Management of patients with nephrotic syndrome

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					Review article                                                         S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 2 9 – 3 0 ) : 4 1 6 – 4 2 2 · w w w . s m w . c h   416
Peer reviewed article

                        Management of patients with nephrotic
                        Sophie de Seigneux, Pierre-Yves Martin
                        Service de Néphrologie, Département de Médecine Interne, HUG, Switzerland

                            Nephrotic syndrome is characterised by pro-                   Urinary protein loss leads to several compli-
                        teinuria >3.5 g/24h, oedema, hypoalbuminaemia                 cations: water and sodium retention, hyperlipid-
                        and hyperlipidaemia.                                          aemia, increased risk of thromboembolism and
                            Several glomerular diseases, either primary or            infection, anaemia and alteration of mineral me-
                        secondary, may lead to nephrotic syndrome. In-                tabolism. Each of these complications must be
                        vestigations for nephrotic syndrome include im-               identified and their treatment is discussed in this
                        munological and infectious evaluations. Renal                 review.
                        biopsy is often mandatory, except in diabetes. De-
                        pending on aetiology specific treatment, often                     Key words: nephrotic syndrome; proteinuria; kid-
                        with immunosuppressive agents, may be imple-                  ney; oedema; hypertension
                        mented. In any cases nonspecific treatment
                        should be started with ACE inhibitors or ARBs.

                        Introduction and definition
                            Nephrotic syndrome is defined by the associ-              The aetiological causes of nephrotic syndrome
                        ation of a proteinuria higher than 3.5 g/24 hours,            are however miscellaneous, ranging from primary
                        hypoalbuminaemia, oedema and dyslipidaemia.                   renal diseases to systemic illnesses with various
                            The prevalence of this syndrome is high,                  histopathological presentations (tables 1 and 2).
                        mainly due to its frequency in diabetic patients.                 The renal disease revealed by nephrotic syn-
                                                                                      drome must be precisely characterised, since al-
Table 1                 Primary glomerular diseases (frequent; rare)
                                                                                      though many therapeutic strategies are common
Primary glomerular
                                                                                      to all nephrotic patients, specific treatments exist
                        Membranous glomerulopathy
diseases associated                                                                   and must be evaluated in each case.
with nephrotic          Focal and segmental glomerulosclerosis                            Independently of the underlying disease, uri-
                        Minimal change disease (MCD) glomerulopathy                   nary protein loss may lead to several complica-
                        IgA nephropathy                                               tions due either to the toxicity of proteinuria on
                        Membranopoliferative glomerulonephritis                       the kidney, or to plasma depletion of specific pro-
                        C1q glomerulopathy
                                                                                      teins. The purpose of this review is to make rec-
                                                                                      ommendations for the evaluation of the nephrotic
                        Fibrillar glomerulopathy
                                                                                      syndrome and the implementation of nonspecific
                        Congenital podocyte anomaly
                                                                                      treatment for nephrotic patients.

                        Aetiology and investigations
                            Nephrotic proteinuria, mainly albuminuria,                of these elements, resulting in leakage of albumin
                        involves a glomerular lesion since tubular lesions            from the vascular to the tubular compartment.
                        alone will not result in heavy albuminuria. In-                   Nephrotic syndrome may result from either
                        creased glomerular permeability may occur when                primary glomerular or systemic disease leading to
 No conflict            a lesion is present, either in the endothelium,               renal insult (tables 1 and 2). Aetiologies of
 of interest.
                        podocytes, basement membrane or a combination                 nephrotic syndrome vary depending on the pa-
                                                                                     S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 2 9 – 3 0 ) : 4 1 6 – 4 2 2 · w w w . s m w . ch   417

Table 2
                        Medications (non exhaustive)                                                     Allergens, immunisations
Causes of secondary     NSAIDs, pamidronate, rifampicin, IFN alpha, gold, lithium,                       Pollens, seric illness, vaccines, bee sting
nephrotic syndrome
                        interferon alpha
(most frequent).
                        Infections                                                                       Systemic illnesses (most frequent)
                        Bacterial: Endocarditis, syphilis, tuberculosis, mycoplasma infections           Systemic lupus erythematosus (SLE),
                        Viral: HIV, HBV, HCV, EBV, CMV, VZV                                              Rheumatoid polyarthritis,
                        Protozoal: Toxoplasmosis, malaria                                                Schonlein-Henoch purpura
                        Helminthic: Schisostomiasis, trypanosomiasis, filariasis                         MGUS, amyloidosis
                        Neoplasia                                                                        Metabolic diseases and heredofamilial (non exhaustive)
                        Solid tumours                                                                    Type I and II diabetes
                        Haemo- or lymphopathies                                                          Hypothyroidism
                        Multiple myeloma                                                                 Alport syndrome
                        GVHD post marrow transplantation                                                 Graves disease
                                                                                                         Fabry disease
                        Miscellanous (examples)
                        Chronic allograft failure
                        Nephronic reduction
                        Renal artery stenosis
                        Heart failure (right/left) and pericarditis

