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Edema in renal diseases – current view on pathogenesis

Abstract

Edema is a common complication of numerous renal disease. In the recent past several aspects of the pathophysiology of this condition have been elucidated. We herein present a case of nephrotic syndrome in a 30 year-old men. The discussion revolves around the following key questions on fluid accumulation in renal disease:

1. What is edema? What diseases can cause edema?

2. What are the mechanisms of edema in nephrotic syndrome?

  2a. The “underfill” theory

  2b. The “overfill” theory

  2c. Tubulointerstitial inflammation

  2d. Vascular permeability

3. What are the mechanisms of edema in nephritic syndrome?

4. How can the volume status be assessed in patients with nephrotic syndrome?

5. What are therapeutic strategies for edema management?

6. What are the factors affecting response to diuretics?

7. How can we overcome the diuretics resistance?

  7a. Effective doses of loop diuretics

  7b. Combined diuretic therapy

  7c. Intravenous administration of diuretics

  7d. Albumin infusions

  7e. Alternative methods of edema management

8. Conclusion.

Nephrol @ point care 2016; 2(1): e47 - e55

Article Type: QUESTIONS @ POINT OF CARE

DOI:10.5301/pocj.5000204

OPEN ACCESS ARTICLE

Authors

Irina Bobkova, Natalia Chebotareva, Lydiya Kozlovskaya, Evgenij Shilov

Article History

Disclosures

Financial support: No grants or funding have been received for this study.
Conflict of interest: None of the authors has any financial interest related to this study to disclose.

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Case presentation

A 30-year-old male patient was referred to the nephrology clinic with massive periorbital, upper and lower extremities and scrotal edema, 10 kg weight gain, foamy urine and reduction of the urine output. His edema was resistant to oral furosemid administration (80 mg/day). His blood pressure was 110/70 mmHg. The past medical history was unremarkable. One month before admission minimal proteinuria was found.

Physical examination did not reveal any significant signs and symptoms beyond edema.

Urinalysis demonstrated nephrotic range proteinuria (10 g/day) without any abnormalities of the urinary sediment. Total blood count showed hemoglobin 12.5 g/dL, an erythrocyte sedimentation rate of 40 mm/h, hematocrit 54%. The main biochemical data are summarized in Table I.

The biochemical data of the patient with nephrotic syndrome

GFR = glomerular filtration rate (estimated by CKD-EPI formula); FENa+ = fractional excretion of sodium (was calculated by the formula (urine Na+ × serum creatinine/Serum Na+ × urine creatinine) × 100; ratio Uk+/(UNa + UK+) - index of RAAS activation with stimulation of Na+/K+ exchange in the distal nephron.
Serum total protein (g/dL) 4.0
Serum albumin (g/dL) 1.9
Serum cholesterol (mmоl/L) 11.0
Serum creatinine (mg/dL) 0.9
GFR (mL/min) 83
Serum Na+ (mEq/L) 140
Serum K+ (mEq/L) 4,2
Urine Na+ (mEq/L) 10
Urine K+ (mEq/L) 240
Urine creatinine (mg/dL) 640
FENa+ (%) 0,01
Uk+/(UNa+ + UK+) (%) 96%

No monoclonal component was found either in the serum or the urine. Thromboembolic events were not observed. Ultrasonography revealed two normal-sized kidneys and presence of ascites. Chest plain radiography revealed bilateral hydrothorax.

Limitation of the oral sodium intake to 2.5 g daily was recommended. The intravascular volume was corrected by intravenous infusions of 20% albumin (2 mL/min for 1-1.5 hours). Intravenous infusions of furosemide (initial bolus - 60 mg, followed by continuous infusions - 60 mg/h) were started. The restriction of sodium intake and the diuretic strategy resulted in a positive natriuresis with moderate reduction of edema and a body-weight loss of 900-1000 mg/day.

A kidney biopsy was performed and on light microscopy normal glomeruli were found. Immunofluorescent microscopy did not reveal any immune complex deposits. Electron microscopy confirmed the absence of electron-dense deposits and demonstrated hypertrophy and vacuolization of some podocytes and foot process effacement. Based on these findings minimal change disease was diagnosed.

The patient was started with oral prednisone 60 mg/day (1 mg/kg), while the diuretic therapy was discontinued. A urinary output of 3 L/day was observed in a week after the initiation of steroids. Two weeks later remission of NS was achieved. The full dose of prednisone was continued for the next two weeks. After achieving a complete remission, it was tapered slowly over 6 months.

What is edema? What diseases can cause edema?

Edema is defined as an abnormal accumulation of fluid in the interstitial space of the body.

Edema is the reason for visiting the doctor, and for a careful differential diagnosis. Various diseases (renal, cardiac, hepatic, thyroid glands and others) may be causative (summarized in Tab. II).

