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| Year : 2000 | Volume
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| Issue : 3 | Page : 303-314 |
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| Atherothrombosis in the Nephrotic Syndrome |
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Jorge Joven
Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Calle Sant Joan s/n, 43201, Reus, Spain
Click here for correspondence address and email
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How to cite this article:
Joven J. Atherothrombosis in the Nephrotic Syndrome. Saudi J Kidney Dis Transpl 2000;11:303-14 |
Proteinuria is the hallmark of the nephrotic syndrome
The nephrotic syndrome is characterized by the concomitant occurrence of proteinuria, hypoalbuminemia, edema and hyperlipoproteinemia and is the common end-point of several disease processes. It may be caused by primary glomerular diseases, with wellknown and differentiated alterations in the glomeruli, or by other secondary diseases such as infections, drug-related, malignancy, multisystemic or hereditary disorders. Therefore, it is immediately apparent that generalizations about extrarenal complications of nephrotic syndrome or, more precisely, about the presence of atherosclerosis, thrombosis or both may be an inaccurate intellectual exercise; each patient should be evaluated individually.[1]
There is, however, a common factor: the important disturbance of the permeability properties of the glomerular capillary wall that leads to an excessive leakage of plasma proteins into the urine. Arbitrarily, total urinary protein excretion rates in excess of 3.5 g per 1.73 m 2 surface area per day, which roughly corresponds to urinary protein concentration greater than 0.4 mg/mmol creatinine [3.5 mg/mg], are considered to be in the nephrotic range.[1]
However, it is not only the amount of protein lost into the urine, which is important, but also the final composition of this urine. The size and charge of individual proteins determines whether they can be filtered through normal glomerular basement membranes (roughly 0% at 70 kDa and 100% at < 10 kDa). [1] Proteins that pass through this membrane are absorbed and catabolized in the tubular cells or excreted in the urine.[2],[3] In the nephrotic syndrome, the function of this barrier is severely disrupted; small, medium-sized, and even very large proteins are lost in massive quantities, thereby causing changes in the plasma composition.[2],[4]
The immediate effects of proteinuria on atherothrombosis:
Hypoalbuminemia
Most patients with the nephrotic syndrome develop hypoalbuminemia at some stage during the course of the disease. Some patients normalize the plasma albumin concentration despite significant proteinuria, but in general, the greater the magnitude of the proteinuria, the lower the plasma albumin concentration.
The actual cause of hypoalbuminemia is probably multifactorial and poorly understood. The loss of albumin in the urine is important, but the rate of hepatic albumin synthesis [normal, 12-14 g/day] [5] may increase by at least threefold and should easily be able to compensate for the usual urine losses. The rate of albumin synthesis is frequently normal or above normal if dietary protein is adequate, [4],[6] and low- or high-protein diets should be carefully indicated and followed. The dietary protein intake is also important because it can influence the rate of degradation of albumin in the kidney or the gastrointestinal tract. In some instances, hypercatabolism may be even more important than the urine losses and frank hypoalbuminemia may develop with proteinuria as low as 4 g/day. The way in which hypoalbuminemia is managed is important because hypoalbuminemia itself has many deleterious effects and plays a role in atherothrombosis in the nephrotic syndrome.
Edema
Edema, the clinical expression of an expanded extracellular fluid compartment, is usually characterized by swelling of the lower limbs or unexpected weight gain, and frequently is the reason why the patient with the nephrotic syndrome seeks medical advice. It was previously thought that reduced plasma oncotic pressure (π) could cause hypovolemia (and then hemoconcentration) and sodium retention. However, adult patients with the nephrotic syndrome are often found to have normal or even increased plasma volume. [7] Although some patients are primarily plasma volume contracted, and sometimes this is clinically evident, they are the exception rather than the rule. [8] The cause of edema is highly controversial but many observations and animal models suggest a primary retention of sodium in the kidney. [9],[10],[11] However, there are other contradictory arguments [12],[13] and no single mechanism can be invoked in all cases. Edema is important in the pathogenesis of thrombosis because patients may have episodes of blood volume contraction and this is even more frequent after treatment with diuretics. Therefore, in this situation, patients are more prone to acute episodes of thrombosis and occasionally even acute renal failure.