                        tient’s age. Among secondary causes, type I or II                           phonates, NSAIDs, heavy metals etc). Nephrotic
                        diabetes remain the most frequent aetiology in                              syndrome patients require a thorough workup
                        adults, although approximately 10% of nephrotic                             and our recommended initial evaluation of
                        syndrome cases in diabetes are due to other renal                           nephrotic patients is summarised in table 3. Eval-
                        diseases. Other systemic diseases, such as systemic                         uation of proteinuria can be done by 24-hour col-
                        lupus erythematosus (SLE), amyloidosis, hepatitis                           lections initially and then followed by iterative
                        B and C, HIV, neoplasms or haematologic dis-                                measurement of the protein-on-creatinine ratio.
                        eases may also be associated with glomerular dis-                           This ratio relies on the fact that adults excrete on
                        orders causing nephrotic syndrome. Finally, drugs                           average 1 g creatinine per day. It can safely be
                        or toxic substances must be considered (bisphos-                            used to monitor the evolution of proteinuria and
                                                                                                    is a good renal prognosis factor [1].
Table 3                 Complete medical       Blood tests                                                Renal biopsy plays a major role in the evalua-
Initial evaluation of                          Blood count, electrolytes ( CRP, Na, K,              tion of nephrotic patients, since several histologi-
nephrotic patients                             BUN, creatinine, albumin, serum proteins,
(except diabetes).                                                                                  cal lesions are associated with nephrotic syn-
                                               calcium, phosphate, bicarbonates,
                                               chloride) Urinary spot and sediment                  drome. Diabetic glomerulosclerosis, membranous
                                                                                                    glomerulopathy, focal segmental glomeruloscle-
                                               24-hour proteinuria and/or protein/
                                               creatinine ratio                                     rosis and minimal change glomerulopathy are the
                                                                                                    most common in adults. The three latter may be
                                               Serum and urinary electrophoresis
                                               and immuno-electrophoresis                           either primary or a component of a systemic dis-
                                               Lipid profile
                                                                                                    ease. The sharing and variability of clinical mani-
                                                                                                    festations among these different glomerular dis-
                                               Liver tests
                                                                                                    eases do not allow accurate diagnosis based on
                                               HBV, HCV, HIV serology                               clinical and laboratory features alone. Renal
                                               Immunological profile ( ANA, RF)                     biopsy is therefore mandatory for every nephrotic
                                               glycaemia                                            patient except the diabetic patient, in order to de-
                                               TSH                                                  fine the disorder accurately and optimise treat-
                                               Coagulation tests
                                                                                                    ment. In diabetic patients atypical features such as
                                                                                                    a rapidly progressive nephrotic syndrome or acute
                        Complete physical      Additional tests
                                                                                                    renal failure, presence of glomerular haematuria
                                               Renal duplex echography
                                                                                                    and/or absence of associated microvascular le-
                                               ECG et chest x-ray                                   sions (retinopathy, neuropathy) are indications for
                                               Renal biopsy                                         renal biopsy.

                             Vital prognosis is mainly influenced by the                                 Renal prognosis is dependent on non-modifi-
                        disorder causing nephrotic syndrome. However,                               able variables such as the cause of nephrotic syn-
                        nephrotic proteinuria confers per se a higher car-                          drome, renal function and age at presentation, as
                        diovascular risk, and nephrotic patients are at risk                        well as the extent of renal interstitial lesions on
                        of several systemic complications to be detailed                            the biopsy. Prognostic factors are not similar for
                        later.                                                                      all nephrotic syndromes. A well studied example is
Management of patients with nephrotic syndrome                                                                                   418

