Faculty/Presenter Disclosure

Faculty/Presenter Disclosure
CFPC CoI Templates: Slide 1 Faculty/Presenter Disclosure Faculty: Dr. Donna Birbrager Relationships with commercial interests: Speakers Bureau/Honoraria: Merck, Astra-Zeneca, Eli Lilly, Boehringer-Ingelheim, Impres Pharma Consulting Fees: Takeda, Otsuka This slide must be visually presented to the audience AND verbalized by the speaker.

Disclosure of Commercial Support
CFPC CoI Templates: Slide 2 Disclosure of Commercial Support I have no industry-related financial conflicts of interest to declare This slide must be visually presented to the audience AND verbalized by the speaker.

Mitigating Potential Bias
CFPC CoI Templates: Slide 3 Mitigating Potential Bias No particular drugs are being discussed in this program content This slide must be visually presented to the audience AND verbalized by the speaker.

CLINICAL PEARLS: CASE BASED EXAMPLES OF IMPORTANT ISSUES NEPHROLOGY 2014
Donna Birbrager MD, FRCPC Nephrologist, Lakeridge Health May 14, 2014

Overview and Objectives
What constitutes a true renal emergency? Management of gout in CKD Appreciate that we often over treat BP in CKD. Review the 2012 CHEP guidelines for HT targets in Non DM CKD Review the results of ESA in CKD and review the 2012 KDIGO Anemia Guidelines in CKD Review the role of Tolvaptan in PKD. Review the results of the Tempo 3:4 trial

Case 1: Mr. C.K. 57 y.o. PMH: Nil, Pipe smoker
Fam Hx: Dad died 69 of MI MEDS: None HPI: 2 weeks of increased SOA Facial edema in AM Feels weak and unwell O/E: BP 110/74, 92 kg JVP low, 3+ edema Chest clear, dull bases Nil else Lab: Cr = 86 eGFR = 96 ACR > 100, UA bland 24 H Urine 8 g/d TG = 4.0, HDL = 2.1 LDL = 5.1, TC = 7.0

Case 1 : Edema Low Albumin Proteinuria > 3g High Cholesterol
(Lipiduria) Dx: Nephrotic Syndrome This is a renal emergency!!!

What Are Renal Emergencies / Urgencies?
Urgent: Sudden rise in Cr > 25% New Dx of CKD 5 (or high risk CKD 4) Accelerated HT Hyperkalemia Nephrotic Syndrome Systemic illness with hematuria and proteinuria with rising Cr (need to r/o RPGN) Immediate: (Go to ER) HT Emergency / Malignant HT ARF/AKI Hyperkalemia > 7

Case 2 : Mr. G.C. 54 y.o. Teacher Question:
PMH: Obesity, T2DM, CKD 2, HT, OA, Gout x 4 years – no Rx, exsmoker, nil else Last seen 3 months ago routine: BP 120/76 A1C = 6.1, Lipids Optimal, UA 522 Cr 110, eGFR = 49, No change x 4 ys ACR = 2.1 Meds: Ramipril 10, Atorvastatin 10, Metformin 500 BID, ASA 81 Seen in ER after recent syncope episode: ECG: Sine wave arrhythmia  emergent management Cr = 490, K+ = 7.6 Treated by ER doc, ``shift therapy`` Question: What are you thinking here?

Hyperkalemia EKG

Case Further Hx: 1 week ago – Gout Flare right forefoot Seen at W.I.C
Rx: Indocid 50 BID and colchicine Developed diarrhea followed by Nx and Vx last few days Continued to take ACEi during this period DISCUSSION/Outcomes

“SICK DAY” MEDICATION ADVICE:
Dear Patient: If you become acutely ill, especially if you have diarrhea or vomiting, the following types of medication should be held until you are better. These drugs are good at protecting the kidney and the heart as well as for blood pressure control, but paradoxically they can be harmful if you are dehydrated. ACE-inhibitors -Ramipril (Altace) -Fosinopril (Monopril) -Enalapril (Vasotec) -Perindopril (Coversyl) -Lisinopril (Zestril) -Cilazapril (Inhibace) -Trandolopril (Mavik) Angiotensin Receptor Blockers -Telmisartan (Micardis) -Candesartan (Atacand) -Olmesartan (Olmetec) -Valsartan (Diovan) -Losartan (Cozaar) -Irbesartan (Avapro) -Eposartan (Teveten) Direct Renin Inhibitors -Aliskerin (Rasilez) Diuretics (“Water Pills”) -Furosemide (Lasix) -Indapamide (Lozide) -Hydrochlorothiazide (HCTZ) -Chlorthalidone -Spironolactone (Aldactone) You can restart your medications again as soon as you feel better. If your illness requires holding these medications for over a week, contact your MD.