List of the diseases, presenting with edema

ADH = antidiuretic hormone.
Renal diseases Nephrotic and nephritic syndromes in acute and chronic glomerulonephritis (idiopathic or secondary) and other glomerulopathies; acute and chronic renal failure
Cardiovascular diseases Chronic heart failure as a result of coronary arteries disease, cardiomyopathy, rheumatic and congenital heart valve defects, etc.
Hepatic diseases Hepatic cirrhosis, thrombosis of hepatic veins, etc.
Intestinal diseases Diarrhea, malabsorption in chronic enteritis, Whipple’s disease, intestinal amyloidosis, etc.
Endocrine diseases Hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion, premenstrual syndrome cyclical edema, etc.
Vascular diseases Vein thrombosis, thrombophlebitis, tumor compression, etc.
Diseases of the lymphatic system Lymphostasis as a result of filariasis, nonspecific lymphangitis, metastatic lymphatic vessels, etc.
Allergic diseases Effects of different allergens (food, drug, pollen, cosmetics, etc.)
Idiopathic edema in women Imbalance of sympathetic nervous system trophic function, of estrogen-progesterone system; increased adrenal sensitivity to angiotensin II, and renal tubules sensitivity to aldosterone and ADH
Side effects of mediations Ca+-channel blockers, estrogens, minoxidil, rosiglitazone, corticosteroids; anabolic steroids, etc.

The leading causes of renal edema are nephrotic and nephritic syndromes (Tab. II).

Confirmation of the renal nature of the edema requires a precise diagnosis of the renal disease with an assessment of its clinical and morphological activity. All this information is important for defining the treatment strategy, including the administration of diuretics.

What are the mechanisms of edema in nephrotic syndrome?

Edema is one of the cardinal clinical features of nephrotic syndrome (NS), and may range from localized puffiness to massive anasarca.

The pathophysiological mechanisms of edema formation in NS were discussed over several decades. Abnormal accumulation of interstitial fluid results from the combination of:

abnormal renal sodium retention(primary and secondary)

increased capillary wall permeability(related to the release of vascular permeability factor and other cytokines).

Given the wide spectrum of renal diseases leading to the NS, more than one single mechanism may be responsible for the renal salt retention observed in these diverse conditions (1-2-3-4-5-6).

The “underfill” theory

According to classic theory, also called the “underfill” hypothesis, sodium retention inNS is secondary to hypovolemia. Urinary protein losses lead to the decrease of plasma albumin concentration and lowering of the plasma oncotic pressure resulting in imbalance of the Starling forces (Fig. 1). These events lead to fluid redistribution from the intravascular space towards the interstitial space, causing the decrease in effective arterial blood volume. The plasma volume contraction triggers adaptive neurohumoral responses through activation of the sympathetic nervous system (particularly efferent renal nerves), stimulation of the renin-angiotensin-aldosterone system (RAAS), an increase of antidiuretic hormone (ADH) release, renal sodium and water retention. The decrease in atrial natriuretic peptide (ANP) secretion facilitates salt retention and subsequent edema formation (Fig. 1).

Pathophysiological mechanism of edema formation in nephrotic syndrome.

However, there are many arguments against this theory.

Clinical observations indicate that most of the edematous patients with the different histological forms of NS have either a normal or even expanded intravascular volume, whereas only a minority of nephrotic patients have a depleted intravascular volume (7, 8). So, some patients with early phases of severe NS (usually in rapidly developing relapse of minimal changes disease (9-10-11)) demonstrate a temporary hypovolemia, because the mobilization of interstitial albumin to the blood is not sufficiently fast to prevent it, there is disequilibrium between plasma and extravascular albumin stores. Later, when the albumin redistribution becomes complete, a new equilibrium is established, during which blood volume is maintained.

There is increasing experimental and clinical evidence that hypoalbuminemia cannot explain the development of edema in NS (for reviews see (1, 2)). In particular, it has been shown that young analbuminemic Nagase rats do not develop edema despite low plasma oncotic pressure (12). This phenomenon has also been demonstrated in humans with NS (13, 14).

Furthermore, decrease in plasma oncotic pressure does not affect the volume of the intravascular space in NS (15, 16), and intravenous administration of albumin to induce volume expansion promotes only mild natriuresis (12).

These data suggest that there might have been sodium retention in patients with NS, not mediated by volume depletion.

The “overfill” theory

Unlike the “underfill” hypothesis, the “overfill” concept presumes a primary intrinsic defect of salt and water excretion in the nephrotic kidney (1, 2). This theory postulates that there are also consequences of the proteinuria other than just hypoalbuminemia, which lead to enhanced tubular sodium reabsorption, progressive extracellular fluid volume expansion and edema formation by an overflow mechanism (Fig. 1).