Hyperlipidemia
In nephrotic patients plasma lipoproteins may be increased because of increased rate of synthesis, decreased rate of removal, increased mobilization from fat stores, or combinations of these factors. Moreover, whatever the mechanism(s) involved, it should be taken into account that hypoalbuminemia plays an essential role in generating hyperlipidemia, but proteinuria per se might play a concurrent role in decreasing lipoprotein removal [14]
Hyperlipidemia was first noted by John Blackall [15] in 1811 and described as "milky plasma even when fasting", indicating the presence of hyperchylomicronemia. The presence of chylomicrons is rarely, if ever, associated with nephrotic hyperlipidemia. [16] In this respect, we postulated the presence of a concomitant primary lipoprotein disturbance and we found apoprotein E2 homozygosity. Moreover, we noted a residual type III hyperlipoproteinemia with high plasma apo E levels even when the plasma albumin was normalized.[17]
In a previous report, [18] we described that either hypercholesterolemia or hypertriglyceridemia, or both, are invariably seen in nephrotic patients. The probability of finding raised plasma triglyceride concentration is higher in severely hypoalbuminemic patients. [19] According to the usual standards for classification, [20] 30% had high concentrations of serum low density lipoproteins (LDL) and normal concentrations of very low density lipoproteins (VLDL) (type IIa), 60% had high concentrations of LDL and VLDL (type IIb) and 7% had normal concentrations of LDL and high concentrations of VLDL (type IV). More recently, the frequent association of high serum concentrations of intermediate density lipoproteins (IDL) and lipoprotein (a) has been reported. [21],[22] However, this pattern is expected to be different if the nephrotic syndrome is complicated with diseases such as diabetes mellitus and renal failure that may cause secondary hyperlipidemia. [23] Furthermore, high density lipoproteins (HDL) are normal or elevated in the plasma of the nephritic patients.
Plasma protein derangements
Proteinuria, among other possible factors, is responsible for considerable changes in the composition of plasma proteins. Again, it is difficult to assess the nature of most of the plasma protein abnormalities because patients with the nephrotic syndrome are a heterogeneous group. Proteinuria triggers a rapid and quantitatively important response of the liver, [24] but other tissues are also probably involved. The synthesis of some proteins increases while others stay the same or even decrease.[4],[5],[6],[18],[25] In patients with membranous nephropathy, we have measured the concentrations of 25 plasma proteins. [26] The plasma concentration of some large proteins was increased; there were also large proteins with low plasma concentrations, but small or medium-sized proteins showed uniformly lower plasma concentration than controls. Plasma colloid osmotic pressure (π) and viscosity (r) were not interrelated but showed positive and significant correlation with plasma concentrations of small and medium-sized proteins and plasma concentrations of large proteins, respectively. Nephrotic plasma is not efficient at maintaining plasma 1t but highly efficient at maintaining plasma r). Therefore, the relative composition of the nephrotic plasma depends heavily on the size of different proteins. The plasma antithrombin III (65 kDa) concentration in nephrotic patients is lower than controls and plasma fibrinogen (340 kDa) is higher see [Figure - 1]. This may be important because all of our patients whose plasma antithrombin III was lower than 0.25 g/L had a high plasma fibrinogen concentration and presented with clinical thrombosis. However, it is also true that some patients with relatively normal concentration of these proteins also have clinical thrombosis. As a general rule, the probability of patients with plasma albumin concentration lower than 20 g/L to have thrombosis is 80%, but it is only 20% if the plasma albumin concentration is higher than 30 g/L. These figures, however, may change considerably if we explore aggressively the asymptomatic patients.[27]
The special issue of hyperhomocysteinemia
Concentrations of homocysteine, a sulfur containing aminoacid, rise in chronic renal failure.[28],[29] The increased plasma levels of this amino acid are associated with atherosclerosis, [30] including coronary artery disease. [31],[32] Cross sectional studies have also demonstrated that hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. [33]
We found that plasma homocysteine levels increased in patients with the nephrotic syndrome (unpublished data) and that this was not entirely due to a reduced glomerular filtration rate. Anecdotical, but illustrative is the case of a young man with nephrotic syndrome, renal vein thrombosis, and folate deficiency. [34]
Folate deficiency, clinical or subclinical, might be caused by increased urinary excretion of folate and may be the reason for the development of hyperhomocysteinemia in some cases. Long-lasting hyperhomocysteinemia has been found to constitute a risk factor for premature atherosclerosis, mediated by homocysteineinduced endothelial cell injury.[35]
Thromboembolism and atherosclerosis in the nephrotic syndrome
Thromboembolism is one of the most serious complications in the course of the nephrotic syndrome and it is a determinant in the prognosis of glomerulonephritis. [36] The incidence of deep vein thrombosis and pulmonary embolism, ranges from 8.5% to 44% (mean, 20%) and renal vein thrombosis is observed in 5% to 62% (mean 35%) of affected adults. [37],[38],[39],[40] However, thrombosis may be found anywhere. [41] Factors contributing to this thromboembolic tendency are outlined in [Table - 1].