“The Gout”

Gout is a chronic and progressive disease.
The progression of gout can be divided into 4 stages: asymptomatic hyperuricemia, acute flares, intercritical/ between flare periods, and advanced gout. About 5–8% of the United States population has hyperuricemia with no symptoms. This period lasts anywhere from months to lifetime. During this period, urate crystal deposition can occur. Lifestyle modification, but no therapeutic treatment is usually recommended.1,2 For up to half a million patients, acute gout develops as acute flares caused by phagocytosis of MSU crystals. The acute flares lasts for hour to days and subside to a painless intercritical period. the estimated flare recurrence rate is 60% within 1 year, 78% within 2 years, and 84% within 3 years. Less than 10% will not have a recurrence over a 10-year period.3 As the disease progresses, the frequency of gout increases, and pain-free intercritical periods shorten. The acute gout flare phase lasts a decade.2 Left untreated or suboptimally treated, up to Canadians progress to chronic or advanced gout. There is no pain-free intercritical periods.1 References: Becker MA, Jolly M. Clinical gout and the pathogenesis of hyperuricemia. In: Koopman WJ, et al, eds. Arthritis and Allied Conditions. 15th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005. Hahn PC. Management of hyperuricemia. In: Koopman WJ, et al, eds. Arthritis and Allied Conditions. 15th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005. Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008;75(Suppl 5):S5-S8.

The Normative Aging Study evaluated serum uric acid levels of 2,046 healthy and asymptomatic men over 14.9 years, while monitoring for the first episodes of gouty arthritis The incidence rate of gouty arthritis was (in addition to slide information): Annual incidence: 0.1% in patients with sUA < 420 µmol/L Annual incidence: 0.5% in patients with sUA 420–540 µmol/L Annual Incidence: 4.9% in patients with sUA ≥ 540 µmol/L 5-year cumulative incidence: 22% in patients with sUA ≥ 540 µmol/L Acronyms: sUA = serum uric acid Reference: Campion EW, et al. Asymptomatic hyperuricemia: risk and consequences in the Normative Aging Study. Am J Med. 1987;82:

Pathophysiology of Gout: Acute Flares
Common Sites Frequency: Big toe % Ankle/foot 50% Knee % Finger % Elbow/wrist 10% >1 site simult.11% The initial gout attack often occurs with explosive suddenness. Pain frequently begins in the middle of the night or early morning. Many patients will describe awakening with pain in the foot that is so intense that they are unable to support their own weight. This regularly interrupts sleep, prevents walking, and interferes with daily activities. Untreated, the initial attack will usually resolve in 3 to 14 days. Subsequent attacks tend to last longer and may involve more joints.1,2 Gout can present in many areas and initial attacks do not necessarily occur in the first metatarsophalangeal joint of the great toe The rapid onset of intense pain and tenderness, swelling, and shiny erythema associated with the acute flare is characteristic of gout. It is at this stage that gout may first be diagnosed1,2 Acute gout is more likely to occur during an infectious process or other illnesses, hospitalisation and trauma3 The lower extremities are believed to be more susceptible to gout attacks possibly because of their lower body temperature3 It is unknown why gout attacks often strike in the middle of the night Multiple small joints of the hands may be involved. Flares involving multiple joints in the upper extremities are a more common feature in early gout in women than in men.4 As disease progresses, flares tend to ascend from lower extremities up3 References: Becker MA, Jolly M. Clinical gout and the pathogenesis of hyperuricemia. In: Koopman WJ, et al, eds. Arthritis and Allied Conditions. 15th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008;75(Suppl 5):S5-S8. Gibson T. Clinical features of gout. In: Hochberg MC et al, eds. Rheumatology. 4th ed. Mosby Elsevier limited 2008: Becker MA. Ruoff GE. What do I need to know about gout? J Fam Prac. 2010; 59:S1-S8. Mandell BF. Cleve Clin J Med. 2008;75:S5-S8. Gibson T. In Rheumatology. 4th ed. Mosby Elsevier limited 2008:

sUA Levels as a Diagnostic Marker
sUA levels may be normal ~50% of the time during a flare Normal sUA at the time of a flare does not rule out a gout diagnosis!!! Measure sUA after a flare resolved(may take up to 2 weeks) Laboratories often report hyperuricemia based on population norms sUA levels are often normal during a flare, so measurements should be made at least 2 weeks post flare It is important to note that patients with elevated sUA may not have acute gout flares and that patients with acute flares may not have elevated sUA. A fall in sUA level usually precedes the acute attack. This fall encourage tophus dissolution In the Urano study, sUA levels during the acute attack were normal in 49% of patients. The mean levels of sUA in these patients during the acute gout attack (7.5 ± 1.4 mg/dL or 450 μmol/L) were significantly lower than those in the intercritical phase (8.5 ± 0.9 mg/dL or 510 μmol/L ); p<0.0001) Clinical laboratories often define hyperuricemia as above the normal sUA range based on population norms, which can range up to μmol/L , where clinically significant hyperuricemia is an sUA >360 μmol/L In physiologic terms, any level above 360 μmol/L is hyperuricemia, since it exceeds the soluble concentration of MSU in body fluid References: Urano W, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol. 2002; 29: Zhang W, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65: Gibson T. Clinical features of gout. In: Hochberg MC et al, eds. Rheumatology. 4th ed. Elsevier limited 2008: Urano W. et al. J Rheumatol. 2002; 29: Zhang W. et al. Ann Rheum Dis. 2006; 65:

