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

CFPC CoI Templates: Slide 1

Disclosure of Commercial Support

I have no industry-related financial conflicts of interest to declare

CFPC CoI Templates: Slide 2

Mitigating Potential Bias

No particular drugs are being discussed in this program content

CFPC CoI Templates: Slide 3

Overview and Objectives

1. What constitutes a true renal emergency?

2. Management of gout in CKD3. Appreciate that we often over treat

BP in CKD. Review the 2012 CHEP guidelines for HT

targets in Non DM CKD4. Review the results of ESA in CKD and

review the 2012 KDIGO Anemia Guidelines in CKD

5. Review the role of Tolvaptan in PKD. Review the results of the Tempo 3:4 trial

Case 1: Mr. C.K. 57 y.o.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 SOAFacial edema in AMFeels weak and unwell

O/E: BP 110/74, 92 kgJVP low, 3+ edemaChest clear, dull basesNil else

Lab: Cr = 86 eGFR = 96 ACR > 100, UA bland24 H Urine 8 g/d

TG = 4.0, HDL = 2.1LDL = 5.1, TC = 7.0

PMH: Nil, Pipe smoker

Fam Hx: Dad died 69 of MI

MEDS: None

HPI: 2 weeks of increased SOAFacial edema in AMFeels weak and unwell

O/E: BP 110/74, 92 kgJVP low, 3+ edemaChest clear, dull basesNil else

Lab: Cr = 86 eGFR = 96 ACR > 100, UA bland24 H Urine 8 g/d

TG = 4.0, HDL = 2.1LDL = 5.1, TC = 7.0

Case 1 : EdemaLow AlbuminProteinuria > 3gHigh Cholesterol(Lipiduria)

Dx: Nephrotic Syndrome

This is a renal emergency!!!

What Are Renal Emergencies / Urgencies?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

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. TeacherCase 2 : Mr. G.C. 54 y.o. Teacher

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?

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 EKGHyperkalemia EKG

Case Further Hx: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

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:

 “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.

 

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”“The Gout”

Pathophysiology of Gout: Acute Flares

Pathophysiology of Gout: Acute Flares

Common SitesCommon Sites

Frequency:

•Big toe 76%

•Ankle/foot 50%

•Knee 32%

•Finger 25%

•Elbow/wrist 10%

•>1 site simult.11%

Mandell BF. Cleve Clin J Med. 2008;75:S5-S8.Gibson T. In Rheumatology. 4th ed. Mosby Elsevier limited

2008:1829-1837

sUA Levels as a Diagnostic MarkersUA 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 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

Urano W. et al. J Rheumatol. 2002; 29:1950-3.Zhang W. et al. Ann Rheum Dis. 2006; 65:1301-

11.

Risk Factors and Associated Comorbidities

Risk Factors and Associated Comorbidities

ComorbiditiesHypertension Cardiovascular diseaseChronic kidney diseaseDiabetes mellitusDyslipidemiaMetabolic syndrome

LifestyleObesity (high BMI) Diet rich in meat and seafoodHigh alcohol intakeFrequent consumption of high-fructose corn syrup

ComorbiditiesHypertension Cardiovascular diseaseChronic kidney diseaseDiabetes mellitusDyslipidemiaMetabolic syndrome

LifestyleObesity (high BMI) Diet rich in meat and seafoodHigh alcohol intakeFrequent consumption of high-fructose corn syrup

MedicationsThiazide diureticsLow-dose aspirinCyclosporineNicotinic acidLevodopa

Demographic FactorsAdvanced ageMalePostmenopause in women

MedicationsThiazide diureticsLow-dose aspirinCyclosporineNicotinic acidLevodopa

Demographic FactorsAdvanced ageMalePostmenopause in women

Link between gout and higher risk of death from all causes including CVD

Choi HK, et al. Ann Intern Med. 2005;143:499-5161. Kim SY. et al. Arth Care & Res. 2010; 62: 170–180.

Krishnan E. et al. Arch Intern Med. 2008;168:1104-1110. Kou D-F.et al. Rheumatology 2010;49:141–146.

Resolve the Acute Flare RapidlyResolve 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

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

Zhang W. et al. Ann Rheum Dis 2006;65:1312-1324.

ColchicineColchicine

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 50+ mL/min: 0.6 mg BID

eGFR 30-50 mL/min: 0.6 mg once daily

eGFR 15-30 mL/min: 0.6 mg every 2 days

eGFR <15 mL/min: not recommended

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 50+ mL/min: 0.6 mg BID

eGFR 30-50 mL/min: 0.6 mg once daily

eGFR 15-30 mL/min: 0.6 mg every 2 days

eGFR <15 mL/min: not recommended

Gout Flares during Urate Lowering Therapy Effect of Concomitant Anti-Inflammatory Prophylaxis

Gout Flares during Urate Lowering Therapy Effect of Concomitant Anti-Inflammatory Prophylaxis

Borstad GC. et al. J Rheumatol. 2004;31:2429-2432.