The cellular mechanisms of this primary sodium retention in NS are associated with:

activation of the expression of Na+/H+exchanger3 (NHE3) in the apical membrane of the proximal tubules by the tubular albumin (17-18-19)

proteinuria-induced stimulation of the basolateral Na,K-ATPase pump in the collecting ducts (20-21-22)

activation of the apical epithelial amiloride-sensitive sodium channels (ENa+C) in the collecting ducts induced by urine proteases (plasminogen/plasmin) (2, 23-24-25-26)

tubular resistance to ANP (the result of an increased cyclic guanosine monophosphate (cGMP) phosphodiesterase activity and depletion of cGMP, which is the ANP second messenger) (2, 27-28-29).

Tubulointerstitial inflammation

There is also strong evidence that tubulointerstitial inflammationand glomerulo-interstitial cross-talks are involved in sodium retention and nephrotic edema formation (30). It has been demonstrated that proteinuria induces infiltration of the interstitium by inflammatory cells (T-cells and monocyte/macrophages). Production of vasoactive mediators by these cells (increase of angiotensin II and decrease of nitric oxide) can cause a reduction in glomerular ultrafiltration coefficient and single nephron GFR (30, 31) as well as a decline in sodium filtration with an increase of tubular reabsorption, resulting in primary sodium retention (Fig. 2). Interstitial inflammation in longstanding NS, stimulating tubulointerstitial fibrosis and atubular glomeruli formation, can lead to a more permanent decrease in glomerular filtration rate (GFR) and thus to sodium retention.

The role of tubulointerstitial inflammation in the pathogenesis of nephrotic edema. Adapted from Rodriguez-Iturbe et al (30). Kf = ultrafiltration coefficient, GFR = glomerular filtration rate, AT-II = angiotensin II, NO = nitric oxide.

Vascular permeability

The asymmetric expansion of the interstitial volume in NS is explained by changes in intrinsic properties of the endothelial capillary barriers, including its increased hydraulic conductivity and permeability to proteins, rather than to an imbalance of the Starling forces (2, 32-33-34). Increase of capillary permeability could be related to the release of numerous vascular permeability factors and other cytokines, from immune cells, including histamine, endotoxins, anaphylatoxins, catecholamines, vascular endothelial growth factor, interleukin-1, interleukin-2, and tumor necrosis factor-alpha.

What are the mechanisms of edema in nephritic syndrome?

Acute glomerulonephritis is the prototypical form of nephritic edema (35). Overexpansion of the vascular compartment is responsible for the hemodynamic characteristics of patients with nephritic syndrome (increased effective arterial blood volume, plasma volume, blood pressure, and cardiac output) (36). Hypervolemia and edema in such patients result from primary salt retention and GFR reduction due to glomerulopathy. The glomerular damage leads to urinary protein loss with following increase of tubular albumin reabsorption and urine proteases concentration, which activates renal salt and water retention. The glomerular lesion results in the reduction of Kf, which is driven by the effective capillary wall hydraulic permeability and total capillary surface area per glomerulus (37). At the onset of the disease the GFR remains normal for some period of time. The initially preserved GFR is maintained by the equilibrium between the increased transcapillary hydraulic pressure, which is the driving force for filtration, and the reduced Kf. The progressive GFR deterioration observed in more advanced stages of this disorder is the consequence of the further reduction of Kf. The significant fall of Kf leading to subsequent reduction of GFR results in the decrease of sodium filtration with sodium and water retention.

How can the volume status be assessed in patients with nephrotic syndrome?

Evaluation of the volume status is crucially important for edema management. Table III summarizes the typical clinical and laboratory features for distinguishing nephrotic patients with underfill or overfill physiology. Сlinical characteristics of hypovolemia include low blood pressure, postural hypotension, tachycardia, signs of peripheral vasospasm (pallor, cool extremities), abdominal pain secondary to decreased intestinal perfusion. Diarrhea and vomiting, provoking dehydration and hypovolemia, demand attention from the doctor. By contrast, in hypervolemic NS, high blood pressure without postural hypotension and other signs of volume depletion are found.

Evaluation of the predominant volemic status in patients with nephrotic syndrome

a Not available for routine practice and quick diagnosis.
b Influenced by therapy with diuretic.
GFR = glomerular filtration rate; FENa+ = fractional excretion of sodium.
Underfill Clinical characteristic:
Low normal or low blood pressure, postural hypotension, tachycardia, peripheral vasospasm (pallor, cool extremities), abdominal pain. Diarrhea and vomiting (may provoke dehydration and hypovolemia)
Laboratory features:
Serum albumin level <2 g/dL
Urinary sodium concentration <20 mEq/Lb
High urinary potassium concentrationb
FENa+ <1% (often below 0.2%) (on diet without salt restriction)b
Urinary (K+/K++Na+) >60%
GFR >75% of normal
High hematocrit
Elevated plasma renin, aldosterone, vasopressina
Low atrial natriuretic peptidea
Central venous pressure <5 сm H2O or <2 mmHg
Ultrasonographic determination of inferior vena cava diameter and its change with respiration:
(d<1.5 cm, inferior vena cava collapsibility index >50%)
Overfill Clinical characteristic:
Normal or high blood pressure without tachycardia or orthostatic symptoms and no signs of peripheral vasospasm
Laboratory features:
Serum albumin level >2 g/dL
GFR <50% of normal
FENa+ >1% (on diet without salt restriction)b
Urinary (K+/K++Na+) <60%b
Elevated blood level of urea disproportionate to creatinine
Decreased renin, vasopressina
Low or normal plasma aldosteronea
High atrial natriuretic peptidea
Central venous pressure >12 сm H2O or >8 mmHg
Ultrasonographic determination of inferior vena cava diameter and its respiratory changes:
(d>2.5 cm, inferior vena cava collapsibility index <20%)