Risk Factors and Associated Comorbidities
Hypertension Cardiovascular disease Chronic kidney disease Diabetes mellitus Dyslipidemia Metabolic syndrome Lifestyle Obesity (high BMI) Diet rich in meat and seafood High alcohol intake Frequent consumption of high-fructose corn syrup Medications Thiazide diuretics Low-dose aspirin Cyclosporine Nicotinic acid Levodopa Demographic Factors Advanced age Male Postmenopause in women Link between gout and higher risk of death from all causes including CVD Hyperuricemia is a metabolic disorder that is associated with many comorbidities and risk factors Comorbidities: Many comorbidities have been linked to hyperuricemia and gout.1 Studies are now clearly demonstrating the risk of high sUA and cardiovascular risk. Evidence is growing that hyperuricemia increases the risk of cardiovascular disease independent of traditional cardiovascular disease risks.1 A systematic review and meta-analysis including 26 studies and over adults found that hyperuricemia was associated with an increased risk of coronary heart disease incidence and mortality. For each 60 µmol/l increase in uric acid level, the pooled multivariate RR for CHD mortality was (95% CI ). Interestingly, this review found a more pronounced risk for CHD mortality in women than men with hyperuricemia.1 Among middle-aged men, a diagnosis of gout with high sUA imparts significant independent CVD mortality risk. A 17-year follow-up of 9,105 mean aged 41–63 with above average CVD risk in MRFIT study. Unadjusted CVD death was 10.3/1000 person-years in patients with gout, a 30% increase compared to gout-free patients.2 Lifestyle: large-scale studies have clearly demonstrated the relationship between lifestyle factors, hyperuricemia, and gout.3 Key dietary risk factors for hyperuricemia and gout include: meat, seafood, beer, liquor, adiposity, weight gain, hypertension and diuretic use. Other putative risk factors, such as protein and purine-rich vegetables were exonerated, and interestingly a potential protective effect of dairy products was identified. A small study found that consumption of skim milk led to a 10% reduction in serum urate concentrations, while soy milk consumption led to a 10% increase in serum urate concentrations likely related to its high purine content.4 Renal impairment: Many patients with gout are renally impaired and have reduced urate excretion based on age and vascular impairment due to hypertension, hyperlipidemia, and diabetes. Medications: The medications listed on this slide may increase the risk of gout by reducing net renal urate excretion5 References Choi HK, et al. Pathogenesis of gout. Ann Intern Med. 2005;143: Kim SY, et al. A Systematic Review and Meta-Analysis: Hyperuricemia and Coronary Heart Disease. Arth Care & Res. 2010; 62: 170–180. Krishnan E, et al. . Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med. 2008;168: Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol 2010; 22:165–172 Dalbeth N, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis published online May 14, 2010 Scott JT. Drug-induced gout. Baillieres Clin Rheumatol Apr;5(1):39-60. Kou C-F, et al. CHD mortality in women than men with hyperuricemia. Rheumatology 2010;49:141–146. Choi HK, et al. Ann Intern Med. 2005;143: Kim SY. et al. Arth Care & Res. 2010; 62: 170–180. Krishnan E. et al. Arch Intern Med. 2008;168: Kou D-F.et al. Rheumatology 2010;49:141–146.

Resolve the Acute Flare Rapidly
Rapidly initiate a sufficient dose of anti-inflammatory therapy NSAIDs Colchicine Corticosteroids (IA/PO/IV/IM) Consider drug limitations due to comorbidities Evaluate NSAIDS gastropathy risk Remember: anti-inflammatory agents do not treat the underlying cause of the disease Before the chronic disease can be managed, the acute attack must first be treated with the appropriate anti-inflammatory drug Pharmacotherapy for acute gout includes NSAIDs such as naproxen, celecoxib, flurbiprofen, indomethacin, and sulindac, corticosteroids such as prednisone, intra-articular triamcinolone or intra-muscular deposteroids and colchicine. Oral colchicine and/or NSAIDs are first line agents for systemic treatment of acute gout. In the absence of contraindications an NSAID is a convenient and well accepted option. (EULAR recommendation) It is important to maintain treatment for an adequate duration. References: Zhang W, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65: Zhang W. et al. Ann Rheum Dis 2006;65:

Colchicine Effective but limited by adverse effects
(nausea, vomiting, diarrhea) Clearance of colchicine is reduced in patients with CKD, increasing the risk of neuromyopathy and bone marrow supporssion Acute flare in CKD: Usual dose is 0.6 mg TID for 6 doses Reduce to 0.6 mg daily in CKD 3-5 Prophylaxis: eGFR mL/min: 0.6 mg BID eGFR mL/min: 0.6 mg once daily eGFR mL/min: 0.6 mg every 2 days eGFR <15 mL/min: not recommended

