Geriatric NephrologyTomasz BebenUC San Diego and VA San Diego Internal Medicine and Nephrology

Objectives• Describe Renal Changes with Aging

• Glomerulus• Vasculature• Tubules

• Describe Clinical Implications• Medications• When to refer to nephrology?• Dialysis Implications

Review of Renal Physiology

http://analytical.wikia.com/wiki/Nephron

Measuring Kidney Function• Glomerular Filtration Rate: Volume of fluid

filtered from GC to BS per unit time

GFR Determinants• Renal Plasma Flow (25% cardiac output)

• (PAorta – PRenal Vein)/Renal resistance• Hydraulic Pressure

• Aortic pressure and renal resistance (afferent and efferent arterioles)

• Oncotic Pressure• Negligible in Bowman’s

Space• Filtration Equilibrium

• Glomerular Properties• Total surface area and

permeability

Shiraishi, et al. The FASEB Journal. 2003;17:2284-2286.

Autoregulation• Stimuli:

• Myogenic stretchreceptors

• TubuloglomerularFeedback

Costanzo Physiology 2002

Glomerular Filtration Rate• After age 40, GFR decreases by 0.8-1

mL/min/year on average• Renal plasma flow decreases by 10% per

decade• In part due to reduced mass, but also reduced

when adjusted for mass• An unavoidable consequence of aging?• Confounded by comorbidities:

• Prevalence of hypertension, vascular disease, and diabetes increase with age

Not Everyone Declines• Baltimore Longitudinal Study of Aging

• 254 normal subjects followed 23 years• Mean decline of CrCl: 0.75 mL/min/year• But 36% showed no decline

• Bronx Longitudinal Aging Study• 141 very elderly followed 6 years• BUN and Cr actually decreased slightly• Likely due to decreased muscle mass

• Controversy: Simple aging or pathology?

Structural Changes• Atrerionephrosclerosis =

Nonspecific• Similar to HTN and DM

• “If you have a kidney from a 45 year old and you see arterionephrosclerosis – you know it is hypertension. If you have a kidney from a 75 year old and have arterionephrosclerosis – you don’t know what it is.” –Bleakley Chandler

Silva, F. International Urology and Nephrology (2005) 37:185–205http://medicinembbs.blogspot.com/2011/02/hyaline-arteriolosclerosis.html

Gross Changes• Kidney weight declines after 4th decade

• Atrophy of cortex• Relative sparing of the medulla

• At Birth: 50 g• 4th Decade: 400 g• 9th Decade: 300 g• Granular surface:

• Fibrosis andContraction

• Similar to hypertensive changeshttp://www.wwu.edu/depts/healthyliving/PE511info/kidney/causespage.html

Structural Changes• Increase in sclerotic glomeruli• Less glomerular lobulation• Increased aglomerular arterioles

• Shunt from afferent toefferent side

• Thickening of thebasement membrane

• Hyalinosis of arterioles

Zhou, et al. Kidney International (2008) 74, 710–720

Decrease in Glomeruli• What is a normal number of glomeruli?

• Per kidney: 333,000 – 1,100,000• Certain people start with more

• Proportional to birth weight• Number declines with age

• More Sclerotic Glomeruli• Cause? Brenner Hypothesis:

• Compensatory Hyperfiltration leads to HTN and further glomerular injury

Glomerular Properties• Reduced permeability• Reduced total surface area

• Because fewer intact glomeruli• To compensate and maintain GFR:

• Afferent resistance decreases• Glomerular pressure increases

• Altered podocytes and abnormal GBM function• More proteinuria

Abnormal Podocytes • Fused or absent foot processes in an

experimentalmodel ofaging mice

Hartleben, et al. J Clin Invest. 2010; 120(4):1084–1096

What Causes The Changes?• Franz Volhard (clinician) and Theodor

Fahr (pathologist)• Collaborators and rivals

• Chicken or the Egg Controversy?• Volhard argued that HTN leads to fibrosis• Fahr argued that fibrosis and inflammation

leads to HTN• Both were probably right

Heidland, et al. Journal of Human Hypertension (2001) 15, 5-16

Other Factors• Sporadic insults and chronic diseases

• Accelerate the process• Scarring (AKI, pyelonephritis, hypotension)• Advanced Glycation End Products• Hyperfiltration as compensation

