Chronic Kidney Disease:An Update

(Part II)

Yassin Ibrahim El-ShahatConsultant: Nephrology & Hypertension

Chief Medical OfficerBurjeel Hospital, Abu Dhabi

Objectives

Upon completion of this talk the attendant will be able to:

· Understand the pathophysiology of Chronic Kidney Disease

· Recognize the signs and symptoms of Chronic Kidney Disease

· Identify the disease progression and treatment interventions

Plan

Management of CKD?

ESRD&

death

Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies

Complications

Screening for CKD

risk factors

CKD riskreduction;

Screening forCKD

Diagnosis& treatment;

Treat comorbid

conditions;Slow

progression

Estimateprogression;

Treatcomplications;

Prepare forreplacement

Replacementby dialysis

& transplant

Normal Increasedrisk CKDDamage GFR

Natural History of CKD

· Most CKD has a logarithmic progression and is predictable

Early treatment can make a difference

100

10

0

No TreatmentCurrent TreatmentEarly Treatment

4 7 9 11

Time (years)

Kidney Failure

GFR

(mL/

min

/1.7

32)

CKD is prevalent in CVD

Ix, et al., 2003; Anavekar, et al., 2004; Shlipak, et al., 2004.

0

20

40

60

CADGFR ≤60 mL/min

AMI GFR ≤60 mL/min

CHFGFR ≤60 mL/min

23%

46%

33%

Patie

nts

With

CK

D (%

)

In addition to ESRD, CKD leads to CVD

Go, et al., 2015

1.0

2.8

3.4

2.0

1.4

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

≥ 60 45-59 30-44 15-29 < 15

Adj

uste

d H

azar

d R

atio

eGFR

Adjusted* hazard ratio for CVD events

· Leading cause of morbidity and mortality in patients with CKD at all stages

· Ischemic CAD· Hypertension and LVH· Congestive heart failure· Uremic pericarditis

CKD=

CVD

How should clinicians treat cardiovascular risk factors?

Complications of CKD

· Intensive glycemic control lessens progression from microalbuminuria in Type 1 diabetes–goal in Type 2 is less clear- DCCT, 1993

- ACCORD, 2008

· Antihypertensive therapy with ACE Inhibitors or ARBs lessens proteinuria and progression- Giatras, et al., 1997- Psait, et al., 2000- Jafar, et al., 2001

· Blood pressure below 130/80 is beneficial - Sarnak, et al., 2005

We can have an impact on progression of CKD

Treatments to slow the progression of CKD

Therapeutics in CKD

· Non Pharmacologic· Risk Factor Modification

· Pharmacologic· Treatment of complications

“Traditional” Risk Factors for CKD and Associated Interventions

What non-drug therapies should clinicians recommend?

· Quit smoking, and exercise 30 min/d on most days· Limit alcohol intake · Maintain BMI within normal range · Eat a diet high in fruits, vegetables, and whole grains · DASH diet recommended if GFR >60 mL/min per 1.73 m2

and high normal blood pressure or stage 1 hypertension· If hypertension present: restrict salt intake <2.0 g/d · Most patients with CKD should avoid high-protein diets· Stage 4 or 5: consider low-protein diet (0.6 g/kg/d)

Therapeutics in CKD

· Non Pharmacologic· Risk Factor Modification

· Pharmacologic· Treatment of complications

Parameter Target Agent usedBP 130/80 mmHg or

125/75 in DM and those with proteinuria.

Start with ACEI or ARBs if proteinuria or DM microalbuminuria - caution in the elderly and those with atherosclerosis. Monitor eGFR within 1-2 weeks of initiation, review if eGFR decreases by ≥15%, stop at ≥25%.

Proteinuria Lowest achievable ACEI/ ARBs

S. Cholesterol Refer to national guidelines

Lifestyle Standard CV risk reduction measures, including salt restriction

Avoid NSAIDs, COX2s and radiocontrast agents

Anaemia Hb 10.5-12.5 g/dl Replace deficienciesErythropoietin in CKD stage 4-5

Renal osteodystrophy(Stages 4 & 5 only)

Ca: 2.2-2.35 mmol/lPO4 <1.7 mmol/l

Calcium carbonate / AlfacalcidolPhosphate binders

Acidosis Venous Bicarbonate > 22 mmol/l

Sodium bicarbonate

Undernutrition Adequate calorie & normal protein intake

Infections Chest infectionsHepatitis B

Immunize: influenza & pneumococcusvaccination (CKD stages 4-5)

CKD management guidelines

Pharmacology in CRF

Pharmacokinetics – drug absorption, distribution,

metabolism & excretion

Pharmacodynamics –A drug’s mechanism of action

and effect at the target site

Alterations in Drug Responses in CRF

· Gastrointestinal impairments affect absorption of medications

· Volume of distribution (Vd) – the availability of a drug distributed in body tissues is increased or decreased by alterations in body composition or protein binding

· Metabolism of medications altered - the kidneys produce many enzymes involved in drug metabolism including cytochrome P-450

· Decreased glomerular filtration rate affects drug excretion

Campoy, S, Elwell, R.(2005). Pharmacology & CKD. AJN, 105(9),60-72.

Medication Considerations in CKD

· Dilantin – increased Vd related to protein binding changes and low albumin, increasing risk of drug toxicity

· Digoxin – increased Vd leading to toxicity due to decreased renal excretion

· Insulin – metabolism of insulin decreases, requiring dose reduction

· Tylenol and procainamide – liver metabolized drugs with metabolites that are excreted renally, can accumulate leading to drug toxicity

Campoy, S, Elwell, R.(2005). Pharmacology & CKD. AJN, 105(9),60-72.

Medication Considerations in CKD (Cont.)

Impaired renal excretion leads to toxic drug accumulations with:

DiamoxAminoglycoside antibiotics -(tobramycin & gentamycin)

AtenololCaptoprilLithium

VancomycinMetforminNeurontinTopamax

What is the role of Blood Pressure control in patients with diabetes and CKD?

· Identify and treat factors associated with progression of CKD· HTN· Proteinuria· Glucose control

Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

Hypertension in Chronic Kidney Disease

Management of Hypertension in CKD

• Investigations into the nature of the patient’s renal disease

• Blood pressure goal

• Non-pharmacological treatment

• Pharmacological treatment

What is the role of blood pressure management?

· To reduce CVD risk, treat to <140/90 mm Hg · If proteinuria is significant or urine albumin-to-creatinine ratio

>30mg/g: treat to <130/80 mm Hg· Use ACE inhibitors and ARBs (improve kidney outcomes)

Combination therapy often needed Diuretics reduce extracellular fluid volume, lower BP, and reduce

risk for CVD

Diuretics also potentiate effects of antihypertensives

Thiazide-type diuretic if GFR ≥30 mL/min per 1.73 m2

Loop diuretic if GFR <30 mL/min per 1.73 m2

Clinical Practice Guidelines for Management of Hypertension in CKD

Type of Kidney Disease Blood Pressure Target

(mm Hg)

Preferred Agents for CKD, with or

without Hypertension

Other Agents to Reduce CVD Risk

and Reach Blood Pressure Target

Diabetic Kidney Disease

<130/80

ACE inhibitor or ARB

Diuretic preferred, then BB or CCB

Nondiabetic Kidney Disease with Urine Total

Protein-to-Creatinine Ratio 200 mg/g

Nondiabetic Kidney Disease with Spot Urine

Total Protein-to-Creatinine ratio <200 mg/g None preferred

Diuretic preferred, then ACE inhibitor, ARB, BB

or CCB

Kidney Disease in Kidney Transplant Recipient

CCB, diuretic, BB, ACE inhibitor, ARB

Blood Pressure Goals in CKD

Nicholas SB et al. Curr Opin Cardiol 2013

12

KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012

KDIGO Guidelines

• Non-diabetic adults with CKD:≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric

• Diabetic adults with non dialysis-dependent CKD:≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric

• Kidney transplant recipients:≤130 mmHg systolic and ≤80 mmHg diastolic

• Elderly people with CKD:probably ≤140 mmHg systolic and ≤90 mmHg diastolic, but set targets after consideration of co-morbidities

Aim for <130/80 mmHg if albuminuria is present

SummaryManagement of Hypertension in CKD

ESH/ESC 2013 Guidelines

AHA/ACC/CDC Scientific Advisory

JNC 8 ASH/ISH Statement

In general

<140/90 <140/90 ≥ 60 years: <150/90< 60 years: < 140/90

>140/90

Exceptionor special comment

Elderly > 80 years < 150/90Elderly < 80 years < 150/90Fit elderly < 140/90Diabetes < 140/85CKD+Proteinuria < 130/90

„lower“ targets for• elderly• LVH• systolic or

diastolic LV dysfunction

• diabetes• kidney disease

Diabetes < 140/90CKD < 140/90

< 80 years < 150/90

CKD + Proteinuria < 130/80

Pharmacological Treatment

Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012

• Generalised arterial vasodilatation:Reduction of blood pressure

• Vasodilatation particularly of the efferent glomerular arteriole:Reduction of glomerular pressureReduction of proteinuriaLong-term renoprotection

• Reduction of adrenal aldosterone secretion: But note aldosterone breakthrough

ACEIs and ARBs

• Indicated in all hypertensive patients with CKD, especially in proteinuric diabetic and non-diabetic CKD.

