Aging and Kidneys

1. Aging kidney

2. Introduction
Kidneys are among the organs affected by the
aging process
Aging kidneys are characterized by progressive
scarring and measurable declines in renal
function .

3. Biology of aging
1. Pathway –m TOR pathway
Inhibition is associated with extended life span
2. SIRTUINS –implicated in aging , transcription , apoptosis,
inflammation and .stress resistance
These are proteins posses ADP- ribosyl transferase ,NAD
dependent protein deacetylase enzyme ,
3. KLOTHO deficiency ; only anti-aging hormone
Type 1 membrane protein
roles: co receptor of FGF-23
Regulates oxidative stress
Antagonizes TGF-B signaling

4. Others
• Oxidative stress
• Telomeric shortening
• Accelerated apoptosis
• Glomerular hypertension and hyper filtration
• Endothelial dysfunction
• Renal TGF-B expression
• Renal ischemia
• AGEs

8. Anatomical changes
• The most important pre-renal change
affecting kidney function is vascular
degeneration.
• In young adults, renal blood flow is estimated
to be approximately 600ml/min
• In older people often reduced by half due to
normal age related changes in blood vessels

9. • Such blood vessel changes usually lead to
ischemia ,particularly renal cortex .
• Tissue replaced with scar tissue ,giving outer
surface of aged kidneys a granular or mottled
appearance .
• Arterioles leading to glomeruli show hyaline
deposition and collagen below the endothelium
reducing diameter of the vessels
• Aged blood vessels experience a general
reduction in the synthesis of the potent
vasodilator ( NO) ,, resulting in decrease blood
flow

10. RENAL CHANGES
• Both kidney mass and weight decrease
significantly after the age of 50
• 20’ yrs kidney weighs 250-270 gms
• Whereas in 90’s it drops to 180 gm-200 gms
• There is gradual collagen deposition leading to
progressive kidney fibrosis .

11. Glomerular abnormalities
• Glomerulosclerosis increases , typically leading
to progressively capillary collapse.
• by 80’s 30% glomeruli are sclerosed .
• Filtration membrane – some nephron display a
progressive thickening and wrinkling of filtration
membrane in glomerulus and bowman ‘s
capsule
• Filtration membrane also becomes increasingly
permeable ,allowing large molecules such as
protein ( proteinuria )

14. GFR
• GFR peaks in the third decade of life ,as high as
140 ml/min/1.73m2.
• it drops by 8ml/min per decade after the age of
30
• The gfr in 80’s may be only 60-70% of what it was
when they were young adults ,
• At age of 90 typically falls to 65ml/min/1.73m2
• Many maintain stable gfr through out life ,which
suggests variables other than aging contribute to
the decline .

16. Tubule abnormalities
• Some tubules gradually degenerate and are
replaced by scar tissue ( tubulo interstial fibrosis
) .
• Irregular thickening of basal membrane
• DCT often shrinks and may develop small
pouches (distal diverticula) , which can in turn
become fluid filled cysts , increasing the risk of
kidney infection and pyelonephritis .

17. • Anemia secondary to a low
serum erythropoietin secretion
is one of the main feature in
ckd
Proximal tubule function is
preserved in oldest old and their
serum erythropoietin andhbare
normal .
• Serum urea is raised in ckd pt
Fractional excretion of
urea is increased in
both settings , serum
urea level is normal in
elderly
• Increased Fe of calcium ,phosphate
• Fe of magnesium is normal . Fe of potassium
is increased in ckd
Serum levels of
calcium , Mg and
phosphate in normal
in healthy oldppl

18. Polyuria and nocturia
• Progressive loss of nephron makes kidneys less
efficient at concentrating urine therefore
greater volume of water is required to excrete
toxic waste products
• ADH effect is blunted in elderly people –
resulting in large volume of diluted urine
leading to polyuria
• Fluids drunk in the evening take longer to be
processed ,leading to nocturia

21. Mediators of age related physiological
changes
• While systemic RAS is suppressed in aging ,
intrarenal RAS may not be equivalently
suppressed ,
• Pharmacological RAS blockade has shown to
slow the progression of age related ckd .
• Renin and aldosterone synthesis is decreased
conversely due to prolonged low levels of renin
and aldosterone may result in secretion
exaggerated response to these components of
the RAS when present

