Decrease in Glomerular Filtration (Senile Glomerulosclerosis)

In senile glomerulosclerosis, the glomeruli are replaced by fibrous tissue (glomerular obsolescence), a process that begins at approximately 30 years of age, and is present in between 1% and 30% of persons aged 50 years or older. The mesangium increases to nearly 12% by age of 70, and microangiographic examination shows the obliteration particularly of the juxtamedullary nephrons that is followed by the formation of a direct channel between afferent and efferent arterioles (aglomerular circulation). Presumably, this change contributes to medullary hypotonicity (wash-out) in the aged. These changes with ageing are accompanied by a decrease in the glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF). However, because ERPF decreases proportionally more than GFR—10% per decade from 600 ml min−11.73 m−2 in youth to 300 ml min−11.73 m−2 by the age of 80 years, the filtration fraction (FF), which is the ratio of GFR/ERPF, usually increases in the elderly because the denominator (EFRF) is disproportionately lower than the numerator (GFR).2–4

Measurement of the GFR with 51Cr EDTA confirms that the healthy elderly have a lower GFR than the young. At the third decade of life, GFR peaks at approximately 140 ml min−11.73 m−2, and from then on, GFR progressively declines at an approximate rate of 8 ml min−11.73 m−2 per decade. A similar fall in creatinine clearance (Ccr) is accompanied by a concomitant decrease in creatinine production (senile sarcopenia), and consequently serum creatinine does not increase with the progressive decrease in GFR.5

However, in approximately one third of old people the GFR does not decrease with age. Since Kimmel et al. have demonstrated that old people who were on a high protein diet maintained a normal GFR, it has been hypothesized that ‘normal’ GFR in the elderly could be the consequence of increased protein intake that is followed by glomerular hyperfiltration.5

In clinical practice, Ccr is estimated using the Cockcroft and Gault equation: Ccr = (140-age)  ×  (body weight)/72  ×  serum creatinine (15% lower in women).6 Another frequently used equation is the MDRD (modification of diet in renal disease) formula: GFR = 186  ×  serum creatinine−1.154 ×  age (in years) −0.203  ×  (0.742 if female)  ×  (1.210 if black race). When applied to the elderly each of these formulas has its advantages and disadvantages. Thus, the Cockcroft-Gault formula underestimates GFR in people >80 years, while the MDRD equation has the advantage of not requiring the patient’s weight for calculating GFR. There is a poor correlation between GFR obtained by MDRD formula and the measured creatinine clearance with cimetidine, which is a proxy of the GFR gold standard measured by inulin clearance; conversely this study showed a good correlation between the Ccr obtained by Cockcroft-Gault (CG) formula and that measured by creatinine clearance with cimetidine.6 Keller believes that the easiest formula for estimating GFR in people between 25 and 100 years old is as follows: GFR = 130-age (in years) ml min−1, but this has not been validated by direct comparison with creatinine clearance with cimetidine.5–8

Regarding cystatin-C as a GRF marker, it has been demonstrated that in elderly persons with glomerular filtration lower than 60 ml min−1, it is not superior to that calculated by the CG and MDRD formulae.5, 9

Consequences of Senile Hypofiltration

• A serum creatinine concentration of 1 mg dl−1 reflects a GFR of 120 ml min−1 in a 20-year-old and 60 ml min−1 in an 80-year-old.5, 9
  
• Senile hypofiltration and diastolic cardiac failure predispose healthy old people to cardiac failure, and to lung congestion after a saline load.9
  
• The dose of prescribed drugs must be adjusted to the estimated GFR in the elderly.8
  
• In old people senile hypofiltration differs from chronic kidney disease because the glomerular filtration value is stable over a period of 6–12 months and there is no haematuria or significant proteinuria (>0.30 g day−1).10

Glomerulonephritis

Renal biopsy is useful in guiding the prognosis and therapy for renal disorders in this population. In the elderly who underwent a diagnostic renal biopsy, 59% had primary glomerulonephritis, and 20% secondary glomerulonephritis. Even though the aged accounted for only 23% of patients undergoing biopsy, the elderly in the biopsy series were more numerous than the proportion of elderly people in the general population (16%). Primary glomerulonephritis was the most frequent biopsy-proven renal disease in the elderly, even more frequent than primary glomerulonephritis in adults. Although the indications and incidence of complications of renal biopsy are the same for both elderly and adults, when older persons have a complication of renal biopsy, generally such complications are more serious. Crescentic, membranous nephropathy, membrano-proliferative glomerulonephritis, minimal change disease, and acute post-streptococcal glomerulonephritis are all more frequent in the elderly than in younger patients. Only focal segmental glomerulosclerosis, IgA and non-IgA mesangioproliferative nephritis were less frequent in elderly patients than in the younger ones.11–13

