The nephrotic syndrome is defined by a set of biological signs secondary to proteinuria sufficiently abundant to cause disturbances in plasma. It combines proteinuria classically greater than 50 mg / kg / 24 h and albumin less than 30 g / L.In fact, when the plasma albumin level is very low, the concentration of urinary proteins decreases and we often find numbers below 50 mg / kg / 24 h.
Nephrotic syndrome is always secondary to glomerular disease. It is related to an increase in the permeability of the glomerular basal membrane (MBG) to plasma proteins. In the normal subject, plasma albumin, negatively charged, does not pass the glomerular filter, essentially due to the anionic charge of the basal membrane. During idiopathic nephrotic syndrome, the essential factor is loss of anionic charges of MBG, while glomeruli appear normal under light microscopy. Indeed, in the normal subject, proteins of the same molecular weight as albumin but having a neutral electrical charge cross the MBG. In other glomerular nephropathies, proteinuria is usually explained by histologically visible lesions of MBG which may also be associated with loss of anionic charges.
The nephrotic syndrome is clinically characterized by edema.
Edema becomes clinically detectable when hydrosodic retention exceeds 3 to 5% of the body weight. This edema is localized at the level of the legs and ankles in the standing position, and at the level of the loins in the prone position.They are white, soft, painless edema, keeping pressure marks. Anasarca can develop with ascites, pleural effusion, pericardial effusion. Abdominal distension may be major, but it is rarely accompanied by dyspnea.
Periorbital edema can limit the opening of the eyes when it is important. If it is more moderate, it should not be mistakenly related to an allergic problem. The edema of the scrotum in the boy or the labia majora in the girl is sometimes important. Abdominal pain may occur in the rapid formation of ascites. These abdominal pain may also be secondary to a complication such as peritonitis, thrombosis or pancreatitis. Hypovolemic shock can be seen in a sudden drop in albumin, accompanied by abdominal pain, cold extremities and hypotension.
It is not uncommon for the nephrotic syndrome to be discovered during a systematic urinalysis showing proteinuria.Finally, the nephrotic syndrome can be revealed by a complication, especially infectious or thromboembolic complication.
Proteinuria is often detected with urine strips.
Urine is collected in a clean, dry container. The reading is done after 1 minute by comparison with a color scale, or with the aid of an automatic reading device. Visual results will appear as crosses (0, traces: 10-20 mg / dL; +: 30 mg / dL; ++: 100 mg / dL; +++: 300 mg / dL and + +: 1 g / dL), whereas automated reading gives a semi-quantitative evaluation of 0 to more than 3 g / L. The test strip is more sensitive to albumin than to other proteins. The quantitative determination shows proteinuria rates usually higher than 50 mg / kg / day or 40 mg / h / m 2 , but the values may be very high at the beginning because the urinary concentration of proteins depends on the plasma concentration of albumin . In small children, it is often difficult to obtain a 24-hour urine collection and the urine protein / creatinine ratio on a urine sample is useful. The level of this ratio in the nephrotic syndrome is between 200 and 400 mg / mmol.
The amount of proteins excreted in the urine does not represent the totality of the filtered albumin due to catabolism and partial reabsorption of these molecules in the proximal bypass tube. The nature of the urinary proteins can be assessed by polyacrylamide gel electrophoresis or by determination of the selectivity index. The selectivity index is the ratio of clearances of immunoglobulin G (IgG) (molecular weight [PM]: 150,000 Da) and albumin (PM: 70,000 Da) or transferrin (PM: 80,000 da). A low selectivity index is usual in patients with nephrotic syndrome with minimal glomerular lesions, whereas values greater than 0.15 often reflect greater glomerular lesions. However, this test has limited practical interest.
The nephrotic syndrome is accompanied by a sodium retention with a very low natriuresis, less than 5 mmol / d.Sodium retention is typically explained by the decrease in oncotic pressure, which leads to hypovolemia and leakage of sodium and water in the extravascular area with expansion of the interstitial space.
Hypovolemia is responsible for stimulation of the renin angiotensin system with hyperaldosteronism responsible for sodium reabsorption in the distal tube. This is certainly not the only explanation for sodium retention, as blood volume can be normal as can plasma aldosterone levels. There are additional phenomena, in particular a decrease in atrial natriuretic factor, and intrarenal phenomena that do not depend on circulating factors. Experimentally, when nephrotic syndrome is induced in the rat by injection of puromycin into a single renal artery, pathological kidney natriuresis is collapsed while healthy contralateral kidney natriuresis is conserved, although the level of plasma albumin is decreased. The exact pathogenesis of sodium retention is therefore not yet completely elucidated. Hypovolemia also stimulates the secretion of antidiuretic hormone, which stimulates the reabsorption of water at the collecting tube.
The edematous syndrome is related to the conjunction of the decrease of the oncotic pressure and the hydrosodic retention, the water and the sodium diffusing in the interstitial sector. When sodium retention is poorly marked, for example in subjects with sodium restriction or diuretics, edema may be absent.
Plasma disturbances are secondary to albumin urine leakage. Albuminuria causes hypoalbuminemia when hepatic synthesis is no longer sufficient to compensate for urine leakage. It seems that the reduction of the oncotic pressure secondary to hypoalbuminemia is the regulating factor of the hepatic synthesis of albumin and the other proteins synthesized by the hepatocytes. Protidemia is markedly decreased and plasma lipids are usually increased.Protidemia is often less than 50 g / L and albuminemia falls below 30 g / L. In severe nephrotic syndromes, albumin levels may fall below 10 g / L. Protein electrophoresis shows not only hypoalbuminaemia, but also an increase in alpha-2-globulins and, to a lesser extent, betaglobulins, while the level of gamma globulins varies according to the cause of the nephrotic syndrome. For example, during Idiopathic nephrotic syndrome, the IgG level is significantly decreased, IgA decreases decreased and IgM is increased. On the other hand, the level of Ig is increased during systemic lupus erythematosus. For other proteins, levels of fibrinogen and betalipoproteins are increased, while that of antithrombin III is decreased.
Hyperlipemia is the result of: 1) an increase in the synthesis of cholesterol, triglycerides and lipoproteins, 2) a decrease in the catabolism of secondary lipoproteins, and a decrease in the lipoprotein lipase activity which, (LDL), 3) decreased LDL receptors, and 4) increased high density lipoprotein (HDL) urinary leakage. Total cholesterol and LDL cholesterol are increased while HDL cholesterol is normal or decreased, resulting in an increase in the LDL cholesterol / HDL cholesterol ratio.
When the hypoalbuminaemia is deep, triglycerides and VLDL are increased. The apoproteins (apoB, apoCII and apoCIII) are also increased. Lp (a) lipoprotein is increased during nephrotic syndrome, which further increases the risk of cardiovascular complications and thrombosis.
