Complications of nephrotic syndrome

 

Complications of nephrotic syndromeIntroduction:

Nephrotic syndrome (SN) is defined as proteinuria greater than 3 g / d with hypoalbuminemia below 30 g / l. For many authors, SN is better defined by an abundant proteinuria greater than 3 g / d, without mentioning threshold values ​​of albuminemia and protidemia which are arbitrary, all the more so as the complications or consequences of this syndrome are mostly related to proteinuria.

The physiopathology of these complications is complex and still incompletely described despite significant advances in recent years.

Hydrosodic retention and edema formation:

Edema represents an abnormal expansion of interstitial volume. This expansion of the interstitial volume is secondary to the accumulation of sodium in the extracellular sector due to inappropriate sodium retention and changes in the forces of the Starling law which regulate the transfer of fluid through the soft tissue capillaries .

Improper sodium renal retention:

Several mechanisms have been suggested to explain the inappropriate retention of sodium by the kidney. Numerous concordant data indicate that activation of the Na, K-ATPase pump at the basal pole of the collector tube main cell plays a central role in the inappropriate reabsorption of sodium during SN. Indeed, microponent techniques have shown that the localization of sodium renal reabsorption is located in the collecting tube. A stimulation of the hydrolytic activity of the Na, K-ATPase pump was demonstrated in the collecting tubes of different SN animal models. This stimulation is specific to the cortical collector tube and is not found in other segments of the renal tubule. It is contemporaneous with the decline in the final urinary concentration of sodium and the positivity of the sodium balance.Finally, urinary excretion of sodium is correlated with the activity of the sodium pump during the phase of constitution of the edema. This activation is independent of aldosterone and proteinuria and appears to be secondary to an overexpression of the α -subunit of the basolateral membrane of the main cell.

These results suggest that the exclusive activation of the sodium pump in the cortical collector tube is the active phenomenon of sodium renal retention in the NS. This excess of reabsorption should normally be compensated by a secretion of sodium in the internal medullary part of the collecting tube under the influence of the atrial natriuretic factor, but its tubular action is inhibited in experimental SN and idiopathic SN. This inhibition is secondary to the reduction of the intracellular production of cyclic guanosine monophosphate, the second messenger of the atrial natriuretic factor.

The classical physiopathological pattern of sodium retention is based on a sequence of events associating hypoalbuminaemia, a decrease in oncotic pressure, fluid transfer from the vascular to the interstitial space, hypovolemia, hyperaldosteronism, decreased l urinary excretion of sodium. Nevertheless, this hypothesis does not explain certain clinical and experimental facts, and a completely opposite physiopathological pattern has been proposed: a primary tubular dysfunction, causing excessive sodium reabsorption and then volemic expansion, would feed the transfer of liquid to the interstitial space and the formation of edema. Measurement of the volume of nephrotic patients does not support either theory, as about 33% have a lowered plasma volume, 42% have volume within the normal range, and 25% have an increase in volume. In addition, patients with and without symptoms of hypovolaemia have identical “amounts of edema”. Finally, volume expansion by an infusion of albumin does not make it possible to reverse the sodium balance of nephrotic patients with edema. Volmia is therefore not determinant in the constitution of edema, nor in the renal retention of sodium. The increase in capillary permeability and the deregulation of tubular sodium reabsorption are therefore two primary and independent mechanisms that explain the constitution of edema independently of the volume of blood.

Other mechanisms than activation of the renin angiotensin-aldosterone system (RAAS) have been proposed to explain the inappropriate retention of sodium.

The rate of vasopressin is significantly higher in patients with NS with minimal glomerular lesions. Vasopressin can stimulate the hydrolytic activity of the sodium pump in the collecting tube by mobilizing an intracellular functional reserve on the surface of the main cell and inducing its transcription. Nevertheless, the constitutive absence of vasopressin in some animal models of SN does not alter either the clinical picture or the hydrolytic activity of the sodium pump and it was found that vasopressin did not induce the sodium pump functional reserve in nephrotic rats.

It has also been suggested a direct effect of proteinuria on sodium reabsorption. In a one-sided SN model in rats induced by injection of puromycin aminonucleoside (PAN) into the left renal artery with drainage of the venous effluent to avoid general contamination, the kidney exposed to PAN is proteinuric and excreted two to three times less sodium than the kidney controls while the systemic environment is the same. The presence of proteins in the tubule could thus modify the operation of the collecting tube. Nevertheless, the greater decline in natriuresis obtained by systemic injection of PAN and the precession of sodium renal retention on proteinuria in this same model can not be explained by this hypothesis. Finally, it is possible that changes in the composition of plasma proteins with, in particular, an increase in circulating proteases and / or growth factors intervene directly on tubular functioning.

Formation of edema:

The expansion of the extracellular sector is mainly for the benefit of the interstitial sector while the vascular sector is only slightly or not modified. This distributional anomaly is due to an increase in the transcapillary flow of fluid in nephrotic patients.

