Kidney Disease -Presentation to Primary Care Internal Medicine: Principles & Practice Course.

2019 David Steele MD

Renal Unit Massachusetts General Hospital

Boston MA.

I have no conflicts of interest to declare

Conflicts of Interest

• HealthReveal – Consultancy • Fresenius Medical Care – Medical Director

Aims

• Gather a sense of the demographics and natural history of Chronic Kidney Disease (CKD)

• Understand the impact of CKD on the patient and it’s associated co-morbidities

• Review ESRD management options including medical management

Advanced Kidney Health Initiative

Released July 10, 2019 as Executive Order and HHS proposal Three goals outlined: • 25% decrease in ESRD by 2030 • 80% of new ESRD patients on home dialysis or receiving a transplant • Doubling of available kidneys for transplant by 2030 Approach: • Public health surveillance to improve at risk populations and early CKD • Adoption of evidence-based interventions to delay or stop CKD progression • Improve access to and quality of person-centered treatment options • Development of innovative therapies to replace dialysis • Increase utilization of available deceased organs by increasing organ recovery and reducing organ discard rate • Increase living donation by removing financial disincentives • New value-based kidney disease payment models that align provider incentives with patient preferences and improve quality of life

Question All of the following adult patients should be referred for nephrology

consultation, EXCEPT? A. Initial visit: eGFR 26 & 3 months later: eGFR 28 (mL/min/1.73m2) B. Initial visit: eGFR 55, & 3 months later: eGFR 43 confirmed with

repeat eGFR 45 (mL/min/1.73m2) C. Initial visit: urine Albumin to Creatine Ratio (ACR) 450 & 3 months

later: Albumin to Creatine Ratio 355 (mg/g) on both dates the eGFR >60 mL/min/1.73m2

D. Initial visit: eGFR >60 & 3 months later: eGFR >60 (mL/min/1.73m2) with personal history of Autosomal Dominant Polycystic Kidney Disease

E. Initial visit: eGFR 42 & 3 months later: eGFR 44 (mL/min/1.73m2) on both dates the ACR <30 mg/g

www.kidney.org/CKDinform

Question All of the following adult patients should be referred for nephrology

consultation, EXCEPT? A. Initial visit: eGFR 26 & 3 months later: eGFR 28 (mL/min/1.73m2) B. Initial visit: eGFR 55, & 3 months later: eGFR 43 confirmed with

repeat eGFR 45 (mL/min/1.73m2) C. Initial visit: urine Albumin to Creatine Ratio (ACR) 450 & 3 months

later: Albumin to Creatine Ratio 355 (mg/g) on both dates the eGFR >60 mL/min/1.73m2

D. Initial visit: eGFR >60 & 3 months later: eGFR >60 (mL/min/1.73m2) with personal history of Autosomal Dominant Polycystic Kidney Disease

E. Initial visit: eGFR 42 & 3 months later: eGFR 44 (mL/min/1.73m2) on both dates the ACR <30 mg/g

www.kidney.org/CKDinform

Distribution of Costs General Medicare Population CKD and ESRD

USRDS ADR 2010

Combined costs to Medicare for CKD and ESRD are on par with the other two large chronic disease categories: Diabetes and CHF

CKD and ESRD Demographics and Clinical Outcomes

• As of Dec 31, 2016, there were 726,331 prevalent cases of ESRD in the United States: – This represents an increase of

3.0% since 2015, and of 86.0% since 2000

– 63.1% receiving hemodialysis, – 6.9% peritoneal dialysis – 29.6% kidney transplant

• ESRD incidence rate increasing 1-3% pa – 124670 patients initiated HD in

2016

USRDS ADR 2018

Defining Chronic Kidney Disease (CKD)

DM40%

HTN25%

Glom Dz10%

Non Glom Dz5%

Tx Loss5%

Urological2%

Other13%

• Kidney damage of > 3 months

• GFR < 60ml/min/1.73m2 • Albuminuria >30mg/g • CKD results from many

pathophysiologically distinct diseases which share a common natural history

• CKD should be staged using eGFR (eg MDRD)

Clinical Practice: Steps needed to optimize CKD Patient Care

1. Does the patient have CKD? – Assess GFR, albuminuria.

2. Determine etiology. 3. Assess for evidence of progression. 4. Assess for associated complications. 5. Patient education. 6. Assess life expectancy and patient wishes for

dialysis/transplantation.

