A limited presentation about a) age related renal functional changes b) management of CKD, including advance care planning and transplantation referral c) management of potentially risky drugs in the elderly with CKD (NOACs)

1. The aging kidney and what
we should (not?) do about
it
Christos Argyropoulos MD PhD FASN
Division of Nephrology
University of New Mexico

2. Learning Objectives
• Physiological changes in renal function and renal
function tests with aging
• Evaluation and management of chronic kidney
disease in the older adult
• Management of common medical problems and
drug dosing in renal functional impairment
(including patients on dialysis)

3. Physiological changes in
renal function as we age

4.  Filtration
 Reabsorption
 Secretion
 Fluid and electrolyte
homeostasis
 Endocrine function (renin,
erythropoietin, activation of
25(OH)D to the active 1,25
(OH)2D
 Metabolic function
(gluconeogenesis, drug
metabolism and insulin)
All renal physiology in one slide:
The kidney functions to maintain balance

5. Renal Filtration Declines With Age(but
we disagree about the rate)
~ 8 ml/min (~10%) per
decade after the age of 40
Longitudinal Studies tell a
more complex story
• B(altimore)LSA:
• 0.95 ml/min/yr
• 36% will not decline
• B(ronx)LAS:
• Minimal change over time in male pts
over 6 yrs
• FDA Registrational Trial Data
Am J Kidney Dis. 2003 Jan;41(1):1-12.
J Am Geriatr Soc. 1985 Apr;33(4):278-85.
J Am Geriatr Soc. 1995 Apr;43(4):412-4.
Biopharm Drug Dispos. 2015 Dec;36(9):613-21

6. Tubular Function Age Related
Changes
• Failure to conserve sodium under salt deprivation
(risk for prerenal AKI/ARF)
• Renal Acidosis Type IV (hyperkalemia)
• Maximal Concentrating Capacity Diminishes
• Nocturia
• Dehydration
• Hypernatremia
• Maximal Diluting Capacity Diminishes
• Hyponatremia when fluid challenged
Kidney Int. 2008 Sep;74(6):710-20.

7. Endocrine Function Age Related
Changes
• Levels of EPO will slightly increase with age
• However anemic elderly patients have lower levels than
anemic young ones (esp in iron deficiency)
• Lower levels of calcitriol (osteoporosis AND falls)
• Calcitriol supplementation reduced falls by ~50%
• Insulin Clearance Declines
• Insulin Resistance Increases
Kidney Int. 2008 Sep;74(6):710-20.

8. Age Related Changes In Renal
Vascular Function
• Renal Vasodilation more dependent on
• Prostaglandins
• Nitric Oxide

9. Age-Related Structural Changes
• Glomerulosclerosis
• 5% (<40) vs 30% (>80)
• Consider pathological
when % > (age/2) -10
• Arteriosclerosis
• Intimal fibrosis (similar
to DM or HTN)
• Interstitial Fibrosis
• Kidney weight declines
and Cortex thins
Kidney Int. 2008 Sep;74(6):710-20.

10. Pathogenesis of Renal Senescence
Kidney Int. 2008 Sep;74(6):710-20.

11. Evaluation and
Management of CKD In
The Elderly

12. We try to keep kidney disease
simple in the clinical chemistry lab
•Test of renal function:
•estimated glomerular filtration rate
•Test of renal damage:
•“protein” in the urine

13.  GFR is equal to the sum of the filtration rates in all of
the functioning nephrons.
 GFR is not routinely measured in clinical settings.
 Estimation of the GFR (eGFR) gives a rough measure of
the number of functioning nephrons:
 Formula based on age, gender, race, creatinine (+/-
cystatin, beta-trace protein, beta 2 microglobulin)
 Various formulas in use (Cockroft-Gault, MDRD, CKD-EPI)
What is the glomerular filtration rate (GFR)?

14.  A typical “normal” reference range of
0.6–1.2 mg/dL listed on many lab reports does not
account for muscle mass, age, gender,
and race.
 A 28-year-old African American man with serum
creatinine of 1.2 has an eGFR > 60.
 A 78-year-old white woman with serum creatinine of
1.2 has an eGFR of 43.
“Normal” serum creatinine
may not be normal

15. A fistful of eGFR formulas
Int Urol Nephrol (2017) 49:1979–1988

16.  Do not use with:
− Rapidly changing creatinine levels
 Example: acute kidney injury
− Extremes in muscle mass, body size, or altered diet patterns
− Medications that interfere with the measurement of serum
creatinine
− Not all estimating equations are created equal
 Not all estimating equations are created equal
− MDRD is “blind” above 60 ml/min/1.73m2
Creatinine-based estimates of kidney
function have limitations

17. Performance of eGFR equations in the
elderly (> 70 years old)
Int Urol Nephrol (2017) 49:1979–1988
The Berlin equations seem to work
somewhat better than MDRD/CKD-Epi

18. Cystatin – C v.s. Creatinine
• Cystatin – C is a “novel”
measure of renal
function
• Estimating equations
have been developed to
use Cys-C alone or with
SCr
• These equations do not
always agree !