• Will lead to deterioration of renal function in short term but then to slower progression of renal failure in longer term.

IDNT and RENAAL Studies

Brenner BM et al. NEJM 2001Lewis EJ et al. NEJM 2001

Time to primary composite end point (doubling of serum creatinine, end-stage renal disease, or death)

Non-diabetic CKD: GISEN

The Gisen Group. Lancet 1997

When should clinicians prescribe ACE inhibitors versus ARBs?

· Prescribe either for reducing progression of diabetic nephropathy

· Prescribe either in hypertension or in diabetes when urine albumin excretion >30mg / 24h

· Prescribe either in non-diabetic proteinuria· Do not combine an ACE inhibitor with an ARB in CKD stage

IV and CKD stage V · Monitor patients closely for side effects and adjust dose as

needed · Safe to continue medication if GFR declines < 30% over 4

months and serum potassium <5.5 mEq/L

ACEIs and ARBs: Side Effects

HyperkalaemiaHigher risk of hyperkalaemia in combination with potassium-sparing diuretics

ACEI: mainly renal excretion (except fosinopril, trandolapril), ARB mainly hepatic excretion, therefore reduce dose (stop?) at GFR <15 mL/min

Other treatment strategies in Hyperkalaemia:

• Dietary advice• Furosemide• Dose reduction of ACEI/ARB

ACEIs and ARBs: Side Effects

Schoolwert AC et al. Circulation 2001

AKI, especially in:

• Bilateral renal stenosis• Diabetes and sepsis• Combination with

NSAIDs• State of volume

depletion (diarrhoea/vomiting)

Diuretics

Thiazide diuretics: e.g. Hydrochlorothiazide, Bendroflumethiazide

Thiazide-like diuretics: e.g. Chlorthalidone, Indapamide

Loop diuretics: e.g. Furosemide, Torasemide

Widely used as patients with CKD are characterised by sodium and water retention

For antihypertensive therapy:

GFR >50 mL/min: Thiazides alone or in combination with distal diuretics (e.g. spironolactone)

GFR <30 mL/min: Loop diuretics. Avoid distal (potassium sparing) diuretics.

Calcium Channel Blockers

• Antihypertensive action

• Oedema and fluid retention

• Dihydropyridines predominantly dilate the afferent arteriole and thereby increase GFR but also the glomerular pressure

• Non-DHPs seem not to have this effect.

Calcium Channel Blockers

KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012

Beta-Blockers

• Beta-blockers reduce increased sympathetic activity in CKD

• Indication in heart failure (but not in acute LVF)

• Often combined with diuretics in RCTs but no reason why not combine with others

• No robust evidence for superiority of certain beta-blockers

Alpha-Blockers

• Alpha-blockers have additional antiproliferative properties

• Hepatic excretion• Beneficial in prostate hypertrophy

Often Combination Therapy will be Required

2013 ESH/ESC Guidelines. J Hypertens 2013

What is the role of glycemic control in patients with diabetes and CKD?

· Identify and treat factors associated with progression of CKD· HTN· Proteinuria· Glucose control

What is the role of glycemic control in patients with diabetes and CKD?

· Good glycemic control reduces: · Progression of CKD· Incidence proteinuria· Maybe end-stage renal disease

· However, CKD increases risk for hypoglycemia

· Current CKD guidelines recommend a goal A1c level ~7% · Avoid using Metformin if GFR <30 mL/min per 1.73 m2

Lancet 1998; 352: 837-53

UKPDS

· 3867 patients with type 2 DM (median age 54 yrs) over ten years

· Intensive tx with sulfonylureas and insulin (HbA1c 7.0%) vs conventional tx (7.9%)

· 25% RR in microvascular complications (95% CI 7-40; p=0.0099)

Therapeutics in CKD

· Non Pharmacologic· Risk Factor Modification

· Pharmacologic· Treatment of complications

Pathophysiology of CKD

Metabolic changes with CKD

· Hemoglobin/hematocrit

· Bicarbonate

· Calcium

· Phosphate

· PTH

· Triglycerides

· Monitor and treat biochemical abnormalities· Anemia· Metabolic acidosis· Mineral metabolism· Dyslipidemia· Nutrition

Acid Base Imbalance

· Damaged kidneys are unable to excrete the 1 mEq/kg/day of acid generated by metabolism of dietary proteins. · NH3 production is limited because of loss of nephron mass· Decreased filtration of titrable acids – sulfates, phosphates· Decreased proximal tubular bicarb reabsorption, decreased

positive H ion secretion

· Arterial pH: 7.33 - 7.37; serum HCO3 rarely below 15 – buffering offered by bone calcium carbonate and phosphate

· Should be maintained over 22

· Treatment: Sodium bicarbonate, calcium carbonate, sodium citrate

· Metabolic acidosis· Seldom significant until GFR <30 mL/min per 1.73 m2 · Contributes to CKD progression, insulin resistance,

decreased cardiorespiratory fitness, altered bone metabolism

· Use alkali therapy with serum bicarbonate <22 mmol/L to maintain serum bicarbonate levels within normal range

How should clinicians manage metabolic complications?

Metabolic acidosis

· Muscle catabolism

· Metabolic bone disease

· Sodium bicarbonate· Maintain serum bicarbonate > 22 meq/L· 0.5-1.0 meq/kg per day· Watch for sodium loading

· Volume expansion· HTN

Hematological Abnormalities

· Anemia· Chronic blood loss, hemolysis, marrow suppression by uremic

factors, and reduced renal production of EPO· Normocytic, normochromic· Rx: Iron and Epo as needed

· Coagulopathy· Mainly platelet dysfunction – decreased activity of platelet factor

III, abnormal platelet aggregation and adhesiveness and impaired thrombin consumption

· Increased propensity to bleed – post surgical, GI Tract, pericardial sac, intracranial

· Increased thrombotic tendency – nephrotic syndrome

Major MinorInflammation/infection HyperparathyroidismIron deficiency Aluminium toxicityInadequate dialysis B12/folate deficiency Haemolysis Bone marrow disorders Haemoglobinopathies Anti-EPO antibodies = PRCA

(pure red cell aplasia) Non-adherence

Causes of ESA Hyporesponsiveness (Macdougall, 2003)

Mechanisms in anemia leading to myocardial damage in chronic kidney disease: Combination of factors secondary to diminished glomerular

filtration rate (GFR) and low hemoglobin. Consequences of anemia include the hemodynamic compensatory mechanisms th...

Madhumathi Rao, Brian J.G. Pereira, Kidney International, Volume 68, Issue 4, 2005, 1432–1438

Optimal anemia management reduces CV morbidity, mortality, and costs in CKD

Conclusions: Treatment of Anemia in CKD

· Target Hgb· < 12 g/dL· RCTs in both D-CKD and ND-CKD· CHOIR Post-hoc analysis: Hgb level and Epo dose

· Getting to Target· Problem of Hgb cycling· Causes of Hgb cycling multifactorial · Difficult to achieve Hgb in narrow range: broader range or no range

· Hyporesponsive patient· 30-40% of D-CKD· DRIVE 1 and 2 support greater role for iron therapy· Using iron is cost-effective

Causes of Anaemia in CKD

• EPO deficiency• Chronic blood loss (via GI tract/haemodialyser)• Iron deficiency• Vitamin B12 or folate deficiency• Hypothyroidism• Chronic infection or inflammation• Hyperparathyroidism• Chronic blood loss• Aluminium toxicity• Malignancy• Haemolysis• Bone marrow infiltration• Pure red cell aplasia

Clinical Effects of Anaemia

SymptomsFatigueDecreased exercise capacityExertional dyspnoeaAnorexiaCognitive impairmentDiminished quality of lifePoor memoryReduced libidoPallorPoor sleep patternReduced immune functionReduced platelet function

Cardiovascular EffectsIncreased cardiac output/stroke volumeTachycardiaDecreased vascular resistanceWorsening of pre-existing anginal symptoms/myocardial ischaemiaLeft ventricular hypertrophyImpairment in nitric oxide synthesisLimited oxygen reserveAbnormal angiogenesis

How should clinicians manage patients with anemia?