                       membranous nephropathy, where the best param-            complete elimination of proteinuria results in
                       eters for predicting the evolution of renal func-        renal function preservation, in diabetic or non-di-
                       tion are creatinine clearance at diagnosis, the ex-      abetic patients [4].The magnitude of proteinuria
                       tent of proteinuria (< or >4 g/day) and the slope of     and its correction is therefore a major modifiable
                       creatinine clearance over a six months’ observa-         risk factor for progression to end-stage renal fail-
                       tion period. Partial or complete remission of pro-       ure. The main therapeutic goal in nephrotic pa-
                       teinuria at six months accurately predicts the risk      tients is to reduce proteinuria to the lowest possi-
                       of progression in this disease [2, 3]. Several stud-     ble level.
                       ies have also demonstrated that either partial or

                       Specific treatments
                            In diabetes, metabolic control is the mainstay      three diseases. Immunosuppressive or im-
                       of treatment. In other secondary causes of               munomodulatory drugs are therefore the main-
                       nephrotic syndrome specific treatment varies de-         stay of treatment, therapeutic strategies depend-
                       pending on the causative illness, e.g. curative or       ing on the clinical and histological features. The
                       palliative treatment of a neoplastic disease, antivi-    decision to treat and how to treat the patients can-
                       ral treatment of hepatitis or immunosuppressive          not be detailed here and many options are possi-
                       therapy of a systemic disease.                           ble. Several regimens which generally include cor-
                            Among primary renal diseases the most fre-          ticosteroids have been studied and are not detailed
                       quently encountered are membranous glomeru-              here. However, irrespective of these specific treat-
                       lopathy, focal segmental glomerulosclerosis and          ments, nonspecific protective therapies must be
                       minimal change glomerulopathy. An underlying             implemented in patients with nephrotic syn-
                       immunological disorder is suspected in these             drome.

                       Nonspecific treatments of proteinuria
                            These treatments are therefore either comple-       of glomerular lesions leading to proteinuria. RAA
                       mentary to a specific treatment or the sole therapy      system blockade has been shown to be successful in
                       available to lower proteinuria. In contrast to spe-      reducing proteinuria in both animal and human
                       cific treatment, complete remission of proteinuria       studies.ACE inhibitors and ARBs are therefore rec-
                       cannot be expected with these treatments. A rea-         ommended as first line treatment in proteinuric
                       sonable goal is to aim at a 50% reduction in pro-        diseases, even in the absence of hypertension.Their
                       teinuria, or, even better, at proteinuria below          antiproteinuric effect relies on the decrease in
                       1g/day, which seems to be a critical threshold for       glomerular pressure due to their preferential va-
                       long term renal survival.                                sodilatory effect on the glomerular efferent arteri-
                                                                                ola, rather than on their antihypertensive effect per
                       Antihypertensive treatment                               se. There is also experimental evidence of a direct
                            Tight blood pressure control is critical to renal   protective effect of these drugs on the glomerular
                       function preservation in all cases of proteinuric re-    filtration barrier [6].
                       nal diseases, aiming at upper systolic and diastolic          Both drugs have exhibited their nephroprotec-
                       values of 125 and 75 mm Hg respectively. It should       tive action in either type I (ACE inhibitors) or type
                       also be mentioned that low blood pressure likewise       II (ARB) diabetes or in the nondiabetic population
                       appears to be detrimental and lowering blood pres-       [6–9].This favourable effect on renal survival is well
                       sure below 110 mm Hg systolic should be avoided          correlated to the extent of proteinuria reduction
                       [5].All classes of antihypertensive drugs can be used    [7].
                       to meet these targets, and a combination of 2–4 dif-          Introduction of ACE inhibitors or ARBs may
                       ferent drugs is often necessary. 24-hour ambulatory      be risky in nephrotic patients, in particular when re-
                       blood pressure measurement is often needed to as-        nal dysfunction is present. Plasma creatinine often
                       sess optimal control and optimise treatment. Asso-       rises after treatment initiation and a 30% increase
                       ciation of a low salt diet (6 g/day) is mandatory to     should be tolerated. If plasma creatinine rises more
                       optimise the action of antihypertensive drugs.           than 30% transient interruption of the treatment is
                                                                                recommended and a search for a precipitating con-
                        Angiotensin conversion enzyme (ACE)                     dition such as renal artery stenosis or relative hy-
                        inhibitors and angiotensin type 1 receptor              povolaemia (diuretics, severe hypoalbuminaemia
                        antagonists (ARBs)                                      <20 g/L) should be conducted. It should be borne
                            Stimulation of the renin-angiotensin-               in mind that proteinuria per se stimulates tubular
                        aldosterone (RAA) system is critical to the genesis     creatinine secretion and therefore induces overes-
                                              S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 2 9 – 3 0 ) : 4 1 6 – 4 2 2 · w w w . s m w . ch   419