Urinary sodium and potassium concentration, fractional excretion of sodium (FENa+) and index of RAAS axis activation may be useful tests for evaluation of renal sodium handling and volume status in nephrotic patients.

FENa+ is the ratio of sodium excreted to that filtered by the renal tubules.

FENa+(%) = (urinary Na+ × serum creatinine/serum Na+ × urinary creatinine) × 100.

A urinary sodium concentration below 20 mEq/L and FENa+ below 1% indicate sodium retaining conditions. The blockade of sodium reabsorbtion by diuretic increases urinary sodium concentration and fractional sodium excretion to a greater or lesser extent (38). Loop diuretics can increase FENa to 30%, thiazides to 5%-10% and potassium sparing diuretics to 2%-3% (39).

Vande Walle and coworkers revealed significant positive correlations between the ratio of urinary concentrations of K+ to the sum of K+ and Na+ [K+(mEq/L)/K+ (mEq/L) + Na+(mEq/L)], reflecting of Na+/K+ exchange in the distal nephron, and increased serum concentrations of renin, aldosterone and ADH, which are observed in hypovolemic children with minimal lesion nephrotic syndrome (8-9-10). The ratio has been offered as an index of activation of RAAS axis. A ratio K+/K++Na+ more than 60% suggests activation of the axis and renal potassium wasting (8-9-10).

Patients with NS and hypovolemia typically show low FENa+ (often below 0.2%) and a high urinary K+/K++Na+ index (greater than 60%) (8, 39-40-41-42-43). Management of edema in such patients demands correction of the intravascular volume with infusion of albumin ore non-protein colloids before initiation of diuretic therapy. Active usage of diuretics without adequate volume correction poses a risk to hypovolemic shock. In hypovolemic patients with relapse of steroid responsive NS treatment with corticosteroids leads to rapid decrease of proteinuria, steroid-induced diuresis within 7-10 days. It may be better to avoid giving furosemide to these patients if possible and wait for the diuretic effects of remission due to corticosteroid treatment.

Patients with edema and clinical and/or laboratory features of hypervolemia (FENa+>1% and urinary K+/K++Na+ index <60%) can safely be treated with diuretics (8, 39-40-41-42-43). Intravascular infusion of albumin and colloids in such patients put them at risk of volume overload and lung edema.

It should be noted that the prior therapy with diuretic may limit the practical utility of these urinary tests for distinguishing patients with underfill or overfill physiology. Therefore, close monitoring of both clinical and laboratory features (Tab. III), are required for evaluation of predominant mechanism of nephrotic edema formation and therapeutic decision.

What are therapeutic strategies for edema management?

Treatment of renal edema is directed to the limitation of further sodium retention, and to the enhancement of the sodium and water excretion, sequestered in the interstitial compartment. Diuretics are fundamental for edema treatment in NS; this type of medication ensures diuresis by inhibiting of sodium reabsorption in the different segments of the renal tubular system (2, 39).

The efficacy of diuretics is determined by site of their action in the nephron. Major proportion of filtered Na+ is reabsorbed in the proximal tubule (55%-60%) and in the loop of Henle (25%-30%); only 5%-7% of filtered sodium is reabsorbed in the distal segments of the renal tubular system. However, in NS the efficacy of diuretics acting in proximal segments is hampered by compensatory increase of sodium and water by distal reabsorption in the ascending limb of Henle’s loop. Therefore, loop diuretics, which can increase FENa+ up to 30%, remain the first choice for edema treatment in patients with NS. Nevertheless, the treatment of edematous patients should be individualized according to their clinical manifestations.

The general principles of edema management are as follows:

Sodium intake restriction to 100 mEq Na+/day should be recommended to all patients with edema (1 mEq Na+ = 23 mg Na+ = 58.3 mg of NaCl)

Strict limiting sodium intake (to 1 mEq/kg/day) is necessary only in subjects with refractory edema

Diuretics are not required for minimal periorbital puffiness or feet edema. Most of such patients demonstrate reduction of edema with moderate restriction of sodium intake

Mild edema in patients with steroid responsive NS resolve under treatment with corticosteroids, which usually leads to steroid-induced diuresis within 7-10 days

Patients with moderate-to-severe edema, beyond sodium restriction, also need treatment with one or more diuretic agents

Evaluation of volume status is necessary for edema management

Albumin infusions with diuretic co-administration should be recommended to subjects with hypovolemia or refractory severe edema.