· Measure hemoglobin and hematocrit, RBC indices, reticulocyte count, serum iron, percent transferrin saturation, vitamin B12 and folate levels, serum ferritin

· Identify potential sources of bleeding · Treat with erythropoietin when hemoglobin drops below 9-

10 g/dL· Prescribe oral / IV iron as needed to maintain iron stores · Maintain hemoglobin levels <11.5 g/dL· Use caution with active malignancy or history of stroke

Bone Disease

NEJM 2000; 342(20): 1478-83

Mineral metabolism

· Calcium and phosphate metabolism abnormalities associated with:· Renal osteodystrophy· Calciphylaxis and vascular calcification

· 14 of 16 ESRD/HD pts (20-30 yrs) had calcification on CT scan

· 3 of 60 in the control group

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Anemia

Mineral metabolism

Mineral metabolism

Anemia

Mineral metabolism

Mineral metabolism

Mineral metabolism

Anemia

Mineral metabolism

Mineral metabolism

Mineral metabolism

Mineral metabolism

Therapeutic targets for phosphate binders and calcitriol

Calcium or Aluminium Containing

Non-Calcium, Non-Aluminium Containing

Aluminium Hydroxide Lanthanum Carbonate

Calcium Acetate Magnesium Carbonate

Calcium Carbonate Sevelamar Hydrochloride and Carbonate

Summary of Phosphate Binders

Parathyroid sestamibi scan (with technetium Tc 99m-MIBI) demonstrating uptake in all 4 glands consistent with 4-

gland hyperplasia

Secondary Parathyroid Adenoma

Top Tip: Utilise dietary phosphate restriction, a phosphate binder and calcitriol in all ESRD patients.

• Secondary hyperparathyroidism occurs as a result of hyperphosphataemia, hypocalcaemia and impaired synthesis of renal vitamin D with reduction in serum calcitriol levels

• Patients with secondary hyperparathyroidism have a range of symptoms• The aim of treatment is is to reduce: (1) the occurrence and/or severity of uraemic bone

disease; and, (2) cardiovascular morbidity and mortality caused by elevated serum levels of PTH and 'calcium x phosphate' product

• Treatment includes control of phosphate retention, maintaining serum calcium concentration within the normal range and prevention of excess PTH secretion

• The UK Renal Association recommends measuring serum calcium, phosphate and PTH levels when GFR is < 60ml/min/1.73m 2 (CKD stage 3 and above). It also recommends, in dialysis patients:

• Serum calcium, should be maintained within the normal range and be between 2.2 and 2.5 mmol/L, with avoidance of hypercalcaemic episodes

• Serum phosphate should be maintained between 1.1 and 1.7 mmol/L• The target range for parathyroid hormone (measured using an intact PTH assay) should be

2-9 times the upper limit of normal for the assay used

Tailor dosing to guideline targets

JAMA 1993; 269(23): 3015-23

Dyslipidemia

· Abnormalities in the lipid profile· Triglycerides· Total cholesterol

· NCEP recommends reducing lipid levels in high-risk populations

· Targets for lipid-lowering therapy considered the same as those for the secondary prevention of CV disease

Nutrition

· Think about uremia· Catabolic state· Anorexia· Decreased protein intake

· Consider assistance with a renal dietician

Key Clinical Trials

Normal Hematocrit Study (Besarab, 1998) • Open-label trial of 1233 HD patients with heart failure/IHD • Epoetin given either to maintain a normal (42 ±3 %) or low (30 ±3 %) haematocrit • Primary endpoint – MI/death • Study was stopped after 29 months due to the higher (albeit non-statistically significant) death rate in the normal haematocrit group – 183 vs 150 deathsNote: this study raised concerns regarding the risks of trying to attain a higher level of haemoglobinCHOIR (Singh, 2006) • Open-label trial of 1432 CKD patients randomised to either a low-Hb (11.3 g/dl) or high-Hb arm (13.5 g/dl) • Primary endpoints included death and CV events (and CVA) • 125 events occurred among the high-Hb group and 97 events among the low-Hb group (HR 1.34; P = 0.03) • No quality-of-life difference between the two groups CREATE (Drueke, 2006) • Multicentre trial of 603 CKD patients randomised to high-Hb (13.0-15.0 g/dl) or low-Hb (10.5-11.5 g/dl) • No difference between groups in terms of primary endpoints (CV/death) • Study ended up being underpowered TREAT (Pfeffer, 2009) • Multicentre, double-blind, placebo-controlled RCT • Darbepoetin (Aranesp) (aiming for Hb 13 g/dl) vs placebo* (Hb of 9 g/dl) in 4038 predialysis CKD patients with type 2 diabetes and anaemia • No difference in primary CV endpoint/death • Improved symptoms in treatment arm • Two-fold increased risk of CVA in treatment arm • Death from cancer higher in ESA group (7.4% versus 0.06%, P=0.002) • More iron therapy administered to the placebo group (*with rescue ESA therapy to maintain an Hb of 9 g/dl, which was subsequently discontinued once Hb > 9 g/dl)

Treatment

Increase the Adequacy of DialysisIncreasing the dialysis prescription has been shown to augment the response to ESA therapy.

Iron Management The causes and diagnosis of iron deficiency in CKD are listed above. If a patient is considered deficient in iron, then there are a number of iron preparations (both oral and intravenous) that are available.

Erythropoiesis-Stimulating Agents (ESAs)EPO is a large glycoprotein (30.4 KDa) that is injected intravenously (HD patients), or subcutaneously. Current UK guidance recommends starting therapy when the Hb falls below 11 g/dl, but of late there has been a tendency for lower Hb’s to be accepted before intervening with ESA therapy following data from the TREAT trial (see Key Clinical Trials). ESA therapy is effective in correcting anaemia in the vast majority of patients, with 5-10% of patients deemed ESA hyporesponsive.

Correction of Haematinic Deficiency Folate (and less commonly vitamin B12) is a low molecular weight substance that may be lost during haemodialysis (especially high-flux. Serum folate is not as accurate as red cell folate level, as a marker of folate deficiency, but is the most commonly used initial screening test.

Top Tips: Consider an ESA in any CKD patient with Hb <11 g/dL. Keep Ferritin >200 ng/L

• There is no worldwide consensus concerning target ranges for haemoglobin and iron/ferritin levels. The new KDIGO renal anaemia guidelines are expected in mid-late 2012

• Functional iron deficiency occurs when stored iron is sufficient but circulating iron is deficient. It may be detected when serum ferritin levels are decreased and TSAT levels are <20%, but this is not a hard and fast rule

• TSAT (transferrin saturation) is calculated by the following formula: Serum Fe ÷ TIBC x 100%

• Blood transfusions distort patients’ red cell indices, and it can take 3-4 months for the normal steady state to be resumed

• Treatment includes Erythropoiesis-Stimulating Agents (ESAs), correcting iron deficiency, treating infection/inflammation and increasing dialysis dose

• Major causes of ESA hyporesponsiveness are iron deficiency, inflammation/infection and inadequate dialysis

Specific targets and potential therapeutic strategies to inhibit or slow the progression of CKD

Antifibrotic strategies for treating CKD

Agent Setting Primary outcome and/or results

Preclinical studies

Anti-TGF-β antibody Leprdb/db diabetic mice3, 4

Reduction in plasma TGF-β1 levels, prevention of increases in plasma creatinine levels and glomerular mesangial matrix expansion, associated with decreased renal mRNAs encoding collagen IV and fibronectin

Anti-TGF-β antibody Rats with chronic allograft rejection nephropathy5

Reduction of proteinuria, attenuation of mononuclear cell infiltration and interstitial fibrosis along with downregulation of mRNA levels of TGF-β1, TGF-β2, and proinflammatory cytokines, or with upregulation of mRNA levels of HGF, BMP-5, and BMP-7

Anti-TGF-β antibody Mice with STZ-induced diabetes12

Prevention of glomerular hypertrophy, attenuated gain in kidney weight, and attenuation of increased mRNA levels of TGF-β1, type II TGF-β receptor, collagen IV, and fibronectin

Anti-TGF-β antibody Rats with puromycin aminonucleoside nephropathy13

Reduction of TGF-β isoform mRNA expression and collagen III production, and amelioration of histological sclerosis with low dose of antibody

