. Steady decline in urine phosphate excretion1 Progressive depletion of 1,25(OH)2D31 Decline in urine calcium excretion1 1400 50 250 1200 40 200 * 1000 * * 30 150 † Urine calcium (mg/24 hours) 1,25-dihydroxyvitamin D(pg/mL) † 800 Urine phosphate (mg/24 hours) 20 100 ‡ † 600 10 50 400 200 0 0 n= CKD114 CKD275 CKD3180 CKD443 CKD57 n= CKD115 CKD287 CKD3221 CKD4156 CKD543 n= CKD114 CKD274 CKD3179 CKD443 CKD57 CKD Stage CKD Stage CKD Stage (n=319) (n=522) (n=317) *P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4 *P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4 ‡P<0.05 CKD4 vs CKD5 *P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4 Alterations in Mineral Metabolism Occur in Early Stages of CKD An increasingly compromised system leads to disturbances in mineral metabolism Shading=statistical significance between levels. • Urine phosphate excretion decreases and leads to phosphate retention • 1,25D production decreases, leading to 1,25D depletion and contributing to elevated PTH • Urine calcium excretion decreases, impacting calcium balance Adapted from Craver L, et al. Nephrol Dial Transplantation. 2007;22:1171-1176.

  15. Serum Phosphorus Levels and Mortality in CKD Non-Dialysis Patients Mortality rates by phosphate category 72% of patients (n=3,289) • Mortality risk increases as phosphorus levels rise, even within normal range • Each 0.5 mg/dL increase in serum phosphorus was associated with increased mortality • Statistically significant increases in mortality were noted when phosphorus levels reached 3.5 mg/dL or above Adapted from Kestenbaum B, Sampson JN, Rudser KD, et al. J Am Soc Nephrol. 2005;16:520-528.

  16. <3 3-4 4-5 5-6 8-9 >9 6-7 7-8 Elevated Serum Phosphorus and Mortality Risk in Dialysis Patients 2.2 N = 40,538 2.0 1.8 Relative risk of death* 1.6 Referent Range 1.4 1.2 1.0 0.08 0.00 Serum phosphorous concentration (mg/dL) *Multivariable adjusted With permission from Block GA, Klassen PS, Lazarus JM, et al. J Am Soc Nephrol. 2004;15:2208-2218.

  17. KDIGO Focus: Normal Treatment Target Ranges for Phosphorous and Calcium Emphasis on individual levels of serum calcium and phosphorus rather than Ca x P product • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):S1-S130. • National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

  18. Survival according to phosphate levels relative to KDOQI guidelines. Eddington H et al. CJASN 2010;5:2251-2257 ©2010 by American Society of Nephrology

  19. Common phosphate binders • Aluminum hydroxide • Calcium carbonate • Calcium acetate • Lanthanum carbonate • Sevelamer

  20. Summary Slide • Despite early phosphate retention, many patients have serum phosphorus levels within normal range • Mortality risk increases as phosphorus levels rise, even when levels remain within normal range • Increased serum phosphorus levels are associated with CV events and mortality

  21. Importance of Vitamin D in CKD-MBD

  22. Normal metabolism of vitamin D: production of active hormone1,2 Dietary sources Sunlight Vitamin D(parent compound) Liver Hydroxylation of the 25 carbon 25(OH)D or 25D–Inactive metabolite– In a CKD patient, the ability to convert 25D to 1,25D is lost as kidney function declines. This would require treatment with vitamin D hormone (1,25D). Kidney 1 α hydroxylation 1,25(OH)2D or 1,25D–Active hormone– Released into plasma and carried to target organs where it binds to vitamin D receptors Hepatic and Renal Metabolism of Vitamin D2 and D3 • Drueke TB, Moe SM, Langman CB. Treatment approaches in CKD. In: Olgaard K, ed. Clinical guide to bone and mineral metabolism in CKD. New York, NY: National Kidney Foundation;2006:119-127. • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guidelines for the diagnose, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MED). Kidney Int. 2009; 76(suppl 113):S1-S130.

  23. Impact of CKD on Vitamin D Normal 1,25(OH)2D 25(OH)D 1-hydroxylase Decreasing Renal Mass CKD 25(OH)D 1,25(OH)2D 1-hydroxylase In a CKD patient, the ability to convert 25D to 1,25D is lost as kidney function declines. • Levin A, et al. Kidney Int. 2007;71:31-38. • Holick MF. N Engl J Med. 2007;357:266-281.

  24. 25(OH)D Major Circulating Metabolite 1,25(OH)2D Biologically Active Kidney Calcium and Phosphorus Homeostasis Bone Health Physiologic Effects of Vitamin D Throughout the Body Colon Prostate Macrophages Keratinocytes Breast, etc. Immunomodulatory Effects Multiple Sclerosis Type 1 Diabetes(via ß-islet cell destruction) Psoriasis Rheumatoid Arthritis Inflammatory Bowel Disease Periodontal Disease Cardiovascular Effects Renin-Angiotensin Regulation Decreased Risk for: Hypertension Type II Diabetes(via stimulation of pancreatic insulin production) Heart Failure Growth & Regulation Antiproliferation Prodifferentiation Apoptotic Anti-angiogenic Prostate, Colon, Breast Cancers etc. Neuromuscular Effects Muscle Mass Muscle Strength Better Balance Adapted from: Holick MF. Mayo ClinProc. 2006;81:353-373.

