Proteinuria is present abnormal quantity of serum protein in urea in children who are under the twelve years. It also says albuminuria or urine albumin; it is a condition which urine contains an abnormal amount of serum protein (1).This is not a direct indication (11).
This can be signified as a renal disease. But heavy proteinuria with edema suggests nephritic syndrome (3). Generally proteinuria isassociated with many diseases and conditions.
Amyloidosis, bladder cancer, congestive heart failure, diabetes, drug therapies that are potentially toxic to the kidneys, glomerulonephritis, goodpasture's syndrome, hypertension, heavy metal poisoning, Kidney infection, multiple myeloma, Polycystic kidney disease, systemic lupus erythematous, urinar tract infection are some of examples for the conditions and diseases (5).
Types of proteinuria
Interminent proteinuria
Postural (orthostatic) proteinuria
Nonpostural proteinuria
Persistent proteinuria
Glomerular proteinuria
Tubular proteinuria
Transient proteinuria
Transient proteinuria is called functional proteinuria. This is not a long term disease and clears when the affected factor is removed.10% of children have been detected as children with proteinuria by a single dipstick measurement. But only 1% of children have been detected as persistent proteinuria when measured on 4 separate occasions. This phenomenon is called transient proteinuria. As well as this is caused by temperature > 38.30C (1010F), fever, exercise, dehydration, congestive heart failure, cold exposure, seizures, or stress. Not only that, hemodynamic alterations in glomerular blood flow also causes to transient proteinuria (2, 7, 12).
Nonpostural proteinuria
Fever, exercises, anatomically abnormities of urinary track & glomerular lesions cause to nonpostural proteinuria (1).
Orthostatic proteinuria
Orthostatic proteinuria is called postural proteinuria. Postural proteinuria may be the reason for the most of patients with persistent proteinuria. It is about 60% of all cases of asymptomatic proteinuria in children (2, 8). This is a common disease in school age children and mainly it can be seen in adolescence (12). In some patient with high level of protein in the urine occur during the day and absent at night and when the patient is in lying down position. They are suffering from orthostatic proteinuria (5). However the cause of orthostatic proteinuria is not understandable. But the anatomic compression of the left renal vein is considered as the reason. In the diagnosis of postural proteinuria, normal protein excretion thus negative dipstick test result or UPr/Cr of 0.2 or less is the value expected from the patient in the first- morning urine sample after the child was kept supine for the entire night. But increased protein excretion thus positive dipstick test result or UPr/Cr greater than 0.2 at least four to six hours after the child was kept upright (12).
Persistent proteinuria (Fixed proteinuria)
Persistent proteinuria can be divided in to glomerular and tubular protinuria in origin. In these two diseases the causes are primary stemming intrinsically from the renal tissue and secondary cause is systemic diseases. If proteinuria is related with hematuria renal dysfunction and hypertension, significant renal disease will occur. Some of patients who have significant proteinuria on 3 repeated days are believed that they have fixed proteinuria (2, 12).
Glomerular proteinuria
Glomerular diseases can be seen often than tubulointerstitial diseases. Albumin and immunoglobulin G in the urine is the main cause for glomerular disease. Isolated asymptomatic proteinuria, damaged to glomerular basement membrane, less or reduction of basement membrane anione change, & increased permeability in residual nephrons causes to glomerular proteinuria (1). And it may nephrotic or nephritic features. But it is difficult to differentiate these two conditions. Nephrotic syndrome can be identified by heavy proteinuria which is greater than 1 g per mper day or UPr/Cr greater than 2.0, edema, hypoalbuminemia which is less than 25 g per, and hyperlipidemia. Nephritic features include hematuria, hypertension, oliguria, and active urinary sediments, such as red blood cells, white blood cells, and cellular casts. IgA nephropathy, acute postinfectious glomerulonephritis, lupus nephritis, alport syndrome are causes for glomerulars disease with proteinuria as a feature. Focal segmental glomerulosclerosis, mesangial proliferative glomerulonephritis, membranous nephropathy, membrenoproliferative glomerulonephritis, Amyloidosis, diabetic nephropathy, and sickle cell nephropathy are causes for glomerulars diseases characterized by isolated proteinuria (2, 12).
