An overview OF NEPHROTIC SYNDROME BY AMIR EL OKELY MRCP, MD

Clinical definition of adult NS

Definition of NS in children

Pathphysiology

How many pathological types causes nephrotic syndrome?

Proteinuria Proteinuria can be caused by systemic overproduction, tubular dysfunction, or glomerular dysfunction. Glomerular proteinuria is responsible for protein loss in nephrotic syndrome Albumin is the principal urinary protein but other plasma proteins including clotting inhibitors, transferrin and hormone carrying proteins such as vitamin-D binding protein.

Mechanisms of proteinuria

Hypoalbuminemia Hypoalbuminemia is a consequences of the proteinuria. It is also due to the catabolism of filtered albumin by the proximal tubule as well as to redistribution of albumin within the body. This in part accounts for the inexact relationship between urinary protein loss, the level of the serum albumin, and other secondary consequences of heavy albuminuria.

Edema The salt and volume retention in the NS may occur through at least two different major mechanisms. In the classic theory, proteinuria leads to hypoalbuminemia, a low plasma oncotic pressure, and intravascular volume depletion. Subequent underperfusion of the kidney stimulates the priming of sodium-retentive hormonal systems such as the RAS axis, causing increased renal sodium and volume retention, In the peripheral capillaries with normal hydrostatic pressures and decreased oncotic pressure, the Starling forces lead to transcapillary fluid leakage and edema.

Edema {cont} In some patients, however, the intravascular volume has been measured and found to be increased along with suppression of the RAS axis. An animal model of unilateral proteinuria shows evidence of primary renal sodium retention at a distal nephron site, perhaps due to altered responsiveness to hormones such as atrial natriuretic factor. Thus, local factors within the kidney may account for the volume retention of the nephrotic patient as well.

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Hyperlipidemia Most nephrotic patients have elevated levels of total and low-density lipoprotein (LDL) cholesterol with low or normal high-density lipoprotein (HDL) cholesterol. Lipoprotein (a) [Lp(a)] levels are elevated as well and return to normal with remission of the nephrotic syndrome. Hypertriglyceridemia usually result from impaired metabolism rather than enhanced synthesis.

Histological pattern and feature of primary NS

Common secondary causes of NS

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Classification by the response to treatment of NS

Examination findings of primary NS

Examination findings of secondary NS

Complications It leads to a multitude of other consequences, such as predisposition to infection and hypercoagulability. In general, the diseases associated with NS cause chronic kidney dysfunction, but rarely they can cause ARF. ARF may be seen with minimal change disease, and bilateral renal vein thrombosis.

Protein malnutrition A loss in lean body mass with negative nitrogen balance often occurs in patients with marked proteinuria, although it may be masked by increasing edema Gastrointestinal symptoms of anorexia and vomiting may also contribute to malnutrition

Hypovolemia Symptomatic hypovolemia can occur in nephrotic patients, as a result of over diuresis in those with serum albumin less than 1.5 g/dl. Severe hypoalbuminemia cause fluid movement into the interstitum and hypovolemia.

Acute kidney injury AKI can develop in some patients with nephrotic syndrome, particularly minimal change disease Aki may also occur in patients with collapsing focal glomerulosclerosis associated with HIV. AKI may occur in some patients treated with NSAIDs and in membranous nephropathy with superimposition of crescentic GN

Acute kidney injury {cont} Patients with MCD who develop AKI tend to have more proteinuria, hypoalbuminemia, high BP and much older than stable patients. Different mechanisms may be responsible for AKI as: - Reduced glomerular pearmeability. - Ischemic tubular injury. - interstitial edema and diuretic therapy. - NSAID, contrast nephropathy and traditional medicines may also involved.

Infection Patients with nephrotic syndrome are susceptible to infection due to: - Reduced serum concentration of immunoglobulins. - Impaired ability to make specific antibodies. - Decreased level of the alternative complement pathway factor B and D. - Immunosuppressive therapy.

Infection {cont} The frequency and type of infection was evaluated in Indian study of 60 children with nephrotic syndrome without steroid therapy. There were 57 episodes of infection, which include: - Upper resp infection - 16 episode - UTI – 13 episodes - Peritonitis – 9 episodes - Pneumonia – 8 episodes - Severe acute gastroenteritis – 6 episodes - Empyema – 3 episodes

Endocrine dysfunction in nephrotic syndrome Thyroid function tests Urinary loss of albumin and hormone binding-proteins are responsible for many of the metabolic derangements and endocrine abnormalities in these patients. A decrease in TBG can cause marked changes in various thyroid function tests, although patients are clinically euthyroid. When renal failure complicates the nephrotic syndrome, the thyroid function abnormalities are often more severe.{TSH} Steroids can cause small reduction in TSH secretion inhibit peripheral conversion of T4 to T3.{FT4}

Endocrine dysfunction in nephrotic syndrome {Cont} Vitamin D and calcium metabolism Nephrotic syndrome is associated with urinary loss of VDBP and calcidiol which is the precursor of the most active metabolite calcitriol. Hypocalcemia is a common finding in nephrotic syndrome. Only a subset of patients with nephrotic syndrome develop clinically important abnormalities in vitamin D, calcium, and bone metabolism. Suggested predisposing factor include increasing age, prolonged duration of disease, renal insufficiency, marked proteinuria and steroid therapy.

Endocrine dysfunction in nephrotic syndrome {Cont} Anemia Despite normal renal function, anemia may develop in patients with nephrotic syndrome due to decrease EPO synthesis and proteinuria. Such patients appear to respond to EPO therapy.