timation of renal function. Proteinuria correction           secondary to a systemic or primary glomerular dis-
will therefore decrease this secretion and increase          ease, the therapeutic strategy may differ, a recent
plasma creatinine levels without actually altering           meta-analysis having shown that dual RAA block-
renal function.                                              ade was safe and had an additional antiproteinuric
     Hyperkalaemia may also be a limiting factor.            effect despite a tendency to increase plasma potas-
Plasma potassium up to 5.5 mmol/L is tolerated.              sium levels [11]. The dual blockade can therefore
Above this level, ACE inhibitors or ARB should               be recommended if proteinuria persists despite a
be decreased in dosage or even stopped. Impor-               maximum dose of either ACE inhibitors or ARB,
tantly, concomitant medications, such as beta                conditional on careful renal and electrolyte moni-
blockers, spironolactone, potassium sparing di-              toring.
uretics and cyclosporine may potentiate a rise in
plasma potassium level.                                      Diuretics
     When starting a patient on ACE inhibitors or                 Diuretics are an integral part of the treatment
ARBs, serum creatinine and potassium levels must             of nephrotic syndrome, given the presence of
be checked with a second blood test within five              oedema. In addition to their effect on oedema, dis-
days after the start of the treatment and after each         cussed later in more detail, diuretics are also criti-
dose modification. Once stable, monthly blood                cal for blood pressure control, potentiating the ef-
testing is recommended in nephrotic patients.                fect of either ACE inhibitors or ARBs. This syner-
     Finally, if clinical and biological tolerance of        gistic effect is also observed on proteinuria reduc-
the medication is good, dosage should be in-                 tion.
creased to the maximum recommended level to
maximise the antiproteinuric effect. Small studies           Aldosterone antagonists
have demonstrated that supramaximal doses of                     Spironolactone is a mineralocorticoid receptor
ARBs (e.g. irbesartan 900 mg) could further re-              antagonist which possesses a diuretic effect, partic-
duce proteinuria. We recommend however tar-                  ularly in cases or primary or secondary stimulation
geting only maximum doses, except in very lim-               of the RAA system. It also has potential antipro-
ited situations.                                             teinuric effects, small studies having demonstrated
     In the event of persistent heavy proteinuria            that addition of spironolactone to either ACE in-
despite maximal doses of either one treatment                hibitors, ARBs or both in nondiabetic proteinuric
(ACE inhibitors or ARBs), dual blockade of the               patients may have an additive effect on proteinuria
RAA system may be useful.                                    reduction. In diabetic patients similar results are
     Recently, however, the “On Target” trial [10]           observed with the association of spironolactone to
has raised issues regarding the validity of this as-         maximum doses of either an ACE inhibitor or an
sociation. This multicentric study comparing                 ARB [12].These studies, however, were short-term
three groups of high risk cardiovascular patients            and not designed to assess preservation of renal
(a group treated with ACE, a group treated with              function.
ARB or a combination of ACE and ARB) failed to                   The triple association (ACE,ARB and spirono-
demonstrate a beneficial role of the combination             lactone) can therefore be considered in specific pa-
with respect to survival and hard renal endpoints,           tients with refractory proteinuria despite optimal
such as renal failure progression and beginning of           ACE and ARB treatment. The risks of hyper-
dialysis, despite an additive effect on proteinuria          kalaemia well documented with spironolactone
reduction. The association even appeared delete-             must be carefully considered [13]. Eplerenone, an-
rious in some patients, with an increased rate of            other mineralocorticoid receptor antagonist, can
hypotensive episodes, hyperkalaemia and acute                be regarded as equivalent to spironolactone al-
renal dialyses.                                              though not yet accepted in this indication.
     Before citing additional information on more
detailed analyses of subgroups of patients from              Direct renin inhibitors
this large study (25 000 patients), we need to inte-              Aliskiren, a direct renin inhibitor, is now com-
grate these results into our practice. In a patient          mercially available in Switzerland. This drug di-
aged over 55 with diabetes and/or vascular prob-             rectly inhibits the enzymatic activity of renin. A re-
lems and nephrotic syndrome, the aim will be to              cent study showed that addition of aliskiren to an
normalise blood pressure and reduce proteinuria.             ARB in diabetic proteinuric patients was beneficial
Either an ACE inhibitor or an ARB will then be               in reducing albuminuria [14]. These results are in-
chosen and the dosage adjusted according to clin-            teresting, but the short follow-up (six months) and
ical and biological tolerability. Other antihyper-           the specific type of population studied require ad-
tensive drugs may be added to achieve optimum                ditional studies to define the exact place of this new
blood pressure control. The combination of ACE               class of drugs compared toACE inhibitors andARB
inhibitors and ARB is not recommended in this                in nephrotic patients.
case.                                                             There are no data regarding the triple associ-
     In a young (<55 years old) or older patient with        ation of ACE inhibitors, ARBs and aliskiren,
no increased cardiovascular risk (no hypertension,           and hence this combination cannot be recom-
no diabetes), presenting with nephrotic syndrome             mended.
Management of patients with nephrotic syndrome                                                                                    420