In the absence of emergency situations, the body-weight reduction under the diuretic treatment should be targeted to 1% of body weight.

Edema is considered refractory if therapy with maximum doses of diuretics results in the daily weight loss less than 1% of body weight.

The algorithm of edema management in patients with NS is shown in Figure 3.

The algorithm for edema management in patients with nephrotic syndrome.

What are the factors affecting response to diuretics?

The efficacy of loop diuretics is restricted by the functional resistance of nephrotic patients to the natriuretic effect of these drugs (2, 39, 44, 45).

Several mechanisms may contribute to diuretic resistance in patients with NS, including:

Decreased gastro-intestinal drug absorption.

(Bowel wall edema impairs absorption of oral medications)

Decreased diuretic entry into the tubular lumen.

(Loop diuretics are highly bound to proteins, and significant hypoalbuminemia results in the reduced free drug secretion into the tubules)

Increased distal sodium reabsorption, so called rebound effect or braking phenomenon.

(With long-term use of loop diuretics sodium, that originates from Henle’s loop to the distal segments, causes hypertrophy of distal nephron cells with concomitant increase of the sodium reabsorption)

Use of non-steroidal anti-inflammatory drugs (NSAIDs)

(Through blocking the synthesis of prostaglandins, NSAIDs can cause vasoconstriction, reduction of renal perfusion and sodium retention. In addition, NSAIDs can competitively inhibit the secretion of diuretic into proximal tubule, preventing their effects).

The binding of furosemide to albumin in the tubular fluid has been demonstrated in the experiment, but has not been confirmed in the human study.

How can we overcome the diuretics resistance?

Effective doses of loop diuretics

The diuretic effect relies on an adequate amount of the drug reaching its site of action in the renal tubules. Primarily, in patients with NS and edema it is necessary to increase the dose of loop diuretics to maximally effective oral dose (furosemide 480 mg/day, torasemide 50 mg/day, bumetanide 6 mg/day). Higher doses of oral diuretics do not exert any additional effect, while the frequency of side effects is greatly increased. Diuretics with a high bioavailability are preferred (50% for furosemide, 80% for torasemide, 90% for bumetanide).

Second, to overcome the sodium reabsorption in the distal tubules after the termination of the loop diuretic’s action, they can be prescribed more than once per day. The daily dose may be divided into two parts, provided that each dose reaches an effective concentration.

Combined diuretic therapy

In patients with NS adding thiazides (hydrochlorothiazide 25-100 mg/day or metolazone 100 mg/day) on top of furosemide markedly increases the natriuresis (46).

First off all, thiazide diuretics have a longer half-life and prevent or reduce the sodium retention after termination of the loop diuretic’s action, prolonging its natriuretic effect.

Second, administration of the thiazide may interfere with the so-called rebound effect, following loop diuretic treatment. Thiazide diuretics block the nephron sites, prone to sodium-induced hypertrophy, accounting for the synergistic response of the combination of thiazide and loop diuretics. In the combined administration, thiazide diuretics have to be prescribed 1 hour before the loop diuretics in order to achieve full blockade of the distal tubules.

Nephrotic patients also demonstrate intensive sodium reabsorption in the connecting and cortical collecting tubules. Thus, co-administration of furosemide and amiloride in patients with NS increases urinary sodium excretion and promotes edema resolution (47). Amiloride inhibits the above-mentioned Na+/H+exchanger in the proximal tubules and ENa+C in the distal tubules. Moreover, amiloride has recently been shown to inhibit the synthesis of the urokinase receptor uPAR. This molecule converts plasminogen to plasmin at the cell surface of distal tubular cells, which subsequently upregulates ENa+C activity, resulting in salt and water retention and edema formation (47, 48).

Spironolactone, the inhibitor of mineralocorticoid receptors in the collecting tubules, is used to counteract aldosterone-mediated sodium reabsorption. The presence of hyperreninemic hyperaldosteronism in patients with NS and hypovolemia is an indication to spironolactone’s administration. Adding spironolactone (2-3 mg/kg/day) to loop diuretics in patients with NS and hypovolemia increases urinary sodium excretion, reduces refractory edema, and prevents hypokalemia.

Intravenous administration of diuretics

Intravenous administration of loop diuretics is preferred in patients with refractory edema, where high doses of oral diuretics are ineffective. The maximal natriuretic response occurs by intravenous furosemide boluses 1-2 mg/kg, or the equivalent doses of bumetanide and torasemide, which should be administered slowly over 10-15 minutes (not exceeding the rate 4 mg/min). However, bolus diuretic therapy may be associated with a higher incidence of diuretic resistance due to prolonged intervals of sub-therapeutic drug concentrations in the kidney.