• Molecular mechanisms• Telomere shortening• Klotho protein

• Oxidative stress• Vitamin E improved GFR in experimental rats with

CKD and associated oxidative stress

Other Factors• Renin-angiotensin system seems to

increase reactive oxygen species, fibrosis• ACE-I may be beneficial for multiple reasons

• Nitric oxide seems to be protective• Beneficial hemodynamic effects• Decreases mesangial matrix expansion• Endothelial nitric oxide synthase decreases

with age• Metalloproteases are protective

• Break down mesangial matrix and decrease its expansion

Summary of Renal Aging

Zhou, et al. The aging kidney. Kidney International (2008) 74, 710–720

Impaired Vasodilation• More dependent of prostaglandins for

vasodilaton• More dependent on NO for dilation

• Increased eNOS inhibitors (ADMA)• Lower L-arginine and NO levels

• More prone to AKI:• NSAIDs• ACE-I• Hypovolemia

http://www.uptodate.com/contents/chapter-2d-regulation-of-gfr-and-renal-plasma-flow

Example: ACE-Inhibitors• ACE-I decreases efferent resistance• Lowers glomerular pressure and GFR• Elderly cannot compensate well by

afferent vasodilation• Less Nitric Oxide and L-arginine

Estimating GFR in the Elderly• Exogenous markers• Endogenous markers• Estimating equations• 24 hour urine collection

Exogenous Markers• Filtered but not reabsorbed or secreted• Examples

• Inulin• Iothalamate, 125I-iothalamate• EDTA (51Cr-ehtylenediaminetetraacetic acid)• DTPA (99mTc-diethylenetriaminepentaacetic

acid)• Iohexol

• GFR = [U]xV/[P]x

Exogenous Markers• Continuous Infusion to Steady State• Single Infusion: GFR=Q0λ/C0

Endogenous Markers• Present in body = convenient• Ideally:

• Steady state production• Physiologically inert• Freely filtered• Not Secreted or Reabsorbed

• Creatinine and BUN mainly used• Cystatin C is used at times (clinically and

in research)

Creatinine• Nonenzymatic Cyclization Metabolite of

Creatine and Phosphocreatine• Depends on muscle mass, dietary meat• Filtered and Secreted

• 15-50% secreted (higher in CKD)• Trimethoprim and cimetidine inhibit secretion

• Extrarenal Clearance• Enteric Bacteria (Creatininases)• 2 mL/min equivalent clearance• May form toxins and carcinogens

Creatinine in Elderly• Lower Creatinine Production

• Decreased muscle mass and meat intake• Plasma Creatinine may remain stable

despite loss of GFR in elderly

Creatinine Clearance• GFR = [UCr x V]/SCr

• Ignore secreted creatinine

• 24 hour urine collection• Cumbersome for most people, especially the

elderly

• Mixed results: either over- or under-estimates true GFR• Confounded by incomplete or over-collection,

decreased muscle mass and variable percent secretion and extrarenal clearance of Cr

GFR Estimation Equations

Xun et al. Archives of Gerontology and Geriatrics 2010; 51: 13–20

Levey et al. Ann Intern Med. 2009; 150:604-612

CKD-EPI: Elderly Patients?

Levey et al. Ann Intern Med. 2009; 150:604-612

Discordant Estimates

Willems. BMC Geriatr. 2013; 13: 113.

GFR Estimation Equations• Based on Creatinine

• Elderly often have lower muscle mass and lower meat intake

• Results in lower creatine and creatinine levels• None of the equations have been

rigorously validated for those >70 y/o• CG: tends to underestimate GFR in elderly• MDRD: tends to overestimate• Some studies show 60% discordance!