Tubular proteinuria
Proteinuria related with renal tubular disorders is normally mild. Heredity like cystinisis, lowe syndrome,Wilson disease, proximal tubular acidosis, galactosomia & acquired condition like interstitial nephrititis, acute tubular necrosis, post renal transplantations, heavy metal poison (Au/Pb/Hg/), analgestic abuse, drugs, renal dysplasia, polycystic kidney disease, reflux nephropathy causes to tubular proteinuria (1). Tubulointerstitial diseases may be the rare causes of proteinuria. generally low-molecular-weight proteins are involved.Tubular proteinuria cause to make a diagnostic problem as the basic disease is detected regularly before the proteinuria (12).
Causes of proteinuria in children
Proteinuria is normally occurred by chronic kidney disease, hypertension, diabetes mellitus, allergy, cytomegalovirus, Epstein Barr virus toxoplasmosis, cardiac failure & any other disease that cause in inflammation in the kidneys. HIV, leukemia, malaria, syphilis, primary glomerulonephritis polycystic kidney disease, fabry disease, filariasis, leprosy, lymphoma are rare causes for the proteinuria in children, and acute post infectious glomerulonephritis are common medical causes for proteinuria (1, 8, 11).
Nephrotic syndrome is a disorder which is 15 times more common in children than adults. Leaking protein into the urine by kidneys is the condition of nephrotic syndrome and it is caused by increased permeability of the glomeerular capillary wall, the basement membrane of the kidney's filtering system. Heavy protinuria, hypoalbuminia, edema and hyperlipidemia are characteristic features of this syndrome. The low blood protein levels cause to make a swollen child as a result of increasing water in the tissues. The patients with nephrotic syndrome have increased intravascular volume with decreased plasma levels of rennin and aldosterone (2, 8).
Acute postinfectious glomerulonephritis is an inflammation of the kidney with the affection of streptococcal infection (ex: - strep throat). Fluid accumulation and tissue swelling initially in the face and around the eyes, later in the legs, low urine output which is named oliguria, hematuria which is the condition of blood in the urine, protein in the urine named proteinuria, joint pain or stiffness and high blood pressure are the symptoms of acute poststreptococcal glomerulonephrists Most of children about 95%, entirely get well within a subject of weeks or months (2, 8).
Mechanism of Proteinueria
It is protein present in children's urine. When blood goes through the kidneys, blood is filtered by them. Mainly water, excess fluid and salt such as K+ , Na+ , Cl- , serum protein, glucose. In proximal xxxxx tube & distal xxxx tube, most of filtered solution reabsorbed in to them, except wastes products which produced by metabolism activities.
If protein is found in your child's urea, it is say that your child's kidney is not working properly. Sometime it may be inflammation & swelling. In addition to there will be infection or chemical damage in kidneys. Because of these maters also protein will be present in urea.
Proteinuria is a main feature of renal diseases. Sometime proteinuria associates with hematuria it is much more significant. In normal person protein filtration is occur in very low quantity. In normal condition <96,000 molecular weight substances are not be filtered through renal tubule. It is called change & size selectively of glomerular filtration barrier (1). There are three layers of glomerular barrier which are the fenestrated endothelium, the basement membrane, and the podocytes can form both a size-selective and electrostatic filter (12). Small molecular weight proteins were cleared more readily than the large ones and it is called 'selectivity (6).
That filtration occurs through podocytes in broman tissue. Can't go so large protein molecules through the spaces of podpcytes in the normal condition. That is the one reason for selective permeability. And other reason is protein´s charge. Proteins are negatively charged molecules. The filtration barrier also negatively charged. Because it contain sialoprotein & proteoglycans. Heparin sulfate is proteoglycan like this. So negatively charged protein molecules unlike to go through the negatively charged molecules. So protein filtration is minimum. There is a collagen meshwork before the podocytes it also called visceral glomerular epitheial cells (1). patients with specific symptoms like macroscopic haematuria or nephrotic syndrome are in a risk of having proteinuria. As well as patients who have non-specific symptoms which are generally looking to exclude urinary tract infection are also victims of proteinuria. Not only that it is asymptomatic in some of children with of proteinuria (9).
Increased glomerular permeability cause to proteinuria, it may be affected on below causes.
Loss of the negative charges in the filtration barrio.