The increase in ultrafiltration of the plasma through the capillary wall is not exclusively related to the drop in the oncotic pressure. Analbuminemic patients have a low oncotic pressure sufficient to induce hypercholesterolemia and hypertriglyceridaemia, but have edema limited to transient or even completely absent ankles. The only decrease in the oncotic pressure therefore does not explain the constitution of a large amount of edema. A primary endothelial permeability disorder is likely in idiopathic SN. Indeed, the lymphocyte culture supernatants taken from patients with thrushing cause a significant increase in vascular permeability. In addition, the endothelium shares common molecular structures with the podocyte, including adherent junctions (ZO-1, P-cadherins, catenins).

They are connected with the network of actin and actinin which also constitutes the cytoskeleton membrane of the endothelial cells and plays a decisive role in the sealing of the endothelial barrier with respect to water and its solutes.

The glomerular permeability factors that disrupt the equilibrium of these macromolecular complexes in the podocyte could affect the same equilibria in the endothelial cell and directly modify their sealing properties.

Changes in the hydraulic conductivity of the endothelial barrier, due to changes in the intercellular junctions, probably account for the distributional anomaly of the extracellular sector in the NS.

Thromboembolic complications:

The incidence of thromboembolic events is high, complicating 10% to 40% of NPs according to the series. The incidence of renal vein thrombosis is particularly high, especially in patients with extramembraneous glomerulonephritis (GEM) or membranoproliferative glomerulonephritis (GNMP). Asymptomatic forms of renal vein thrombosis, diagnosed on ultrasound scan, computed tomography, or magnetic resonance imaging (MRI), are more frequent than symptomatic forms, revealed by lumbar pain, macroscopic hematuria, rapid deterioration renal function if they are bilateral, or a sudden increase in proteinuria. In case of thrombosis of the renal veins, the risk of pulmonary embolism is important. Peripheral vein thrombosis is common and the incidence is estimated to be about 12%.Unusual venous thrombosis (subclavian, axillary, splenoportal, cerebral sinus) and arterial venous thrombosis have also been described. Different anomalies of haemostasis have been described during the NS and may explain this high incidence of thromboembolic diseases. High levels of various coagulation factors (fibrinogen, factors V, VIII, XIII) are frequently found in the NS. The elevation of fibrinogen is the most constant anomaly. In most series, the average fibrinogen concentration of nephrotic patients exceeds 6 g / l. The increased levels of fibrinogen, fibronectin, factors V, VIII, and XIII are the consequence of increased hepatic synthesis of these proteins, in relation to hypoalbuminemia.Low levels of factor XII have been described and are probably related to intravascular consumption. Factors II, VII, IX, and X are generally found at normal levels. As regards natural anticoagulant proteins, it is conventionally found: normal or low levels of antithrombin III, high levels of protein C, low levels of free protein S, high levels of heparin cofactor II and a 2 -macroglobulin, and normal levels of tissue pathway inhibitor factor. Lower levels of antithrombin III are related to urinary loss of antithrombin III, which is not always compensated for by increased synthesis.Thrombocytosis is present in a large number of nephrotic patients. Platelet hyperagregity in the presence of different agonists (ADP, collagen, arachidonic acid, ristocetin) has been documented. Hypoalbuminemia, which increases the bioavailability of arachidonic acid for thromboxane A 2 synthesis, hypercholesterolemia, and high levels of fibrinogen and von Willebrand factor, are responsible for platelet activation. Fibrinolysis is generally decreased in the SN due to decreased binding of plasminogen to fibrin and an increase in fibrinolysis inhibitors. The elevation of lipoprotein A (Lpa) plays an important role in the hypofibrinolysis of SN.

Dyslipidemia:

Plasma concentrations of cholesterol and phospholipids increase early in the course of NS and worsen with NS severity. Triglyceride levels are more variable, especially at the onset of disease, but also increase with progression of the NS. Changes in SN-characteristic lipoproteins are: elevation of low density (LDL), very low density (VLDL) and intermediate density (IDL) lipoproteins unmodified or associated with a slight increase in high density lipoprotein (HDL) ). However, there are potentially atherogenic qualitative abnormalities of HDL cholesterol in the NS with a reduction in HDL2 and an increase in HDL3 due to lecithin cholesterol acyltransferase (LCAT) deficiency. In addition, Lpa is increased regardless of the isoforms of apolipoprotein A and this increase is corrected after remission of SN or after symptomatic treatment with antiproteinuric. Besides these quantitative changes, qualitative modifications of the lipid balance exist. The cholesterol / triglyceride and cholesterol ratios, cholesterol esters, phospholipids / proteins are indeed increased. There is also an accumulation of lipoproteins rich in phospholipids and esterified and non-esterified cholesterol, resembling VLDL or chylomicron remnants. Apolipoproteins B and C-III are increased in the SN, whereas the concentrations of apo AI, A-II, and C-II are not modified.