  25. 25(OH)D vs 1,25(OH)2D Deficiency Patients with CKD have a high prevalence of both 25(OH)D and 1,25(OH)2D deficiency1 Nutritional vitamin D supplements can replete diminished 25(OH)D substrate in stages 1-5 CKD2 A single monthly 50,000 IU ergocalciferol capsule safely repletes almost all vitamin D-deficient dialysis patients within 6 months3 The ability to convert 25(OH)D to its active form (1,25(OH)2D) in the kidney is lost as renal function declines4 Active vitamin D therapy is given to correct 1,25(OH)2D deficiency in stages 3 to 5 CKD2 • Wolf M, et al. Kidney Int. 2007;72:1004-1013. • Jones G. Semin Dial. 2007;20:316-324. • Saab G, et al. Nephron Clin Pract. 2007;105:c132-138. • Levin A, et al. Kidney Int. 2007;71:31-38.

  26. Progressive Vitamin D Deficiency in CKD Prevalence of 1,25(OH)2D3 and 25(OH)D3 deficiency by GFR 100 25 (OH)D3 <15 ng/mL 1,25 (OH)2D3 <22 pg/mL 80 60 Patients (%) 40 20 0 ≥80 (n=61) 79-70 (n=117) 69-60 (n=230) 59-50 (n=396) 49-40 (n=355) 39-30 (n=358) 29-20 (n=204) <20 (n=93) GFR level (mL/min) Adapted from Levin A, et al. Kidney Int . 2007;71:31-38.

  27. 1,25(OH)2D3 Levels and Mortality in Dialysis Patients A B 10 8 6 4 2 0 10 8 6 4 2 0 Active vitamin D therapy Active vitamin D therapy No active vitamin D therapy No active vitamin D therapy * * * Odds ratio of CV mortality Odds ratio of all-cause mortality R R <5 6–13 >13 <5 6–13 >13 1,25-dihydroxyvitamin D (pg/mL) 1,25-dihydroxyvitamin D (pg/mL) 1,25-dihydroxyvitamin D levels and 90-day all-cause (A) and CV mortality (B) in hemodialysis patients according to whether patients received active vitamin D therapy *P<0.05 for the comparison of the individual vitamin D level―vitamin D treatment groups with the corresponding referent groups. R=subjects treated with active vitamin D and 1,25-dihydroxyvitamin D levels ≥13 pg/mL. With permission from Wolf M, et al. Kidney Int. 2007;72:1004-1013.

  28. Summary • Patients with CKD have a high prevalence of both 25(OH)D and 1,25(OH)2D deficiency • As kidney function declines, patients lose the ability to convert 25(OH)D to 1,25(OH)D • Patients with lower levels of 1,25(OH)2D had a higher risk of mortality

  29. Chronic Kidney Disease and Secondary Hyperparathyroidism (SHPT)

  30. CKD-MBD: Dysregulation and Clinical Manifestations of an Increasingly Compromised System

  31. Compensatory Mechanism of PTH During Disturbances in Mineral Metabolism Median values of 1,25-dihydroxyvitamin D, 25 Hydroxyvitamin D, and intact PTH by GFR levels 50 150 1,25-dihydroxyvitamin D (pg/mL) 45 25 Hydroxyvitamin D (ng/mL) 40 Intact PTH (pg/mL) 35 100 30 1.25-dihydroxyvitamin D (pg/mL) 25 Hydroxyvitamin D (ng/mL) 25 Intact PTH (pg/mL) 20 50 15 10 5 0 0 >80 79-70 69-60 59-50 49-40 39-30 29-20 <20 GFR level (mL/min) With permission from Levin A, et al. Kidney Int. 2007;71:31-38.

  32. Elevated PTH Levels and Cardiovascular Disease in Patients with CKD Stages 3 and 4 P<0.001 Rate of cardiovascular disease, % Parathyroid hormone level, pg/mL With permission from Bhuriya R, et al. Am J Kidney Dis. 2009;53 (4 suppl 4):S3-S10.

  33. Elevated PTH and All-Cause Mortality CKD Stages 3 to 5 (non-dialysis patients) N = 515 2 1 0 -1 2 1 0 -1 CKD STAGE 3 CKD STAGE 4–5 Log relative hazard Log relative hazard 30 55 80 105 130 155 180 50 100 150 200 250 380 PTH (pg/mL-1) PTH (pg/mL-1) Estimated log relative hazard Estimated log relative hazard 95% pointwise CI 95% pointwise CI With permission from Kovesdy CP, et al. Kidney Int. 2008;73:1296-1302.

  34. KDIGO Focus: Consider Normal Limit for PTH *In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (2C) • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):S1-S130. • Adapted from National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

  35. Treatment of Secondary Hyperparathyroidism • Intact PTH most the earliest and most sensitive marker for abnormal bone metabolism • If PTH above recommended range, initiate replacement therapy with active 1,25-OH vitamin D substitute or CaR agonist • Calcitriol (Rocaltrol) • Doxercalciferol (Hectorol) • Paricalcitol (Zemplar) • Cinacalcet (Sensipar) Is not a vitamin D but CaR agonist • Monitor PTH, Calcium, and Phosphorous monthly while adjusting therapy

  36. Summary • Elevated PTH levels are a compensatory mechanism for 1,25D depletion — both are prominent and progressive across the CKD continuum • Elevated PTH levels and 1,25D depletion have each been independently associated with higher mortality

  37. Future Research:the bone-kidney endocrine axis • FGF 23 (Fibroblast Growth Factor 23) • Klotho Hu MC, et al. J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  38. Thank YouQuestions? Akram Al-Makki, MD, FACP, FASN IU HealthNephrology Department Lafayette, Indiana, USA (765)838-6365