Text Book Reading

AGING OF THE
KIDNEY
HAZZARD’S GERIATRIC MEDICINE AND GERONTOLOGY 7TH
EDITION
DR. NADYA MEILINAR SAMSON
 CLINICAL
RELEVANCE
 Clinical Relevance
 Kidney failure is a growing problem in the older population
 Information published in the 2014 USRDS annual data report shows that
approximately 1.3 in 1000 persons aged 65 to 69 years are initiating
treatment for ESKD each year.
 For the 70- to 75-year-old age group the incidence rate is 1.68 per 1000
persons, a growth rate of 7.1% per year.
 The kidney undergoes significant age-related change. Other common
diseases such as hypertension and diabetes accelerate these changes.
THE AGING
PROCESS
 The aging process
 Aging in the kidney is characterized by changes of both structure and
function.
 Aging in the kidney is generally characterized by spontaneous
progressive decline in renal function accompanied by thickening of the
basement membrane, mesangial expansion, and focal
glomerulosclerosis.
 Functional changes
 Changes in renal function with age are well documented both in
human and animal models.
 Although baseline homeostasis of fluids and electrolytes is maintained
with normal aging, there is a progressive decline in renal reserve →
compromise in the kidney’s ability to respond to either a salt or water
load or deficit.
 This manifests clinically in patients being vulnerable to superimposed
renal complications during acute illnesses.
 Functional changes
 Chronic conditions such as hypertension accelerate this age-
related loss of renal reserve and increased vulnerability in these
patients should be anticipated.
 Age-related changes in function will be considered by separate
functional domain within the kidney.
 Renal blood flow
 Average renal blood flow decreases about 10% per decade
 This is accompanied by increasing resistance in both afferent and
efferent arterioles.
 These changes occur independent of a decline in cardiac output or
reductions in renal mass → decline in renal blood flow → decline in
efficiency with which the aging kidney responds to fluid and
electrolyte load and loss.
 Glomerular filtration rate
 Newer data have shown a wide variation in the rate and extent of
changes in the kidney within the older population.
 Approximately 30% of the population shows no measurable decline in
renal function with normal aging.
 The bulk of the population loses about 10% of glomerular filtration
rate (GFR) and 10% of renal plasma flow per decade after the fourth
decade of life → between 5% and 10% of the population shows
accelerated loss, even in the absence of identifiable comorbidities.
 Glomerular filtration rate
 Since there is also a steady loss of muscle mass with age, with
concomitant reduction in creatinine production, serum creatinine
should remain constant.
 Elevations in serum creatinine should therefore be taken
seriously and not dismissed as normal aging.
Glomerular filtration rate
 This steady decline in renal function
with age manifests itself clinically as
impaired ability to excrete a salt or
water load.
 Extra care should be taken when
replacing fluids in an older individual

to prevent extracellular fluid overload.

 Glomerular filtration rate
 In 1999, an improved formula for estimating GFR was developed
known as the MDRD formula
 Several investigators have studied its performance in older patients
and compared its efficacy with Cockcroft Gault, creatinine clearances
based on 24-hour urines or iothalamate clearances, or a combination
of these methods → large discrepancies between these methods in
patients with advanced age and at both extremes of the weight
spectrum → these limitations should be kept in mind when using the
formula in clinical geriatric practice.
 Glomerular filtration rate
 Iothalamate clearance is the gold standard → expensive and impractical
for routine use.
 The most reliable results come from calculating creatinine clearances
based on 24-hour urine collection. It is however more reliable than the
formula estimations in the very old and frail people.
 A new modification of MDRD—the CKD-EPI equation was developed
→ more accurate than the original formula → used primarily for
research, not routine clinical practice.
 Using cystatin C as a measure of GFR circumvents the problem of the
decline in creatinine production with age → limited to research studies,
not routinely used in clinical medicine.
Classification of kidney disease
 Classification of kidney disease
Proteinuria
 Not a normal feature of the aging process
 Is always a pathological finding and requires a full work-up
Tubular Function
 Older individuals are well known to be more susceptible to acute
renal failure
 Functional magnetic resonance imaging (MRI) in older volunteers
has demonstrated decreased ability to modulate renal medullary
oxygenation → the clinical result is increased sensitivity to acute
ischemic renal failure.
 Classification of kidney disease
Tubular Function
 Studies have also demonstrated impaired capacity to acidify urine
manifested clinically as reduced excretion of an acid load → older
individuals are less likely to be able to maintain normal homeostasis
when challenged.
 Although there is an age-related decline in tubular functions such as
glucose and amino acid transport, these declines closely parallel the
decline in GFR and are believed to correlate with the loss of nephrons
rather than age effects in the tubule.