In patients poorly responding to bolus doses of the loop diuretics, a continuous intravenous infusion can be recommended. After an initial bolus of 1-2 mg/kg, furosemide, continuous infusion should be started with a dose of 0.1 mg/kg/h, which may be increased up to 1 mg/kg/h. Continuous infusions of furosemide result in a more constant delivery of diuretic to the tubules and more substantial natriuresis. Moreover, infusions of diuretics are associated with lower peak plasma concentrations and a lower incidence of side effects.

Albumin infusions

Treatment of edema in severe resistant NS and hypovolemia requires high doses of loop diuretics combined with albumin infusions. Volume repletion in this type of nephrotic patients plays a pivotal role in the management of edema. In order to achieve a temporary increase of intravascular volume and to facilitate binding of the diuretic to albumin, an intravenous infusion of 5% albumin (10-20 mL/kg over 30-60 minutes, infusion rate 5 mL/min) or 20% albumin (1 g/kg over 1-4 h) in combination with maximum doses of furosemide (120 mg) may be performed. The 20% albumin solution increases the vascular volume to 3-4 mL per 1 mL of infused solution. The rate of 20% albumin infusion should not exceed 2-3 mL/min. Usually albumin is administered as an undiluted solution, but it may be diluted with isotonic saline or 5% dextrose to increase the infused volume. Furosemide may be administered as a bolus in the midst or after the end of albumin infusion. To achieve a maximum effect, both medications may be mixed before intravenous administration. Since the effect of albumin infusion is transient the infusion should be repeated for achieving a sustained reduction in edema. On the other hand, infusion of hyperoncotic albumin in nephrotic patients without decrease of intravascular volume may trigger the development of pulmonary edema and congestive heart failure. Therefore, albumin infusions should be restricted to subjects with hypovolemia or refractory severe edema.

Alternative methods of edema management

Excess of fluid in patients with refractory edema and oliguria can be removed by prolonged veno-venous ultrafiltration with highly permeable membranes, or by hemofiltration. These methods are more effective and safe compared to a further increase of the doses of diuretics. If these methods are not available, it is also possible to use intermittent hemodialysis with isolated ultrafiltration.

Head-out water immersion (3-4 h/day) is a quite physiological method for management of patients with massive edema. There is perfect distribution of gravity on the surface surrounding the body in water immersion. Increased venous return due to hydrostatic pressure results in release of ANP, increasing natriuresis and diuresis, with a reduction of edema. However, this procedure is not widely applicable in current renal practice.

Conclusion

Renal edema is associated with renal sodium retention as a result of different pathogenetic mechanisms, including “underfill” and “overfill” pathways.

In a great number of patients with NS, the pathophysiology of edema is not related to hypoalbuminemia, hypovolemia and secondary RAAS activation, but is associated with a primary renal defect in sodium excretion. Proteinuria itself up-regulates the tubular sodium reabsorption through stimulation of NHE3 expression in the apical membrane of the proximal tubules and thick ascending limb cells, induction of Na,K-ATPase synthesis and activation of apical amiloride-sensitive ENa + C in the cortical collecting ducts.

Proteinuria-induced interstitial inflammation in persistent NS is also involved in edema formation. Both a decrease in sodium filtration and increase in sodium reabsorption occur due to production of vasoconstrictive substances in the interstitium, driven by the inflammatory cell infiltrate. Another mechanism of sodium and water retention in NS is associated with markedly blunted diuretic and natriuretic response of medullar collecting ducts to ANP. Finally, increased capillary hydraulic conductivity and hyperpermeability to proteins play an important role in the pathophysiology of nephrotic edema.

In patients with nephritic syndrome, overexpansion of the vascular compartment and edema formation result from primary salt retention and reduction in Kf and GFR.

The understanding of the mechanisms involved in edema formation is important for efficient treatment strategy. Treatment with diuretics for minimal edema is not required, and salt restriction should be recommended to such patients. Mild edema in patients with steroid-responsive NS resolves promptly upon the initiation of corticosteroid therapy. Evaluation of volemic status is necessary for rational diuretic usage. In the majority of patients, edema can be managed adequately with oral administration of an effective dose of loop diuretics. The treatment of patients with refractory edema is more difficult and comprises a strong salt restriction, treatment with intravenous furosemide, additional use of thiazide, amiloride, spironolactone and intravenous albumin. Albumin infusions should be restricted to patients with hypovolemia or refractory severe edema. Infusion of hyperoncotic albumin in nephrotic patients without decrease of intravascular volume may trigger the development of pulmonary edema and congestive heart failure.

Further clarification of sites and cellular mechanisms of primary sodium retention in patients with renal edema should be continued to create new therapeutic options.