Soluble β-glycan Leprdb/db diabetic mice14Reduction in serum creatinine, albuminuria, and structural renal damage

siRNA for TGF-β type II receptor Mice with UUO15Decreased TGF-β receptor and α-SMA overexpression at the mRNA level, collagen deposition, and fibrotic area

Tranilast

Rats with remnant kidney,28 rats with chronic cyclosporin-induced nephrotoxicity,29 hypertensive Ren-2 rats with STZ-induced diabetes,30 and rats with UUO31

Inhibition of TGF-β-induced glomerulosclerosis and tubulointerstitial fibrosis, reduction in albuminuria and plasma creatinine, attenuation of macrophage accumulation, and decreased oxidative stress

Analogue of tranilast (FT061) Rats with progressive diabetic nephropathy6 Reduction of albuminuria

Analogue of tranilast (FT011)5/6 nephrectomized rats and rats with STZ-induced diabetic nephropathy35

Reduction in proteinuria, inflammation, and glomerulosclerosis

Pirfenidone Leprdb/db diabetic mice25 and 5/6 nephrectomized rats26

Reduction in ECM accumulation and inflammatory cell infiltration

CTGF antisense oligonucleotide Mice with STZ-induced diabetes19 and Leprdb/db diabetic mice19

Reduction in CTGF mRNA expression, decreased proteinuria and albuminuria, attenuation in mRNA expression of fibronectin, and collagens I and IV

CTGF siRNA Rats with chronic allograft rejection nephropathy20

Reduction in mRNA CTGF expression, amelioration of serum creatinine level, reduction in mRNA expression of α-SMA and collagens I and IV

miR-21 Leprdb/db diabetic mice39 Amelioration of albuminuria, renal fibrosis, and inflammation

Recombinant human BMP-7 Mouse model of CKD44

Decreased damage to renal tubular epithelial cells, in association with reversal of chronic renal injury

Exogenous HGFRats with remnant kidney,46,48, 50 5/6 nephrectomized rats,52 and mice with STZ-induced diabetic nephropathy53

Amelioration of renal fibrosis and tubulointerstitial collagen deposition; decreased renal inflammation, glomerular hypertrophy, and sclerosis

Hgf gene transfection Mouse model of chronic graft-versus-host disease49

Prevention of proteinuria and histopathological changes associated with glomerulonephritis

Genetic deletion of CDA1 Diabetic mice with CDA1 knockout55

Reduction in ECM accumulation, decreased mRNA levels of TGF-β, TGF-β receptor, and Smad3

Clinical studiesAnti-TGF-β antibody (fresolimumab)

Phase I Patients with primary steroid-resistant FSGS17 Single dose was well tolerated

Anti-TGF-β antibody (LY2382770)

Phase II (ongoing)Patients with type 1 or type 2 diabetes mellitus and diabetic nephropathy16

Change in serum creatinine levels from baseline to 12 months, results not yet reported

TranilastPhase IPatients with diabetic nephropathy32

Amelioration of urinary excretion of type IV collagen and albumin

Analogue of tranilast (FT061)Phase IPatients with type 2 diabetes mellitus and diabetic nephropathy36

Reduction in proteinuria, inflammation, and glomerulosclerosis

PirfenidonePhase IPatients with diabetic nephropathy27

Encouraging results for increased mean eGFR but without improvement in proteinuria

Anti-CTGF monoclozal antibody (FG-3019)

Phase IPatients with diabetic nephropathy21

FG-3019 was well tolerated and associated with decreased albuminuria

Anti-CTGF monoclonal antibody (FG-3019) and ACE inhibitors or ARBs

Phase IPatients with type 1 or type 2 diabetes mellitus and diabetic nephropathy22

Safety and tolerability of two doses of FG-3019 administered for 12 weeks; results not yet reported

Anti-CTGF monoclonal antibody (FG-3019)

Phase IIPatients with type 2 diabetes mellitus and diabetic nephropathy23

To assess the effect of FG-3019 on proteinuria as assessed by urinary ACR, trial terminated

Anti-CTGF monoclonal antibody (FG-3019)

Phase IPatients with steroid-resistant FSGS24

To assess safety and tolerability of FG3019; trial terminated

Non-antifibrotic strategies for treating CKD

Agent Setting Primary outcome and/or results

Vascular calcification

Klotho overexpression Mice with CKD62Enhanced phosphaturia, improved renal function, and decreased calcification

Exogenous Klotho Mice with UUO67 and mice with adriamycin-induced CKD67

Inhibition of renal β-catenin activation, suppression of myofibroblast activation, reduction in extracellular matrix protein expression, and amelioration of renal fibrosis

Oxidative stress and NADPH oxidases

NOX-2 deficiency Mice with STZ-induced diabetic nephropathy74

No beneficial effect on renal function, and marked increase in NOX-4 at the protein level in the kidney

GKT136901* Leprdb/db diabetic mice80,81 Reduction in albuminuria and oxidative stress

GKT137831* Diabetic Apoe−/− mice83

Reduction in ROS production, inflammation, vascular complications, and profibrotic markers, such as CTGF, collagen IV, and fibronectin

GKT137831*

Ongoing phase I/II study in patients with type 2 diabetes mellitus and diabetic nephropathy84

GKT137831 was well tolerated

NOX-4 deficiencyMice with STZ-induced diabetes,76 mice with UUO,76 and 5/6 nephrectomized mice76

No beneficial effect on renal function

NOX-4 deficiency Mice with UUO85

Increased tubulointerstitial fibrosis, increased oxidative stress, and decreased antioxidant markers, such as NRf2, at the protein level as well as glutathione S-transferase α at the mRNA level

NF-κB

PDTC

Rats with gentamicin-induced nephropathy,86 5/6 nephrectomized rats,87 and rats with aldosterone and salt-induced CKD88

Attenuation of renal inflammation and renal injury

Celastrol Leprdb/db diabetic mice89

Reduction in albuminuria and glomerular mesangial matrix along with reduced TGF-β expression at the protein level and collagen IV deposition

Energy sensing

AICAR High-fat-diet-induced kidney disease in mice102

Reduction in albuminuria, glomerular mesangial matrix, renal inflammation, and lipid accumulation

AICAR OVE26 mice104

Reduction in albuminuria and renal hypertrophy along with decreased NOX-4 and tumour-suppressor p53 expression at the protein level

C

Treating Anemia

· Epoetin alfa (rHuEPO; Epogen/Procrit)· HD: 50-100 U/kg IV/SC 3x/wk· Non-HD: 10,000 U qwk

· Darbepoetin alfa (Aranesp)· HD: 0.45 g/kg IV/SC qwk· Non-HD: 60 g SC q2wks

Other Abnormalities

· Neuromuscular· Central, peripheral and autonomic neuropathy· Peripheral Sensory/Motor Neuropathy· Stage 4 for more than 6 months· Restless leg syndrome

· Gastrointestinal· Uremic fetor· Gastritis, peptic disease, mucosal ulcerations, AVMs

· Endocrine· Glucose metabolism· Estrogen levels – amenorrhea, frequent abortions· Male: oligospermia, germinal cell dysplasia, delayed sexual

maturation· Dermatologic

· Pallor, ecchymoses, hematomas, calciphylaxis, pruritus, uremic frost

Additional Clinical Interventions for Adults with GFR <60 ml/min

How should clinicians manage metabolic complications?

Vitamin D and phosphorous metabolism· Derangements occur if GFR <30-40 mL/min per 1.73 m2

· Use dietary phosphorous restriction, phosphate binders, and vitamin D supplementation

Hyperkalemia Dangerous elevations occur mostly only in stages 4 / 5 Use dietary potassium restriction, and if necessary, sodium

polystyrene sulfonate Hyperkalemia >6mEq/L or hyperkalemic EKG change requires

emergency treatment with IV calcium gluconate, glucose, insulin, bicarbonate (if acidosis present), and sodium polystyrene sulfonate

If these measure fail, hemodialysis may be needed

How should clinicians treat cardiovascular risk factors?

CKD=

CVD

Anemia

Anemia

C

Syndromes Acute cardio-renal (type 1)

Chronic cardio-renal (type 2)

Acute reno-cardiac (type 3)

Chronic reno-cardiac (type 4)

Secondary CRS (type 5)

Organ failure sequence

Definition

Acute worsening of heart function (AHF–ACS) leading to kidney injury and/or dysfunction

Chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction

Acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction

Chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction

Systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney

Primary events

Acute heart failure (AHF) or acute coronary syndrome (ACS) or cardiogenic shock

Chronic heart disease (LV remodelling and dysfunction, diastolic dysfunction, chronic abnormalities in cardiac function, cardiomyopathy)

AKI CKDSystemic disease (sepsis, amyloidosis, etc.)