Natremia is often normal. It may be diminished due to haemodilution secondary to abnormal fluid retention secondary to hypovolemia and inappropriate secretion of antidiuretic hormone. Moderate hyponatremia is often an artefact related to hyperlipidemia. Serum potassium may be increased in patients with renal insufficiency with oliguria. Calcium is still low because of hypoprotidemia. Ionized calcium may also be low in patients with prolonged nephrotic syndrome due to urinary leakage of 25-OH vitamin D. The plasma creatinine level is usually normal but may be discretely increased due to decreased filtration glomerular.
Hemoglobin and hematocrit are increased in case of hypovolemia. Microcytic anemia is sometimes observed in prolonged nephrotic syndromes, probably due to the urinary leakage of siderophilin. The platelet level is often increased and may be as high as 5-10 5 to 10 6 / mm 3 .
ACUTE RENAL FAILURE:
Renal function is usually normal, but a reduction in glomerular filtration can be observed due to hypovolemia. In some cases of idiopathic nephrotic syndrome, glomerular filtration is decreased despite normal blood flow. A close relationship between the degree of fusion of pedicels of the podocytes and the glomerular filtration rate has been demonstrated, suggesting that the fusion of the pedicels may result in a reduction of the filtration surface and / or the permeability to water and small molecules. This reduction in glomerular filtration is transient. Renal insufficiency may be secondary to bilateral thrombosis of the renal veins. Finally, interstitial nephritis is another possible cause of renal failure, particularly after administration of furosemide.
Stunted growth is often observed in children with prolonged nephrotic syndrome. This growth disorder is partly secondary to the urinary leakage of certain hormones. The urinary leakage of iodinated proteins is responsible for a hypothyroidism that can be corrected by a substitutive treatment. Leakage of carrier proteins also explains the low levels of somatomedin B (IGF I) and somatomedin A (IGF II).
Bacterial infections are common in patients with nephrotic syndrome. These infections can occur at the onset of the disease. The most frequent infection is peritonitis, most commonly pneumococcal. Other microorganisms may be involved: Escherichia coli, Group B Streptococcus, Haemophilus influenzae or other Gram-negative organisms.
Apart from peritonitis, patients may develop meningitis, pneumonia or cellulitis. Cellulites are often favored by the maintenance of venous perfusions.
Several factors explain the susceptibility to bacterial infections: decreased IgG levels, urinary leakage of factor B and alterations in T cell functions. Factor B is the cofactor of C3b in the alternative complement pathway, which plays an important role in l opsonization of bacteria such as pneumococcus.
Patients with nephrotic syndrome have a high risk of developing thrombosis. Several factors explain this increased risk: hypercoagulability, hypovolemia (favored by the prescription of diuretics), immobilization (bed rest is not indicated in a nephrotic child, quite the contrary) and infection. Numerous hemostatic disturbances have been described in the course of the nephrotic syndrome: increased platelet counts and aggregability, increased fibrinogen levels and factors V, VII, VIII, X and XIII, antithrombin III, cofactor of heparin, protein C, protein S and factors XI and XII, are decreased, the fibrinolytic system is increased, and in particular the tissue plasminogen activator (EPA) and plasminogen activator inhibitor 1 (PAI-1). The incidence of thromboembolic complications in children is close to 3%. However, this percentage is likely to be underestimated, as shown in a study where a pulmonary scintigraphy was routinely performed in children with corticodependent nephrosis; 28% had images consistent with sequelae of pulmonary embolism. Pulmonary embolism should be suspected in case of respiratory signs or cardiac abnormalities, unexplained abdominal pain. The diagnosis can be confirmed by a pulmonary scintigraphy or angiography if there is pleural effusion making the scintigraphy uninterpretable. Renal vein thrombosis is suspected in patients with sudden macroscopic hematuria, accompanied by lumbar pain, or acute renal failure. Doppler ultrasound shows an increase in the size of one or both kidneys and the absence of blood flow in the renal vein. The occurrence of neurological disorders should lead to suspicion of cerebral thrombosis or of the superior longitudinal sinus. Thromboses can also affect arteries, such as the pulmonary arteries. Punctures of the radial or femoral arteries, as well as the placement of venous catheters, are additional supporting factors.
Symptomatic treatment of nephrotic syndrome:
Bed rest, which increases the risk of thrombosis, should be avoided. The diet should provide a protein ration of 1 to 2 g / kg. It must be low in salt and a water restriction is indicated only in cases of hyponatremia below 125 mmol / L.
Hypovolemia, in connection with rapid protein leakage, can be aggravated by prescribing diuretics. It manifests itself in collapse. This complication requires emergency treatment with a 20% albumin perfusion (1 g / kg) under strict control of blood pressure. Diuretics should only be prescribed if the edematous syndrome is severe and poorly tolerated, after correcting for hypovolemia. Furosemide, 1 to 2 mg / kg, or spironolactone, 2 to 10 mg / kg, are the most commonly used.
These children are at risk of thrombosis. Prevention of this complication involves the mobilization, rapid treatment of hypovolemia or an infectious complication. Prophylactic treatment with either antivitamin K or aspirin and dipyridamole may be indicated in cases of hypoalbuminemia below 20 g / L, fibrinogen levels above 6 g / L or antithrombin III levels below 70 %. In case of thrombosis, treatment with heparin is started, knowing that the doses needed to obtain effective anticoagulation are often high due to the low level of antithrombin III.
Lipid abnormalities secondary to the nephrotic syndrome are reversible with the disappearance of proteinuria, as is the case with corticosteroid therapy in corticosensitive nephrosis. The treatment of hyperlipidemia in patients with persistent nephrotic syndrome is discussed. The diet has little effect. Some propose the use of statins, inhibitors of hydroxy-3-methylglutaryl coenzyme A reductase (HMG co-A reductase).
Prophylactic antibiotic therapy is not routine, but bacterial infections should be treated promptly. Pneumococcal vaccination may be performed, but it does not fully protect children from this type of infection. Varicella and measles may be life-threatening in children receiving immunosuppressive therapy. Varicella serology should be monitored and, in the case of tumors, specific gamma globulins and acyclovir should be administered if the disease develops clinically.
Idiopathic nephrotic syndrome or lipoid nephrosis:
Idiopathic nephrotic syndrome is by far the most common cause of nephrotic syndrome in children, accounting for 90% of cases of nephrotic syndrome before age 10 and 50% of cases after that age. Idiopathic nephrotic syndrome is defined by the association of a nephrotic syndrome with minimal glomerular lesions or non-specific glomerular lesions, such as segmental and focal hyalinosis or diffuse mesangial proliferation. There is usually no deposition of Ig or complement in immunofluorescence. Nevertheless, mesangial deposits of IgM are sometimes found and this allowed some authors to individualize a particular entity, “IgM nephropathy”. The significance of these deposits is discussed, with some authors describing a lower response to corticosteroid therapy, while others have no effect on the initial response to corticosteroids and long-term outcomes. The study in electron microscopy makes it possible to find an erasure of the pedicels of the podocytes.