Key messages

Assessment of circulatory volume is the key to determining management approaches to reduce edema and avoid common complications in NS - acute kidney insufficiency in patients with “underfill”, or hypertensive and pulmonary complications in patients with “overfill”.

Albumin infusions with diuretics co-administration should be recommended to patients with hypovolemia or refractory severe edema.

Mild edema in patients with steroid-responsive NS resolves promptly following therapy with corticosteroids.

Edema in patients with NS and hypervolemia can safely be treated with diuretics.

Disclosures

Financial support: No grants or funding have been received for this study.
Conflict of interest: None of the authors has any financial interest related to this study to disclose.
References
  • 1. Rondon-Berrios H [New insights into the pathophysiology of oedema in nephrotic syndrome]. Nefrologia 2011 31 2 148 154 Google Scholar
  • 2. Doucet A Favre G Deschênes G Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications. Pediatr Nephrol 2007 22 12 1983 1990 Google Scholar
  • 3. Siddall EC Radhakrishnan J The pathophysiology of edema formation in the nephrotic syndrome. Kidney Int 2012 82 6 635 642 Google Scholar
  • 4. Bockenhauer D Over- or underfill: not all nephrotic states are created equal. Pediatr Nephrol 2013 28 8 1153 1156 Google Scholar
  • 5. Hamm LL Batuman V Edema in the nephrotic syndrome: new aspect of an old enigma. J Am Soc Nephrol 2003 14 12 3288 3289 Google Scholar
  • 6. Schrier RW Fassett RG A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Kidney Int 1998 53 5 1111 1117 Google Scholar
  • 7. Geers AB Koomans HA Boer P Dorhout Mees EJ Plasma and blood volumes in patients with the nephrotic syndrome. Nephron 1984 38 3 170 173 Google Scholar
  • 8. Vande Walle JGJ Donckerwolcke RA Koomans HA Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease. J Am Soc Nephrol 1999 10 2 323 331 Google Scholar
  • 9. Vande Walle JG Donckerwolcke RA van Isselt JW Derkx FHM Joles JA Koomans HA Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms. Lancet 1995 346 8968 148 152 Google Scholar
  • 10. Van de Walle JGJ Donckerwolcke RAMG Greidanus TB Joles JA Koomans HA Renal sodium handling in children with nephrotic relapse: relation to hypovolaemic symptoms. Nephrol Dial Transplant 1996 11 11 2202 2208 Google Scholar
  • 11. Vande Walle J Donckerwolcke R Boer P van Isselt HW Koomans HA Joles JA Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome. Kidney Int 1996 49 5 1471 1477 Google Scholar
  • 12. Joles JA Willekes-Koolschijn N Braam B Kortlandt W Koomans HA Dorhout Mees EJ Colloid osmotic pressure in young analbuminemic rats. Am J Physiol 1989 257 1 Pt 2 F23 F28 Google Scholar
  • 13. Lecomte J Juchmès J [So-called absence of edema in analbuminemia]. Rev Med Liege 1978 33 21 766 770 Google Scholar
  • 14. Koomans HA Geers AB vd Meiracker AH Roos JC, Boer P, Dorhout Mees EJ. Effects of plasma volume expansion on renal salt handling in patients with the nephritic syndrome. Am J Nephrol 1984 4 4 227 234 Google Scholar
  • 15. Manning RD Jr Guyton AC Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J Physiol 1983 245 2 H284 293 Google Scholar
  • 16. Camici M Molecular pathogenetic mechanisms of nephrotic edema: progress in understanding. Biomed Pharmacother 2005 59 5 215 23 Google Scholar
  • 17. Besse-Eschmann V Klisic J Nief V Le Hir M Kaissling B Ambuhl P Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN) induced nephrotic syndrome. J Am Soc Nephrol 2002 13 9 2199 2206 Google Scholar
  • 18. Klisic J Zhang J Nief V Reyes L Moe OW Ambuhl PM Albumin regulates the Na+/H+ exhanger in OKP cells. J Am Soc Nephrol 2003 14 12 3008 3016 Google Scholar
  • 19. Deschenes G Feraille E Doucet A Mechanisms of oedema in nephrotic syndrome: Old theories and new ideas. Nephrol Dial Transplant 2003 183 454 456 Google Scholar
  • 20. Deschenes G Doucet A Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes. J Am Soc Nephrol 2000 11 4 604 615 Google Scholar
  • 21. Feraille E Vogt B Rousselot M et al Mechanism of enhanced Na-K-ATPase activity in cortical collecting duct from rats with nephrotic syndrome. J Clin Invest 1993 91 1295 1300 Google Scholar
  • 22. Vogt B Favre H Na+,K+-ATPase activity and hormones in single nephron segments from nephrotic rats. Clin Sci 1991 80 599 604 Google Scholar
  • 23. De Santo NG Pollastro RM Saviano C et al. Nephrotic edema. Semin Nephrol 2001 21 3 262 268 Google Scholar