ULT = urate-lowering therapy;
Gout Flares during Urate Lowering Therapy Effect of Concomitant Anti-Inflammatory Prophylaxis Anti-inflammatory prophylactic therapy is not a chronic treatment; its use is recommended for up to 6 months. It is only needed to prevent mobilization flares upon the initiation of urate-lowering therapy while sUA levels are normalizing As urate-lowering therapy reduces the uric acid pool, urate crystals become mobile and shedding (breakdown) occurs. Mobilization and shedding causes phagocytosis to recur and therefore patient experiences flare. Mobilization flares can be indicative of an effective response to urate-lowering therapy, however, their occurrence may reduce patient compliance with the medication regimen In this study, colchicine administration during initiation of allopurinol for chronic gouty arthritis reduced the frequency and/or severity of mobilization flares, as measured on a visual analog scale (VAS) Subjects treated with colchicine experienced fewer total flares (0.52 vs. 2.91, P =.008), fewer flares from 0 to 3 months (0.57 vs. 1.91, P =.022), fewer flares from 3-6 months (0 vs. 1.05, P =.033), less severe flares (3.64 vs. 5.08, P=.018), and fewer recurrent gout flares (P=.001) Treating patients with colchicine during initiation of allopurinol therapy for 6 months was supported by these data Acronyms: ULT = urate-lowering therapy; BID = twice daily Reference: Borstad GC, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31:2429–2432. *P = vs. Colchicine; †P = vs. Colchicine; ULT = urate-lowering therapy; BID = twice daily Borstad GC. et al. J Rheumatol. 2004;31:

Indomethacin/NSAIDs Renal impairment: NSAID use may compromise existing renal function Patients with impaired renal function, especially those taking diuretics, and ACE-i/ARB/DRI, are at greater risk of renal toxicity. Hyperkalemia

NSAIDS Head-to-head comparisons have shown that NSAID efficacy/benefits in acute gout are similar, with no evidence for individual superiority. NSAID choice should be made dependent on a patient’s: concurrent medication comorbidities prior tolerability NSAIDs should be used with caution and even avoided in patients with peptic ulcer disease, gastritis, renal insufficiency, heart failure, liver failure, and in those receiving anticoagulation therapy. To minimize GI toxicity, NSAIDs can be co-administered with GI protectors, such as proton pump inhibitors, or COX-2 selective inhibitors can be used. It is important to maintain treatment for an adequate duration. References: Zhang W, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65: e-Therapeutics. Accessed July 16, 2010

Prednisone Prednisone 30 to 50 mg daily for 3-5, no taper needed but may rebound – so for severe attacks may taper over 10 to 14 days Usually add colchicine to prevent rebound More potent than NSAIDs

Just because clinically evident MSU deposits are undetectable does not mean that they are not present1 Recurrent Flares5 In a 2009 study, Lee et al enrolled gout patients from arthritis clinics, primary care centers, and healthcare systems in 3 major cities (n=371) to assess health-related quality of life using Short Form-36 Of the patients who reported a gout diagnosis (n=298), nearly half of the patients (n=147) reported at least 3 gout flares during the past year About two-thirds (n=195) reported taking anti-gout medication (allopurinol, colchicine, or both). Of those on anti-gout medication, >80% (n=159) were taking allopurinol alone or with colchicine Tophi6 More than a quarter of chronic gout patients may have tophi, which can lead to joint erosion and damage. Tophi are more common in longstanding disease and with sUA levels exceeding 540 µmol/L. Tophi should be considered markers of more severe disease. Patients with tophi should consequently be more aggressively treated. Patients with recurrent attacks or severe, long standing or polyarticular attacks should have radiographs of affected regions to disclose damage associated with MSU deposit although not clinically evident on physical examination. References: Yu JS, et al. MR imaging of tophaceous gout. Am J Roentgenol. 1997;168:523-7. Zhang W, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65: Li-Yu J, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol. 2001;28: Shoji A. et al. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Care Res. 2004;51: Lee SJ, et al. Perceptions of disease and health-related quality of life among patients with gout. Rheumatology 2009;48: Perez-Ruiz F, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47:

Chronic ULT Management options in 2014
DIET MEDICATIONS: Allopurinol Febuxostat Uricosuric Probenecid, Losartan, High Dose ASA

Patients should consider lifestyle and dietary changes to reduce their sUA, but this approach is unlikely to reduce sUA levels to a target of <360 µmol/L1 Diet Items that raise sUA2 Alcohol: The effect of individual alcoholic beverages on sUA levels varies: Beer and spirits confers a larger increase than wine , whereas moderate wine drinking does not increase sUA levels Surf’N Turf: Higher levels of meat and seafood consumption are associated with higher levels of sUA due to their high purine content Fructose: Soft-drinks or food items high in fructose are associated with high levels of sUA as they increase uric acid production. Diet/Lifestyle Adjustments that lower sUA2 Physical activity and weight reduction. Weight loss reduces uric acid levels. Physical activity improves cardiovascular outcomes Milk: milk and dairy products increases urinary urate excretion (uricosuric effect). Vegetables/nuts/legumes: Even purine rich vegetables do not increase the risk of gout and all offer excellent health benefits. Coffee: Caffeine is an xanthine and likely exerts its protective effect by through inhibition of xanthine oxidase. Moderate coffee drinking (<4 cups per day) may help reduce sUA. Vitamin C: Vitamin C supplements have been found to reduce serum uric acid levels and the future risk of gout in clinical trials. References: Emmerson BT. The management of gout. In: Hochberg MC, et al, eds. Rheumatology. 4th ed. Philadelphia, Pa: Mosby; 2008: Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol 2010; 22:165–172.