Criteria for primary events ESC, AHA/ACC ESC, AHA/ACC RIFLE–AKIN KDOQI Disease-specific

criteria

Secondary events AKI CKD

AHF, ACS, arrythmias, shock

CHD (LV remodelling and dysfunction, diastolic dysfunction, abnormalities in cardiac function), AHF, ACS

AHF, ACS, AKI, CHD, CKD

Criteria for secondary events

RIFLE–AKIN KDOQI ESC, AHA/ACC ESC, AHA/ACCESC, AHA/ACC, RIFLE/AKIN ESC, AHA/ACC KDOQI

Cardiac biomarkers

Troponin, CK-MB, BNP, NT-proBNP, MPO, IMA

BNP, NT-proBNP, C-reactive protein

BNP, NT-proBNPBNP, NT-proBNP, C-reactive protein

C-reactive protein, procalcitonin, BNP

Renal biomarkers

Serum cystatine C, creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Serum creatinine, cystatin C, urea, uric acid, C-reactive protein, decreased GFR

Serum creatinine, cystatin C, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Serum creatinine, cystatin C, urea, uric acid, decreased GFR

Creatinine, NGAL, IL-18, KIM-1, NAG

Prevention strategies

Acutely decompensated heart failure and acute coronary syndromes are most common scenariosInciting event may be acute coronary ischaemia, poorly controlled blood pressure, and noncompliance with medication and dietary sodium intakeRandomized trials improving compliance with heart failure care management have reduced rates of hospitalization and mortality, and a reduction in the rates of acute cardio-renal syndrome (type 1) can be inferred

A common pathophysiology (neurohumoral, inflammatory, oxidative injury) could be at work to create organ dysfunctionDrugs that block the renin–angiotensin system reduce the progression of both heart failure and CKDIt is unknown whether other classes of drugs can prevent chronic cardio-renal syndrome (type 2)

Acute sodium and volume overload are part of the pathogenesisIt is unknown whether sodium and volume overload is prevented with different forms of renal replacement therapy and if this will result in lower rates of cardiac decompensation

The chronic processes of cardiac and renal fibrosis, left ventricular hypertrophy, vascular stiffness, chronic Na and volume overload, and other factors (neurohumoral, inflammatory, oxidative injury) could be at work to create organ dysfunctionA reduction in the decline of renal function and albuminuria has been associated with a reduction in cardiovascular eventsThe role of chronic uraemia, anaemia, and changes in CKD-mineral and bone disorder on the cardiovascular system is known in chronic reno-cardiac syndrome

Potential systemic factors negatively impact function of both organs acutelyIt is uncertain if reduction/elimination of the key factors (immune, inflammatory, oxidative stress, thrombosis) will prevent both cardiac and renal decline.

Management strategies

Specific—depends on precipitating factorsGeneral supportive—oxygenate, relieve pain & pulmonary congestion, treat arrhythmias appropriately, differentiate left from right heart failure, treat low cardiac output or congestion according to ESC guidelines(a); avoid nephrotoxins, closely monitor kidney function.

Treat CHF according to ESC guidelinesa, exclude precipitating pre-renal AKI factors (hypovolaemia and/or hypotension), adjust therapy accordingly and avoid nephrotoxins, while monitoring renal function and electrolytesExtracorporeal ultrafiltration

Follow ESC guidelines for acute CHFa specific management may depend on underlying aetiology, may need to exclude renovascular disease and consider early renal support, if diuretic resistant

Follow KDOQI guidelines for CKD management, exclude precipitating causes (cardiac tamponade). Treat heart failure according to ESC guidelinesa, consider early renal replacement support

Specific—according to etiology. General—see CRS management as advised by ESC guidelines* 2008

Cardio–renal syndrome pathophysiology

C

Cardiovascular Abnormalities

Trends in the interactions of diabetes, CHF & CKD: 2002-2003

· LVH and dilated CM are the most ominous risk factors for excess mortality and morbidity· High cardiac output· Extracellular fluid overload· AV shunt· Anemia

Medicare: general Medicare CKD patients continuously enrolled in Medicare Parts A & B for two consecutive years (numbers estimated from 5 percent sample)

Hillege et al, 2002 Arnlov et al, 2005

Microalbuminuria and Survival

CKD and CVD Risk

HOORN Study, Henry et al, 2002 Pooled Analysis, Weiner et al, 2004

eGFR<60

eGFR>60

Kidney Int 1995; 47(1): 186-92

CV disease I

· 70% of HD patients have concomitant CV disease

· Heart disease leading cause of death in HD patients

· LVH can be a risk factor

Am J Kidney Dis 2001; 37(6): 1191-200

CV disease II

· Patients with CKD (non-HD) have poor prognosis after MI

· Prospective CCU registry of 1724 pts with STEMI

· Graded increase in RR of post-infarct complications: arrhythmia, heart block/asystole, acute pulmonary congestion, acute MR, and cardiogenic shock

· Decreased survival over 60 months (RR 8.76; p<0.0001)

How should clinicians treat cardiovascular risk factors?

· Aggressively reduce risk factors for atherosclerosis · Encourage a healthy lifestyle regarding smoking, exercise, alcohol

intake, and BMI

· Assess for other cardiovascular risk factors· Check BP, and treat hypertension · Screen for diabetes, and treat elevated blood glucose· For people with CKD, ACC/AHA guidelines recommend treatment with

statin or statin/ezetimibe combination regardless of cholesterol level

Plan

How should clinicians monitor patients with CKD?

How should clinicians monitor patients with CKD?

Once a year check BP; GFR; hemoglobin level; and serum potassium, calcium, phosphorous, PTH, and albumin

More frequent monitoring may be needed if CKD is moderate to severe

History of rapid decline in kidney function

There are risk factors for faster progression (smoking, poorly controlled hypertension or diabetes, proteinuria)

Exposure to a cause of acute kidney injury

Active or changing therapeutic interventions to treat CKD, hypertension, or proteinuria

Plan

What are the indications for renal replacement therapy?

What are the indications for renal replacement therapy?

· Volume overload unresponsive to diuretics· Pericarditis· Uremic encephalopathy· Major bleeding secondary to uremic platelets· Hypertension that does not respond to treatment· Hyperkalemia and metabolic acidosis that cannot be

managed medically · Progressive “uremic” symptoms, which include fatigue;

anorexia, nausea or vomiting; malnutrition; and insomnia

Plan

When should clinicians consider consulting with a nephrologist for treat

patients with CKD?

When should clinicians consider consulting a nephrologist for treating patients with CKD?

· To manage complications of advanced CKD· For assistance with a care plan for advanced or complex

renal disease · For therapeutic decision-making about complex acute or

chronic glomerular and tubulointerstitial diseases· When dialysis is anticipated· When GFR first falls below 30 mL/min per 1.73 m2 · To discuss treatment for end-stage renal disease· For counseling, psychoeducational interventions, and referral

for fistula placement

Should clinicians screen patients for CKD? If so, how?

Screen individuals at increased risk for CKD Those older than 55 years

Those with hypertension, diabetes, or obesity

Screening: estimate GFR and test for kidney damage markers Serum creatinine to estimate GFR

Urinalysis for leukocytes and red blood cells

Qualitative test for urine albumin (or protein) with dipstick; if positive, measure amount to calculate an albumin-to-creatinine (or a protein-to-creatinine) ratio

Are preventive measures useful for patients at increased risk for CKD?

Diabetes· Hyperglycemia is associated with development and progression

of diabetic nephropathy· Good glycemic control reduces CKD risk· Maintain hemoglobin A1c ~7% with dietary interventions, oral

hypoglycemic medications, and insulin

Hypertension Hastens renal function decline

Treatment reduces CV risks but not CKD risk

Maintain blood pressure <140/90 mm Hg with lifestyle modification and antihypertensive drug therapy

People with CKD do progress to kidney failure–especially those middle-aged and younger

Levey, et al., 2015

0

10

20

30

40

50

60

70

80

Progressed to KidneyFailure

Died Before KidneyFailure

Died After KidneyFailure

Prop

ortio

n of

pat

ient

s

Long term (7 year) follow up of 408 non-diabetic CKD patients (mean initial GFR=39, mean initial age=52 year old)

Primary care providers – First line of defense against CKD

• Primary care professionals can play a significant role in early diagnosis, treatment, and patient education

• Therapeutic interventions for diabetic CKD are similar to those required for optimal diabetes care

• Control of glucose, blood pressure, and lipids• A greater emphasis on detecting CKD, and managing it

prior to referral, can improve patient outcomes

CKD is Part of Primary Care

ESRD 0.1%

Undetected CKD: 10-15%?!