19. Cystatin OR the Combination of Cystatin C
and Creatinine may be better ways to
assess renal function in the Elderly
Int Urol Nephrol (2017) 49:1979–1988

20. Proteinuria/Albuminuria
• Marker of kidney damage that independently predicts
cardiovascular disease.
• It is in the definition of stage 1 and stage 2 CKD.
• Controversial whether isolated microalbuminuria always
represents kidney disease or whether it could reflect
endothelial dysfunction without kidney damage.

21.  Dipstick
− Semi-quantitative, screening only
 Affected by urine concentration, highly variable
− Detection of urine albumin > 300 mg/day
(1+ approximates albumin excretion of 30 mg/day)
 Urine protein/creatinine ratio
‒ All proteins, not just albumin (myeloma/CIN)
 Urine albumin-to-creatinine ratio (UACR)
‒ Quantifies urine albumin
− Steps toward standardization currently in progress
− Standard for public health, clinical care, and research
Use which urine test?

22. Definition of Albuminuria
Method Normal
Micro-
albuminuria
Overt/Macro-
albuminuria
24 hour excretion <30 mg/day 30-300 mg/day >300 mg/day
Timed urine specimen <20 g/min 20-200 g/min >200 g/min
Spot-urine albumin
specific dipstick
(screening)
<3 mg/dl >3 mg/dl N/A
Spot urine albumin/
creatinine ratio (ADA)
< 30 mg/g 30-300 mg/g >300 mg/g
Spot urine albumin/
creatinine ratio (gender
specific) (K/DOQI)
<17 mg/g (men)
<25 mg/g (women)
17-250 (men)
25-355 (women)
>250 (men)
>355 (women)
K/DOQI and ADA

23. Urinary ACR is NOT perfect

25. Screening for CKD
1. Guidelines disagree (ACP/USPSTF vs ASN)
2. One will find low eGFR in the elderly if one looks
for it
3. Consensus is that patients with diabetes should
be screened (eGFR/albuminuria) but ?? older
people (>60 y/o) or those with hypertension
4. Cost-effectiveness of screening largely dependent
on the health care system

26. Adverse Outcomes Associated With
eGFR : Death and Dialysis
Adv Chronic Kidney Dis. 2016 Jan;23(1):8-11
J Am Soc Nephrol. 2007 Oct;18(10):2758-65.

27. Interface between
PC and Nephrology
KDIGO guidelines

28. CKD Checklist for PCPs
• Slowing Progression
• BP < 140/90
• HBA1c ≤ 7% within 6 mos
• Annual screen for proteinuria
• On ACEi/ARB if DM or microalb
> 30mg/g
• Smoking cessation
• Discuss avoidance of
NSAIDs/nephrotoxins
• LDL < 100 within the last year
• 5 year pneumovax
• Yearly flu
• Tx of Complications
• CBC, iron studies within the
year
• Ca, P, PTH (q 6 mo if eGFR <
60, q 3 mo if eGFR < 30)
• Nephrology Referral
• GFR < 30
• Persistent proteinuria despite
ACEi
• Persistent hyperK
• Resistant HTN (≥4 meds)
• ↓GFR by 30% (“certain drop”)
irrespective of eGFR
• Unclear etiology of CKD
• Anemia requiring ESAs
• ↑ P, PTH
CJASN 9:1526-1535, 2014

29. The Elderly Dialysis
Patient

30. Outcomes of the elderly patient
receiving renal replacement
Kidney Int. 2012 Aug;82(3):261-9.

31. Choice of Initial Dialysis Modality
Kidney Int. 2012 Aug;82(3):261-9.
Kidney Int Rep (2017) 2, 645–653;

32. Shared Decision Making and
Conservative Management of CKD
Rosansky et al. BMC Nephrology (2017) 18:200

33. When to Discuss Dialysis And When
Not in your >75 year old patient
Rosansky et al. BMC Nephrology (2017) 18:200
ΔeGFR
ml/min/1.73m2
Low
Comorbidity
High
Comorbidity
< 3 Conservative Conservative
3-5 Dialysis Conservative
> 5 Dialysis SDM
AKI Dialysis Conservative