Chronic Gout Management Benefits of Serum Urate < 360 µmol/L
Reduction in Acute Flares in Years 2 and 3 of Treatment1 2 4 6 8 Serum Urate, mg/dL Tophus Reduction, mm/month 0.5 1 1.5 2.5 Allopurinol (n = 24) Benzbromarone (n = 25) Combined (n = 14) Tophus Size Reduction2 100 N = 267 80 Percentage of Patients With Gout Flare Recurrence 60 40 Numerous studies have proven the importance of long-term, continuous lowering of serum acid level to < 360 µmol/L in patients with gout. Theses benefits include: Reduced recurrence of acute flares1-3 Depletion of crystals from joints2,4 Reduction in tophus size and recurrence of tophi1,2,5 The study on the left retrospectively examined 267 patients with gout over 3 years. The graph above shows the relationship between the average serum urate concentration and the incidence of acute gouty arthritis more than 1 year after each patient’s first visit. Among the 81 patients in the study whose average serum urate concentrations were < 360 µmol/L, 86% had no recurrent gouty attacks during the observation period.3 The study on the right involves 63 patients with tophaceous, crippling gout. Patients, as part of clinical practice in Europe, were given allopurinol), benzbromarone (uriscouric agent not available in United States) or a combination. Mean time to disappearance of tophi was 20.8 months (range 6–64 months). The lower the serum urate, the faster was the disappearance of tophi.5 Dotted lines on both graphs depict goal of urate-lowering to 360 µmol/L. References: Becker MA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353: Li-Yu J, et al. Treatment of chronic gout: can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol. 2001;28: Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis. 2007;66: Perez-Ruiz F, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47: Shoji A, et al. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51: 20 300 330 360 390 420 450 480 510 540 570 600 1. Shoji A. et al. Arthritis Rheum. 2004;51: 2. Perez-Ruiz F. et al. Arthritis Rheum. 2002;47: Mean Serum Urate, µmol/L

Allopurinol Initiation during an acute attack can theoretically worsen the arthritis, although the absolute risk is not clear Considerable interpatient variation in the daily dose required to achieve control of the serum urate concentration

Allopurinol Half-life of allopurinol and oxypurinol are prolonged in renal failure Reduce the starting allopurinol dose eGFR < 60 allopurinol 200 OD eGFR < 30 allopurinol 100 OD eGFR < 15 consider discontinuing

Chronic Gout Management Febuxostat
Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production1 Rapidly and well absorbed with no accumulation Extensive hepatic metabolism Renal excretion No dose adjustments needed in people with decreased renal function Febuxostat directly and selectively inhibits xanthine oxidase, inhibiting the enzyme involved in purine metabolism leading to a reduction in the production of uric acid and sUA Febuxostat has a good pharmacokinetic profile, with extensive absorption, dose-proportional increases in exposure, and a half-life which allows for once-a-day dosing without accumulation. Inhibition of other enzymes involved in purine and pyrimidine synthesis and metabolism is not expected with febuxostat. Clearance is mainly by hepatic metabolism and renal elimination is minimal. clinical studies have shown that febuxostat is unlikely to be involved in drug-drug interactions References: 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA 2. Pacher P, et al. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58: 3. Emmerson BT. The management of gout. N Engl J Med. 1996;334: 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA 2. Pacher P. et al. Pharmacol Rev. 2006;58: 3. Emmerson BT. N Engl J Med. 1996;334:

Febuxostat Efficacy Conclusions
Core Introduction (CI) 4/14/ :37 AM Febuxostat Efficacy Conclusions 80 mg effectively lowers and maintain sUA <360 µmol/L 80 mg superior to allopurinol 300mg 80 mg is effective in subjects with renal impairment without dose adjustment Maintenance of sUA <360 µmol/L is critical to decreases in gout flares and tophi resolution DRAFT 34 34

Chronic Gout Management Febuxostat
Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production1 Rapidly and well absorbed with no accumulation Extensive hepatic metabolism Renal excretion No dose adjustments needed in people with decreased renal function Febuxostat directly and selectively inhibits xanthine oxidase, inhibiting the enzyme involved in purine metabolism leading to a reduction in the production of uric acid and sUA Febuxostat has a good pharmacokinetic profile, with extensive absorption, dose-proportional increases in exposure, and a half-life which allows for once-a-day dosing without accumulation. Inhibition of other enzymes involved in purine and pyrimidine synthesis and metabolism is not expected with febuxostat. Clearance is mainly by hepatic metabolism and renal elimination is minimal. clinical studies have shown that febuxostat is unlikely to be involved in drug-drug interactions References: 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA 2. Pacher P, et al. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58: 3. Emmerson BT. The management of gout. N Engl J Med. 1996;334: 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA 2. Pacher P. et al. Pharmacol Rev. 2006;58: 3. Emmerson BT. N Engl J Med. 1996;334:

Acute Gout Management Pathway
Acute Flare Goal -> Resolve rapidly to suppress pain and inflammation NSAID (including coxibs) ± PPI or Colchicine Corticosteroid (i.a., oral, i.m., i.v.) Other options: Centrally acting analgesic, opioids Treat as soon as possible Review at weeks Assess lifestyle factors Check serum urate, Check blood pressure, Renal function & Glucose in all patients Further attacks (or risk factors +++) Treat acute attack Consider Serum Urate Lowering Therapy when acute attack resolved if: >2 acute attacks per year or any of the following: Tophi, sUA >360 μmol/L, combined gout and urolithiasis, severe or difficult to treat acute attacks of gout, chronic persistent gouty arthritis Resolution All patients Optimize weight Increase exercise Modify diet Reduce alcohol intake Maintain fluid intake Treat underlying cardiovascular risk factors Adapted from Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46:

Chronic Gout Management Pathway
Acute attack resolved Frequent gout attacks (>2 per year) or any of the following: Tophi (detected clinically or by imaging) Uric acid overproduction (sUA >360 μmol/L Combined gout and urolithiasis Severe or difficult to treat acute attacks of gout Chronic persistent gouty arthritis Check renal function If CrCl mL/min Start ALLOPURINOL ( mg QD) or Start FEBUXOSTAT (80 mg QD*) *No dose adjustments need for reduced renal function If CrCl >100 mL/min Start ALLOPURINOL (300 mg QD^) or Start FEBUXOSTAT (80 mg QD) if CrCl >60 ml/min start PROBENECID (1-3 g BID or TID) ^Upward dose titration may be needed to achieve target Title: Therapeutic algorithm for Family Practitioners – serum urate lowering in patients with gout Anti-inflammatory prophylaxis for up to 6 months Check sUA regularly Maintain sUA lowering therapy to achieve and maintain sUA <360 μmol/L

Case 3: Mr. S.S. WHAT IS THE TARGET BP?? 66 y.o. retired salesman
History of: Hypercholesterolemia Erectile dysfunction Osteoarthritis Hypertension CKD / HT Meds: Atorvastatin 20 ASA 81mg BP 152/89 mmHg Cr = 129, eGFR = 52 ACR = 31 mg/mmol WHAT IS THE TARGET BP??

Chronic kidney disease and proteinuria *
X. Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease Target BP: < 140/90 mmHg Chronic kidney disease and proteinuria * ACEI or ARB Additive therapy: Thiazide diuretic. Alternate: If volume overload: loop diuretic Combination with other agents ACEI/ARB: Bilateral renal artery stenosis * albumin:creatinine ratio [ACR] > 30 mg/mmol or urinary protein > 500 mg/24hr Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB Combinations of a ACEI and a ARB are specifically not recommended in the absence of proteinuria 39

XI. Treatment of Hypertension in Patients with Renovascular Disease
Does not imply specific treatment choice Renovascular disease Caution in the use of ACEI or ARB in bilateral renal artery stenosis or unilateral disease with solitary kidney Close follow-up and intervention (angioplasty and stenting or surgery) should be considered for patients with: uncontrolled hypertension despite therapy with three or more drugs, or deteriorating renal function, or bilateral atherosclerotic renal artery lesions (or tight atherosclerotic stenosis in a single kidney), or recurrent episodes of flash pulmonary edema. 40

The ups and downs of BP targets in CKD
1999: ADDED new recommendation lowering BP targets in CKD– MDRD For patients with proteinuria that is greater than 1 g/day, target blood pressure is lower than 125/75 mm Hg (MAP 92) (GRADE C) 2006: REMOVED recommendation – REIN-2. Target of 130/80 still supported based on AASK, MDRD 1999 added new recommendation based on findings from MDRD suggesting that patients with MAP less than 92 and more than 1g per day of proteinuria. CHEP panel concluded that the AASK followup data was methodologically suspect based on their switch of primary outcomes from that used in the original study 2010- revisiting the AASK followup data: little support for lower targets except (maybe) for those with proteinuria…. Triggering revisiting of overall recommendation 41

Studies of BP targets in CKD patients
Upadhyay , Ann Intern Med. 2011;154: MDRD AASK REIN-2 N Target BP ~125/75 ~125/ /80 vs.~140/90 vs.~140/90 vs. x/90 1o outcome change in GFR composite ESRD Mortality ND ND ND CVD events ND ND x GFR decline ND ND ND ESRD ND ND ND

In 2012, CHEP revisited the CKD BP targets following publication of significant new data
For patients with nondiabetic chronic kidney disease, target BP is <130/80 mm Hg (Grade C). For patients with nondiabetic chronic kidney disease, target blood pressure is <140/90 mm Hg (Grade B).