                       NSAIDs                                                    Dietary factors
                           Non-steroidal       anti-inflammatory     drugs            Sodium intake should imperatively be reduced
                       (NSAIDs) reportedly decrease proteinuria [15].            to less than 6 g/day in order to minimise oedema
                       This effect is essentially mediated by a decrease in      and hypertension, and to potentiate the effect of
                       glomerular filtration rate consecutive to inhibition      ACE inhibitors and ARBs.
                       of vasodilatory prostaglandins and the treatment is            Protein intake has been a subject of debate in
                       restricted to very limited cases of symptomatic           nephrotic syndrome. Various studies have demon-
                       nephrotic syndrome refractory to other classical          strated that a high protein diet (to correct for the
                       treatments. In these cases iatrogenic reduction of        urinary losses) was ineffective in correcting hy-
                       glomerular filtration rate may play a beneficial          poalbuminaemia [17]. Moreover, the increased
                       symptomatic role.                                         protein intake tends to further increase proteinuria
                                                                                 and glomerular hyperfiltration, and is therefore
                       Calcium channel blockers                                  probably deleterious. Conversely, low protein diets
                           Calcium channels blockers are potent antihy-          (<0.8 g/kg/d) have a slight anti-proteinuric effect
                       pertensive drugs. They are therefore useful in            which might be valuable [18]. Vegetable proteins
                       meeting blood pressure targets and hence may con-         appear to be beneficial compared to animal pro-
                       tribute to decreasing proteinuria. This is observed       teins in reducing proteinuria. However, muscle
                       with both verapamil, diltiazem or dihydropiridine         wasting being a major problem in nephrotic pa-
                       calcium channel blockers. The latter may have a           tients, and a low protein intake diet increasing the
                       synergistic vasodilatory effect with ACE inhibitors       risk of malnutrition, it is not recommended.
                       or ARB on the efferent artery, and may have car-               In practice we recommend a protein intake of
                       dioprotective effects [16].                               0.8–1 g/kg/d, with a preference for vegetable and
                           These drugs are therefore useful in nephrotic         fish proteins. Intravenous supplementation of al-
                       syndrome, their major drawback being the occur-           bumin is not beneficial and is not recommended,
                       rence or aggravation of peripheral oedema.                except in cases of very severe hypovolaemia.
                                                                                      A nutritionist consultation is recommended to
                                                                                 every nephrotic patient.