34. Weighing the options
Rosansky et al. BMC Nephrology (2017) 18:200

35. Referral for Renal Transplant
Kidney Int. 2012 Aug;82(3):261-9.
Kidney Int Rep (2017) 2, 645–653;
Appropriateness of renal transplant referral
• Require estimated survival > 5 years
• Variability in expected survival very
high in the elderly (poor models)
• Wait-list times routinely exceed 6 years
• Clinical score developed to guide
referral of older patients
• Shared decision making between
patient, family, nephrologist and
transplant center
• An option for the “healthy” old patient
Time required for cumulative survival after kidney
transplantation to exceed cumulative survival on
the waiting list, by age group

36. Advance Care Planning (ACP) in CKD
and ESRD
Intervention Flow Chart Improving ACP in CKD / ESRD
Clinical Kidney Journal, Volume 10, Issue 1, 1 February 2017,
Pages 68–73

37. Pharmacotherapy of
Common Medical
Problems in CKD

38. Drug Dosing Considerations
• Renal impairment may alter both
pharmacodynamics and pharmacokinetics
• MOST DRUGS HAVE NEVER BE TESTED IN
CKD POPULATIONS
• There is a higher risk for Adverse Drug
Reactions as a result of renal functional
impairment AND comorbidities AND age in
CKD patients

39. Cockroft Gault ≠ MDRD for drug dosing
Ann Pharmacother 2012;46:1174-87
For patients with advanced age, low weight, and modestly elevated serum
creatinine, further work is needed before the MDRD equations can replace the CG
equation for dose adjustment in the labeling.

40. The
cautious
approach
to drug
dosing in
CKD
Pharmacotherapy. 2011;31(11):1130-1144.

41. Anticoagulation
management

42.  Alternatives to warfarin that are licensed for
use without Therapeutic Drug Monitoring
− Rivaroxaban (Xarelto) : Xa inhibitor
− Apixaban (Eliquis): Xa inhibitor
− Dabigatran (Pradaxa): DRI
 They are removed by the kidneys
 Safety signals for older individuals with renal
impairment
 Dialytic clearance substantial only for dabigatran
Novel Oral AntiCoagulants (NOACs) in CKD

43. Safety of NOACs in CKD (major or
clinically relevant bleeding)
eGFR(50-79) eGFR(30-49)
Canadian Journal of Cardiology 30 (2014) 888- 897

44. Efficacy of NOACs in mild CKD
(eGFR 50-79)
Stroke VTE or VTE related death
Canadian Journal of Cardiology 30 (2014) 888- 897

45. Efficacy of NOACs in moderate CKD
(eGFR 30-49)
Stroke VTE or VTE related death
Canadian Journal of Cardiology 30 (2014) 888- 897

46. NOACs – Dosing Recommendations
• Apixaban 2.5 mg- 10mg BID (depending on indication)
• 2.5 mg BID if one of the following (Wt<60 kgr, age>80), SCr > 1.5 mg/dl
• Dabigatran 150 mg BID
• 75 mg BID if CrCl 15-30 ml/min
• Rivaroxaban 10 -20 mg QD (depending on indication)
• VTE prophylaxis (use w caution for ClCr 30-50, avoid for ClCr < 30)
• Afib: 20mg/d (ClCr > 50), 15 mg/d (15-50 ml/min, avoid for ClCr <15)
• NOACs not recommended for non dialysis dependent CKD
stage V (ClCr < 15)
• In patients on dialysis may only use Apixaban:
• 5 mg po BID unless one of the following (Wt<60 kgr, age>80): use 2.5
mg bid

47. Diabetes

48.  Glyburide
 Metformin (US label SCr>1.4-1.5 ex-
US eGFR>30)
 Alpha-glucosidase inhibitors
 Exenatide
 Glimepiride
 Sitagliptin
 Repaglinide
 Insulin (dose decrease by 25-50%)
 Glipizide
 Pioglitazone
− Fluid retention
 Nateglinide
 Pramlintide
 Canaglifozin/empaglifozin (eGFR>45)
 Dapaglifozin (eGFR>60)
Diabetes medications may be
discontinued or adjusted in CKD
Reference: Reilly & Berns Seminars in Dialysis 2010; 23(2):163–168.
Farxiga/Invokana/Jardiance PIL