Case 4: Ms R.O. What work up does the anemia require?
Mr R.O. is a 51-year-old with CKD 3b due to Diabetes eGFR =35 ml/min Medications include ACEi,CCB, HCZ,statin. Insulin Presents to MD for physical and flu shot Bloodwork: Cr = 152 eGFR = 35, ACR = 22 mg/mmol K = 4.8, Lipids optimal A1c = 6.9% Hb = 104 What work up does the anemia require? What treatment is indicated?

3 RCTs Designed to Address Whether Anemia Correction in CKD May Improve CV Morbidity and Mortality
CREATE (Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin beta) - Completed Determine the impact of early vs late anemia correction on mortality and cardiovascular morbidity in patients with CKD CHOIR (Correction of Hemoglobin and Outcomes In Renal insufficiency) – Terminated Early Determine the impact of degree of anemia correction on mortality and cardiovascular morbidity in patients with CKD TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) - Enrolling Determine the impact of anemia therapy (yes/no) on mortality and cardiovascular morbidity in patients with CKD and type 2 diabetes

Conclusion The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke For many persons involved in clinical decision making, this risk will outweigh the potential benefits

Treatment of Anemia with Erythropoietin Stimulating Agents (ESAs): What We Know
Dialysis CKD Improvements Hb Reduces Transfusion /- Quality of Life /- CV Outcomes no 3 RCTs

Frequency of Anemia Testing in CKD
CKD 4-5ND CKD 5HD and 5PD CKD patients without anemia At least annually At least twice per year At least every 3 months CKD patients with anemia but not treated with an ESA At least monthly in 5HD and at least every 3 months in 5PD Adults and children >15 years old Hemoglobin (g/l) Male <130 Female <120

Investigation of anemia in CKD
In patients with CKD and anemia ( regardless of age and CKD stage), include the following tests in initial evaluation of anemia: Complete blood count ( CBC) including Hb concentration, red cell indices, WBC count and differential and platelet count Absolute reticulocyte count Serum ferritin level Serum transferring saturation ( TSAT) Serum vitamin B12 and folate levels

Iron Studies Not Super Useful in CKD:
Sensitivity and specificity of TSAT and serum ferritin (ferritin) and their combination (TSAT þ ferritin) and bone marrow iron (BM iron) to identify correctly a positive erythropoietic response (Z1- g/dl [Z10-g/l] increase in Hb [DHb]) to intravenous iron in 100 nondialysis patients with CKD (areas under the ROCs).

Iron Therapy in CKD Choice of FE Rx
Patient Type Clinical Parameters Treatment Plan Adult CKD patients with anemia not on iron or ESA therapy - If an increase in HB concentration without ESA treatment is desired* and -TSAT is ≤30% and ferritin is ≤500µg/l We suggest a trial of IV iron or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy (2C) Adult CKD patients on ESA therapy, not receiving iron supplementation - If an increase in HB concentration** or a decrease in ESA dose is desired*** and -TSAT is ≤30% and ferritin is ≤500µg/l Select the route of iron administration based on: The severity of iron deficiency Availability of venous access Response to prior oral iron therapy Side effects with prior oral or IV iron therapy Patient compliance Cost

We recommend using ESA therapy with great caution, if at all, in:
CKD patients with active malignancy, in particular when cure is the anticipated outcome (1B) CKD patients with a history of stroke ( 1B) CKD patients with a history of malignancy (2C)

ESA in CKD ND Hb < 100 Hb >100
We suggest that the decision whether to initiate ESA therapy be individualized based on (2C): The rate of fall of Hb concentration Prior response to iron therapy The risk of needing a transfusion The risks related to ESA therapy The presence of symptoms attributable to anemia We suggest that ESA therapy not be initiated (2D)

ESA in CKD 5D We suggest that ESA therapy be used to avoid having the Hb concentration fall below 90 g/l by starting ESA therapy when the hemoglobin is between g/l (2B) In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD. (2C) In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl (130 g/l). (1A)

Case 5 Mr C.O. Mr O. is a 48-year-old with hypertension, high chol
Medications include CCB, statin. Presents to MD for flank pain NYD US : Cysts +++ LAB: Cr 130 with eGFR = 52 No Family History Referred to for ? PKD

Genetic Renal Cystic Disease
Non-Genetic Renal Cystic Disease Genetic Renal Cystic Disease ARPKD (Autosomal Recessive PKD) ADPKD (Autosomal Dominant PKD) Juvenile Nephronophthisis – Medullary CD Juvenile Nephronophthisis (autosomal recessive) Medullary Cystic Disease (autosomal dominant) Congenital Nephrosis (autosomal recessive) Familial Hypoplastic Glomerulocystic Disease (autosomal dominant) Others – e.g. Cystic Fibrosis, VHL Multicystic Dysplastic Kidney Benign Multilocular Cyst (Cystic Nephroma) Simple Cysts – Bosniak Classification Medullary Sponge Kidney Sporadic Glomerulocystic Kidney Disease Acquired Renal Cystic Disease Calyceal Diverticulum Cystic Renal Cell Carcinoma

