In patients with renal diseases characterized by proteinuria, the initial insult to the kidney is usually followed by a progressive decline in the glomerular filtration rate. This decline may be initiated by the loss of nephrons. As a result, afferent arteriolar tone decreases more than efferent arteriolar tone, and therefore, the hydraulic pressure in glomerular capillaries rises (4) and the amount of filtrate formed by each nephron increases. These changes increase the filtration capacity of the remaining nephrons, thus minimizing the functional consequences of nephron loss, but they are ultimately detrimental. (5) Therapies that attenuate these adaptive changes limit the decline in the glomerular filtration rate and minimize structural damage (e.g. angiotensin-converting-enzyme (ACE) inhibitors, which reduce intraglomerular capillary pressure more effectively than other antihypertensive drugs). (6,7) or diabetes mellitus (8,9) from progressive renal injury.
Why should hemodynamic changes -- specifically, glomerular hypertension -- lead to progressive renal injury? One possible explanation is that the high glomerular capillary pressure enlarges the radius of the pores in the glomerular membrane by a mechanism that is mediated at least in part by angiotensin II. (10,11) This enlargement impairs the size-selective function of the membrane so that the protein content of the glomerular filtrate increases, which in turn increases the endocytosis of protein by tubular epithelial cells, ultimately resulting in a nephritogenic effect (i.e. The ability to resorb protein from the ultrafiltrate exceeds the relatively low threshold receptor mediated mechanism, and results in increased processing through the lysosomal system). (12) A vicious circle is then established in which changes in renal hemodynamics due to the loss of nephrons lead first to proteinuria and then to the loss of more nephrons.
Filtered proteins are reabsorbed by proximal tubular cells, in which they are degraded by lysosomes. Albumin is taken up by a dual pathway: a low-capacity one that reabsorbs physiologic amounts, and a high-capacity one that comes into play when the concentration in tubular fluid is high. (16)
Early observations suggesting the importance of proteinuria as a contributing factor in the pathogenesis of progressive nephropathies included:
A number of different factors have been implicated in mediating nephron loss. They include:
The common theme is that when the lysosomal system is utilized to augment protein reabsorption in the proximal tubule, cytokines are released. The resorption of protein is adaptive, but it comes at a cost, cytokine mediated progressive nephropathy.
In patients with chronic proteinuric nephropathies, the ratio of protein to creatinine in a single morning urine specimen correlated with 24-hour urinary protein excretion and predicted the rate of decline in the glomerular filtration rate and the progression to end-stage renal disease better than measurement of 24-hour urinary protein excretion. (82-85) For example, a urinary protein:creatinine ratio of 1.0 or more distinguished patients in whom renal disease subsequently worsened from those in whom it did not (Figure 3a). Patients with a urinary protein:creatinine ratio of less than 1.0 had no decline in the glomerular filtration rate and no end-stage renal disease, whereas those with a ratio of 1.0 or more had a decrease in the glomerular filtration rate during a one-year follow-up period. In this group the higher the ratio, the more rapid the rate of decline in the glomerular filtration rate and the higher the risk of end-stage renal disease. The risk exceeded 30 percent per year in patients with a urinary protein:creatinine ratio of more than 4.0. For these patients, the expected time to dialysis was less than one year (Figure 3b).