The isolated minimal glomerular lesions are characterized by a favorable response to corticosteroid therapy in more than 90% of cases and a good prognosis in the long term. Conversely, patients in whom objective renal biopsy of segmental and focal hyalinosis lesions or diffuse mesangial proliferative lesions are frequently resistant to corticosteroid therapy. It is for these reasons that many authors have individualized several entities according to abnormalities found on the renal biopsy: nephrotic syndrome with minimal change disease, nephrotic syndrome with segmental and focal segmental glaucoma (focal and segmental glomerular sclerosis) and nephrotic syndrome with diffuse mesangial proliferation. Nevertheless, iterative renal biopsies show that some patients initially have minimal glomerular lesions and may subsequently develop segmental and focal hyalinosis lesions. In addition, some patients whose renal biopsy reveals segmental and focal hyalinosis lesions respond to corticosteroid therapy and have a favorable outcome. The risk of corticoresistance is higher if the renal biopsy also shows tubulointerstitial fibrosis lesions or renal function is impaired. If the different histological aspects have a prognostic value in terms of response to corticotherapy and long-term evolution, they do not allow to distinguish several entities.
When analyzing long-term prognosis and therapeutic indications, it is preferable to distinguish between two categories of patients: corticosensitive and corticoresistant.
CORTICOTHERAPY DURING NEPHROSIS:
Corticosteroids should not be started too early, as spontaneous remissions may occur in 5% of cases.
When the diagnosis of idiopathic nephrosis is very likely or after renal biopsy has been performed, corticosteroids are instituted. It is preferable to administer prednisone rather than prednisolone. It is given at a dose of 60 mg / m 2 / day, in two doses, with a maximum of 60 mg / d. Proteinuria generally disappears between the 8th and 15th day of treatment. Prednisone at the same dose is continued for 30 days and then discontinued 1 day in 2, in a morning dose, at the same dose for 2 months. Thereafter, the dose is decreased by 15 mg / m 2 every 15 days. The total duration of treatment for the first outbreak is thus 4 and a half months.
When the duration of treatment for this first outbreak is shorter, the percentage of patients with relapses is higher. If proteinuria persists at the end of the first month of treatment, corticosteroid therapy should be increased. In this situation, a series of three methylprednisolone (Solu-Medrol t ) infusions at a dose of 1000 mg / 1.73 m 2 every two days is indicated in the hospital setting, as the side effects of these infusions are less important than the increase in doses of prednisone per os. The persistence of proteinuria at the end of this treatment defines the corticoresistant nephrotic syndrome. In this situation, renal biopsy will link the nephrotic syndrome to idiopathic nephrosis or another glomerular nephropathy.
EVOLUTION AND TREATMENT OF CORTICOSENSIBLE IDIOPATHIC NEPHROTIC SYNDROME:
In the majority of cases in children (85%), idiopathic nephrosis is corticosensitive. Approximately 30% of the children only develop a flare and are then definitively cured as a result of corticosteroid therapy. Ten to 20% of children relapse several months after discontinuation, and cure usually occurs after two or three episodes, each of which responds to a standard 4 and a half month corticosteroid therapy. In 40 to 50% of the cases, the children present frequent relapses either as soon as the corticosteroid is stopped or when the corticosteroid is decreased. These children often have difficult therapeutic problems.
These patients, corticodependent, can be treated with repeated cures of corticosteroids for 1 to 2 months. Another approach recommends treating relapses with daily corticosteroids of 40 to 60 mg / m 2 / d until proteinuria disappears.Four to five days after remission, treatment is discontinued and the dose is decreased to 15 to 20 mg / m 2 1 day out of 2 depending on the level of corticodependence, ie the dose at which relapse occurred. This treatment is continued for 12 to 18 months. If the first approach allows a better definition in terms of the number of relapses, it exposes to a significant number of relapses. On the other hand, the second approach, which we advocate, results in fewer side effects as the cumulative dose of corticosteroids is lower.
Over the past decade, levamisole has been used in corticosensitive and corticosteroid-dependent nephrosis, and several studies have shown that this treatment may reduce or stop corticosteroid therapy. The British pediatric nephrology group performed a multicentre trial in which 61 children received levamisole at a dose of 2.5 mg / kg every other day or placebo. Fourteen of the patients receiving levamisole and only four of those receiving placebo were still in remission 4 months after starting treatment despite the discontinuation of prednisone. This significant difference demonstrates the efficacy of levamisole in this indication. Nevertheless, most children relapsed 3 months after discontinuation of treatment. Regular haematological checks should be performed because the most important side effect is neutropenia, reversible after withdrawal of levamisole.
Patients with corticosteroid-dependent nephrosis may develop signs of steroidal intoxication such as slowing statural growth, obesity, osteoporosis, cataracts or psychic disorders. This is observed when the level of corticosteroid therapy that maintains remission is too high. It has been shown for several years that alkylating agents, cyclophosphamide or chlorambucil, are useful in these situations.
The duration of remission induced by cyclophosphamide varies from one patient to another and may be short-lived.Data from the literature show a remission rate of 67-93% at 1 year, and 36-66% at 5 years after cyclophosphamide therapy. The therapeutic effect is directly related to the duration of the treatment. In a German study, 67% of children with corticosteroids were in remission 2 years after a 12-week treatment with cyclophosphamide at a dose of 2 mg / kg / day, while only 30% of children receiving an 8-week treatment in remission at 2 years. The daily dose of cyclophosphamide should not exceed 2.5 mg / kg. The response to cyclophosphamide is also related to the response to corticosteroid therapy.
Seventy-five percent of children with relapsed relapses after discontinuation of corticosteroid therapy remain in remission after an 8-week course of cyclophosphamide, while only 30% of children with corticosteroids have prolonged remission. Remissions can also be obtained with chlorambucil.
Chlormethine may be useful, resulting in an average rapid remission after 7 days. After this treatment, administered at a total dose of 0.8 mg / kg by venous route in two series of four injections of 0.1 mg / kg each, performed 1 month apart, most children remain in remission without corticosteroid therapy but the rate of remission is only 15% after 3 years in corticodependent children.
The side effects of alkylating agents limit their use.
Medullary toxicity requires regular hematological checks. If the number of white blood cells drops below 3 000 / mm 3 , treatment should be stopped until leucopenia is corrected. This treatment should also be discontinued in case of intercurrent infection. Chicken pox should be explained to parents so that treatment with aciclovir can be started quickly. Alopecia and haemorrhagic cystitis secondary to cyclophosphamide are rarely observed with the doses used in these patients. Long-term toxic effects include the risk of malignant tumors and gonadal toxicity, which appears to be greater in boys than in girls. The threshold for gonadotoxicity is above 200 mg / kg cumulative dose for cyclophosphamide and between 8 and 10 mg / kg for chlorambucil.
