BMH Medical Journal

BMH Med. J. 2020; 7(Suppl): Early Online. Geriatrics & Gerontology Initiative: International Workshop on Care of the Elderly

Abstract

Aging is a natural, progressive and inevitable biological process of life for all living organisms characterized by gradual decline of cellular functions as well as progressive structural changes in every organ system. The anatomic and physiologic changes delineate the process of senescence. This process is influenced by several modifiable factors including genetics, lifestyle choices and environmental exposures, and vary in different organs.

Key words: glomerulosclerosis, nephrosclerosis, tubulointerstitial fibrosis

In almost every country, the proportion of people over 60 years of age is increasing much faster than any other age group as a result of longer life expectancy, better living conditions and improvement in health care system as well as improved socio-economic changes.

Widely considered as one of the most important and complex biological problems of the 21st century, aging is essentially a process of degradation of systems. Every organ of the body show structural and physiological changes over the years. The kidneys are also affected by the aging process which results in numerous effects on the renal system. Structural and functional changes in the kidney with aging can be divided into those seen with healthy aging, aging with expected comorbidity and aging with increased prevalence of kidney diseases. Unique to Nephrology, there has been opportunity to specifically study healthy aging due to the comprehensive evaluation for living healthy kidney donors whose age range in a span over 7 decades. It has been seen that, even in the absence of comorbidities there are substantial structural changes in the aged kidney that accompany a decline in kidney function.

The changes of the normal aging kidney are separate from kidney diseases that are relatively common in the elderly such as diabetic/ hypertensive nephropathy. During the past 15 years, there had been an increasing interest in the aging kidney. Renal mass decreases between the ages of 30 and 80 years with steepest decline seen after the age of 50 years. Fat and fibrosis with scarring may replace a significant percentage of kidney tissue. 30% of the glomeruli are destroyed and display diffuse glomerular sclerosis by the age of 75 and the remaining exhibit impaired filtering ability. The renal plasma blood flow is 40% less in the older age group.

Structural and functional findings in the kidney with healthy aging

Pathogenesis of renal aging

The natural process of aging in the kidney leads to nephrosclerosis, the gradual loss of renal tissue. This process is multi factorial. Age related cellular senescence including genomic instability and telomere loss, oxidative damage, genetic programming and cell death affect every structure in the kidney. Arterial intimal fibrosis and the resultant dysautoregulation of afferent and efferent arterioles of the glomerulus will lead to increased glomerular plasma flow, increased intraglomerular pressure and the subsequent hyperperfusion induced glomerular injury and deposition of mesangial matrix. This process will lead to glomerulosclerosis. Further, age related arterial changes and consequent hypoxia/ ischemia in the kidney will upregulate hypoxia induced genes like hypoxia-inducible factor, vascular-endothelial growth factor, glucose transporter-1 and EPO. These will result in tubulointerstitial fibrosis and deposition of collagen as well as matrix, all leading to nephrosclerosis.

Telomeres which are DNA protein complexes located at the ends of chromosomes protecting the chromosomes from aging shorten with increasing age at the rate of 0.25% length per year and rapidly destroy the cells in the renal cortex and medulla.

Oxidative stress which increases in the aging population will result in increase in AGEs which will lead onto AGE-mediated injury. Oxidative stress can also reduce telomere length. All these will result in tubulointerstitial fibrosis and damage.

Podocyte depletion and increased podocyte detachment also take place in the aged kidney leading to glomerular capillary wrinkling, tuft collapse and periglomerular fibrosis.

In aging, there is a reduced expression of the anti-aging gene Klotho which leads to cell senescence and tubulo-interstitial damage due to oxidative stress.

The increase in high calorie food intake, sedentary lifestyle and obesity have been found to produce focal glomerulosclerosis as well as tubulointerstitial damage leading to a fall in the function of the kidney as age advances.

All these will lead to progressive loss of nephron mass, global glomerulosclerosis, arteriolo-nephrosclerosis and tubulointerstitial fibrosis with scarring in the ‘normal’ aged kidney.

The nephron number decreases with age, at the rate of 6800 nephrons per kidney per year. It has been estimated that the mean number of nephrons per kidney decreases from 990,000 in 18-29 years old to 520,000 in 70-75 years old.

Glomerular Function

After the age of 30 years, the glomerular filtration rate (GFR) begins to fall at an average rate of 1 ml/min/m2/year resulting in an eGFR of 60 ml/min in those above the age of 75 years. This fall in GFR is independant of the presence of hypertension or diabetes or a change in cardiovascular performance. Women also show decline in GFR with age; but is usually lower than men. The slowly decreasing GFR is a normal biological phenomenon and is not necessarily a manifestation of a specific disease.

