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
CFPC CoI Templates: Slide 2
Disclosure of Commercial
Support
 I have no industry-related financial conflicts of interest
to declare
CFPC CoI Templates: Slide 3
Mitigating Potential Bias
No particular drugs are being discussed in this program content
Nephrologist, Lakeridge Health
May 14, 2014
Overview and Objectives
1. What constitutes a true renal
emergency?
2. Management of gout in CKD
3. Appreciate that we often over treat BP
in CKD.

Review the 2012 CHEP guidelines for HT
targets in Non DM CKD
4. 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.
 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
24 H Urine 8 g/d
TG = 4.0, HDL = 2.1
LDL = 5.1, TC = 7.0
ACR > 100, UA bland
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
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)
-Enalapril (Vasotec)
-Lisinopril (Zestril)
-Trandolopril (Mavik)
Angiotensin Receptor Blockers
-Telmisartan (Micardis)
-Valsartan (Diovan)
-Irbesartan (Avapro)
-Fosinopril (Monopril)
-Perindopril (Coversyl)
-Cilazapril (Inhibace)
-Candesartan (Atacand)
-Losartan (Cozaar)
-Eposartan (Teveten)
-Olmesartan (Olmetec)
Direct Renin Inhibitors
-Aliskerin (Rasilez)
Diuretics (“Water Pills”)
-Furosemide (Lasix)
-Hydrochlorothiazide (HCTZ)
-Spironolactone (Aldactone)
-Indapamide (Lozide)
-Chlorthalidone
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”
Pathophysiology of Gout:
Acute Flares
Common 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 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
Urano W. et al. J Rheumatol. 2002; 29:1950-3.
Zhang W. et al. Ann Rheum Dis. 2006; 65:130111.
Risk Factors and
Associated Comorbidities
Comorbidities
 Hypertension
 Cardiovascular disease
 Chronic kidney disease
 Diabetes mellitus
 Dyslipidemia
Link
between
gout
and
 Metabolic syndrome
Medications
 Thiazide diuretics
 Low-dose aspirin
 Cyclosporine
 Nicotinic acid
 Levodopa
higher risk of death from all
causes including CVD
Lifestyle
 Obesity (high BMI)
 Diet rich in meat and
seafood
 High alcohol intake
 Frequent consumption of
high-fructose corn syrup
Demographic Factors
 Advanced age
 Male
 Postmenopause in women
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 Rapidly
 Rapidly initiate a sufficient dose of antiinflammatory 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.
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 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
Colchicine 0.6 mg BID (n=21)
Placebo (n=22)
2.5
1.91*
Mean Number of
Acute Gout Flares
2
1.05†
1.5
1
0.57
0.5
0
0
0 - 3 Months
3 - 6 Months
*P = 0.022 vs. Colchicine;
†P = 0.033 vs. Colchicine;
ULT = urate-lowering therapy;
BID = twice daily
Borstad GC. et al. J Rheumatol. 2004;31:2429-2432.
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
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
Chronic ULT Management options in
2014
 DIET
 MEDICATIONS:
 Allopurinol
 Febuxostat
 Uricosuric
 Probenecid, Losartan, High Dose ASA
Reduction in Acute Flares
in Years 2 and 3 of Treatment1
100
N = 267
80
60
40
20
0
300 330 360 390 420 450 480 510 540 570 600
Tophus Size Reduction2
Serum Urate, mg/dL
Percentage of Patients With
Gout Flare Recurrence
Chronic Gout Management
Benefits of Serum Urate < 360
µmol/L
8
6
4
2
0
0
0.5
1
1.5
2
2.5
Tophus Reduction, mm/month
Allopurinol (n = 24)
Combined (n = 14)
Mean Serum Urate, µmol/L
Benzbromarone (n = 25)
1. Shoji A. et al. Arthritis Rheum. 2004;51:321325.
2. Perez-Ruiz F. et al. Arthritis Rheum.
2002;47:356-360.
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
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 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
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
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 Gout
Management
Pathway
Acute Flare
Goal -> Resolve rapidly to suppress pain and inflammation
Treat as soon as possible
NSAID (including coxibs) ± PPI
or
Colchicine
or
Corticosteroid (i.a., oral, i.m., i.v.)
Other options:
Centrally acting analgesic, opioids
Review at 4 - 6 weeks
Assess lifestyle factors
Check serum urate,
Check blood pressure,
Renal function &
Glucose in all patients
Resolution
Further attacks (or risk factors +++)
Treat acute attack
Consider Serum Urate Lowering Therapy when acute attack resolved
if:
1.>2 acute attacks per year or
2. 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
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;46:1372-4.
Acute attack resolved
Chronic Gout
Management
Pathway
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 30-100 mL/min
Start ALLOPURINOL (100-250 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)
or
if CrCl >60 ml/min start PROBENECID (1-3 g BID or TID)
^Upward dose titration may be needed to achieve target
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.
 66 y.o. retired salesman
 History of:





Hypercholesterolemia
Erectile dysfunction
Osteoarthritis
Hypertension
CKD / HT
 Meds:
BP 152/89 mmHg
Cr = 129, eGFR = 52
ACR = 31 mg/mmol
 Atorvastatin 20
 ASA 81mg
WHAT IS THE TARGET BP??
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
* albumin:creatinine ratio [ACR] > 30 mg/mmol
or urinary protein > 500 mg/24hr
ACEI/ARB: Bilateral
renal artery
stenosis
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
Renovascular
disease
Does not imply specific
treatment choice
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.
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)
x 2006: REMOVED recommendation – REIN-2. Target of 130/80
still supported based on AASK, MDRD
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
For patients with
nondiabetic chronic
kidney disease, target
BP is <130/80 mm Hg
(Grade C).
CHEP 2012
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?
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 patients
without anemia
CKD patients with
anemia but not
treated with an ESA
CKD 3
CKD 4-5ND
CKD 5HD and 5PD
At least annually
At least twice per
year
At least every 3
months
At least every 3
months
At least every 3
months
Adults and children >15 years old
Hemoglobin
(g/l)
Male
<130
Female
<120
At least monthly in
5HD and at least
every 3 months in
5PD
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 (Z1g/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
Patient Type
Clinical
Parameters
- If an increase in HB
concentration
Adult CKD patients without ESA
with anemia not on treatment is
iron or ESA therapy desired* and -TSAT
is ≤30% and ferritin is
≤500µg/l
- If an increase in HB
concentration** or a
Adult CKD patients decrease in ESA
on ESA therapy, not dose is desired***
receiving iron
and -TSAT is ≤30%
supplementation
and ferritin is
≤500µg/l
Treatment Plan
We suggest a trial of
IV iron or in CKD ND
patients alternatively
a 1-3 month trial of
oral iron therapy (2C)
We suggest a trial of
IV iron or in CKD ND
patients alternatively
a 1-3 month trial of
oral iron therapy (2C)
Choice of FE Rx
 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
 We suggest that ESA





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
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)

Multicystic Dysplastic Kidney

ADPKD (Autosomal Dominant PKD)


Juvenile Nephronophthisis –
Medullary CD
 Juvenile Nephronophthisis
(autosomal recessive)
 Medullary Cystic Disease
(autosomal dominant)
Benign Multilocular Cyst (Cystic
Nephroma)

Simple Cysts – Bosniak Classification

Medullary Sponge Kidney

Sporadic Glomerulocystic Kidney
Disease

Congenital Nephrosis (autosomal
recessive)

Acquired Renal Cystic Disease

Familial Hypoplastic Glomerulocystic
Disease (autosomal dominant)

Calyceal Diverticulum

Cystic Renal Cell Carcinoma

Others – e.g. Cystic Fibrosis, VHL
Genetic Renal Cystic Disease
Genetic Renal Cystic
Disease
Non-Genetic Renal Cystic
Disease

ARPKD (Autosomal Recessive PKD)

Multicystic Dysplastic Kidney

ADPKD (Autosomal Dominant
PKD)

Benign Multilocular Cyst (Cystic
Nephroma)

Juvenile Nephronophthisis –
Medullary CD
 Juvenile Nephronophthisis
(autosomal recessive)
 Medullary Cystic Disease
(autosomal dominant)

Simple Cysts – Bosniak
Classification

Medullary Sponge Kidney

Sporadic Glomerulocystic Kidney
Disease

Congenital Nephrosis (autosomal
recessive)

Acquired Renal Cystic Disease

Familial Hypoplastic Glomerulocystic
Disease (autosomal dominant)

Calyceal Diverticulum

Cystic Renal Cell Carcinoma

Others – e.g. Cystic Fibrosis, VHL
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 Med
Volume 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 V2receptor 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
Renal Emergencies
1.


recognize that Nephrotic Syndrome is a renal emergency
Review other renal emergencies briefly
Gout
2.


Acute vs Chronic management
First do no harm, many medications need dose adjusting in CKD
BP targets in CKD:
3.


Diabetes = 130/80
Non DM = 140/90
Anemia Guidelines
4.




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
5.

Treat BP, avoid toxins,drink lots, promising future