In the corticosteroid nephroses, ciclosporin at a dose of 5-6 mg / kg / day maintained remission despite corticosteroid arrest in 85% of cases. Nevertheless, relapses occur in the vast majority of cases, either after the treatment has gone down or after it has stopped. Given the side effects of this treatment, particularly nephrotoxicity, it is necessary to reserve ciclosporin in situations where corticosteroids can not be continued and when alkylating agents have already been used. In some children, remission can only be sustained if high doses of ciclosporin are prescribed.
In these situations and in order to avoid side effects of treatment, we recommend the combination of cyclosporin and low-dose discontinuous corticosteroids.
Treatment with ciclosporin requires close monitoring of renal function and blood pressure. Histological lesions of nephrotoxicity, with spans of interstitial fibrosis with atrophic tubes, can develop without impairment of renal function.This justifies the practice of renal biopsy of control in case of prolonged treatment beyond 2 years.
Idiopathic nephrotic syndrome corticoresistant:
It accounts for 10% of cases of idiopathic nephrotic syndrome. It is actually a heterogeneous entity and recent studies make it possible to affirm that under the same term are classified patients with totally different diseases. Fuchshuber et al described patients with a number of characteristics and for which it is a hereditary condition. Patients enter the disease early in childhood, constantly progressing to renal failure and nephrotic syndrome does not recur after renal transplantation. These features have been found in a number of patients, with a familial character suggesting autosomal recessive transmission. Binding studies using microsatellite markers allowed to locate a gene on the long arm of chromosome 1 with a lodscore of 3.4. The absence of binding to the markers of this region in certain families makes it possible to affirm that there is a genetic heterogeneity. The absence of recurrence after transplantation suggests in this form of nephrotic syndrome a primary abnormality of an MBG protein or podocytic cells. In informative families, prenatal diagnosis is possible. Other familial forms of corticoresistant nephroses are transmitted in the autosomal dominant mode and several genes have been localized on chromosomes 19 and 11. Mutations of the gene coding for actinin 4 and located on chromosome 19 have recently been reported. This protein interacts with actin, a cytoskeletal protein. In contrast, about 30% of patients with corticosteroid-induced idiopathic nephrotic syndrome who have progressed to end-stage renal disease have a recurrence of proteinuria after renal transplantation. In these patients, it is likely that a circulating factor intervenes by increasing the permeability of MBG. The presence of such a factor was found by Savin et al. The disappearance of proteinuria after plasma exchange or treatment with immunoabsorption is also an argument for the role of such a factor in the pathogenesis of the nephrotic syndrome. The analysis of the therapeutic results must therefore take into account the fact that, under the same denomination of corticoresistant nephrosis, patients with different pathogenic disease conditions are included.
The long-term prognosis of corticosteroid-mediated idiopathic nephrotic syndromes is dominated by the risk of progression to end-stage renal disease. Our experience is based on the evolution of 84 children followed for a period of at least 5 years. With a follow-up of 5 to 25 years, 50% of patients had progressed to end-stage renal disease, while 40% were in complete or partial remission. Six out of 12 patients who received no treatment other than initial corticosteroids entered spontaneously in complete remission. There was some correlation between the data from the initial renal biopsy and the progression to end-stage renal disease. In 38% of patients with minimal glomerular lesions, 48% of patients with segmental and focal hyalinosis lesions and 66% of patients with diffuse mesangial proliferation were observed. These data are difficult to compare with those of other series in that they analyze the prognosis of patients with corticosteroid-like nephrotic syndrome with segmental and focal hyalinosis. The high percentage of adverse developments in black American children compared to Caucasian children.
Ingulli and Tejani found in a population of 57 children a rate of progression to end-stage renal failure of 50% at 3 years and 95% at 6 years.
There is no consensus on the treatment of corticoresistant nephrosis.
A treatment combining methylprednisolone infusions, discontinuous oral corticosteroid therapy and an alkylating agent has been proposed by Tune et al. With a mean follow-up of more than 6 years, 21 of the 32 children treated with this protocol were in complete remission, while five had moderate renal insufficiency and three had progressed to end-stage renal disease. The incidence of end-stage renal insufficiency in this series is therefore about 5%, while in an earlier series the incidence was 40%.
A multicenter study involving 15 children treated in a neighboring regimen did not confirm these findings.
It appears that some children who do not respond to corticosteroids at the usual doses may respond to higher doses.
The alkylating agents do not appear to have a beneficial effect in this indication. Despite this demonstrated lack of effectiveness, these treatments are still largely prescribed.
Cyclophosphamide is more often prescribed. The rate of complete or partial remissions is higher in children who initially responded to corticosteroid therapy but became corticoresistant in patients with partial corticosteroid resistance and in those with renal biopsy showing minimal glomerular lesions compared with those primary corticosteroids or those with renal biopsy showing segmental and focal hyalinosis lesions. The only controlled study is that of the International Study of Kidney Diseases in Children (ISKDC) with 60 children with corticosteroid-like nephrotic syndrome with segmental and focal hyalinosis. In the control group, 25 patients received prednisone 40 mg / m 2discontinuously for 12 weeks, while the other 35 children received in addition to cyclophosphamide at a daily dose of 2.5 mg / kg for a period of 90 days. Complete remission was observed in 28% of the control group and 25% of the cyclophosphamide group. The proportions of children who had a decrease, stability or increase in proteinuria were comparable in both groups.
A recent study reports favorable cyclophosphamide perfusion results compared to oral cyclophosphamide in cases of corticosteroid-like nephrotic syndrome with minimal glomerular lesions.
A prospective protocol of the Society of Pediatric Nephrology included 65 children who were treated with ciclosporin (150 to 200 mg / m 2 ) and prednisone (30 mg / m 2 / d) for 1 month and discontinued for 5 months.
Twenty-seven children entered full remission, 42%, while four had partial remission (6%) and 34 (52%) had not responded to treatment. Complete remission occurred rapidly in the first two months of treatment in more than half of the cases, making the causal relationship between treatment and remission likely. The rate of remission is higher among patients with minimal glomerular lesions (48%), compared to those with segmental and focal hyalinosis lesions (30%). The response rate is also higher in patients with corticosteroid-resistant (71%) compared to patients who are corticosteroid-resistant (33%). Of the patients who entered full remission, eight relapsed after discontinuation of ciclosporin therapy, but all responded to the resumption of corticosteroid therapy. Thus, some patients initially corticoresistant have become corticosensitive after treatment with ciclosporin and prednisone. Progression to chronic or terminal renal insufficiency was observed only in patients who had partial remission (one in four patients) or in those who did not respond (12 of the 34 patients) .
Gregory et al treated 15 children with corticosteroid-idiopathic nephrotic syndrome with a combination of moderate doses of ciclosporin and prednisone and observed remission in 13 of them after a mean treatment duration of 2 months. Lieberman and Tejani reported, in a control trial, the beneficial effect of ciclosporin compared to placebo.