22. NITRIC OXIDE (NO)
• NO
• NO plays diverse roles impacting renal vasculature and cell
growth .
• NO inhibits mesangial cell growth and matrix production
• Factors leading to NO LEVELS LOW
• oxidative stress
• Cofactor required for NO synthesis – tetrahydrobiopterrin.
• L- arginine is a key substrate for NO synthesis –declines
with decreased food intake .
• NO synthase is degraded by asymmetric dimethyl arginine
(ADMA)

23. Vasoconstrictors and vasodilators
Balance btn these two play an imp role in
kidneys response to acute injury ,
Impaired ability to auto regulate can lead to fall
in GFR

24. Hormones
• Gender affects the age related changes in RAS and NO
systems
• Progression of ckd is slower in females
• E2 estradiol – decreases tissue levels and activity of Ang II
and ACE
• TESTOSTERONE increases RAS activity
• NO and E2 relation – stimulates release of NO synthase
• ADMA --increase is delayed in premenopausal women
• Metallo proteases – break down matrix ,helps prevent in
matrix expansion ( key element in ckd progression )
• Levels increase in female than aging males

25. • Dosage of water soluble drugs such as certain
antibiotics , amphetamines and digitalis needs
reduction in dosage .
• Insulin clearance – kidneys removes 50 %
secreted insulin from peripheral blood ability
to clear it reduces .
• EPO – tubular degeneration and interstial
fibrosis leads to reduced EPO causing anemia
• CALCITRIOL – synthesis is reduced affecting
calcium and phosphate metabolism .

26. Ageing and urinary incontinence
• Urinary sphincter often weakens with age and
this may lead to urinary incontinence –problem
compounded by age related changes in nervous
system
• Also not seen in many individuals never
experience
• 11.6% of ppl aged 65-80 yrs experience
incontinence
• 35% in >85 yrs ,69% over 90’ s

27. Ageing of urethra and prostate
• Most middle aged and older men experience a
benign enlargement of the prostate gland (
prostatic hyperplasia) results in a gradual
compression of urethra .

28. Clinical relevance
• More susceptible to aki( nsaids , contrast agents ) ,
should be cautiously used .
• Increase cardiovascular morbidity
• Cystatin-c might contribute to the prediction f
cardiovascular outcomes along non- gfr biological
pathways , such as inflammation and atherosclerosis
• ESRD – lower eGFR (creatinine) is associated with increased
risk of kidney failure than elderly with fair Gfr
• Albuminuria – UACR is used to assess in elderly with
considering (age , sex , body weight ,race ) multiplying
the UACR by expected 24- hr urine creatinine .

29. • Glomerular diseases
• Diabetic nephropathy ( most common )
• ANCA associated small vessel vasculitis
• Primary amyloidosis
• Monoclonal Ig deposit disease
• Membranous nephropathy
• tubular diseases
• AKI –contrast /NSAID induced
• OBSTRUCTIVE UROPATHY –prostatic hypertrophy
• Cervical carcinoma
• RENAL CELL CARCINOMA
• VASCULAR
• RENAL ARTERY STENOSIS
• CHOLESTEROL EMBOLISATION SYNDROME
• CHRONIC ISCHEMIC NEPHROPATHY

30. • RENAL REPLACEMENT THERAPY

32. LIVING KIDNEY DONOR EVALUATION
• Many transplant programs only require pre-
donation GFR to be appropriate for donor’s
age and permit certain CKD risk factors ( mild
hypertension ) to be in present in older donors
without rejecting them as candidate
• The use of an age-calibrated measured GFR
may improve the living donor-selection
process.