 Older individuals are also more sensitive to nephrotoxic injury and
risk factor for the development of radiocontrast
nephropathy. Careful thought should be given to the choice and
dosing of antibiotics and other nephrotoxic drugs and before tests
requiring radiocontrast are ordered.
 Classification of kidney disease
Donor Organ Viability
 Age also impacts the viability of kidneys for transplantation.
 With the steady increase in living related and unrelated donations, more
organs have become available for use in the older population.
 Many transplant programs are routinely offering transplantation to people
in their late sixties and early seventies if they are otherwise in good health.
 Age of the donated organ appears to be an independent risk factor for graft
survival.
 These organs typically show delayed graft function post-transplant, with
chronic allograft nephropathy and result in higher baseline serum
creatinines in the long term. Newly published evidence suggests that older
kidneys show more podocyte stress → shortened graft survival.
 Underlying structural changes
Gross anatomy
 Renal mass starts to decline after the fourth decade and continues its decline
throughout the remaining life span.
 Most of the decline in weight and volume appears to happen in the cortex,
with relative sparing of the medulla.
Glomerulus
 There is a steady decline in nephron number with age that starts
around the fourth decade → driven by podocyte loss.
 By age 50 years, all subjects examined had some evidence of sclerosis, with
the percentage of sclerotic glomeruli increasing steadily with age.
 Underlying structural changes
Age Related Glomerulosclerosis
 Sclerotic glomeruli typically first appear in the fourth decade of life. This
starts as a segmental process with one part of a glomerulus becoming
acellular and the normal architecture being replaced by extra cellular matrix.
The glomerular tuft becomes adherent to Bowman capsule.
 Gradually an entire glomerulus becomes sclerosed and shrivels down with
resultant loss of that nephron and its filtration capacity.
 The glomerular tuft increases in size with age. Concomitant with this
expansion is an increase in endothelial and mesangial cells, such that the
ratio of cells to glomerular area remains constant.
 Underlying structural changes
Age Related Glomerulosclerosis
 Podocytes, the specialized cells that form the filtration barrier in the
glomerulus, are postmitotic. They are not able to multiply in response to the
increase in tuft volume and become a progressively smaller percentage of
the total cells making up the glomerular tuft.
 As the filtration area that they have to cover increases, it is believed that
they may detach from the basement membrane, leaving a denuded area
behind.
 It is this area of bare basement membrane that acts as the trigger for the
sclerosing process.
Underlying structural changes
 Underlying structural changes
Age Related Glomerulosclerosis
 Some authors have suggested a role for the mesangial cell in initiating the
sclerosis process.
 With aging, there is an increase in mesangial matrix and in mesangial cell
numbers. However, this increase is just as marked in strains of rat that do not
develop age-related glomerulosclerosis, as it is in strains that do.
 Several investigators have studied mesangial cell activation in rat models of
glomerulosclerosis and found little or none. This suggests that
mesangial expansion is a benign manifestation of the aging process rather
than a pathological one.
 Underlying structural changes
Tubule
 With the loss of the glomerulus, the tubular section of the nephron usually
degenerates and is replaced by connective tissue.
 Tubular hypertrophy then occurs in the remaining nephrons, principally in
the proximal convoluted tubule. This appears to result from both
hypertrophy and hyperplasia.
 With thinning of the cortex, there is a decrease in tubule length and
development of diverticuli in the distal convoluted tubule.
 As nephrons are lost, there is generalized tubular interstitial fibrosis.
 Underlying structural changes
Vasculature
 Renal arteries undergo age-related thickening, similar to that seen
throughout the circulation. Smaller arteries may become tortuous and show
luminal irregularities.
 When a glomerulus becomes sclerosed, there is frequent formation of an
arteriovenous shunt as the afferent and efferent arterioles develop a direct
connection when the glomerular capillary is lost. This shunt is very
important in maintaining medullary blood flow.
 Physiologic studies in both animals and humans have documented a decline
in renal blood flow and an increase in vascular resistance with age.
 Underlying structural changes
Vasculature
 Studies of renal perfusion in healthy older individuals from a pool of
potential kidney donors have shown steady declines in renal perfusion with
age that exceeded the reduction in renal mass → declines in blood flow
were a significant factor in the changes seen in renal function with age.
 Infarcts may occur in the kidney
 The kidney is also particularly susceptible to embolization . If other
signs of embolization are visible clinically, it is highly probable that the
kidney is also undergoing embolization, and embolic disease should
certainly be kept in mind in an older individual with widespread vascular
disease who demonstrates accelerated loss of renal function.