In patients with various renal diseases, reducing urinary protein excretion slows the rate of decline in the glomerular filtration rate, (86) and reducing blood pressure slows the decline in the glomerular filtration rate more in patients with a high rate of urinary protein excretion at base line than in those with a low rate. (78) In patients with diabetic nephropathy, lowering blood pressure with an ACE inhibitor decreases urinary protein excretion and slows the decline in the glomerular filtration rate more than does lowering blood pressure to similar levels with beta-blockers and diuretics. (87) In a study of patients with type 1 diabetes and some renal failure, captopril preserved renal function better than did diuretics, beta-blockers, or other antihypertensive drugs and halved the need for dialysis and transplantation. (88) During follow-up, the reduction in blood pressure was similar in the two groups; urinary protein excretion decreased in the patients treated with captopril and increased in the other groups. (89)
In the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study, (90) which included 583 patients with renal insufficiency due to various nephropathies, the risk of a doubling of the serum creatinine concentration was lower in patients who received an ACE inhibitor than in those who received a placebo, but the blood pressure of patients in the placebo group was also higher. This finding leaves unanswered the question of whether the renoprotective effect of the ACE inhibitor was related to its antiproteinuric effect or to its antihypertensive effect. The majority of the patients in this trial had a urinary protein excretion of less than 2 g per 24 hours and a remarkably slow rate of progression of renal failure. These patients did not benefit from ACE-inhibitor therapy, and its renoprotective value was confined to patients with urinary protein excretion of more than 3 g per 24 hours at base line and in whom urinary protein excretion decreased during treatment
The Ramipril Efficacy in Nephropathy Study was designed to address formally whether excessive ultrafiltration of proteins influenced the progression of renal disease and whether an ACE inhibitor (ramipril) was superior to placebo and other antihypertensive drugs, at similar levels of blood-pressure control, in reducing proteinuria, limiting the decline in the glomerular filtration rate, and preventing end-stage renal disease in patients with hypertension (87 percent of the patients) and in those without hypertension. (91) In this trial, the mean rate of decline in the glomerular filtration rate in the 90 patients whose urinary protein excretion was 1 to 3 g per 24 hours at base line was one third of that in the 87 patients whose urinary protein excretion was more than 3 g per 24 hours. (92) Among the patients with base-line urinary protein excretion of more than 3 g per 24 hours, the mean (±SE) rate of decline in the glomerular filtration rate was significantly lower in the ramipril group than in the control group (-0.53±0.08 vs. -0.88±0.13 ml per minute per month), and the risk of reaching the combined end point of a doubling in the base-line serum creatinine concentration or end-stage renal disease was also significantly lower in the ramipril group. Systolic and diastolic blood pressures were similar in the two groups at base line and during follow-up (with differences consistently less than 2 mm Hg), providing evidence that ramipril slowed the decline in renal function through a renoprotective effect that was largely independent of changes in blood pressure. On the other hand, the finding that the ramipril-induced reduction in urinary protein excretion was the only time-dependent covariate that predicted a slower rate of decline in the glomerular filtration rate and progression to end-stage renal disease clearly indicated that renoprotection is linked to a reduction in protein excretion.
The Modification of Diet in Renal Disease Study found a correlation between higher mean blood pressures (for values of more than 98 mm Hg in patients with base-line urinary protein excretion of 0.25 to 3 g per 24 hours and of more than 92 mmHg in patients with base-line protein excretion of more than 3 g per 24 hours) during follow-up and a faster decline in the glomerular filtration rate that depended on the level of urinary protein excretion at base line. In addition, the decline in the glomerular filtration rate during the study was more effectively slowed by tight blood-pressure control in patients with higher rates of urinary protein excretion at base line than in those with lower rates. (78) On the basis of these findings, the authors recommended that the target blood pressure should be less than 125/75 mm Hg in patients with urinary protein excretion of more than 1 g per 24 hours and less than 130/80 mm Hg in those with urinary protein excretion of 1 g per 24 hours or less.
In patients with lower rates of urinary protein excretion, the glomerular filtration rate is less likely to decline with time, regardless of which antihypertensive drug is given. (93) For example, a meta-analysis showed that in patients with diabetic nephropathy, non-nifedipine calcium-channel blockers and ACE inhibitors had similar effects on the rate of decline in the glomerular filtration rate when urinary protein excretion was reduced to a similar extent. (94,95) On the other hand, treatment with other antihypertensive drugs was less effective in decreasing urinary protein excretion and preventing a decline in the glomerular filtration rate.
Progression to irreversible renal parenchymal damage and end-stage renal disease is the final common pathway of chronic proteinuric nephropathies and is relatively independent of the type of initial insult. In animals, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that are intended to sustain renal function but may be detrimental in the long term. High glomerular capillary pressure impairs glomerular permeability to proteins, which are then filtered in excessive quantities and reach the lumen of the proximal tubule. The secondary process of reabsorption of filtered proteins can contribute substantially to renal interstitial injury by activating intracellular events, including up-regulation of vasoactive and inflammatory genes. The corresponding molecules formed in excessive amounts by the renal tubules cause an interstitial inflammatory reaction that normally precedes renal scarring and correlates with declining renal function.
In several studies, the increase in urinary protein excretion correlated with the tendency of the renal disease to progress more than with the underlying renal disease itself. Whenever urinary protein excretion is reduced, the decline in the glomerular filtration rate slows or stops. Thus, ACE inhibitors and other antihypertensive drugs, to the extent that they lower the rate of urinary protein excretion, effectively limit the progressive decline in the glomerular filtration rate.
Quantification of urinary proteins helps predict the risk of disease progression and the need for dialysis, and measurement of the protein:creatinine ratio in a single morning urine specimen is an excellent alternative to measurement of protein in a 24-hour urine collection. Physicians can now predict the risk of dialysis for individual patients
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