The aging of kidneys has important implications for our patients as we choose treatments and consider the overall burden of care. As life expectancies are increasing worldwide there is an increase in our senior and elderly populations. At the pace we are going, the senior populations will comprise between 20 - 27 % of the total population by 2030 in most of the developed world. During 1995-2005 the adjusted point prevalence rates per million population of reported ESRD increased by 73% in the 75 + age group.

The aging kidney may be affected by many diseases, none of which are specific to the elderly. The term arterionephrosclerosis of aging is a loosely used term which does not have any specific morphological criterion described. Specific glomerular, tubulointerstitial and vascular diseases need to be ruled out before a diagnosis of age related decline in kidney function can be implicated.

AGE RELATED CHANGES IN KIDNEY STRUCTURE

At birth the kidney weighs about 50 gm, 400 gm in the fourth decade and 300 gm by ninth decade. Loss of renal mass is mostly cortical with relative sparing of the medulla. Grossly the kidney appears granular and has pitting. Microscopically one can appreciate global glomerulosclerosis, tubular atrophy and interstitial fibrosis. The number of glomeruli decreases with age along with a greater percentage of glomeruli exhibiting global glomerulosclerosis. In normal subjects less than 40 years of age, up to 10% of the glomeruli may be globally sclerotic. When the number of globally sclerosed glomeruli exceeds patient's’ age divided by 2 and minus 10 then it should be considered pathological.

The aging kidney also exhibits sclerotic glomeruli with afferent and efferent arterioles communicating directly with each other, bypassing the glomeruli. The glomerular shape changes, with diminished lobulation, decreased length of the glomerular tuft perimeter. The glomerular basement membrane undergoes thickening and folding, and there is collagen deposition internal to bowman's capsule.

In addition to all the above there is mesangial matrix expansion which is a nonspecific finding. As Erythropoietin (EPO) and 1,25 dihydroxyvitamin D are produced by tubular and peritubular cells, their injury may contribute to the EPO and Vitamin D deficiency often seen in the elderly.  The distal renal tubules develop diverticula which are precursors to simple cysts seen in the elderly. These promote bacterial growth and contribute to frequent renal infections.

AGE RELATED CHANGES IN KIDNEY FUNCTION

We will consider glomerular, tubular and endocrine functions separately.

At the age of two years the GFR nears adult levels and remains at 140 ml / min / 1.73 m til the fourth decade. After 40 years of age the GFR declines by about 8 ml / min /1.73 m per decade. This rate of decline is accelerated in hypertension, lead exposure, smoking, atherosclerotic vascular disease and male gender. It is still debatable whether decline in GFR is due to normal aging or the result of associated co-morbidities. 

The only way to truly assess GFR is to measure it by inulin clearance. Creatinine clearance is influenced by nutritional status, protein intake and muscle mass and therefore not a true indicator of GFR in our senior populations. There are many ways to measure creatinine clearance, the most common the Cockroft-Gault formula (CG) and The Modification of Diet in Renal Disease (MDRD)  Study Group Formula. The latter is considered more accurate, though none have been validated in people more than 70 years of age. Hence their accuracy in estimating GFR is questionable. Clinically these measures are important for calculating drug dosages. Since the MDRD generally yields higher estimated GFR than the CG equation it could potentially overestimate the GFR and cause drug toxicity. Therefore the CG equation is preferred. 

In the healthy elderly there is a marked reduction in renal plasma flow (RPF) and GFR when maximal renal vasodilatation is induced by infusion of amino acids and dopamine. This reduction in renal reserve makes the elderly more vulnerable to acute renal injury.

The aging kidney displays multiple changes in tubular function. Due to a decrease in distal tubular sodium reabsorption, there is an increased susceptibility to hyponatremia from salt loss caused by excessive diaphoresis or GI losses. The renal concentrating capacity is impaired, due to a decrease in tubular water transport in response to arginine vasopressin release thereby causing a decreased response to hyperosmolar and volume deprived conditions. The renal diluting capacity is also impaired, possibly due to a decrease in GFR causing a decreased response to hyperosmolar and volume overloaded conditions. There is an increased susceptibility to metabolic acidosis due to impaired acid and ammonium excretion. Potassium handling is also impaired predisposing the elderly to drug induced hyperkalemia.

Another very important factor is the increased susceptibility to drug toxicity in the elderly. Contributing factors are altered drug pharmacodynamics, pharmacokinetics in the elderly with comorbid conditions, altered body composition with reduced water and increased fat and declining hepatic metabolism.

EPO levels are lower in anemic elderly because of a blunted response to low hemoglobin and a reduced EPO production by the kidney. There is a decreased conversion of 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D in the aging kidney. A CrCl of less than 65 ml / min is an independent risk factor for falls and associated fractures in the elderly with osteoporosis.Calcitriol reduced the incidence of falls.

Insulin is removed by the kidney ie 50% of the insulin in the peripheral circulation. This is by glomerular filtration and proximal tubular uptake and degradation. This function is diminished in elderly persons with reduced renal function thereby putting them at a greater risk for hypoglycemia.  The kidneys also play a role in sympathetic regulation. A decreased GFR causes an increased sympathetic tone which may contribute to the arterial stiffening with aging. 

PATHOGENESIS OF THE AGING KIDNEY

The pathogenesis glomerulosclerosis is multifactorial. Autoregulation of afferent and efferent arterioles of the glomerulus causes increased glomerular plasma flow and hyperperfusion glomerular injury, which may lead to cytokine mediated mesangial matrix expansion and glomerulosclerosis. There is arterial intimal fibrosis which causes ischemia and subsequently cortical and later juxtamedullary glomerulosclerosis.

Another area of interest is the arterial aging or arteriosclerosis contributing to the aging kidney.  Ongoing systemic microvascular changes also affect the kidneys just like any other organ in the body.

In summary, understanding the aging kidney and its pathogenesis is very important when we are starting new medications, intravenous fluids and antibiotics.

Reference: MKSAP and Geriatric Review Slides (AGS)