Endocrine dysfunction in nephrotic syndrome {Cont} Glucocorticoid metabolism Cortisol-binding globulin lost in urine of nephrotic patients, and serum cortisol concentration may be reduced. Percentage of unbound cortisol is increased, serum free cortisol are normal and symptomatic hypocortisolism does not occur.

Renal vein thrombosis Epidemiology Etiology diagnosis management

Patients with the nephrotic syndrome are at increased risk of developing venous and arterial thrombosis, particularly RVT The mechanism of thromboembolism in nephrotic syndrome and optimal diagnostic and anticoagulant management strategies remain controversial

A retrospective study involving 298 patients with mean follow up of 10 years showed annual incidences of VTE and ATE of 1.02% and 1.48% respectively { 8 times general population } Risks of both VTE and ATE were particularly high within the first 6 months of NS (annual incidences 9.85% and 5.52% respectively) Mahmoodi et. Al Circulation Jan 15;117(2):224-30

Clinical features RVT may be unilateral or bilateral and may extend into the inferior vena cava RVT most often has an insidious onset and produces no symptoms referable to the kidney

Acute RVT is usually due to trauma, severe dehydration or a generalized hypercoagulable state It typically presents with symptoms of renal infarction, including flank pain, microscopic or gross hematuria, a marked elevation in serum lactate dehydrogenase, and an increase in renal size on radiographic study Bilateral RVT may present with acute renal failure

Increased platelet aggregation Thrombocytosis, decreased red blood cell deformability, and increased von Willebrand factor levels in NS favor platelet transport towards the vessel wall and increase platelet adhesion Hypoalbuminemia results in increased availability of normally albumin-bound arachidonic acid, leading to increased formation of thromboxane A2 in platelets, a stimulus for platelet aggregation Elevated levels of LDL cholesterol may increase platelet aggregation

Activation of the coagulation system Patients with nephrotic syndrome demonstrate urinary loss of plasma proteins that include factors IX, X, and XII, prothrombin, antithrombin, and α2- antiplasmin In contrast, proteins of higher molecular weight, including factor V, factor VIII, von Willebrand factor, fibrinogen, and α2-macroglobulin accumulate, presumably because of increased synthesis

Factor VIII levels are typically increased as much as 2- to 3-fold compared to controls and increased factor VIII may be a risk factor for venous thromboembolism There is an inverse correlation between serum albumin and fibrinogen levels in nephrotic syndrome Hyperfibrinogenemia may contribute to the procoagulant state by providing more substrate for fibrin formation and by promoting platelet hyperaggregability, increased blood viscosity, and red blood cell aggregation

Decreased endogenous anticoagulants Antithrombin deficiency occurs in 40% to 80% of patients with NS Plasma levels of antithrombin correlate negatively with proteinuria and positively with serum albumin level, presumably due to urinary loss of this factor The association between antithrombin deficiency and venous thromboemolism is inconsistent among different studies

Additional factors predisposing to thromboembolism in NS Intravascular volume depletion and exposure to steroids Loss of fluid across the glomerulus causing hemoconcentration in the postglomerular circulation which is worsened by diuretic therapy Clotting activation and thrombin formation might occur in the diseased kidney The nature of immunologic injury itself

Screening Routine screening for RVT is not recommended in patients with nephrotic syndrome  No proven benefit to diagnosing occult disease  A patient with a negative study may develop RVT at a later time

It is also not useful to evaluate for RVT in a patient who experiences an overt embolic event such as PE  It cannot be proven that the pulmonary embolus originated in the renal veins  In situ pulmonary thrombosis may occur  Patients will be treated with anticoagulants whether or not RVT is present

Diagnosis Estimated sensitivity and specificity of CT with contrast was 92.3% and 100%, respectively Only a small number of studies have evaluated the value of MRI with or without contrast enhancement in the identification of RVT Only one study has prospectively evaluated Doppler ultrasonography in the diagnosis of RVT and found it to be 85% sensitive and 56% specific Intravenous pyelography was found to have a sensitivity of 34.1% and a specificity of 87.2% Selective renal venography is the reference standard diagnostic test for RVT

Treatment The risks associated with asymptomatic RVT have not been compared to the risks of long term anticoagulation therefore prophylactic anticoagulation is not recommended There are no definitive studies that have evaluated the role of anticoagulation in patients with an asymptomatic RVT, but case series report treating such patients

Treatment (cont) Patients with a symptomatic RVT or a thromboembolic event in the absence of RVT are treated with low molecular weight heparin and then warfarin Some patients are partially resistant to heparin therapy due to severe antithrombin deficiency Warfarin therapy is given for a minimum of 6 to 12 months and some people recommend continuing treatment for as long as the patient remains nephrotic Local thrombolytic therapy with or without thrombectomy in patients who have signs of acute RVT has been successfully performed in small numbers of patients

Can renal vein thrombosis cause the nephrotic syndrome?

Animal studies in which main renal vein occlusion was produced experimentally, have failed to demonstrate the development of heavy proteinuria unless the contralateral normal kidney is removed RVT in the absence of nephrotic syndrome has been reported in the literature Nephrotic patients with RVT who have undergone histologic evaluation show evidence of an identifiable glomerulopathy

In a case report of a patient with unilateral RVT and nephrotic syndrome due to membranous nephropathy, bilateral ureteral catheterization studies showed no difference in protein excretion or creatinine clearance between the two kidneys In retrospective studies, the sequence of nephrotic syndrome leading to renal vein thrombosis was clearly established However bilateral RVT has been reported to cause nephrotic syndrome

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