Tubular Function

The tubules and the interstitium are destroyed in the process of fibrosis in aging and will manifest with a reduction in urinary sodium excretion, increased susceptibility to volume depletion or over hydration, deranged handling of potassium and the predisposition to develop hyperkalemia. There can be failure to concentrate or dilute the urine resulting in higher rate of nocturia and the predisposition to dehydration hypernatremia or hyponatremia. The aged kidney also has heightened susceptibility to drug toxicity due to altered drug pharmacokinetics.

Endocrine Function

The production of erythropoitein will be less in the aged resulting in anemia. The aged kidney will be unable to convert 25-dihydroxy vitamin D to 1,25-dihydroxy vitamin D3 resulting in low calcium, low 1,25-dihydroxy vitamin D3 and osteoporosis.
A decline in renal function in the elderly will lead to reduced insulin clearance resulting in the increased level of circulatory Insulin and better control of diabetic state.

Sympathetic nervous system activity is elevated in the elderly which will contribute to arteriolosclerosis and further fall in GFR.

Structural changes of the aging kidney

The aged kidney gradually becomes smaller and contracted and appears granular and with pitting of the external surface secondary to changes in the cortex resulting from glomerulosclerosis, tubular atrophy and interstitial fibrosis. There will be thinning of the renal cortex and the weight of the kidneys progressively decline after the fifth decade of life. The distal renal tubules develop diverticulae that increase in number as age advances. These diverticulae may be the precursors of simple Renal Cysts that are seen in half of the subjects older than 40 years. In addition, hyperdense Cysts, angiolipomas, para pelvic Cysts and masses may develop which may become infected or turn malignant later.

Diseases that commonly affect the aging kidney

Prevalence of chronic kidney disease in the elderly

The prevalence of chronic kidney disease (CKD) as currently defined by an eGFR<60 ml/min per 1.73 m2 or albuminuria (urine albumin-creatinine ratio > 30 mg/g) persisting for 3 months or more is reportedly seen in 10-13% of the adult population world over. However, the prevalence by these criteria markedly increases with age from 10% of adults aged 20-39 years to 47% of adults aged 70 years or older. This remarkable increase in the prevalence in the elderly is due to an age related fall in eGFR than due to increase in albuminuria. In young adults, 75% of such CKD is due to albuminuria. While in older adults, 20% of such CKD is due to albuminuria and 80% is due to an age related fall in eGFR which is physiological and not a disease per se.

However, CKD associated with co-morbid conditions like diabetes, hypertension, atherosclerosis, other metabolic diseases is common in older individuals and its prevalence increases in parallel with age. As of other age groups, the incidence of dialysis-dependent kidney disease also steadily increases in elderly people.

Mortality and Kidney Failure Risk with Age-Related Reduction with GFR

The CKD Prognosis Consortium assessed the risk of mortality over 2 million adults recently and found that in persons over 75 years without albuminuria, hypertension or diabetes, an eGFR of 45-70 ml/min/1.73㎡had the lowest risk of developing End Stage Renal Failure in 2-3 year time as compared to younger patients with the same eGFR.

Combating Renal Aging

1) Weight Reduction, Lifestyle modification and activation of sirtuins:

Lifestyle modifications including calorie restriction has been shown to increase lifespan and to restrict aging process as well as age related diseases including Cancer, Diabetes, Brain atrophy, Cardiovascular diseases and Kidney aging. Numerous molecules like Sirtuin-1 (SIRT1) mediate the beneficial effect of calorie restriction. SIRT1 activators like resveratrol may help to protect age related glomerulosclerosis.

2) Drugs to prevent senescence

Drugs targetting cellular senescence (senolytics) including SiRNA therapies, the experimental agent NAVITOCLAX and the licensed drugs like DASTINIB and QUERCETIN are in the pipeline to combat kidney aging.

3) Anti-fibrosis therapy

Antifibrotic therapeutic agents including Pirfenidone, BMP7 antagonist and captopril have been tried to combat the aging process.

4) Klotho

Klotho gene over expression has been shown to extend lifespan and to reduce the effects of aging. Klotho deficiency may be a candidate for therapeutic target for kidney aging.

When the elderly has to take medications which are water-soluble and cleared by the kidney, the dose has to be modified on the basis of the patient’s eGFR and not as per body surface area. Nephrotoxic medications including NSAIDs, radiocontrast agents and aminoglycosides should be avoided whenever possible.

Conclusion

Renal aging is complex and remains incompletely understood. Decreased protective factors, hypoxia and microenvironmental stress lead onto inflammation, glomerulosclerosis and tubulo-interstitial damage. The resulting fibrosis, senescence and microvascular rarefaction exacerbate damage and promote progression to nephrosclerosis. The future of treating renal aging is in understanding the key initiating events and the common downstream pathways. This knowledge will allow the development of therapies capable of arresting the key mechanisms early to preserve kidney function throughout life.

The Aging Kidney