                       Complications of nephrotic syndrome

                       Oedema                                                    blockade of the nephron is habitually needed, the
                            Pathophysiological mechanisms resulting in           collecting duct being an interesting target in view
                       water and sodium retention are still a subject of de-     of its probable physiopathological role. Mainte-
                       bate. There are two theories in the field. The first      nance of a low salt diet is crucial for the effective-
                       is that decreased oncotic pressure and relative hy-       ness of antihypertensive drugs and diuretics, to-
                       povolaemia are the triggers for renal water and           gether with periods of bed rest (with antithrom-
                       sodium retention due to subsequent activation of          botic prophylaxis). In severe cases intravenous ad-
                       the RAA and vasopressin systems. The second the-          ministration of loop diuretics may be necessary. In
                       ory is in favour of primary renal dysfunction with        the event of profound hypoalbuminaemia (plasma
                       inappropriate sodium retention by the cortical col-       levels <15 g), especially in the acute setting and as-
                       lecting duct [19]. Globally, both mechanisms are          sociated with hypovolaemia, intravenous desalted
                       probably active at different phases of the disease        albumin may be administered. The weight loss
                       and both participate in water and sodium retention        should approximate 1 kg per day and both renal
                       in this disease.                                          function and electrolytes must be carefully moni-
                            In children presenting with pure nephrotic           tored during diuretic treatment.
                       syndrome without hypertension and with normal
                       renal function, amiloride, an inhibitor of the            Lipid metabolism
                       sodium epithelial channel (ENaC) which blocks                  Dyslipidaemia may be marked, with an in-
                       sodium reabsorption in the collecting duct, is often      crease in total cholesterol, LDL, triglycerides and
                       very efficient.                                           lipoprotein (a).
                            In adults, sodium retention is frequently asso-           Dyslipidaemia in nephrotic syndrome con-
                       ciated with a decrease in glomerular filtration rate      tributes to the increased cardiovascular mortality
                       and hypertension. In this situation diuretics should      in these patients, and may also be involved in renal
                       be associated with ACE inhibitors or ARBs. If re-         disease progression. Screening and treatment of
                       nal function is relatively preserved, either              dyslipidaemia are therefore of critical importance.
                       amiloride or thiazides or spironolactone can be                The pathogenesis of dyslipidaemia in
                       chosen as the first alternative.A loop diuretic is usu-   nephrotic patients is not yet totally understood.
                       ally necessary to obtain efficient natriuresis. In-       Decreased plasma oncotic pressure stimulates he-
                       deed, given the intensity of sodium retention and         patic synthesis of different proteins and may con-
                       the diversity of causal mechanisms, a sequential          tribute to the increase in LDL.Acquired HDL me-
                                                                              S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 2 9 – 3 0 ) : 4 1 6 – 4 2 2 · w w w . s m w . ch   421

Table 4            Complication             Recommendations
Summary of         Proteinuria              Specific treatment according to primary disease
                                            In all cases: ACE inhibitors or ARBs increased to maximum dose depending on biological and clinical tolerance
                                            If age <55 or no comorbidities: evaluate ACE and ARB combination
                                            If refractory proteinuria, consider spironolactone
                   Oedema                   Low salt diet
                                            Amiloride in children
                                            Sequential diuretic blockade in adults (loop diuretics, thiazide, spironolactone or amiloride)
                   Hyperlipidaemia          Lipid profile
                                            Statin if pathological or severe long lasting nephrotic syndrome
                   Hypertension             ACE inhibitors or ARBs as first choice
                                            Thiazides or calcium channel blockers in association
                                            Low salt diet
                   Hypoalbuminaemia         High protein diet not indicated
                                            0.8–1 g/kg/day
                   Thromboembolic risk      Prophylactic anticoagulation if immobilisation
                                            Full-dose anticoagulation if thrombotic event or membranous nephropathy and severe hypoalbuminaemia
                                            (alb <20 g/l)
                                            In other cases of NS: to be discussed depending on bleeding risk
                   Anaemia                  Anaemia evaluation
                                            Erythropoietin if required
                                            Target haemoglobin 11–12 g/l
                   Infections               High index of suspicion
                                            Antipneumococcal and influenza vaccinations
                   Bone metabolism          Vitamin D and calcium
                                            Bisphosphonates if steroids and/or pathological osteodensitometry
                   ACE: Angiotensin conversion enzyme / ARB: Angiotensin receptor blocker