Ingulli et al observed interesting findings in black, or Hispanic children with corticoresistant nephrotic syndrome with segmental and focal hyalinosis, and treated with ciclosporin for a prolonged period. The dose of ciclosporin was adjusted for cholesterol to achieve remission. Thus doses, which were initially 6 mg / kg, ranged from 4 to 20 mg / kg.At the end of the treatment, proteinuria had decreased with a parallel rise in albuminemia. Five of the 21 children, or 24%, progressed to end-stage renal disease, a significantly lower percentage than in a similar previous series of 54 children, 42 (78% development.
The therapeutic protocols using ciclosporin expose, as we have seen, a risk of nephrotoxicity.
INHIBITORS OF THE CONVERSION ENZYME:
This type of treatment can be used to reduce the level of proteinuria. This is more of a symptomatic treatment because it does not result in complete remission.
RECONDITION OF NEPHROTIC SYNDROME AFTER RENAL TRANSPLANTATION:
Among patients with corticosteroid-like idiopathic nephrotic syndrome who progress to end-stage renal disease, about 25% have a recurrence of proteinuria after renal transplantation. The beneficial role of ciclosporin in recurrences of nephrotic syndrome after transplantation
renal is still discussed. Following the introduction of ciclosporin in the early 1980s, the incidence of recurrence has not changed. Nevertheless, transplant survival has improved. In our experience, the prognosis of nephrotic syndrome after renal transplantation has improved in recent years. Since 1991, ten children with immediate recurrence have been treated with ciclosporin by the venous route as soon as proteinuria reappears, maintaining plasma levels between 250 and 300 ng / mL. In the short term, treatment was accompanied by complete remission in six children and partial remission in four children. The survival of grafts at 2 years, which was 33% for patients transplanted between 1985 and 1990, is 90% for those transplanted since 1991. Other authors have reported similar results with high doses of ciclosporin.
Plasma exchange, possibly associated with an increase in immunosuppressive therapy, is often accompanied by partial or complete remission. Dantal et al treated eight patients by immunoabsorption on protein-A sepharose columns. Treatment was accompanied in seven patients by a decrease in proteinuria, an average of 82%.
However, the effect was transient, with proteinuria returning to its maximum level after 2 months.
Congenital and infantile nephrotic syndromes:
The term congenital nephrotic syndrome applies to patients whose disease is present at birth or occurs during the first three months of life. When the nephrotic syndrome begins between the third and the twelfth month, it is an infantile nephrotic syndrome. In the majority of cases, the prognosis is severe, with the progression towards end-stage renal disease. The precise diagnosis is based on clinical and histological criteria. Finnish congenital nephrotic syndrome and diffuse mesangial sclerosis represent the two main etiologies. However, there are rarer and possibly curable causes, such as congenital nephrotic syndrome secondary to syphilis or toxoplasmosis.
CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE
This type of nephrotic syndrome is more common in Finland, with an incidence of 1.2 per 10,000 births. It has also been observed in different ethnic groups around the world.
The disease is transmitted in an autosomal recessive manner and thus affects both boys and girls. The gene whose mutations are responsible for the disease has been localized on chromosome 19, both in Finnish families and in families of other origin, and there does not appear to be any genetic heterogeneity of the disease. This gene has recently been cloned. It encodes a protein, the nephrine, of the Ig family. Several mutations have been identified, two of which predominate in the Finnish population. Nephrin is located exclusively at the podocyte level and plays an essential role in the permeability of MBG to proteins.
In optic microscopy, early glomerular lesions consist of mesangial hypercellularity and an increase in the mesangial matrix, with progressive progressive glomerular sclerosis. There are no immunofluorescence deposits. The tubulo-intertitial lesions are more marked, with microcystic dilatations of the proximal tubes.
These lesions are inconstant and not specific to the disease. In the course of the evolution, interstitial fibrosis with tubular atrophy and perglomerular fibrosis develops in parallel with glomerular sclerosis.
Affected children are premature, with a low birth weight for gestational age. The placenta is increased in volume, weighing more than 25% of the birth weight. Neonatal distress is common. The newborn frequently has a small nose and low ears implanted. The joints of the hips, knees and elbows are deformed in flexion.
Edema is present from birth or occurs during the first few days of life. Nephrotic syndrome results in peripheral edema and significant ascites. Proteinuria is very selective, massive, and deep hypoalbuminemia. The Ig level is collapsed.Undernutrition is promoted by protein leakage and feeding difficulties in these anorexic infants.
All these disturbances explain why children are very susceptible to bacterial infections and thromboembolic complications. Hypothyroidism secondary to the urinary leakage of the thyroxine-carrying protein is frequent. Renal function is initially normal, but it gradually deteriorates and terminal renal insufficiency occurs between the ages of 3 and 5 years.
Antenatal diagnosis is possible. Indeed, the nephrotic syndrome begins early during the fetal life, from the fifteenth week of gestation. The first symptom is proteinuria, which explains a very high alphafoetoprotein level, multiplied by 10 compared to normal values. Parallel, but to a lesser degree, increase in alphafetoprotein levels is observed in maternal plasma. These abnormalities are not specific but allow antenatal diagnosis in families at risk. The localization of the gene on chromosome 17 and its recent identification allow an antenatal diagnosis. This can be done by linking studies using microsatellite markers in informative families. Four major haplotypes were identified in Finnish families, making it possible to make a diagnosis in 95% of cases. When the mutation of the gene responsible for the disease has been identified in a child affected in a family, antenatal diagnosis is possible by gene analysis on trophoblast biopsy.
Finnish congenital nephrotic syndrome is still resistant to corticosteroids and immunosuppressants and these treatments, which aggravate the infectious risk, are contraindicated. Only conservative treatment is required. This treatment consists of perfusions of albumin daily or every 2 days, infusions of gamma globulin, a diet high in protein and low in salt and prevention of infectious and thromboembolic complications. Feeding by gastric or parenteral gavage is often necessary. Despite these measures, intercurrent complications are frequent and this often leads to stunted growth and a delay in acquisitions. In some patients, it may be necessary to propose a binephrectomy before the stage of renal insufficiency to prevent massive protein leakage. Dialysis treatment is then required until the child’s weight has reached 8-9 kg and the plasma disturbances of the nephrotic syndrome have been modified before a renal transplant is proposed. The disease does not recur on the graft.
Before considering binephrectomy, it is possible to reduce the degree of proteinuria with a combination of an ACE inhibitor, such as enalapril, and indomethacin. These drugs decrease the renal blood flow and the glomerular filtration rate. In some children, this type of treatment allows to split albumin infusions and to observe an improvement in nutritional status and growth in size.
However, this treatment is not always effective enough, due to the severity of the disease in some children.
DIFFUSE MESANGIAL SCLEROSIS:
Diffuse mesangial sclerosis is the second cause of early nephrotic syndrome leading to renal insufficiency. It is observed exclusively in young children. Family cases have been described, suggesting the possibility for some children of autosomal recessive transmission. Diffuse mesangial sclerosis can be isolated or observed in association with male pseudohermaphroditism and / or nephroblastoma (cf Drash syndrome).