Clinical Evaluation of Patients with CKD

• Blood pressure • HbA1c • Serum creatinine

– Use a GFR estimating equation or clearance measurement; don’t rely on serum creatinine concentration alone.

– Be attentive to changes in creatinine over time--even in “normal” range.

• Urinalysis – Urine sediment

• Albuminuria/Proteinuria • Spot urine for protein-to-creatinine or

albumin-to-creatinine ratio. • Electrolytes, blood glucose, CBC

• Depending on stage: – albumin, phosphate,

calcium, iPTH • Renal imaging • Depending on age and

H&P – Light chain assay, serum or

urine protein electrophoresis (SPEP, UPEP)

– HIV, HCV, HBV tests – Complements, other

serological testing - limited role unless specific reason

Markers of Renal Disease: Serum Creatinine is a useful but imperfect biomarker

Estimated GFR; eGFR measurement is necessary to better define CKD natural history

1. MDRD Equation (mL/min/1.73 m2) GFR = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

2. CKD Epi Equation (mL/min/1.73 m2) GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-

1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black]

Evaluating CKD

Assign Albuminuria Category

Assign GFR Category

Classification of CKD Based on GFR and Albuminuria Categories: “Heat Map”

Tangri et al. JAMA. 2016 Jan 12;315(2):164-74

Predicting CKD Progression

Progression: Albuminuria as a Risk Factor

Progression of CKD - Angiotensin II effects

• Angiotensin II – Hemodynamic effects

• Single nephron increased GFR

• Increased intraglomerular pressure

– Non Hemodynamic effects

• Inflammation and oxidative stress

• Cellular hypertrophy and proliferation Secondary Focal Segmental

Glomerulosclerosis

Hyperfiltration of remaining healthy Nephrons

Primary Injury with loss of Nephron mass

Decline in GFR: ACEI and ARB use in Type 1 and Type 2 Diabetics Lewis et al NEJM 329(20), 1993

Brenner et al NEJM 345(12), 2001

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The Renaal Study

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Captopril Study Group

PlaceboCaptopril

Reduction in risk of doubling serum creatinine •Captopril Study (Lewis) - 48% •Renaal Study (Brenner) - 25%

ACEI/ARB’s in CKD

• ACEI or ARB are indicated for diabetic patients with uAlb/Creat ratio>0.03 (microalbuminuria)

• ACEI or ARB are indicated for CKD patients with uAlb/Creat ratio>0.5 (overt proteinuria)

1. Tolerate a small (15-20%) rise in serum creatinine

2. Attempt to manage Hyperkalemia without withdrawal of ACEI/ARB: – Dietary K restriction – Potassium GI binders prn – Loop diuretics; Fludrocortisone

3. Use ARB in patients intolerant to ACEI (cough)

Weir et al. N Engl J Med 2015;372:211-221.

Novel agents to treat Hyperkalemia: Patiromer (Valtessa) and Sodium Zirconium Cyclosilicate (LoKalma)

Packham et al. N Engl J Med 2015;372:222-231.

SGLT2 Agents: Major kidney Events: ESRD Progression by eGFR cohort

Reduce ESRD progression in full range of eGFR, most significantly in eGFR>90

Zelniker, T. A., (2018). The Lancet, 6736(18)

SGLT2 Agents: Heart Failure by GFR

Reduced hospitalization for HF in eGFR<60

Zelniker, T. A., (2018). The Lancet, 6736(18)

CKD Proteinuria

or eGFR 30-60

T2DM

HFrEF or ASCVD

SGLT2 Prescription Management: It’s Complicated

Nephrology

Diabetology

Cardiology

PCP Role

Question

• The Tromsø study looked at the natural history of CKD in a population of 58000 patients in Scandinavia. 3047 patients were found to have a GFR between 30 and 60 ml/min. Patients were followed for 10 years and the rate of progression to ESRD was:

A. 4% B. 10% C. 12% D. 25%

Answer

• The Tromsø study looked at the natural history of CKD in a population of 58000 patients in Scandinavia. 3047 patients were found to have a GFR between 30 and 60 ml/min. Patients were followed for 10 years and the rate of progression to ESRD was:

A. 4% B. 10% C. 12% D. 25%

Longitudinal Follow-up and Outcomes Among a Population With Chronic Kidney Disease

in a Large Managed Care Organization

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27998 patients identified with GFR < 90ml/min and followed for 5 years

Arch Intern Med. 2004;164:659-663

Strategies for Caring with Patients with CKD 4

• Delay Progression – ACE Inhibition – Manage

metabolic abnormalities

– Minimize AKI risk

– Review dietary options

• Manage Comorbids – Cardiovascular

risk – Anemia

management – Metabolic Bone

Disease Management

• Prepare for ESRD – Isolate high risk

populations – Patient

education – Refer to

Nephrology – Prepare for

angioaccess – Review Medical

Management options

Diet and Lifestyle Diet • CKD patients should receive expert

dietary advice if available • Lower protein intake to 0.8 g/kg/day in

patients with GFR <30 ml/min • Avoid high protein intake (>1.3

g/kg/day) in adults with CKD at risk of progression.