 MECHANISMS
UNDERLYING THE
DECLINE IN
KIDNEY FUNCTION
 Genetic predisposition
 There are as yet no genes known to cause age-related glomerulosclerosis
 Many of the genes identified as playing a role in the aging process, such as
IGF-1 and TOR (target of rapamycin) also seem to play a role in kidney aging
 Animal models
 Since these rats are maintained in pathogen-free environments and are fed
uniform scientifically developed diets, this strongly suggests a genetic
basis for the development of age-related glomerulosclerosis
 Human study
 There are observational data that would support a similar variation in
genetic susceptibility in humans
 Genetic predisposition
 Human study
 Within the African-American population, rates of kidney disease are
much higher than in the Caucasian population independent of the
precipitating cause
 An African-American who develops any predisposing disease, be it
hypertension, diabetes, or lupus, who has a firstdegree relative on renal
replacement therapy has a ninefold increased risk of developing kidney
disease compared to another African-American with the same disease
burden who has no family history of kidney disease
 there is suggestive evidence for a genetic predisposition with respect to
the development of glomerulosclerosis.
 Environmental predisposing factor
 Diet
 One of the most striking aspects of rodent models of age-related
nephropathy is its complete reversal with caloric restriction.
 Both the anatomical and functional changes related to aging in the kidney
are completely abolished in animals that are fed two-thirds of the calories
given to their ad libitum-fed litter mates. Even though these animals live
one-third longer than their ad libitum-fed littermates, they do not develop
age-related glomerulosclerosis.
 Free radicals and lipid peroxides
 One possible explanation for the profound effects of caloric restriction is
a reduction in the generation of free radicals and lipid peroxides
 Environmental predisposing factor
 Free radicals and lipid peroxides
 Increased caloric intake is believed to fuel increased free radical
production with accelerated aging damage → this hypothesis has
generated interest in the role of antioxidants in slowing the aging process.
 Protein restriction
 The benefits of caloric restriction have been attributed to concomitant
reductions in dietary protein → many of these studies have shown a
slowing in the progression of established kidney disease
 There is evidence to support protein restriction in patients with
established renal disease to reduce symptoms of uremia, but none to
support the role of protein restriction to prevent age-related
changes in the human kidney.
 Environmental predisposing factor
 Lipids
 Use of lipid lowering agents in a variety of animal models of
glomerulosclerosis has shown reductions in the incidence of
glomerular damage.
 Patients with established renal disease with or without diabetes have
more rapid deterioration of kidney function in the presence of
hyperlipidemia.
 The relevance of lipids to the age-related decline in kidney function
remains to be established, but it would certainly be reasonable to
recommend a low-fat diet and lipid management in patients with
declining renal function
 Environmental predisposing factor
 Hyperfiltration
 Normal age-related loss of glomeruli causes intraglomerular hypertension
with hypertrophy of remaining glomeruli → persistent intraglomerular
hypertension → pressure-mediated renal injury.
 Long-term follow-up in humans for over 20 years has not shown
accelerated declines in renal function in people who have donated one of
their kidneys for transplantation, even though the remaining kidney does
undergo hypertrophy.
 Excessive intake, particularly of animal proteins, therefore could cause
constant hyperperfusion in the kidney, leading to intraglomerular
hypertension and accelerated glomerulosclerosis.
 Environmental predisposing factor
 Hyperfiltration
 The efficacy of ACE inhibitors in preventing renal hyperperfusion
damage early in the course of diabetes and hypertension would also lend
support to the hyperfiltration hypothesis.
 Angiotensin II appears to be important in maintaining glomerular
filtration pressure by vasoconstricting the efferent arteriole.
 ACE inhibition is believed to preserve renal function by blocking the
vasoconstriction of the efferent arteriole and reducing intraglomerular
pressure
CONSEQUENCES
OF IMPAIRED
KIDNEY
FUNCTION
 Consequences of impaired kidney function
 Patients who show signs of impaired kidney function should be managed with
the idea of preventing them from reaching end-stage disease.
 Aggressive measures should be taken to reduce blood pressure with a goal of
125/75 if tolerated.
 Lipids should also be aggressively managed, as should blood sugar and other
potential accelerators of renal decline.
 Overweight patients should be encouraged to lose weight.
 Avoid potential renal toxins, such as aminoglycoside antibiotics, nonsteroidal
anti-inflammatory drugs (NSAIDs), and radiocontrast dyes.
 Medications excreted by the kidney should be appropriately dosed in amount
and frequency.
Consequences of impaired kidney function
 Summary

 Kidney disease and failure are predominantly diseases of the older population.
 All older patients should have an estimate made of their GFR. If they have a
deficit in their kidney function, they should be managed aggressively to
prevent progression to kidney failure.
 As CKD progresses, special attention should be paid to choice of drugs and
their dosing and to the use of contrast dyes for imaging.
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