Despite the lack of reliable predictors of individual risk, the presence of a plasma albumin concentration below 25 g/L, proteinuria of more than 10 g per day, high fibrinogen levels, hypovolemia and low antithrombin III levels, are considered to be significantly associated with the risk of thromboembolic complications. [42] It is also possible that thrombosis is a much more prevalent condition than reported, because Doppler ultrasonography and/or ventilationperfusion lung scanning are not routinely indicated in asymptomatic patients. Patients in whom the nephrotic syndrome is caused by membranous nephropathy have been reported to have the highest incidence of renal vein thrombosis. This suggests that the nature of the disease underlying the nephrotic syndrome may play a role in its pathogenesis. Renal vein thrombosis occurs to a lesser degree in renal amyloidosis and membranoproliferative glomerulonephrits. It occurs even less commonly, in lipoid nephrosis and lupus nephritis, and it is rare in diabetic nephropathy. [43]
Clinically, the pattern of thrombosis is different in children and adults. [44] Thromboembolic complications occur less frequently in children (5%) but they tend to be more severe and, in half of the cases, arterial. [44],[45] In adults, arterial thrombosis is rare but occurs primarily in the femoropopliteal, renal and coronary arteries. [46],[47]
Hyperlipidemia has a causal role in the generation of vascular disease, in particular arteriosclerosis and myocardial infarction. The changes in plasma lipid concentration that are induced by the nephrotic syndrome, therefore, can be considered as highly atherogenic. However, even though hypertension is the most important of a number of risk factors in the nephrotic patients, a higher incidence of ischemic heart disease is still considered uncertain by some studies. These patients are reported to be at greater risk of suffering from a coronary event [48] but this has been, and still is, questioned [49],[50] because this group is hetero geneous .
When assessing the actual risk imposed by nephrotic hyperlipidemia, the duration, persistence and the pattern of hyperlipidemia, should be taken into account. The cardiovascular risk will be notably higher because of low plasma HDL concentration and the high plasma lipoprotein (a). It is now generally accepted that after adjustment for age, sex, hypertension, and smoking, the relative risk of myocardial infarction in these patients could be around 5.5, and the relative risk of death from coronary thrombosis 2.8.[48]
Therapeutic implications
Atherothrombosis in patients with the nephrotic syndrome is multifactorial and the numerous risk factors should be carefully assessed so that the appropriate prophylactic measures can be taken. Thrombosis is frequently the most dramatic complication in the nephrotic syndrome and I strongly believe that prophylaxis is mandatory and should be instituted aggressively. However, there is no consensus on this topic and many recommendations are not free of major risks.
Edema should be managed with caution. It can only be reversed if a negative sodium balance is induced [51] but the sodium excretion is so low that this cannot be achieved by diet. Loop diuretics alone or in combination with thiazides and potassiumsparing diuretics are recommended. [52] It is difficult to find the optimum dosage because the diuretics bind to albumin in the tubular lumen and also to their target molecules. [53] Edema should be reversed slowly and immobilization avoided. Patients should be carefully monitored and symptoms such as orthostatic hypotension, tachycardia, peripheral vasoconstriction and oliguria, searched for. Hemoconcentration considerably increases the risk of thromboembolic complications and support stockings, heparin or anticoagulants and hyperoncotic albumin must be used if hypovolemia is present.