• Target HbA1c of <7.0% (extended above 7.0% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia)

• Lower salt intake to <2 g per day of sodium

Lifestyle • Undertake physical activity

– 30 minutes 5 times per week • Achieve a healthy weight

– BMI 20 to 25 • Stop smoking • Avoid NSAID’s

Vaccinations • Annual Influenza • Pneumococcal vaccine q 5 years • Hep B for stage 5 CKD and likely

progression to HD

Kidney International Supplements (2013) 3, 5–14

CKD predisposes hospitalized patients to Acute Renal Failure

USRDS ADR 2009

• CKD increases the risk of AKI seven fold in hospitalized patients.

• In AKI patients with CKD, the hazards for: – ESRD 85.0 – Death 3.1

(in AKI patients with no CKD, hazards are 11.7 and 2.5, respectively)

These are the patients who “crash” onto dialysis

NephroPharmacology Renally dose all medications and monitor eGFR and drug

levels as indicated. – Reconsider dose with any significant change in eGFR and

review medications regularly for continued appropriateness. – Prolonged NSAID use should be avoided in early stage CKD. – Counsel patients to consult a physician or pharmacist before

using over-the-counter medications or supplements.

Consider monitoring eGFR more frequently and holding renally cleared and potentially nephrotoxic medications during acute illness or in the perioperative period.

Imaging Studies Iodinated Contrast Studies: • Avoid high osmolar agents • Use lowest possible contrast dose compatible with complete study • Withdraw potentially nephrotoxic agents before and after the

procedure • Give adequate hydration with saline before, during, and after the

procedure • Measure GFR 48–96 hours after the procedure Gadolinium-based contrast studies: • Do not use gadolinium in Pts with GFR <15 ml/min/1.73 m2 (unless

there is no alternative appropriate test) • For pts with a GFR <30 ml/min use a macrocyclic chelate

preparation Bowel preparation: • Avoid oral phosphate-containing bowel preparations in pts with

GFR <60 ml/min due to risk of phosphate nephropathy Kidney International Supplements (2013) 3, v

Cardiovascular Disease in Patients with Chronic Kidney Disease

Abboud H and Henrich W. N Engl J Med 2010;362:56-65.

Lipid Management • Statins decrease risk for CVD

events and death by 20% in pts not on dialysis.

• Pts with traditional CV risks (diabetes, coronary disease, prior stroke, or increased 10-year risk) should receive statin therapy according to current guidelines

• In the absence of traditional risk factors, strongly consider statin therapy if: – Age >50 years – History of transplantation

(cyclosporine increases serum levels of some statins)

Adapted from Tonelli, et al Ann Int Med. 2014; 160:184

MGH POCI Management of Advanced CKD and It’s Complications. Authors: Mary H. Hohenhaus, MD; Shana Birnbum MD. Specialty Reviewer: David J.R. Steele, MD

Management of HTN JNC 8: • In the general population

aged ≥60 years – Treat BP > 150/90

• In the general population <60 years – Treat BP > 140/90

• In the population aged ≥18 years with CKD – Treat BP > 140/90 and use ACEI

or ARB

KDIGO Guidelines: • In diabetic and non-

diabetic adults with CKD and with urine albumin excretion of >30 mg/24 hours – Treat BP >130/80 and use

ACEI/ARB (2D level of evidence)

Relationship Between Achieved BP and Decline in Kidney Function from Primary Renal Endpoint

Trials Nondiabetes • MDRD. N Engl J Med. 1993 • AIPRI. N Engl J Med. 1996 • REIN. Lancet. 1997 • AASK. JAMA. 2002 • Hou FF, et al. N Engl J Med.

2006 • Parsa A et.al. NEJM 2013 Diabetes • Captopril Trial. N Engl J Med.

1993 • Hannadouche T, et al. BMJ.

1994 • Bakris G, et al. Kidney Int.

1996 • Bakris G, et al. Hypertension.