The increase in the C-III / C-II ratio may contribute to the inhibition of lipoprotein lipase (LPL) observed in the SN.Several mechanisms can account for these anomalies. The production of cholesterol and certain apolipoproteins is increased during the NS. The increase in hepatic synthesis of proteins secondary to hypoalbuminemia only partly explains this increase in production. Indeed, the production of some apolipoproteins is not increased and a decrease in proteinuria (under the effect of ACE inhibitors) with no effect on albumin albumin production is accompanied by a decrease in concentrations of cholesterol and triglycerides. There is also a reduction in the catabolism of chylomicrons and VLDLs, partly related to the inhibition of LPL and to changes in their composition.

A decrease in LCAT activity and a greater availability of mevalonate, a precursor of cholesterol synthesis, may also contribute to NL hyperlipidemia. Finally, changes in the permelectivity of the glomerular membrane partly account for lipid abnormalities. Indeed, an alpha 1 acid glycoprotein found in the urine of nephrotic patients corrects the alterations of lipolysis. It is therefore likely that the abnormal catabolism of lipoproteins results at least in part from the urinary loss of certain substances regulating the lipid metabolism.

Infections:

Bacterial infections, particularly pneumococcal peritonitis, were once frequent and severe complications of NOS. They have become rarer, although they are still a problem in immunosuppressed patients.

Bacterial infections are mainly related to decreased immunoglobulin G levels and complement alternate pathway components.

From the therapeutic point of view, there is no consensus on the prevention of infectious risk. Pneumococcal vaccine may be used.

It has been suggested in an uncontrolled study that administration of multivalent immunoglobulins may reduce the rate of bacterial infections in patients with NS.

Other complications:

Many binding proteins are excreted in the urine during the NS. As a result, plasma concentrations of many ions, vitamins, hormones and drugs are lowered because the concentrations of their binding proteins are reduced. The leakage of thyroxine binding globulin may result in abnormal thyroid tests, including lower thyroxine. The loss of cholecalciferol binding protein can lead to a deficiency in vitamin D, with secondary hyperparathyroidism. Increased transferrin excretion can lead to hypochromic microcytic anemia resistant to iron. Deficits of copper and zinc are the result of the urinary leakage of the binding proteins of these metals. Many drugs are bound to albumin.

Hypoalbuminemia decreases the number of available binding sites and thus increases the circulating active drug fraction. In a state of equilibrium, this is counterbalanced by a more rapid metabolism. Higher concentrations of active drug active may become toxic, as has been shown with prednisolone and possibly coumarinics.

Treatment of complications of nephrotic syndrome:

Hydrosodic retention:

The principle of the treatment of the hydrosodic retention rests on the obtaining of a negative soda balance. Dietary sodium intake should be decreased to around 50 mmol / d (approximately 3 g NaCl). Due to the kidney greed for sodium in patients with SN, potent loop diuretics are essential. Furosemide can be given in 2 or 3 daily doses. High doses are required because in addition to kidney greed for sodium, furosemide and other diuretics are bound to albumin in the intratubular light of patients with proteinuria. The binding to albumin is in competition with the binding on the target proteins, that is to say the cotransporters of sodium. Furosemide acts on the cove of Henle. There is papillary hyperplasia and hypertrophy of distal tubular cells during chronic furosemide therapy. It is also possible to reduce the reabsorption of Na at the distal tube by associating thiazides or potassium-sparing diuretics with furosemide. The hydrosoded overload must be corrected slowly.

Rapid natriuresis may induce hypovolemia which may be severe enough to cause acute renal failure, usually functional but sometimes organic by tubular necrosis in hypovolemic shock. Albumin perfusion for volume expansion should only be used in exceptional cases of symptomatic hypotension. It could nonetheless play a role as a carrier protein for furosemide. In other cases, albumin infusions are not effective because perfused albumin is rapidly eliminated in the urine. Moreover, in the medium term, the increase in the passage of proteins through the glomerular wall contributes to the worsening of glomerular permeability anomalies and to the tubulo-interstitial toxicity of the reabsorbed proteins. Ultrafiltration is sometimes necessary in cases of refractory edema with anasarca. Exceptionally, bilateral nephrectomy may be indicated in cases of refractory SN with deep hypoalbuminaemia, severe malnutrition and hypovolemia. Nephrectomy can only be considered if the consequences of NP involve the patient’s prognosis in the short term.

Thromboembolic risk:

Prophylaxis with oral anticoagulants is often proposed, although it remains debatable, and is recommended in nephrotic patients, especially in cases of GEM with or without a history of thrombophlebitis. Prophylactic anticoagulation should be administered as long as the albumin remains below 20 g / l. In other nephropathies, the prophylactic anticoagulation decision must be decided on a case-by-case basis. Concerning the conduct of anticoagulant therapy, it should be remembered that the free fraction of warfarin is greatly increased in the SN, so inhibition of the production of vitamin K dependent factors is increased and the half-life of the molecule reduced.Similarly, the efficacy of heparin is reduced because of the low levels of antithrombin III.

Dyslipidemia:

Because of the cardiovascular consequences of dyslipidemia, and possibly its effects on the progression of renal insufficiency, treatment is often indicated. However, to date there is no evidence of its effectiveness. Dietary measures must be systematic and are effective in reducing LDL cholesterol.

Statins have also shown their efficacy in reducing LDL cholesterol levels in nephrotic patients.

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