49. SGLT2i in Diabetic Kidney Disease
Outcome Cana Dapa Empa
Proteinuria
(short term)
↓ ↓ ↓
Proteinuria
(long term)
↓ ↓ ↓
ΔeGFR (acute) ↑ ↑ ↑
ΔeGFR (chronic) ↓ ? ↓
Hard outcomes (x2
SCr/RRT/renal death)
HR
0.60 (0.47 – 0.77)
Unknown
(DECLARE)
HR
0.61 (0.53 – 0.70)
ARB Hazard Ratio
IDNT composite 0.60 (0.66 – 0.97)
RENAAL composite 0.84 (0.72 – 0.98)
ARB meta ESRD1 0.78 (0.67 – 0.91)
ARB meta x2SCr1 0.79 (0.68 – 0.91)
1doi: 10.1038/ajh.2008.206

50. Renal function has a substantial
effect on dosing of SGLT2i
eGFR range Canagliflozin Dapagliflozin Empagliflozin
>60
ml/min/1.73m2
100-300 mg/d 5-10 mg/d 10-25 mg/d
45-60
ml/min/1.73m2
Not to exceed
100 mg/d
Do not initiate 10-25 mg/d
<45
ml/min/1.73m2
Do not initiate Do not initiate Do not initiate
<30
ml/min/1.73m2
Contraindicated Contraindicated Do not initiate
Adjustments
during therapy
Not recommended
when eGFR
declines
persistently below
45 ml/min/1.73m2
Not recommended
when eGFR
declines
persistently
between 30-60
ml/min/1.73m2
Discontinue if eGFR
persistently falls
below 45
ml/min/1.73m2

51.  There are NO randomized
controlled trials in this
population
 Many studies find U shaped
curves, with mortality
worse when A1c<6% or
>8%
 Existing guidelines:
− Let A1c rise to >7%
− Many nephrologists will
tolerate 7-9%
What is the target for glycemic control in
ESRD?
Ricks et al., Diabetes 61(30):
708–715, 2012).

52.  Dose: To prevent hypoglycemia, insulin may have to be reduced
by 50% when the eGFR<10 (many patients are firmly on their
way to dialysis by then)
 Timing: a single study suggests lowering basal insulin by 25% on
the day after dialysis to provent hypoglycemia
 Titration: In insulin-naïve dialysis patients start at 10-12 units
 Many nephrologists consider insulin based regimens the
treatment of choice for patients with DM and ESRD
Treatment of Diabetes in Dialysis: Insulin
Nephrol Dial Transplant (2016) 31 (1): 8-15. DOI: https://doi.org/10.1093/ndt/gfv258

53.  Sulfonylureas: glipizide is the agent of choice
 Meglitinides:
− repaglinide is >90% metabolized by the liver
− Start at 0.5 mg po tid with meals
− May be used as monotherapy in ESRD
 Biguanides (metformin): no-no
 Thiazolidinedione (pioglitazone):
− Overall low risk of hypoglycemia
− As monotherapy may reduce A1c by 0.5-1% in ESRD
− Pioglitazone may be associated with impr survival
Treatment of Diabetes in Dialysis: Non-insulin agents I

54.  DPP4:
− Lina(gliptin) is the only one that is cleared by the liver (no dose
adjustment): 5 mg po daily
− Sita: 25mg/day (irrespective of timing of dialysis)
 Similar efficacy to glipizide with less severe hypoglycemia in a double blind, RCT
− Saxa 2.5 mg/day (give after dialysis – removes 25%)
− Alo: 6.25 mg/day
 GLP-1 (exenatide, liraglutide): not recommended in patients on
dialysis
 Alpha-glucosidase inhibitors: not recommended in patients on
dialysis
 Amylin analog (pramalintide): renal clearance – not recommended
 SGLT2 inhibitors: cannot be used
Treatment of Diabetes in Dialysis: Non-insulin agents II
Am J Kidney Dis. 2013 Apr;61(4):579-87. doi: 10.1053/j.ajkd.2012.11.043

55. Summary and Unresolved Issues
• Changes in renal physiology imply that one should be very
cautious when:
• Giving fluids
• Restricting fluids
• Adding and dose adjusting meds
• The prevalence of CKD = “low eGFR” is high in older patients
• Variability of outcomes in this population is very high
• If one chooses conservative rather than dialytic management,
frequent clinic visits are essential to manage complications of
CKD
• A multi-disciplinary approach and SDM is essential