Should clinicians screen patients for CKD? If so, how?

Screen individuals at increased risk for CKD Those older than 55 years Those with hypertension, diabetes, or obesity

Screening: estimate GFR and test for kidney damage markers Serum creatinine to estimate GFR Urinalysis for leukocytes and red blood cells Qualitative test for urine albumin (or protein) with dipstick;

if positive, measure amount to calculate an albumin-to-creatinine (or a protein-to-creatinine) ratio

Urine albumin & protein to creatinine ratio

· Albumin-to-creatinine ratio· Normal to mildly increased <30 mg/g· Moderately increased 30-300 mg/g· Severely increased >300 mg/g

· Protein-to-creatinine ratio· Normal to mildly increased <150 mg/g· Moderately increased 150-500 mg/g· Severely increased >500 mg/g

Type 2 diabetes: screen for albuminuria annually Positive when >30 mg/g creatinine in a spot urine sample

· Diabetics· Hypertensives· CVD · Relatives of CKD5· Systemic vasculitis· Recurrent UTIs, and urological problems· Chronic NSAIDs

Screening At-risk Population

ESRD&

death

Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies

Complications

Screening for CKD

risk factors

CKD riskreduction;

Screening forCKD

Diagnosis& treatment;

Treat comorbid

conditions;Slow

progression

Estimateprogression;

Treatcomplications;

Prepare forreplacement

Replacementby dialysis

& transplant

Normal Increasedrisk CKDDamage GFR

Are preventive measures useful for patients at increased risk for CKD?

· Diabetes· Hyperglycemia is associated with development and

progression of diabetic nephropathy· Good glycemic control reduces CKD risk· Maintain hemoglobin A1c ~7% with dietary interventions,

oral hypoglycemic medications, and insulin

Hypertension Hastens renal function decline Treatment reduces CV risks but not CKD risk Maintain blood pressure <140/90 mm Hg with lifestyle

modification and antihypertensive drug therapy

Key points

· The serum creatinine level is not enough!

· Target BP for CKD· <130/80 mm Hg· <125/75 mm Hg in proteinuria

· HTN and proteinuria are the two most important modifiable risk factors for progressive CKD

CLINICAL BOTTOM LINE: Screening and Prevention...

Who to screen Individuals > 55 years of age

Individuals with hypertension or diabetes

How to screen Estimate GFR from serum creatinine, and do a urinalysis

In patients with diabetes

• Screen for proteinuria with urine albumin-to-creatinine or protein-to-creatinine ratio

• Maintain strict glycemic control to prevent CKD

CLINICAL BOTTOM LINE: Diagnosis...

o CKD is defined as kidney damage or a GFR <60 mL/min per 1.73 m2 for > 3 months

o Classify• Diabetic nephropathy• Hypertensive nephropathy• Nondiabetic, nonhypertensive kidney disease• Then, into groups based on levels of GFR and albuminuria

o History and physical exam often point to a causeo Definitive diagnosis requires:

• Diagnostic tests• Renal ultrasound• Sometimes renal biopsy

CLINICAL BOTTOM LINE: Treatment...

The goals are to slow progression of CKD and prevent complications from cardiovascular disease

Maintain normal blood pressure in patients with hypertension Include an ACE inhibitor or an ARB when treating hypertension Control glycemia in patients with diabetes Manage electrolyte disturbances, anemia, secondary

hyperparathyroidism, and malnutrition Refer to a nephrologist as CKD progresses

CKD Management and the PCP

Goals of Care in CKD · Slow decline in kidney function· Blood pressure control1

· ACR <30 mg/g: ≤140/90 mm Hg· ACR 30-300 mg/g: ≤130/80 mm Hg*· ACR >300 mg/g: ≤130/80 mm Hg· Individualize targets and agents according to age,

coexistent CVD, and other comorbidities· ACE or ARB

*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300 mg/g.)2 1) Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney

Int Suppl. (2012);2:341-342.2) KDOQI Commentary on KDIGO Blood Pressure Guidelines. Am J Kidney Dis. 2013;62:201-

213.

Slowing CKD Progression: ACEi or ARB· Risk/benefit should be carefully assessed in the elderly and

medically fragile· Check labs after initiation

· If less than 25% SCr increase, continue and monitor· If more than 25% SCr increase, stop ACEi and evaluate for

RAS· Continue until contraindication arises, no absolute eGFR cutoff· Better proteinuria suppression with low Na diet and diuretics· Avoid volume depletion· Avoid ACEi and ARB in combination1,2

· Risk of adverse events (impaired kidney function, hyperkalemia)

1) Kunz R, et al. Ann Intern Med. 2008;148:30-48.2) Mann J, et al. ONTARGET study. Lancet.

2008;372:547-553.

Goals of Care in CKD: Glucose Control · Target HbA1c ~7.0% · Can be extended above 7.0% with comorbidities or

limited life expectancy, and risk of hypoglycemia· Risk of hypoglycemia increases as kidney function

becomes impaired· Declining kidney function may necessitate changes to

diabetes medications and renally-cleared drugs

NKF KDOQI. Diabetes and CKD: 2012 Update.Am J Kidney Dis. 2012 60:850-856.

Modification of Other CVD Risk Factors in CKD· Smoking cessation· Exercise· Weight reduction to optimal targets· Lipid lowering therapy

· In adults >50 yrs, statin when eGFR ≥ 60 ml/min/1.73m2; statin or statin/ezetimibe combination when eGFR < 60 ml/min/1.73m2

· In adults < 50 yrs, statin if history of known CAD, MI, DM, stroke

· Aspirin is indicated for secondary but not primary prevention

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppls. 2013;3:1-150.

Detect and Manage CKD Complications· Anemia

· Initiate iron therapy if TSAT ≤ 30% and ferritin ≤ 500 ng/mL (IV iron for dialysis, Oral for non-dialysis CKD)

· Individualize erythropoiesis stimulating agent (ESA) therapy: Start ESA if Hb <10 g/dl, and maintain Hb <11.5 g/dl. Ensure adequate Fe stores.

· Appropriate iron supplementation is needed for ESA to be effective

· CKD-Mineral and Bone Disorder (CKD-MBD)· Treat with D3 as indicated to achieve normal serum levels· 2000 IU po qd is cheaper and better absorbed than 50,000

IU monthly dose.· Limit phosphorus in diet (CKD stage 4/5), with emphasis on

decreasing packaged products - Refer to renal RD· May need phosphate binders

Detect and Manage CKD Complications• Metabolic acidosis

o Usually occurs later in CKDo Serum bicarb >22mEq/Lo Correction of metabolic acidosis may slow CKD

progression and improve patients functional status1,2

• Hyperkalemiao Reduce dietary potassiumo Stop NSAIDs, COX-2 inhibitors, potassium sparing

diuretics (aldactone)o Stop or reduce beta blockers, ACEi/ARBso Avoid salt substitutes that contain potassium

1) Mahajan, et al. Kidney Int. 2010;78:303-309.

2) de Brito-Ashurst I, et al. J Am Soc Nephrol. 2009;20:2075-2084.

A Balanced Approach to Nutrition in CKD: Macronutrient Composition and Mineral Content*

Adapted from DASH (dietary approaches to stop hypertension) diet.*Adjust so total calories from protein, fat, and carbohydrate are 100%. Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry.

NKF KDOQI. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

*(CKD Stages 1-4)

What can primary care providers do?· Recognize and test at-risk patients

· Educate patients about CKD and treatment

· Manage blood pressure and diabetes

· Address other CVD risk factors

· Monitor eGFR and ACR (encourage labs to report these tests)

What can primary care providers do?· Evaluate and manage anemia, malnutrition, CKD-MBD, and other complications in at-risk patients

· Refer to dietitian for nutritional guidance

· Consider patient safety issues in CKD

· Consult or team with a nephrologist (co-management)

· Refer patient to nephrology when appropriate

Co-Management, Patient Safety, and Nephrology Specialist Referral

Co-Management Model· Collaborative care· Formal

arrangement· Curbside consult

· Care coordination· Clinical decision

support· Population health

· Development of treatment protocols

Collaborative Care Agreements· Soft Contract between primary care and nephrologist· Defines responsibilities of primary care

· Provide pertinent clinical information to inform the consultation prior to the scheduled visit.