                   tabolism abnormalities resulting in increased                             ent. Primary prophylaxis is a much more difficult
                   triglycerides and decreased HDL synthesis have                            problem [22]. Markov risk benefits analyses have
                   also been observed [20].                                                  demonstrated a higher expected benefit than risk
                        Statins are efficient and safe for the treatment                     from full dose prophylactic anticoagulation in se-
                   of dyslipidaemia in patients with nephrotic syn-                          vere membranous-associated nephrotic syndrome
                   drome. Statins reduce cardiovascular risk in mod-                         (plasma albumin <20 g/l) [23]. This is however not
                   erate renal failure patients [21] and should be im-                       applicable to secondary nephropathies such as dia-
                   plemented as long as nephrotic syndrome is ongo-                          betic nephropathy.
                   ing. Proteinuria reduction is however the best                                In practice, except for diabetic nephrotic syn-
                   treatment for dyslipidaemia correction.                                   drome, institution of primary prophylaxis by full
                                                                                             dose anticoagulation should be discussed accord-
                   Thromboembolism                                                           ing to the type of disease, its severity and individ-
                       Nephrotic syndrome is a risk factor for throm-                        ual haemorrhagic risk, but is usually indicated as
                   boembolic events, mainly in young patients and at                         long as proteinuria is ongoing and serum albumin
                   the beginning of the nephrotic syndrome. The risk                         below 20 g/l.
                   can be as high as 40% in particular forms of renal
                   disease such as membranous nephropathy.Throm-                             Infections
                   boembolic events remain highly suspect in                                      Nephrotic patients present a high risk of in-
                   nephrotic patients.                                                       fection. Encapsulated pathogens (e.g pneumococ-
                       The pathophysiology of thromboembolic                                 cus) are frequently encountered in children (pneu-
                   events is related to imbalance between pro- and an-                       monia, spontaneous peritonitis, dermohypodermi-
                   ticoagulant factors. Urinary loss of antithrombotic                       tis) and are associated with severe disease. In adults
                   factors (mainly antithrombin III) and synthesis of                        the bacterial susceptibility extends to gram-nega-
                   procoagulant factors are implicated in the patho-                         tive rods. This susceptibility is probably related to
                   genesis of this complication. The higher incidence                        loss of various immunoglobulins and alternate
                   observed in some glomerular disorders (e.g. mem-                          complement pathway dysfunctions in part due to
                   branous nephropathy), is unexplained.                                     urinary loss. Immunosuppressive treatments fur-
                       Treatment of an incidental thromboembolic                             ther increase susceptibility to other pathogens such
                   event is similar to a standard event, with the differ-                    as CMV, PCP, etc., usually if nephrotic syndrome
                   ence that full dose anticoagulation should be main-                       persists.
                   tained as long as the nephrotic syndrome is pres-                              Anti-influenza and antipneumococcal vaccina-
Management of patients with nephrotic syndrome                                                                                                                                   422

                       tion is therefore recommended with plasma mon-                                     the erythropoietin level is low, administration of
                       itoring of antibodies (for pneumococcus) after six                                 erythropoiesis synthesis agents (ESA) is indicated,
                       months, given the high risk of immunity loss. A                                    targeting a haemoglobin level of 11–12 g/l.
                       high degree of suspicion should be entertained re-
                       garding infections in these patients.                                              Bone metabolism
                                                                                                               Renal failure is associated with secondary hy-
                       Anaemia                                                                            perparathyroidism and hypovitaminosis D. In
                            Anaemia of chronic renal disease is related to                                nephrotic patients this may be further complicated
                       inadequate erythropoietin production by the kid-                                   by urinary loss of albumin and globulins that are vi-
                       neys (endocrine failure). In nephrotic patients this                               tamin D transporters. Monitoring of serum cal-
                       can be aggravated by urinary losses of erythropoi-                                 cium and phosphates as well as vitamin D and PTH
                       etin, transferrin and iron. The association of                                     measurement is warranted in these patients.
                       nephrotic syndrome with anaemia in the absence                                     Steroid treatments will also alter bone density.
                       or renal dysfunction is still a subject of debate [24].                                 If possible, supplementation with calcium and
                            In cases of anaemia a standard evaluation                                     vitamin D is recommended in all patients. De-
                       should be performed (reticulocytes count, B12, fo-                                 pending on the clinical context and associated med-
                       late, iron status). In the absence of renal dysfunc-                               ications, mostly corticosteroids, a dual absorption
                       tion and with an unexplained aregenerative                                         densitometry and/or bisphosphonate therapy may
                       anaemia, erythropoietin measurement is useful. If                                  be indicated [25].

                           In conclusion, diagnosis and follow up of                                            Correspondence:
                       nephrotic patients require close cooperation be-                                         Pierre-Yves Martin
                       tween general practitioners and nephrologists to                                         Service de Néphrologie
                       ensure the best possible care.                                                           24, rue Micheli du Crest
                           Evaluation and treatment of complications                                            CH-1211 Genève 14
                       are crucial in order to minimise mortality and                                           Switzerland
                       morbidity associated with nephrotic syndrome.                                            E-Mail:

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