The diffuse involvement of the glomeruli is initially characterized by a cross-linked aspect of the mesangial matrix, without hypercellularity but with marked hypertrophy of the podocytes. Later, the floccus is invaded by a fibrillar membranoid material that forms a network within which endothelial and mesangial cells are trapped, while the luminaries of the glomerular capillaries are no longer visible. The podocytes remain voluminous, forming a crown around the floccus. Different lesional stages can coexist on the same biopsy, the less affected glomeruli being located in the deep cortex.
With the same glomerular lesions observed during Drash syndrome, patients with diffuse mesangial sclerosis should be explored for this syndrome. A karyotype should be performed in female phenotype patients seeking male pseudohermaphroditism with an XY karyotype, and an ultrasound should be performed in search of nephroblastoma and gonad abnormalities. It is also indicated to search for a mutation of the WT1 gene, the gene whose mutations predispose to the development of this tumor. Indeed, mutations of this gene have been found in some patients with diffuse mesangial sclerosis isolated, as is the case in patients with Drash syndrome.
Unlike children with Finnish-type nephrotic syndrome, those with diffuse mesangial sclerosis have no symptoms at birth, with normal birth weight and no abnormalities of the placenta. Nevertheless, proteinuria can be present from birth or even appear in utero with an elevation of the alphafoetoprotein level in the amniotic fluid. More often, proteinuria appears after several months, isolated, without hematuria, and its flow increases gradually during the first or the second year. Several associated abnormalities have been reported: nystagmus, cataract, mental retardation, microcephaly, myopia and muscular dystrophy. The evolution is always towards end-stage renal failure, with frequently severe arterial hypertension. This development is rapid, in a few months, often before the age of 4 years.
Diffuse mesangial sclerosis is resistant to corticosteroid therapy and immunosuppressive agents. Nephrotic syndrome is less severe than in Finnish nephrotic syndrome. Treatment is therefore symptomatic. It is intended to maintain hydrosodic balance, ensure good nutritional status, prevent or treat infectious or thromboembolic complications. In the stage of renal insufficiency, dialysis treatment is started. A binephrectomy is performed before or during transplantation, because of the probably more theoretical than real risk of development of a nephroblastoma. The disease does not recur after renal transplantation.
Drash syndrome is defined by the association of diffuse mesangial sclerosis, male pseudohermaphroditism and Wilms tumor. All patients with this syndrome are infants with massive proteinuria and rapidly progressing to end-stage renal disease. Some children present an incomplete form of the syndrome, with diffuse mesangial sclerosis associated with male pseudohermaphroditism or nephroblastoma.
Drash syndrome is most often sporadic, although its occurrence in two children of the same sibling has been reported.
Nevertheless, the majority of patients with this condition have constitutional mutations of the WT1 gene. The WT1 gene is located on chromosome 11, position 11p13. This gene encodes a “zinc finger” protein, a transcription factor.
WT1 is expressed in the kidney at the level of the podocytes and at the level of the gonads, suggesting that the gonadal abnormalities of the Drash syndrome are the consequence of mutations of this gene. This hypothesis was confirmed by the observation of heterozygous constitutional mutations of WT1 in the majority of patients with Drash syndrome. Most of these mutations are false sense mutations at exon 9 which encodes the “zinc finger” 3 that interacts with deoxyribonucleic acid (DNA), and at exon 8 which encodes the “finger” of zinc “2.
The clinical presentation of nephropathy is identical to that of diffuse mesangial sclerosis isolated. However, the Wilms tumor may be the first manifestation of the disease. The tumor may be unilateral or bilateral and associated, in some cases, with islets of nephroblastoma. Male pseudohermaphroditism is characterized by an ambiguity of the external genital organs, a female phenotype, dysgenetic testis or gonadal striae and a 46XY karyotype. Conversely, patients with a 46XX karyotype all have a female phenotype and normal ovaries.
IDIOPATHIC NEPHROTIC SYNDROME:
This form of nephrotic syndrome is rare at birth but can begin during the first year of life. The same histological types as those described in older children can be observed, namely minimal glomerular lesions, segmental and focal hyalinosis lesions and diffuse mesangial proliferation. In the majority of cases, nephrotic syndrome is resistant to corticosteroid therapy, but corticosensitivity is possible.
Congenital syphilis may be responsible for extramembraneous glomerulonephritis (GEM). Histological lesions associate extramembranous deposits with mesangial proliferation. Treatment with penicillin is accompanied by a regression of the nephrotic syndrome.
Congenital toxoplasmosis is a possible cause of nephrotic syndrome. Proteinuria is present at birth or occurs during the first three months, associated with ocular or neurological signs. Renal biopsy shows mesangial proliferation and sometimes segmental and focal hyalinosis. Treatment of toxoplasmosis or corticosteroid therapy leads to a regression of proteinuria. A nephrotic syndrome may also occur in a context of cytomegalovirus infection or human immunodeficiency virus (HIV).
Galloway syndrome is characterized by microcephaly, mental retardation, hiatal hernia and nephrotic syndrome.Nephrotic syndrome is usually severe, corticoresistant. The biopsy shows lesions of segmental and focal hyalinosis.
The GEM is characterized by the presence of diffuse thickening of the walls of the glomerular capillaries in relation to deposits present on the epithelial slope of the basement membrane, separated from each other by spicules. These deposits regularly appear granular and peripheral in immunofluorescence and predominantly fix the anti-IgG serum.The symptomatology of GEM includes an often insidious proteinuria, which may be associated with nephrotic syndrome. Hematuria is common in the first few months. Immediate hypertension or kidney failure are exceptional.Prognosis is usually favorable, proteinuria disappearing gradually in a few months or years. Renal insufficiency occurs in less than 10% of cases. GEM may be apparently primitive or occur in systemic lupus erythematosus, infectious or parasitic disease (congenital syphilis, hepatitis B) or in relation to a medicinal intake (D-penicillamine, captopril or gold salts ).
The membranoproliferative glomerulonephritis (GNMP) is chronic glomerulonephritis of which there are several morphological varieties: type I or GNMP with subendothelial deposits and type II or GNMP with dense deposits intramembranous. These two varieties have a different pathogenesis. Nevertheless, their clinical manifestations are identical. The disease usually begins in the older child. The initial picture may be that of acute glomerulonephritis (GNA). In other cases, the first sign is the appearance of a nephrotic syndrome. Proteinuria is constant, as is hematuria. Nephrotic syndrome is common, and in one third of cases, arterial hypertension and renal failure occur early in the course of the disease. A lowering of the C3 fraction of the complement is common. The presence of the nephritic factor (C3-NEF [C 3 nephretic factor]) is characteristic of glomerulonephritis with dense deposits. The histological examination shows a proliferation of the mesangial cells at the level of the glomeruli and a thickening of the walls of the glomerular capillaries with a laminated or double-edged appearance. In immunofluorescence, there are deposits fixing the anti-C3 serum. In the long term, about half of the patients progress to end-stage renal failure after ten years. Numerous therapeutic trials have been carried out and, to date, none has actually demonstrated its efficacy (corticosteroids, antiplatelet agents).