Simple Cysts (or not) Observed frequently in normal kidneys.
65 to 70 percent of cases of “renal masses” Prevalence: 30 to 49 — 1.9; 1.4 50 to 69 — 15; 6.7 >70 — 32.3; 14.6 Signs/Symptoms: None. Rarely, rupture (hemorrhage), hematuria, pain, abdominal mass, infection, and/or hypertension. Imaging: Simple renal cysts have characteristic changes on US and CT DDx: polycystic kidney disease, complex cysts, and solid masses (such as a renal carcinoma or abscess). Treatment: The vast majority of simple cysts require no treatment. Therapy may rarely be required for symptoms, signs, and/or complications.

Adult Polycystic Kidney Disease
Autosomal dominant 1-2 per 1000 Cysts present at birth, progressively enlarge to compress renal parenchyma Occurs at variable rate, more rapid in males 4th Common cause of ESRD ~ 5- 10%

Genetics Gene PKD1 on chromosome 16 (85%)
The protein, polycystin I, is a membrane glycoprotein involved in regulation of the cell cycle, the mutation leads to fluid secretion Gene PKD2 on chromosome 4 (most of the rest), ESRF occurs 10-15yrs later

Symptoms Age 30-50 Hypertension (+ cLVH) Microscopic/ Gross hematuria
Renin mediated Microscopic/ Gross hematuria Acute loin pain/colic and haematuria due to haemorrhage into a cyst, infection or ureteric stone Incidental finding of liver/kidney cysts on U/S Abdominal discomfort due to pressure Berry aneurysm (~5 - 10%) Chronic renal failure once below 50ml/min, GFR declines by ~5ml/min/year

Associations Cystic change on other organs
esp. liver, spleen, pancreas Berry aneurysms leading to SAH prompt Ix of sudden onset or severe headaches Mitral valve prolapse affects 20%

Screening Patients should have regular BP checks
Offer genetic counseling Family members should be offered: screening for intracranial aneurysms (18-40yrs) renal screening by US (>20yrs)

Imaging

ADPKD - Treatment Role of genetic counseling
Role of hypertension management ACEi, ARB Risk of infection co-trimoxazole, quinolones Avoid nephrotoxins Smoking Calculi: percutaneous removal, lithotripsy etc. Management of pain: medical vs surgical Management of meganephrosis CRF: dialysis and transplant

Polycystin and ADPKD. Polycystin and ADPKD
BRAUN W E Cleveland Clinic Journal of Medicine 2009;76:97-104

The Role of Vasopressin
1. Increasing fluid intake to suppress plasma vasopressin levels (> 3L/Day) 2. vasopressin V2 receptor antagonists, which lower intracellular cAMP levels Inhibit cystogenesis and prevent renal enlargement and dysfunction Less Epithelial Cell proliferation Less Fluid accumulation

Original Article Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4 Trial Investigators N Engl J Med Volume 367(25): December 20, 2012

Study Overview In this trial, patients with autosomal dominant polycystic kidney disease were randomly assigned to tolvaptan, a vasopressin V2- receptor antagonist, or placebo. Tolvaptan 60 to 120 mg (divided into 60 mg in the morning and 30 mg at night). Inclusion criteria included ages 18 to 50 years (mean of 40 years), estimated creatinine clearance >60 ml/min (mean 81 mL/min) and total kidney volume >750 mL (mean 1705 mL). Over 3 years, the increase in total kidney volume in the tolvaptan group was half that in the placebo group.

Most Common Adverse Events and Serious Adverse Events.
Table 2 Most Common Adverse Events and Serious Adverse Events. Torres VE et al. N Engl J Med 2012;367:

Conclusions Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events.

Summary of Treatments:
Increased fluid intake — 3 L/Day to suppress plasma vasopressin levels Tolvaptan (First thing with any clinical benefit) Somatostatin - may reduce renal and liver cyst fluid accumulation among patients with PKD Other approaches being studied: Mammalian target of rapamycin (mTOR) — (e.g. sirolimus Protein restriction does not seem to work Methylprednisolone, urinary alkalinization, taxol, lovastatin, epidermal growth factor receptor tyrosine kinase inhibitors, peroxisome proliferator-activated receptor agonists, cyclin-dependent kinase inhibitors, and mitogen-activated protein kinase inhibitors,

Summary Renal Emergencies Gout BP targets in CKD: Anemia Guidelines
recognize that Nephrotic Syndrome is a renal emergency Review other renal emergencies briefly Gout Acute vs Chronic management First do no harm, many medications need dose adjusting in CKD BP targets in CKD: Diabetes = 130/80 Non DM = 140/90 Anemia Guidelines No need for expensive work-up Treat if Hb < 100 and Sx or < 90 Iron therapy +/- ESA Goals are mainly for QOL and to avoid transfusions PKD Treat BP, avoid toxins,drink lots, promising future

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