1997 • IDNT. NEJM. 2001 • RENAAL. NEJM. 2001 • ABCD. Diabetes Care (Suppl).

2000

Update from Kalaitzidis R and Bakris GL In: Handbook of Chronic Kidney Disease. Daugirdas J (Ed.) 2011.

Anemia Management

• Check hemoglobin in patients with eGFR < 45 ml/min

• Exclude other causes of anemia before attributing to CKD

• If the patient is likely to benefit in terms of quality of life, consider referral for ESA candidacy if Hb < 9g/dl

Studies of Anemia Management and the use of Erythropoetin in CKD

Normal Hct Study Besarab A et al. N Engl J Med 1998;339:584-590

183 deaths and 19 non fatal MI’s in nl-Hct group and 150 deaths and 14 non fatal MI’s in low-Hct group (RR 1.3; 95% CI, 0.9 to 1.9). Study halted.

Pts in nl-Hct group had a decline in the adequacy of dialysis and received more IV iron dextran.

CHOIR Study Ajay Singh et al. N Engl J Med 2006;355:2085-98.

125 events (Death, MI, CHF, Stroke) in the high-Hb group vs 97 events in the low-Hb group (HR, 1.34; 95% CI, 1.03 to 1.74; P = 0.03).

Improvements in the quality of life were similar in the two groups.

CREATE Study Drueke et al N Engl J Med 2006;355:2071-84

No effect on first cardiovascular event

General health and physical function improved significantly (P = 0.003 and P<0.001) in high Hb group.

TREAT Study Marc Pfeffer et al N Engl J Med 2009;361:2019-32

Death or a cardiovascular event in 632 pts in Rx group vs 602 pts in placebo group (P = 0.41)

Fatal or nonfatal stroke in 101 pts in Rx grp vs 53 in placebo group (P<0.001).

Vascular Biology is abnormal in CKD. Coronary-Artery Calcification in Young Adults with End-Stage Renal Disease

Undergoing Dialysis (N Engl J Med 2000;342:1478-83. AIN May 1998 Vol 128:10; 839-847)

1. Coronary-artery calcification is common and progressive in young adults with end-stage renal disease who are undergoing dialysis.

2. The mean serum phosphorus, the mean calcium-phosphorus ion product, and the daily intake of calcium were higher among the patients with coronary-artery calcification

Sample electron-beam computed tomographic scan showing calcification of the left anterior descending coronary artery (thick arrow) and the aortic root (thin

arrow).

Mineral Metabolism in CKD Measure serum calcium and phosphate if eGFR < 45ml/min

Offer bisphosphonates for the prevention and treatment of

osteoporosis in patients with eGFR > 30 ml/min on the same indications as for all other patients

Avoid Hyperphosphatemia

Correct Nutritional 25OH Vit D Deficiency

Treat Secondary Hyperparathyroidism

Restrict dietary phosphate intake

Use phosphate binders when indicated

-Calcium based: CaCO3; Ca Acetate

-Non Calcium Based Sevelamer; (AlOH3)

Consider supplementing with 25OH Vit D if level <30ng/L Eg: Ergocalciferol 50000u/week for 12 weeks

Supplement 1,25 Vitamin D (Calcitriol) according to PTH level; although in cases of non dialysis CKD the optimal PTH is not known

Vitamin D analogues and Calcitriol should not be routinely used but rather on a case by case basis

Current evidence on oral anticoagulant therapy for patients with atrial fibrillation across the spectrum

of chronic kidney disease

Kidney International 2017

Trends in oral anticoagulant prescriptions in patients with ESRD and Atrial Fibrillation

on Hemodialysis in the United States (2010–2015)

Siontis et al. Circulation. 2018 Oct 9;138(15):1519-1529

Preparing for ESRD: Patient and Physician Awareness

Patient awareness Physician Awareness

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McClellan, AJKD 1997, 29:368-75

%Patients under Nephrology Care Prior To Dialysis Start USRDS 2018

Hemodialysis

Advantages of Timely Referral in Patients with Progressive CKD 1. Improves patient preparation for RRT. 2. Greater use of permanent vascular access. 3. Avoidance of emergent hemodialysis initiation. 4. Greater utilization of transplantation and self-

care dialysis (i.e., peritoneal dialysis or home hemodialysis).