Cystatin C• 13.3 kDa protein• Produced by all nucleated cells

• Less dependant on body composition• Freely filtered and then fully metabolized in

tubules• Not excreted in urine• Cannot measure a clearance

• Can be used in GFR Estimation Equations• CKD-EPI Cystatin C

Cystatin C Not a Panacea• May be independently related to:

• Age• Gender• Inflammation (C-reactive protein)• Albumin

• Assays were not always standardized• Now better

• GFR estimating equations based on Cystatin C are relatively new• Limited data in the elderly

MDRD.com

Berlin Initiative Study• BIS-1 and BIS-2

were designed forpopulations >70

• BIS-1 uses Cr• BIS-2 used Cr and Cys• In a study of the elderly

(median age 82),BIS-1, BIS-2, andCKD-EPI Cr-Cys weremost accurate

Guan. Urol Nephrol (2016). doi:10.1007/s11255-016-1359-z

Drug Dosing• GFR estimating equations do not agree

with each other or with CrCl and true GFR• May lead to variable dosages based on

different GFR estimation technique• Elderly also have less TBW, a more

sensitive CNS and other comorbidities• Be careful with renally cleared medications

• Gabapentin, baclofen, lithium, opiates

Hyponatremia• Thiazide diuretics

• Impair urinary dilution

• SSRIs• Promote ADH release

• SIADH• Hypovolemia• Low renal solute diet (Tea and Toast)

• Need solutes to accompany excreted water at maximum dilution

• Maximal dilution of urine is reduced in the elderly (may only be 200 mOsm/kg, not 50 mOsm/kg)

Hyponatremia workup• Review medications

• Stop offending agents

• Review diet• Increase renal solutes in diet (Na, K, and protein

which yields urea).

• Examine for volume status• IVF if hypovolemic

• Check urine electrolytes and osm• Helps to diagnose SIADH or hypovolemia• Let’s you estimate if fluid restriction will help

When to Refer to Nephrology?• CKD 3B and beyond: Estimated GFR 45

mL/min/1.73 m2 or lower• Spot urine protein to creatinine ratio or 24 hour

protein excretion >= 1 g/day• Rapid decline in GFR: >6 mL/min/year.• Concerns for other renal problems:

• Rapidly progressive glomerulonephritis• Active urinary sediment on urinalysis• ANCA, anti-GBM, lupus nephritis• Acidosis, secondary hyperparathyroidism,

anemia in CKD

Dialysis in the Elderly• Your kidneys just have to last you the rest of

your life…• We typically don’t start dialysis until eGFR <10

Nursing Home ResidentsDo poorly on dialysis

Kurella Tamura N Engl J Med 2009; 361:1539-1547

Palliative Care is an option• Take into account functional status and

comorbidities.• For those who choose dialysis vs.

recommended conservative management, average survival is 8.3 vs. 6.3 months.• But more hospitalizations, more transport to

and from the dialysis center.• Health system is poorly setup for palliative care

in ESRD• More work; frequent clinic visits• Less reimbursement than starting dialysis

Da Silva-Gane Clin J Am Soc Nephrol. 2012 Dec 7; 7(12): 2002–2009.

Summary• Age related kidney changes

• Still controversial whether these are an unavoidable part of aging

• None of our GFR estimating equations have been validated in the elderly• CKD-EPI and BIS-1 are probably best

• Elderly kidneys are less able to maintain homeostasis• More prone to electrolyte abnormalities, renal

failure, and adverse drug effects• Dialysis decisions should be highly individualized

Other ReferencesSilva, F. The Aging Kidney: A review – Part I. International

Urology and Nephrology (2005) 37:185–205Weinstein, JR. The Aging Kidney: Physiological Changes.

Adv Chronic Kidney Dis. (2010) 17: 302-307Zhou, et al. The Aging Kidney. Kidney International (2008)

74: 710–720Costanzo, L. Physiology, 2nd Ed. 2002UpToDate: Multiple Topics on Renal PhysiologyGeriatric Review Syllabus 9, Chapter 53 Nephrology