· Initiate a phone call if the condition is emergent· Provide timely referrals with adequate number of visits to treat the

condition.· Defines responsibilities of nephrologist

· Timely communication of consultation (7 days routine & 48 hours emergent) – fax if no electronic information sharing

· No consultation to other specialist initiated without primary care input

Kidneydamage and

normal or GFR

Kidneydamage and

mild GFR

Severe GFR

Kidneyfailure

Moderate GFR

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

NephrologistPrimary Care Practitioner

The Patient (always) and other subspecialists (as needed)

GFR 90 60 30 15

Who Should be Involved in the Patient Safety Approach to CKD?

Patient safety

Consult?

Impact of primary care CKD detection with a patient safety approach

Fink et al. Am J Kidney Dis. 2009,53:681-668

Patient SafetyFollowing

CKD detection

Improved diagnosis creates opportunity for strategic preservation of kidney function

CKD Patient Safety Issues· Medication errors

· Toxicity (nephrologic or other)· Improper dosing· Inadequate monitoring

· Electrolytes· Hyperkalemia· Hypoglycemia· Hypermagnesemia· Hyperphosphatemia

· Miscellaneous· Multidrug-resistant infections· Vessel preservation/dialysis access

Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668.

CKD Patient Safety Issues· Diagnostic tests

· Iodinated contrast media: AKI· Gadolinium-based contrast: NSF· Sodium Phosphate bowel preparations: AKI, CKD

· CVD· Missed diagnosis· Improper management

· Fluid management· Hypotension· AKI· CHF exacerbation

AKI = acute kidney injury; CHF = congestive heart failure; NSF = nephrogenic systemic fibrosis.Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668..

Common Medications Requiring DoseReduction in CKD· Allopurinol· Gabapentin

· CKD 4- Max dose 300mg qd

· CKD 5- Max dose 300mg qod

· Reglan· Reduce 50% for eGFR< 40· Can cause irreversible EPS

with chronic use· Narcotics

· Methadone and fentanyl best for ESRD patients

· Lowest risk of toxic metabolites

• Renally cleared beta blockerso Atenolol, bisoprolol,

nadolol• Digoxin• Some Statins

o Lovastatin, pravastatin, simvastatin. Fluvastatin, rosuvastatin

• Antimicrobialso Antifungals,

aminoglycosides, Bactrim, Macrobid

• Enoxaparin• Methotrexate• Colchicine

Key Points on Medications in CKD · CKD patients at high risk for drug-related adverse events· Several classes of drugs renally eliminated· Consider kidney function and current eGFR (not just SCr)

when prescribing meds· Minimize pill burden as much as possible· Remind CKD patients to avoid NSAIDs· No Dual RAAS blockade· Any med with >30% renal clearance probably needs dose

adjustment for CKD· No bisphosphonates for eGFR <30· Avoid GAD for eGFR <30

*Significant albuminuria is defined as ACR ≥300 mg/g (≥30 mg/mmol) or AER ≥300 mg/24 hours, approximately equivalent to PCR ≥500 mg/g (≥50 mg/mmol) or PER ≥500 mg/24 hours **Progression of CKD is defined as one or more of the following: 1) A decline in GFR category accompanied by a 25% or greater drop in eGFR from baseline; and/or 2) rapid progression of CKD defined as a sustained decline in eGFR of more than 5ml/min/1.73m2/year. KDOQI US Commentary on the 2012 KDIGO Evaluation and Management of CKD

Indications for Referral to Specialist Kidney Care Services for People with CKD• Acute kidney injury or abrupt sustained fall in GFR• GFR <30 ml/min/1.73m2 (GFR categories G4-G5)• Persistent albuminuria (ACR > 300 mg/g)*• Atypical Progression of CKD** • Urinary red cell casts, RBC more than 20 per HPF sustained and

not readily explained• Hypertension refractory to treatment with 4 or more

antihypertensive agents• Persistent abnormalities of serum potassium• Recurrent or extensive nephrolithiasis• Hereditary kidney disease

Observational Studies of Early vs. Late Nephrology Consultation

Chan M, et al. Am J Med. 2007;120:1063-1070.http://download.journals.elsevierhealth.com/pdfs/journals/0002-9343/PIIS000293430700664X.pdfKDIGO CKD Work Group. Kidney Int Suppls. 2013;3:1-150.

Take Home Points· PCPs play an important role· Identify risk factors· Know patient’s GFR using appropriate

screening tools· Help your patient adjust medication· Modify diet· Partner and refer to specialist

Pathophysiology of CKD

Overview of the CV impact caused by the interaction of aldosterone and PTH in patients with chronic HF and aldosterone excess.

Andreas Tomaschitz et al. Cardiovasc Res 2012;94:10-19

Advanced glycation end products and their trafficking

Josephine M. Forbes, and Mark E. Cooper Physiol Rev 2013;93:137-188

Schematic overview of the major areas contributing to diabetic complications

Josephine M. Forbes, and Mark E. Cooper Physiol Rev 2013;93:137-188

Major clinical predictors to be used for the perioperative management of a patient with CKD

Major clinical predictors to be used for the perioperative management of a patient with CKD

Major clinical predictors to be used for the perioperative management of a patient with CKD

Screening Tools: eGFR

· Considered the best overall index of kidney function.

· Normal GFR varies according to age, sex, and body size, and declines with age.

· The NKF recommends using the CKD-EPI Creatinine Equation (2009) to estimate GFR. Other useful calculators related to kidney disease include MDRD and Cockroft Gault.

· GFR calculators are available online at www.kidney.org/GFR.

Summary of the MDRD Study and CKD-EPI Estimating Equations: https://www.kidney.org/sites/default/files/docs/mdrd-study-and-ckd-epi-gfr-estimating-equations-summary-ta.pdf

Screening Tools: ACR

· Urinary albumin-to-creatinine ratio (ACR) is calculated by dividing albumin concentration in milligrams by creatinine concentration in grams.

· Creatinine assists in adjusting albumin levels for varying urine concentrations, which allows for more accurate results versus albumin alone.

· Spot urine albumin-to-creatinine ratio for quantification of proteinuria· New guidelines classify albuminuria as mild, moderately or

severely increased· First morning void preferable· 24hr urine test rarely necessary

C

http://www.google.ae/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiSx6uGxvHQAhWCvxQKHdlLBacQjRwIBw&url=http://intranet.tdmu.edu.ua/data/kafedra/internal/vnutrmed2/classes_stud/en/med/lik/ptn/Internal%20medicine/5%20course/18.%20Main%20symptoms%20and%20syndromes%20in%20nephrology..htm&psig=AFQjCNEtogxOdJtxjasN1-cMlJF6IrJnpw&ust=1481730626574178

Simple schema for the pathogenesis of diabetic nephropathy

Pathophysi-ological events underlying the origin and evolution of diabetic nephropathy

Inflammatory pathways in the pathogenesis of diabetic nephropathy

Jun Wada, and Hirofumi Makino Clin. Sci. 2013;124:139-152

Pathogenesis of Diabetic Chronic Kidney Disease

Specific targets and potential therapeutic strategies to inhibit or slow the progression of CKD

Declèves, A.‑E. & Sharma, K. (2014) Novel targets of antifibrotic and anti-inflammatory treatment in CKD, Nat. Rev. Nephrol. doi:10.1038/nrneph.2014.31

Specific targets and potential therapeutic strategies to inhibit or slow the progression of CKD

Declèves, A.‑E. & Sharma, K. (2014) Novel targets of antifibrotic and anti-inflammatory treatment in CKD, Nat. Rev. Nephrol. doi:10.1038/nrneph.2014.31

Cardio–renal syndrome pathophysiology

Clinical Types of Cardiorenal Syndrome

Syndromes Acute CRS (type 1)

Chronic cardio-renal (type 2)

Acute reno-cardiac (type 3)

Chronic reno-cardiac (type 4)

Secondary CRS (type 5)

Definition

Acute worsening of heart function (AHF–ACS) leading to kidney injury and/or dysfunction

Chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction

Acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction

Chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction

Systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney

Primary events

Acute heart failure (AHF) or acute coronary syndrome (ACS) or cardiogenic shock

Chronic heart disease (LV remodelling and dysfunction, diastolic dysfunction, chronic abnormalities in cardiac function, cardiomyopathy)

AKI CKDSystemic disease (sepsis, amyloidosis, etc.)