  • 24. De Seigneux S Kim SW Hemmingsen SC et al. Increased expression but not targeting of ENaC in adrenalectomized rats with PAN-induced nephrotic syndrome. Am J Physiol Renal Physiol 2006 291 F208 217 Google Scholar
  • 25. Kim SW de Seigneux S Sassen MC et al Increased apical targeting of renal ENaC subunits and decreased xpression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 2006 290 F674 F687 Google Scholar
  • 26. Svenningsen P Bistrup C Friis UG et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol 2009 20 299 310 Google Scholar
  • 27. Plum J Mirzaian Y Grabensee B Atrial natriuretic peptide, sodium retention, and proteinuria in nephritic syndrome. Nephrol Dial Transplant 1996 11 1034 1042 Google Scholar
  • 28. Perico N Delaini F Lupini C et al Blunted excretory response to atrial natriuretic peptide in experimental nephrosis. Kidney Intern 1989 36 57 64 Google Scholar
  • 29. Valentin JP Ying WZ Sechi LA et al. Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann nephritis. J Am Soc Nephrol 1996 7 582 593 Google Scholar
  • 30. Rodriguez-Iturbe B Herrera-Acosta J Johnson RJ Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: A unifying hypothesis. Kidney Intern 2002 62 1379 1384 Google Scholar
  • 31. Franco M Tapia E Santamarıa J et al. Renal cortical vasoconstriction contributes to the development of salt-sensitive hypertension after Angiotensin II exposure. J Am Soc Nephrol 2001 12 2263 2271 Google Scholar
  • 32. Rostoker G Behar A Lagrue G Vascular hyperpermeability in nephrotic dema. Nephron 2000 85 3 194 200 Google Scholar
  • 33. Brenchley PE Vascular permeability factors in steroid-sensitive nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant 2003 18 6 21 25 Google Scholar
  • 34. He P Curry FE Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]. Am J Physiol 1993 265 H74 H82 Google Scholar
  • 35. Vinen CS Oliveira DBG Acute glomerulonephritis. Postgrad Med J 2003 79 206 213 Google Scholar
  • 36. Kurtzman NA Nephritic edema. Seminars in Nephrology 2001 21 3 257 261 Google Scholar
  • 37. Maddox DA Bennett CM Deen WM et al Determinants of glomerular filtration in experimental glomerulonephritis in the rat. J Clin Invest 1975 55 305 318 Google Scholar
  • 38. Bohlin AB Berg U Renal sodium handling in minimal change nephrotic syndrome. Arch Dis Child 1984 59 825 83 Google Scholar
  • 39. Vasudevan A Mantan M Bagga A Bagga A Management of edema in nephrotic syndrome. Indian Pediatr 2004 41 787 795 Google Scholar
  • 40. Donckerwolcke RAMG France A Raes A Vande Walle J Distal nephron sodium-potassium exchange in children with nephrotic syndrome. Clin ephrol 2003 59 259 266 Google Scholar
  • 41. Iyengar AA Kamath N Vasudevan A Phadke KD Urinary indices during relapse of childhood nephrotic syndrome. Indian J Nephrol 2011 21 172 176 41. Google Scholar
  • 42. Matsumoto H Miyaoka Y Okada T et al Ratio of urinary potassium to urinary sodium and the potassium and edema status in nephrotic syndrome. Intern Med 2011 50 551 555 Google Scholar
  • 43. Vande Walle J Donckerwolcke R Pathogenesis of edema formation in the nephrotic syndrome. Pediatr Nephrol 2001 16 283 293 Google Scholar
  • 44. Brater DC Resistance to loop diuretics: Why it happens and what to do about it. Drugs 1985 35 27 43 Google Scholar
  • 45. Loon NR Wilcox CS Unwin RJ Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 1989 36 682 689 Google Scholar
  • 46. Oster JR Epstein M Smoller S Combined therapy with thiazide type and loop diuretic agents for resistant sodium retention. Ann Intern Med 1983 99 405 406 Google Scholar
  • 47. Deschenes G Wittner M Stefano A Jounier S Doucet A Collecting duct is a site of sodium retention in PAN nephrosis: a rationale for amiloride therapy. J Am Soc Nephrol 2001 12 598 601 Google Scholar
  • 48. Warnock D Kusche-Virog K Tarjus A et al. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells. Nat Rev Nephrol 2014 10 146 157 Google Scholar

Authors

Affiliations

  • Nephrology Department of Research Center, I.M. Sechenov First Moscow State Medical University, Moscow - Russia
  • Department of Nephrology and Dialysis of Professional Education Institute, I.M. Sechenov First Moscow State Medical University, Moscow - Russia
  • Department of Internal, Occupational Diseases and Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow - Russia

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