It is a frequent affection that more often affects boys.
The age of discovery is variable, with a maximum frequency between 7 and 13 years. Macroscopic hematuria is the inaugural symptom in three quarters of cases. Macroscopic haematuria is often recurrent and occurs readily within 2 days of the onset of nasopharyngeal infection. In other cases, the disease is discovered on a systematic examination before a microscopic haematuria associated with a more or less important proteinuria. Usually, blood pressure and renal function are normal. The plasma IgA level is high in half of the cases, while the C3 and C4 levels are normal.Histological examination shows glomerular abnormalities, which are often not very important in light microscopy.
The immunofluorescence examination makes it possible to confirm the diagnosis in the presence of deposits predominantly fixing the anti-IgA serum and located at the level of the mesangial axes. In some cases, glomerular involvement is more important in light microscopy, resulting in an aspect of segmental and focal glomerulonephritis or an aspect of endo- and extracapillary glomerulonephritis.
The prognosis is favorable in children. The existence of a permanent proteinuria, especially of increasing degree and accompanied by a nephrotic syndrome, is an element of less good prognosis.
It is in these situations that more severe glomerular lesions are observed and that the long-term evolution can be towards chronic renal failure. This occurs in about 10% of cases, with a 10-year follow-up.
GLOMERULONEPHRITE WITH GLOBULAR BASAL ANTIMEMBRANE ANTIBODY:
Glomerulonephritis by anti-MBG is a rare condition in children. It may be isolated or associated with pulmonary hemorrhage (Goodpasture’s syndrome). It is usually severe glomerulonephritis with nephrotic syndrome and renal insufficiency. In immunofluorescence, there is a characteristic, linear binding of the anti-IgG serum along the MBGs.The circulating anti-MBG antibodies are detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (Elisa) techniques. Treatment should be early and involve plasma exchange, corticosteroid therapy and cyclophosphamide.
The development is often unfavorable, towards end-stage renal failure.
Glomerulonephritis of necrotizing angiitis is defined by the presence of vascular involvement with inflammatory signs and fibrinoid necrosis. In children, it may be a periarteritis nodosa, more rarely a granulomatosis of Wegener.Antibodies directed against the polynuclear cytoplasm are frequently found in the serum. Corticosteroids associated with cyclophosphamide have considerably improved the prognosis of these conditions.
ACUTE POSTENFECTIVE ACUTE GLOMERULONEPHRITE:
GNA usually occurs in the older child, exceptionally before the age of 2 years. The disease begins 10-21 days after an infectious episode (angina, sinusitis, pyoderma).
The onset is abrupt, marked by haematuria often macroscopic and the appearance of edema. GNA may be accompanied by a nephrotic syndrome. Hypertension is found in half of the cases and renal failure in one third of cases, often transient. In some cases, the disease is inaugurated by severe life-threatening manifestations. It may be oliguria or even anuria. It can be cardiovascular overload with acute edema of the lung, cardiomegaly or even asystole. Finally, GNA can be revealed by cerebral edema with headache, convulsions, blindness or coma.
The streptococcal origin of a GNA can be established in response to an increase in the level of serum antibodies, such as antistreptolysins O. The most important argument is the lowering of the total hemolytic complement and the C3 function of the complement. These anomalies must be looked for early because they are transient. The histological examination of the renal biopsy shows hypercellular glomeruli and deposits on the external side of the MBG called humps, very evocative. In the more severe forms, there is an extracapillary proliferation.
In immunofluorescence, there is an anti-C3 serum fixation on the deposits. Renal biopsy is indicated in cases of severe or prolonged renal insufficiency or in cases of significant proteinuria greater than 2 g / d or nephrotic syndrome persisting for more than ten days in order to detect extracapillary proliferation require additional treatment (methylprednisolone infusions, immunosuppressants).
Evolution is usually favorable in a few days.
Hematuria disappears in 6 months and proteinuria often faster. The prognosis depends essentially on the intensity of the extracapillary proliferation, unfavorable evolutions occurring only when there are epithelial crescents affecting a large proportion of the glomeruli. The treatment is above all symptomatic. Renal insufficiency may justify the use of dialysis.
It is characterized clinically by the association of cutaneous signs in the form of purpura, articular signs and very often digestive disorders. Renal manifestations are observed in 30 to 50% of cases. Most commonly, kidney damage occurs during the first 3 months of the disease and may occur later, especially during a flare-up. Hematuria is almost constant, very often macroscopic. It can be isolated or accompanied by proteinuria of variable intensity. When this proteinuria is abundant, it causes a nephrotic syndrome. In the early stages of the disease, renal insufficiency is infrequent.Similarly, high blood pressure is rarely observed at the onset of the disease. In children with rheumatoid purpura, it is recommended to monitor the urine twice a week on the test strip for kidney damage.
If the proteinuria becomes greater than 1 g / 24 h, it is necessary to perform a renal biopsy in order to detect histological lesions liable to respond to a treatment. The biopsy must therefore be performed early before the histological lesions evolve towards fibrosis.
Examination of the renal biopsy in immunofluorescence shows in all cases mesangial deposits of IgA. Histologically, renal biopsy may show mesangiopathic glomerulonephritis characterized by mesangial cell proliferation. More often, it is a segmental and focal glomerulonephritis. The more severe forms generally correspond to endo- and extracapillary proliferative glomerulonephritis with epithelial crescents in a variable number of glomeruli. The severity of nephropathy is related to the percentage of glomeruli with such epithelial crescents.
The long-term outcome is a function of the severity of the initial renal involvement. When the renal signs at the beginning are minimal (hematuria with proteinuria less than 1 g / 24 h), healing is the rule. On the other hand, when the renal signs are more important, the evolution is variable. Indeed, histological lesions can be important and the risk of long-term evolution towards chronic renal failure is all the more worrying that the percentage of glomeruli with epithelial croissants is greater than 50%.
There is no specific treatment for the disease. In renal impairment, when there is a nephrotic syndrome and significant extracapillary proliferation, a series of three methylprednisolone infusions at a dose of 1000 mg / 1.73 m 2 may be proposed. The infusions are relayed by oral corticosteroid therapy. This treatment is all the more likely to be effective as it is applied early in the first months.
DISSEMINATED ERYTHEMATE LUPUS:
Renal involvement is one of the major manifestations of systemic lupus erythematosus. It results in hematuria, possibly associated with a proteinuria of variable intensity. In more severe cases, proteinuria is accompanied by nephrotic syndrome and possibly renal insufficiency and arterial hypertension. Renal biopsy allows to specify the variety of nephropathy, to make a prognosis and to envisage a treatment. The iterative biopsies then make it possible to judge the effectiveness of the treatment and to assess the evolution of the lesions.