5. Management of medications which may help to delay the need for RRT.

6. Gives the nephrologist adequate time to counsel patients through this challenging transition in their lives.

Relative Risk P value of death Diabetics: AVF 1.00 PTFE 1.39 0.0004 Catheter 1.49 0.0004 Non-Diabetics: AVF 1.00 PTFE 1.09 0.26 Catheter 1.72 0.0001

Benefits of a Fistula

Thrombosis following PICC placement

Figure 1. A 38-year-old asymptomatic woman 1 day after PICC placement with inadvertent removal. Venography demonstrates non-occlusive thrombus in a brachial vein

Allen et al, JIVR, 2000

• Identify CKD stages 3,4 or 5, including current hemodialysis, peritoneal dialysis or transplant patients as a special population when planning central venous access

• Plan appropriate venous access in these cases – dorsal hand veins for

phlebotomy – internal jugular veins are

preferred for central venous access

– external jugular veins are acceptable alternative

– Avoid any catheters in subclavian veins

Peritoneal Dialysis • Less than 8% of prevalent ESRD

patients in the US are on PD; significantly less than in other developed countries

– subtle differences in practice patterns – unintended financial considerations

• Medical outcome date would seem to favor more utilization of PD

– Improved mortality

• Most home dialysis units are small – some have minimal clinical experience – consolidation of PD programs may be

needed.

Burkhart J, CJASN 2009 Dec;4 Suppl 1:S125-31

Multidisciplinary pre-dialysis programs increase the proportion of patients initiating dialysis with PD.

Ribitisch et al Peritonal Dial Int 2013 Jul-Aug;33(4):367-71

Timing of the initiation of dialysis: Early versus Late Start.

• 828 patients • Early Start: GFR 10-14ml/min; Late Start:

GFR 5-7ml/min • 76% of late start patients initiated HD with

GFR>7.0ml/min

Consider dialysis initiation before/when one or more of following is present: • Symptoms or signs attributable

to kidney failure (serositis, acid-base or electrolyte abnormalities, pruritus);

• Inability to control volume status or blood pressure;

• Progressive deterioration in nutritional status refractory to dietary intervention;

• Cognitive impairment. Often occurs in the GFR range between 7 and 10 ml/min

Kidney Transplantation Key Concepts • Kidney transplantation is the most cost-

effective modality of renal replacement. • Transplanted patients have a longer life and

better quality of life. • Early transplantation (before [pre-emptive] or

within 1 year of dialysis initiation) yields the best results.

• Living donor kidney outcomes are superior to deceased donor kidney outcomes.

• Early transplantation is more likely to occur in patients that are referred early to nephrologists.

• Refer for transplant evaluation when eGFR <20 mL/min/1.73m2.

Mortality in ESRD

USRDS 2018

Incidence of ESRD: By Age - the ageing of the dialysis population

USRDS ADR 2018

Trends in adjusted ESRD incidence rate, by age group, in the U.S. population, 2000-2015

Trends in the adjusted prevalence of ESRD, by age group, in the U.S. population, 2000-2015

Functional Status of Elderly Adults before and after Initiation of Dialysis

•3702 nursing home residents in the United States •Initiated dialysis dialysis between June 1998 and October 2000. •At least one measurement of functional status was available before dialysis. •Functional status was measured by assessing the degree of dependence in seven ADL’s (on the Minimum Data Set–Activities of Daily Living [MDS–ADL] scale of 0 to 28 points, with higher scores indicating greater functional difficulty).

Tamura et al N Engl J Med 2009;361:1539-47.

A comparative survival study of patients over 75 years with chronic kidney disease stage 5

Kaplan–Meier survival curves comparing the dialysis and conservative groups (P<0.001).

Kaplan–Meier survival curves for those with high comorbidity (score>2), comparing dialysis and conservative groups

Murtagh et al Nephrol Dial Transplant (2007)

Conservative Management of Stage V CKD

• Conservative management should be an option

• It should be supported by a comprehensive management program.

• It should be available to people and families through either primary care or specialist care as local circumstances dictate.

• The comprehensive conservative management program should include: – protocols for symptom and

pain management, – psychological care, spiritual

care – culturally sensitive care for

the dying patient and their family (whether at home, in a hospice or a hospital setting)

– provision of culturally appropriate bereavement support.

Kidney International Supplements (2013) 3, 5–14

Conclusions

• Kidney Disease is common and management is complicated • The majority of patients with CKD have non progressive

disease • Cardiovascular disease is a major co-morbidity • For patients with progressive CKD care strategies should be

initiated early to improve long term morbidity and mortality • A team approach is required • Pre-planning for renal replacement therapies is necessary in

those with progressive disease