Clinical Types of Cardiorenal Syndrome

Syndromes Acute CRS (type 1)

Chronic cardio-renal (type 2)

Acute reno-cardiac (type 3)

Chronic reno-cardiac (type 4)

Secondary CRS (type 5)

Criteria for primary events

ESC, AHA/ACC ESC, AHA/ACC RIFLE–AKIN KDOQI Disease-specific criteria

Secondary events AKI CKD

AHF, ACS, arrythmias, shock

CHD (LV remodelling and dysfunction, diastolic dysfunction, abnormalities in cardiac function), AHF, ACS

AHF, ACS, AKI, CHD, CKD

Criteria for secondary events

RIFLE–AKIN KDOQI ESC, AHA/ACC ESC, AHA/ACCESC, AHA/ACC, RIFLE/AKIN ESC, AHA/ACC KDOQI

Cardiac biomarkers

Troponin, CK-MB, BNP, NT-proBNP, MPO, IMA

BNP, NT-proBNP, C-reactive protein

BNP, NT-proBNPBNP, NT-proBNP, C-reactive protein

C-reactive protein, procalcitonin, BNP

Renal biomarkers

Serum cystatine C, creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Serum creatinine, cystatin C, urea, uric acid, C-reactive protein, decreased GFR

Serum creatinine, cystatin C, NGAL. Urinary KIM-1, IL-18, NGAL, NAG

Serum creatinine, cystatin C, urea, uric acid, decreased GFR

Creatinine, NGAL, IL-18, KIM-1, NAG

Clinical Types of Cardiorenal Syndrome

Syndromes Acute CRS (type 1)

Chronic CRS (type 2)

Acute RCS (type 3)

Chronic RCS (type 4)

Secondary CRS (type 5)

Prevention strategies

Acutely decompensated heart failure, acute coronary syndromes, Poorly controlled BP, and noncompliance with medication and dietary sodium intake. Randomized trials: improving compliance with heart failure has reduced rates of hospitalization and mortality, and a reduction in the rates of acute CRS (type 1)

A common pathophysiology (neurohumoral, inflammatory, oxidative injury) could be at work to create organ dysfunction. Drugs that block the renin–angiotensin system reduce the progression of both CGF and CKD. It is unknown whether other classes of drugs can prevent chronic CRS (type 2)

Acute sodium and volume overload are part of the pathogenesis. It is unknown whether sodium and volume overload is prevented with different forms of renal replacement therapy and if this will result in lower rates of cardiac decompensation.

The chronic processes of cardiac and renal fibrosis, LVH, vascular stiffness, chronic Na and volume overload, and other factors (neurohumoral, inflammatory, oxidative injury) could be at work to create organ dysfunction. A reduction in the decline of renal function and albuminuria has been associated with a reduction in CV events. The role of chronic uraemia, anaemia, and changes in CKD-mineral and bone disorder on the CVS is known in chronic RCS

Potential systemic factors negatively impact function of both organs acutelyIt is uncertain if reduction/elimination of the key factors (immune, inflammatory, oxidative stress, thrombosis) will prevent both cardiac and renal decline.

Clinical Types of Cardiorenal Syndrome

Syndromes Acute CRS (type 1)

Chronic cardio-renal (type 2)

Acute reno-cardiac (type 3)

Chronic reno-cardiac (type 4)

Secondary CRS (type 5)

Management strategies

Specific—depends on precipitating factorsGeneral supportive—oxygenate, relieve pain & pulmonary congestion, treat arrhythmias appropriately, differentiate left from right heart failure, treat low cardiac output or congestion according to ESC guidelines(a); avoid nephrotoxins, closely monitor kidney function.

Treat CHF according to ESC guidelinesa, exclude precipitating pre-renal AKI factors (hypovolaemia and/or hypotension), adjust therapy accordingly and avoid nephrotoxins, while monitoring renal function and electrolytesExtracorporeal ultrafiltration

Follow ESC guidelines for acute CHFa specific management may depend on underlying aetiology, may need to exclude renovascular disease and consider early renal support, if diuretic resistant

Follow KDOQI guidelines for CKD management, exclude precipitating causes (cardiac tamponade). Treat heart failure according to ESC guidelinesa, consider early renal replacement support

Specific—according to etiology. General—see CRS management as advised by ESC guidelines* 2008

Follow-up ofCKD Patients

Goals of Care in CKD

· Slow decline in kidney function

· Blood pressure control1

· ACR <30 mg/g: ≤140/90 mm Hg· ACR 30-300 mg/g: ≤130/80 mm Hg*· ACR >300 mg/g: ≤130/80 mm Hg· Individualize targets and agents according to age,

coexistent CVD, and other comorbidities· ACE or ARB

*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300 mg/g.)2 1) Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int Suppl.

(2012);2:341-342.2) KDOQI Commentary on KDIGO Blood Pressure Guidelines. Am J Kidney Dis. 2013;62:201-213.

pathophysiological events underlying the chronic nephropathy

direct and indirect components of the renin – angiotensin aldosterone system (RAAS) and their effects on the progression of CKD

Nephrotic vs. Nephritic Syndromes

· Nephrotic Syndromes - glomerular disorders that affect the glomerular capillary membrane & increases permeability to plasma proteins

· Nephritic Syndromes – glomerular disorders that initiate the inflammatory response within the glomeruli & initially decreases permeability of the membrane

Nephritic Syndromes

Glomerulonephritis• An inflammatory response in the endothelial, epithelial &

mesangial cells of the glomeruli• Inflammatory process damages the capillary wall-

allowing RBCs into the urineSymptoms:

• 1st oliguria, followed by hematuria, azotemia, low GFR (d/t hemodynamic changes), hypertension

Nephrotic Syndromes

Primary causes:· Lipoid Nephrosis· Focal Segmental

glomerulosclerosis· Membranous

glomerulonephritisSecondary causes:· Diabetes Mellitus· SLE· Amyloidosis

Characterized by:· Proteinuria > 3.5g/day· Lipiduria· Hypoalbuminemia· Hyperlipidemia

Increased permeability of glomerular membrane allows proteins to escape into the filtrate

Pathophysiology of CKD in DM

Jun Wada, and Hirofumi Makino Clin. Sci. 2013;124:139-152

Pathophysiology of CKD

Pathophysiology of CKD

· Final Common Pathway is loss of nephron mass

Structural/ Functional

Hypertrophy of remnant nephrons

Loss of Nephron Mass

Sclerosis of remnant nephrons

Mediated by vasoactive molecules, cytokines and growth factors, renin angiotensin axis

Diabetes Hypertension Chronic GN Cystic Disease Tubulointerstitial disease

Pathophysiological Events Underlying the Nephropathy Caused by Ureteral Obstruction

Mesangial Cell Contribution

Valerie Kolmer 2006

Old Classification of CKD as Defined by Kidney Disease Outcomes Quality Initiative (KDOQI) Modified and Endorsed by KDIGO

Note: GFR is given in mL/min/1.732 m²National Kidney Foundation. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39(suppl 1):S1-S266

Stage Description Classification by Severity

Classification by Treatment

1 Kidney damage withnormal or increased GFR

GFR ≥ 90

2 Kidney damage withmild decrease in GFR

GFR of 60-89 T if kidney transplant

3 Moderate decrease in GFR GFR of 30-59 recipient

4 Severe decrease in GFR GFR of 15-29 D if dialysis

5 Kidney failure GFR < 15 D if dialysis

KDIGO, Kidney Disease: Increasing Global Outcomes

Which patients are at increased risk for CKD?

· Risk factors· Diabetes· Hypertension· Autoimmune diseases· Systemic infections· UTI, nephrolithiasis, lower

urinary-tract obstruction· Hyperuricemia· Acute kidney injury· Family history of chronic

kidney disease

· Sociodemographic risk factors· Older age· Black race· Smoking· Heavy alcohol use· Obesity· NSAIDs

· Diabetes mellitus

· Hypertension

· Cardiovascular disease

o Note on pediatric patients: · CKD may start with childhood

obesity· No recommendations for routine

testing

The people to test are those at greatest risk

· Age > 60 years· Race or ethnic background

· African-American· Hispanic· American Indian· Asian

· History of exposure to chemicals/toxins· Cigarette smoke· Heavy metals

· Family history of CKD

National Kidney Foundation, 20012

Functional Changes of CRF

The Kidneys are unable to:· Regulate fluids and electrolytes· Balance fluid volume and renin-angiotensin system· Control blood pressure· Eliminate nitrogen and other wastes· Synthesize erythropoietin· Regulate serum phosphate and calcium levels

Investigations in Patients with CKD and in Persons with Increased Risk for CKD

Clues to the Diagnosis of CKD fromthe Patient’s History

Signs & Symptoms of CKD at a Glance

Pharmacological Treatment

Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4