Histologically, it may be mesangial glomerulonephritis, segmental and focal glomerulonephritis, diffuse proliferative glomerulonephritis or GEM. Some superadded lesions, known as “active” lesions, show a progressive development of the disease. A more or less diffuse extracapillary proliferation is observed in severe forms. In immunofluorescence,
abnormal mesangial and parietal deposits, mainly binding the anti-IgG serum and also the anti-IgM, anti-IgA, anti-C3, anti-C1q and antifibrin sera. Finally, in advanced forms, these are sclerotic lesions which it is important to identify because they are insensitive to therapeutics.
Corticosteroid therapy remains the treatment of severe forms, in particular diffuse proliferative glomerulonephritis. It can be administered initially as methylprednisolone infusions. The effectiveness of the alkylating agents has been demonstrated. The percentage of progression to end-stage renal disease is decreased and corticosteroid therapy can be reduced more rapidly. GEMs are not sensitive to treatment. The continuation of the treatment depends on the clinical and biological signs, in particular the level of the anti-DNA antibodies and the serum complement. The side effects of corticosteroids can be major, especially in adolescents, with serious physical and psychological repercussions.
Osler’s disease may be accompanied by a nephrotic syndrome, sometimes associated with renal insufficiency. Other infections may give this picture, such as an infection of an atrioventricular bypass with a staphylococcus or any focus of acute suppuration accompanied by bacteremic discharges.
Quartan fever due to Plasmodium malariae is seen mainly in children and young adults with a peak incidence at 5 years. The fever is present only in the initial phase and takes in the typical forms the aspect of quartan fever, with peaks every 72 hours. After the first few weeks, a nephrotic syndrome develops with generalized edema and ascites.Renal insufficiency with arterial hypertension may occur. Spontaneous remission is rare, with progressive development of renal failure in 3 to 5 years. No treatment has been effective. An association between filariasis and glomerular involvement has been described and is reflected either by a nephritic syndrome or more often by a nephrotic syndrome and possibly renal failure. Renal involvement is possible in infections with Onchocerca volvulus, Wuchereria bancrofti and Loa-loa infections. Chronic infection with Schistosoma mansoni is accompanied by glomerular involvement in 10 to 15% of cases. The most frequent histological aspect is that of a GNMP, but other histological aspects can be seen, in particular segmental and focal hyalinosis. The majority of patients have nephrotic syndrome, high blood pressure and renal insufficiency. Pest control may be effective.
Glomerular disease associated with leprosy has also been reported. The lesions observed are either amyloidosis or other forms of glomerular disease.
Other causes of nephrotic syndrome:
Amyloidosis is defined by the ability of certain proteins (such as Ig light chains in AL primary amyloidosis, amyloid A protein in AA type secondary amyloidosis) to form fibrillar deposits. The deposits contain a non-fibrillar component, the amyloid P component that comes from a normal plasma protein. These fibrils can be identified on biopsies by a characteristic feature in electron microscopy and their ability to fix Congo red (giving a green birefringence in polarized light) and thioflavin (producing intense yellow-green fluorescence). In children, it is mainly amylosis secondary to chronic inflammatory diseases (juvenile chronic arthritis, Crohn’s disease), prolonged infection (tuberculosis, bronchial dilation, osteomyelitis), cystic fibrosis or periodic disease. Amyloid deposits are present in mesangium, glomerular capillaries, small arteries and tubular basal membranes. In the case of glomerular deposits, proteinuria with nephrotic syndrome is common, possibly with moderate renal insufficiency. The treatment of inflammatory disease, chronic infection or periodic disease (colchicine) can prevent the progression of the disease.
It is characterized by progressive haematural nephropathy associated with a bilateral hypoacousia of perception.Proteinuria accompanied by a nephrotic syndrome appears during the course of the disease and shows the severity of nephropathy before the degradation of renal function. Ocular abnormalities (anterior lenticone, retinal anomaly and recurrent corneal erosions) are present in about 40% of cases.
Alport syndrome is a heterogeneous genetic entity. In 85% of the families, the transmission takes place according to the dominant mode linked to the X; the outcome is more severe in men than in women. The mutated gene is COL4A5, encoding the alpha chain of collagen IV. In 15% of families, transmission is autosomal recessive. Renal disease progresses as rapidly in women as in men and the terminal stage of renal failure is reached before 30 years, sometimes as early as childhood. The mutated gene is COL4A3 or COL4A4, encoding alpha 3 or alpha 4 chains of type IV collagen.
Apart from the symptomatic treatment, especially of the hypertension, there is no treatment able to slow the progression of the kidney disease.
This is a dominant condition whose gene has been located on chromosome 9. The gene encoding the alpha 1 chain of collagen V is a good candidate gene. The condition associates nail anomalies (absent, hypoplastic or dysplastic nails), abnormalities of the patella (absent or hypoplastic) and elbows, and the presence of iliac horns at the anteroposterior part of the iliac crest. Renal involvement is noted in half of the cases, manifested by proteinuria, sometimes with nephrotic syndrome, haematuria and arterial hypertension. Renal biopsy, in the case of nephrotic syndrome, shows a thickening of MBG and lesions of segmental and focal hyalinosis. Changes to renal failure occur in 30% of cases.
HEMOLYTIC AND UREMIC SYNDROME:
The typical form, which is the most frequent, most commonly affects infants under 2 years of age. After gastroenteritis with bloody diarrhea, renal and haematological signs appear: proteinuria is associated with hematuria, acute renal failure most often reversible, thrombocytopenia and anemia with schizocytes.
Atypical forms are more rare and are seen at any age, without digestive prodromes. The evolution is more insidious with possible relapses. A nephrotic syndrome is more often observed than in typical forms. The progression towards end-stage renal disease is frequent. There are familial cases of autosomal dominant or recessive transmission. It is important to look for a factor H deficiency responsible for a decrease in C3. In the newborn, cobalamin deficiency may be responsible for hemolytic uremic syndrome.
An abundant proteinuria with nephrotic syndrome and possibly renal insufficiency can be observed during homozygous sickle cell anemia. The histological aspect is that of a GNMP with or without deposits of IgG and of C3 in immunofluorescence.
RENAL HYPOPLASIA OR MALFORMATIVE UROPATHY:
Renal hypoplasia is characterized by small kidneys (less than or equal to 2 DS) without associated urological malformation.
In children with renal hypoplasia or malformative uropathy, signs of glomerular disease are absent. The occurrence of proteinuria may be associated with glomerulonephritis. In other cases, it is the control of severe glomerular lesions of segmental and focal hyalinosis attributed to nephron reduction. This proteinuria is sometimes important and is accompanied by a nephrotic syndrome, contemporaneous with a degradation of the renal function.