Reduction of proteinuria is a therapeutic goal because high proteinuria is a predictor of rapid progression of renal failure. [54] Indomethacin has been shown to reduce proteinuria but its side effects have prevented it from being prescribed. [55] The risk of malnutrition in nephrotic patients with low-protein diet is real if they are not carefully supervised and provided with sufficient calories. Most Nephrologists, therefore, recommend normal protein intake. However, considerable improvement has been observed in the urinary protein excretion and serum lipid concentration of patients on a low-fat soy-protein diet providing 0.7 g of protein per kilogram per day. [56] Angiotensin-converting enzyme (ACE) inhibitors should be used even in normotensive patients in an attempt to reduce proteinuria. It takes up to one month for the antiproteinuric effect to be maximal; the effect depends on sodium balance and can be increased by a low-salt diet, a low protein diet or diuretic treatment. [57],[58],[59]
As mentioned, hypoalbuminemia may increase the toxicity of drugs by reducing the number of drug binding sites available and by increasing the circulating levels of free drug when usual doses are administered. Therefore, many drugs, namely hypolipidemic agents and oral anticoagulants should be closely monitored because unpredictable effects are likely.[60],[61] Toxic complications, however, are avoidable if the usual dose of the drug is reduced appropriately.
To my knowledge, there is no controlled study presenting evidences that aggressive treatment of hyperlipidemia may reduce mortality or coronary risk factors in the patients with the nephrotic syndrome. However, hyperlipidemia has the potential to induce cardiovascular disease and accelerate the progression of renal disease. [62] One study has investigated whether or not cholesterol lowering by simvastatin can significantly limit the decline in glomerular filtration rate, but the question is still being assessed. [63] Administering antilipid drugs to all nephrotic is a waste of time and money [15] but I believe that pharmacologic treatment should be considered for all patients in whom the nephrotic syndrome is likely to persist and also in those with membranous nephropathy or a hypercoagulable state. In randomized prospective, double blind, placebo-controlled trials, total and LDL cholesterol decrease considerably (20-30%) with both pravastatin and simvastatin. HDL tends to increase and triglycerides to decrease. [64],[65] Prospective controlled studies are required, particularly in children, to assess the efficacy and safety of lipidlowering drugs. [66] ACE inhibitors, also reduce cholesterol and LDL levels. [67]
There is also some room for nonpharmacologic intervention. A soy-protein diet caused a significant decrease in total and LDL cholesterol, whereas triglycerides did not change. [56] Treatment with fish oil decreased triglycerides and VLDL but increased LDL cholesterol. [68] Hyperhomocysteinemia should be also avoided, and long-term folic acid supplementation has proved to be useful in lowering elevated plasma homocysteine levels in chronic renal failure. [69] Renal patients may also benefit from higher doses of B vitamins than those currently recommended. [33]
Patients with membranous glomerulonephritis may benefit considerably from prophylactic anticoagulation therapy. [70] In uncontrolled series, there is a high rate of mortality from pulmonary embolism among patients not receiving anticoagulant therapy and very low rates of renal-vein thrombosis and pulmonary embolism in patients who do. It has also been established that the number of fatal emboli prevented by prophylactic anticoagulation exceeded the number of fatal bleeding events. [71]
Anticoagulant therapy should be administered in every patient with plasma albumin concentration < 20 g/L. If membranous nephropathy is not found, this treatment should be considered only if the risk is high. Once thromboembolic events are suspected, anticoagulant therapy is mandatory. In patients with the nephrotic syndrome, pulmonary-artery thrombosis and thromboembolism have been successfully treated by thrombolytic therapy with intravenous urokinase or with streptokinase infused into the pulmonary artery. [72],[73],[74] Also, as far as interventional techniques are improved, endovascular therapy might be warranted in symptomatic patients, early in the disease course. [75] Heparin should be given in clinical thromboembolism, but it is difficult to set the dosage because the effect is attenuated by low antithrombin III levels. [76] Finally, and because platelet function is consistently increased, the platelet aggregation inhibitors are a rational choice. Controlled studies are not available, but low-dose aspirin seems effective and there is growing experimental evidence that aspirin may be useful in reducing the risk of thromboembolic disease in the nephritic syndrome. [77],[78]
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Correspondence Address:
Jorge Joven
Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Calle Sant Joan s/n, 43201, Reus
Spain
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PMID: 18209322 
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