33. • Acceptance of elderly kidney donors is controversial
due to higher incidence of co morbidities and greater
risk of post-op complications .
• OBSERVATION –there is no accelerated loss of kidney
function following donation by >60 yr old people
• There is no established renal failure (ESRF) for elderly
donors, it is 0.134 per 1000 years
• Rigorous assessment to be done and predicted GFR
to be at least 37.5ml/min/1.73m2 at the age of 80 ,
• Though elderly donors have less GFR when compared
,proportionate decline after transplant is similar in
young and elderly people

34. Criteria taken for elderly donors
• GFR – should be more or equal to 80
ml/min/1.73 m2 or within two SD for age and
gender , according to many studies .
• BTS guideline recommends that a prospective
donor should not be considered for donation if
the corrected GFR falls below satisfactory level
of kidney function within lifetime of donor .for
ex: predicted GFR of at least 37.5
ml/min/1.73m2 at the age of 80 is min
recommended

35. • Mild or mod htn – not a contraindication
• Depending two or more anti hypertensives and end
organ damage is contraindicated
• Impaired glucose tolerance , obesity likely increases
after donation
• Elderly donors with impaired glucose tolerance
develop more proteinuria and more hypertension .
• Trends in living donation in UK SINCE 2007 , there
have 34% deceased donors were over 60 yrs , living
donors was over 14 % in 2012/2013

36. Effect of uninephrectomy on donors
• Complications in elderly donors
• Velosa et al. evaluated 140 donors ( 105) were less
than 35 years and 35 were more than 55yrs in whom
predonation GFR in young was 113ml/min was
compared to88ml/min in older group
• Postoperative gfr was 68+/- 8 and 65 +/- in young and
older age group respectively .
• This study is similar 539 living donors , 422 from<60 yrs
and 117 >60 yrs during median follow up 5.5 years
max decline in gfr was38% +/ - 9 % on longterm
follow up it is < 60 ml/min in elderly

37. • A study by POGGIO et al of 1015 donors showed decline in
GFR 4ml/min per 1.73 m2 per decade for younger’s less
than 45 years , compared to 8ml/min in those more than
50 years
• Established renal failure (ERF) :Japanese study of eight
donors who developed ERF were compared with control
population of 24 donors matched for age ,sex and one
donor developed ERF following RTA none others developed
ERF immediately after donation
• After 10 yrs however ,development of persistent
proteinuria , cardiovascular event major infections heralded
CKD
• Survey by OPTN – identified 126 cases of ERF AMONG
56458 LIVING KIDNEY TRANSPLANTS (0.22%)
• OVERALL ERF RISK IS 0.134 PER 1000 YEARS WITH AVE
DURATION OF 9.8 YEARS

38. • HTN IN DONORS – METAANALYSIS conducted by
donor nephrectomy outcome research network ,
revealing that kidney donors may have increase of
5mmhg in bloodpressure with in 5 to 10 years after
donation over that anticipated with normal aging .
• El-AGROUDY et al conducted a retrospective
analysis of 146 living donors > 50 yrs old from 1976
to 2005 – reported rate of diabetes and htn are
similar to young age
• NORWEGIAN study of 908 donors followed
retrospectively observed increase in hypertension
rate risk after kidney transplantation .

39. Outcome of transplantation from elder
living donors
• Perioperative complications ;
• in a study comparing 115 recipients of kidneys
>60 yrs with 158 from donors < 60 yrs , the
frequency of acute rejection episodes was similar
in both groups ,
• But delayed graft function occurred more
frequently in former group .
• Frequency of chronic renal allograft dysfunction
in first year of post transplantation was high in
older group .

40. Graft function
• In a series of 147 DCD recipients ,Akoh and Rana
demonstrated higher acute rejection rates in younger
recipients of older DCD grafts inspite of better HLA mis
match profile .
• Kerr and coworkers conducted univariable studiies of
1126 transplants – demonstrated that the graft survival
of kidneys from older living donors is better than
deceased kidneys from younger
• Study from korea – from 269 living donors , 64 were
expanded criteria living donors and 205 were standard
criteria – lower gfr 69.9 and 58.3
• although graft survival is not different

41. CONCLUSION
• Most studies showed kidneys from older donors had
relatively lower graft function ,
• Increased rejection episodes
• Poor long term graft survival compared to kidneys from
younger donors .
• Prevalence of HTN , ERF , QUALITY OF LIFE in donors is
comparable to that of general population .
• A multicentred , long-term and Prospective database ,
which is specifically aimed to address the outcomes of
kidneys from elderly living donors is recommended.

43. Future therapies