In some elderly patients membranous nephropathy is related to drugs ingestion or an underlying malignancy (20%) (mainly lung or colon adenocarcinoma). Regarding minimal change disease, senile structural renal changes make histological diagnosis difficult; its clinical presentation is usually ‘atypical’ with hypertension, microhaematuria and/or renal failure; also it may be associated with drugs (NSAIDs) or malignancies (lymphoma). Crescentic glomerulonephritis reaches its greatest incidence between 60–79 years of age, and its typical clinical presentation is an acute renal failure of rapid evolution. Steroids and other immunosuppressive drugs (cyclophosphamide, etc.) can be used in the elderly as in adults, though with special attention to their side effects. Secondary glomerulopathies such as diabetic nephropathy, nephroangiosclerosis secondary to essential hypertension, glomerular vasculitis, and those associated with abnormal plasma-cell proteins (light chain, fibrillary, immunotactoid nephropathy) are frequent in the elderly. Nephrotic syndrome accounts for 50% of renal biopsy indications, its most prevalent causes are: membranous, minimal change, diabetic and amyloidosis nephropathies.12–14

Senile Renal Vascular Changes

Prearterioles show subendothelial deposition of hyaline and collagen fibres that produce intimal thickening. In the small arteries the intima is thickened due to proliferation of the elastic tissue, and the media shows atrophy. Another characteristic of the ageing kidney is the formation of the above-mentioned aglomerular circulation, and dysfunction of the autonomic vascular reflex.2, 3, 10, 14

Consequences of the Senile Vascular Changes

• Renovascular atherosclerosis, which can lead to renovascular hypertension, ischaemic nephropathy and chronic kidney disease.9, 14
  
• In patients with bilateral renal artery stenosis reversible renal failure may develop after the use of angiotensin-converting enzyme (ACE) inhibitors.14, 15
  
• Intrarenal atheroembolism appears when plaque material breaks free from the diseased renal artery and enters the renal circulation. The kidney rarely recovers from this acute insult.14
  
• Renal dysautonomia leads to kidney damage during hypotensive or hypertensive states.9

Renal Vasculitis in the Elderly

It has become increasingly clear that renal vasculitis is more common with advancing age and probably this disease is the most common primary cause of renal failure in the elderly. The incidence of Wegener’s granulomatosis and microscopic polyangeitis increases with age. Since immunosuppression is the main treatment for these entities, a careful monitoring of therapy can minimize adverse effects in this population.13, 14

Other diseases: renovascular atherosclerosis and atheroembolic disease.

Senile Tubular-Interstitial Changes

Renal tubules undergo fatty degeneration, and irregular thickening of their basal membrane. Diverticula arise from the distal and convoluted tubules, and it has been suggested that, in the aged, these may serve as reservoirs for recurrent urinary tract infections in the elderly. In addition, the aged kidney also shows increasing zones of tubular atrophy and fibrosis.2, 3

Consequences of Tubular-Interstitial Changes

The physiological and clinical consequences of these changes in the aged renal tubules can be summarized in three groups: (1) tubular dysfunction, (2) medullary hypotonicity, and (3) tubular frailty.

• Sodium The 24-hour urinary sodium output and fractional excretion of sodium are significantly greater in old and very old people. The mean half time for the excretion of a sodium load is 17.7 hours in persons under 30 years of age, reaching 30.9 hours in persons over 65. Because GFR declines with age and the amount of filtered sodium is lower than in young subjects, a salt load given to an aged person takes longer to eliminate. However, when sodium is restricted to 50 mmol day−1, the period required to start saving urinary sodium is five days in the young and nine days in the elderly, and therefore the capacity of the ageing kidney to adapt to a low salt intake (50 mmol 24h−1) is clearly blunted. The proximal nephron behaves similarly in the young, old and very old, whereas in the thick ascending loop of Henle the reabsorption of sodium is reduced in the old and very old people. This phenomenon has two important consequences: first, the amount of sodium loss is increased; and second, the capacity of the medullar interstitium to concentrate is also diminished (medullary hypotonicity). Thus, old subjects exhibit both an increased sodium excretion and an inability to maximally concentrate the urine (water saving). Despite this tendency to an exaggerated natriuresis, total body sodium is not significantly decreased with age. The basal plasma concentrations of renin and aldosterone and the response to their stimuli are diminished in old age, which is another mechanism for the enhanced sodium loss in this population. Finally, elevated serum and urinary natriuretic peptide levels in the elderly may be another cause of the characteristic urinary sodium loss of the aged.4, 16, 17