*P = 0.022 vs. Colchicine; †P = 0.033 vs. Colchicine;

ULT = urate-lowering therapy; BID = twice daily

Indomethacin/NSAIDsIndomethacin/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

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

PrednisonePrednisone

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

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

Chronic ULT Management options in 2014

Chronic ULT Management options in 2014

DIET

MEDICATIONS: Allopurinol Febuxostat

UricosuricProbenecid, Losartan, High Dose ASA

DIET

MEDICATIONS: Allopurinol Febuxostat

UricosuricProbenecid, Losartan, High Dose ASA

Chronic Gout ManagementBenefits of Serum Urate < 360 µmol/L

Chronic Gout ManagementBenefits of Serum Urate < 360 µmol/L

1. Shoji A. et al. Arthritis Rheum. 2004;51:321-325.

2. Perez-Ruiz F. et al. Arthritis Rheum. 2002;47:356-360.

Mean Serum Urate, µmol/L

Pe

rcen

tag

e o

f P

ati

ents

Wit

h

Go

ut

Fla

re R

ecu

rre

nc

e

300 330 360 390 420 450 480 510 540 570 6000

20

40

60

80

100

Reduction in Acute Flaresin Years 2 and 3 of Treatment1

0

2

4

6

8

Se

rum

Ura

te, m

g/d

LTophus Reduction, mm/month

0 0.5 1 1.5 2 2.5

Allopurinol (n = 24) Benzbromarone (n = 25)Combined (n = 14)

Tophus Size Reduction2

N = 267

AllopurinolAllopurinol

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

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

AllopurinolAllopurinol

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

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 ManagementFebuxostat

Chronic Gout ManagementFebuxostat

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

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

1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA. 2006.2. Pacher P. et al. Pharmacol Rev. 2006;58:87-114.3. Emmerson BT. N Engl J Med. 1996;334:445-451.

Febuxostat Efficacy ConclusionsFebuxostat 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

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

Chronic Gout ManagementFebuxostat

Chronic Gout ManagementFebuxostat

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

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

1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA. 2006.2. Pacher P. et al. Pharmacol Rev. 2006;58:87-114.3. Emmerson BT. N Engl J Med. 1996;334:445-451.

Acute FlareGoal -> Resolve rapidly to suppress pain and inflammation

NSAID (including coxibs) ± PPI or

Colchicine or

Corticosteroid (i.a., oral, i.m., i.v.)Other options:

Centrally acting analgesic, opioids

Treat as soon as possible

Review at 4 - 6 weeksAssess lifestyle factors

Check serum urate,Check blood pressure,

Renal function & Glucose in all patients

Further attacks (or risk factors +++)Treat acute attackConsider Serum Urate Lowering Therapy when acute attack resolved if:1.>2 acute attacks per year or2. 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

Acute Gout Management

Pathway

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;46:1372-4.

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

If CrCl 30-100 mL/minStart ALLOPURINOL (100-250 mg

QD) or

Start FEBUXOSTAT (80 mg QD*)*No dose adjustments need for reduced

renal function

If CrCl >100 mL/minStart ALLOPURINOL (300 mg QD^)

or Start FEBUXOSTAT (80 mg QD)

or if CrCl >60 ml/min start PROBENECID (1-3 g BID or TID)

^Upward dose titration may be needed to achieve target

Check renal function

Anti-inflammatory prophylaxis for up to 6 months

Check sUA regularlyMaintain sUA lowering therapy

to achieve and maintain sUA <360 μmol/L

Acute attack resolvedChronic Gout Management

Pathway

Case 3: Mr. S.S.

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??

X. Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease

Chronic kidney disease and proteinuria *

ACEI/ARB: Bilateral renal artery stenosis

ACEI or ARB

Combination with other agents

Additive therapy: Thiazide diuretic.Alternate: If volume overload: loop diuretic

Target BP: < 140/90 mmHg

* 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

XI. Treatment of Hypertension in Patients with Renovascular Disease

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.

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

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)

x 2006: REMOVED recommendation – REIN-2. Target of 130/80 still supported based on AASK, MDRD

The ups and downs of BP targets in CKD

2010- revisiting the AASK followup data: little support for lower targets except (maybe) for those with proteinuria….Triggering revisiting of overall recommendation

Studies of BP targets in CKD patients Upadhyay , Ann Intern Med. 2011;154:541-548

MDRD AASK REIN-2

N 840 1094 334

Target BP ~125/75 ~125/75 130/80

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

CHEP 2011 CHEP 2012

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.

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?

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

3 RCTs Designed to Address Whether Anemia Correction in 3 RCTs Designed to Address Whether Anemia Correction in CKD May Improve CV Morbidity and MortalityCKD May Improve CV Morbidity and Mortality

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 3 CKD 4-5NDCKD 5HD and 5PD

CKD patients without anemia

At least annuallyAt least twice per year

At least every 3 months

CKD patients with anemia but not treated with an ESA

At least every 3 months

At least every 3 months

At least monthly in 5HD and at least every 3 months in5PD

Adults and children >15 years old

Hemoglobin(g/l)

Male <130

Female <120

Investigation of anemiain 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 RxPatient 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

We suggest a trial of IV iron or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy (2C)

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 90-100 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

56

Genetic Renal Cystic Disease

Genetic Renal Cystic Disease

Non-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

Genetic Renal Cystic Disease

Genetic Renal Cystic Disease

Non-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)

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

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.

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 MedVolume 367(25):2407-2418

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.

Torres VE et al. N Engl J Med 2012;367:2407-2418

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

1. Renal Emergencies recognize that Nephrotic Syndrome is a renal emergency Review other renal emergencies briefly

2. Gout Acute vs Chronic management First do no harm, many medications need dose adjusting in CKD

3. BP targets in CKD: Diabetes = 130/80 Non DM = 140/90

4. 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

5. PKD Treat BP, avoid toxins,drink lots, promising future