In increase in the effective pore size or number due to the direct damage to components of the filtration barrio.
The hemodynamic effect if angiotensin ii & other vasoactive amines, which may explain the mild proteinuria seen with heart failure. "
Although globulin present in urine, albumin is the pre dominant protein lost in that urine. Because albumin has molecular weight near to 69000. In glomerules, only small molecular plasma proteins are filtered. And most of them are reabsorbed to blood by renal tubule. It can be seen in even urine, by dipstick test. We can get color change according to amount of protein present in the urea, by the dipsticks are impregnated with tetrabromophenol blue. Tetrabromophenol is sensitive to t e albumin. But sometime it may not be detected because low concentration of gamma globulins & Bens Jones proteins. So to detect them, it is needs another method.
Total protein excretion in normal child does not higher than 4mg/h/m 2 . If it is exceed more than 150mg/d, (1) it is called as proteinuria. Like value 40mg/ h/m 2 is the severe condition (4). It is called as nephrotic syndrome. Most of the patients which proteinuria on dipstick test may not have significant renal problem.
Proteinuria may result from
Increased glomerular permeability (glomerulonephritis) (1,4)
Impaired tubular reabsorption (Faconi syndrome, acute tubular necrosis, interstitial nephritis)
Orthostatic or postural proteinuria. A begins condition that result from prolonged periods of standing; it is confirmed by obtaining negative urinalysis result after 8 hours is supine position.
Dipsticks test for trace amount of protein yield positive result at concentrations of 5-10 mg/ 100mg lower than the threshold for clinically significant proteinuria. A result of 1+ corresponds to approximately 30mg of protein per 100ml & is considered positive; 2+ correspond to 10 mg/100ml , 3+ to 300mg/100ml & 4+ to 1000mg/100ml"
For genuine dipsticks tests, needs a 24 hour urine collection. But to small child this method is not success. So in small Childs get a random single sample estimation of urinary protein /creatinine ratio. It will give useful information easily.
Treatments
Primary treatment for the proteinuria witch associate with many diseases by immunomodulator medications and it is believed that it is a very successful treatment. As well as it depends on immune mediated mechanism and it cause to decrease the proteinuria.
ACE inhibitors and angiotensin-receptor blockers can act with antiproteinuric actions. Not only that, they affect on controlling of hypertension which is an affecting cause of the proteinuria. As a solution for the chronic kidney disease which is caused by increased intraglomerular pressure and hyperfiltration, the antiproteinuric action of this mechanism is selective vasodilatation of the efferent arteriole and it decrease the filtration pressure and, the amount of albumin in the ultrafiltrate. But nondihydropyridine calcium channel blockers are not affecting intraglomerular pressure and also reducing albuminuria. ACE inhibitor involves in reduction of angiotensin II and then the decreasing accessibility to bind to angiotensin type-1 receptors in proximal tubule cells and it cause to move reabsorbed albumin away from lysosomal degradation and toward the direct reclamation pathway of whole albumin. via a high-capacity rapid transtubular pathway and its return to the circulation. In here , the high level of albumin-binding sites are established by the apical membrane.
Intraglomerular hypertension is caused by decreased number of undamaged nephrons and it causes to increase mesangial stretch. Trigger release of transforming growth factor β (TGFβ) and other proinflammatory cytokine which can weak the reabsorption of albumin by the proximal tubule (7).
Normal condition
According to the things mentioned above, majority of the filtered protein in glomerular are reabsorbed. But small quantity of protein be excreted by normal child. That value is 4mg/h/m2 or 150mg/24h. albumin get the highest ratio in protein excretion. It is near to 25% of excretion protein. After the heavy exercise, proteinuria is increased to a high value. So that albumin excretion is go up near to 80% in the total excreted urine protein. In healthy state proteins that are low molecular waited than albumin are filtered by the glomerulus and reabsorbed in the proximal tubule (1, 2).
How to detect proteinuria
According to the points which are mentioned above, that test which use to detect proteinuria called dipsticks test. It is go with a dye tetrabromophenol blue. It's color changing occur according to amount of proteins which are presented in the tested urine (1). We can mainly detect the albumiuria by that test. As well as that test is less sensitive for other forms of proteinuria (2).
But with the low concentration of globulin, hemoglobin, Benes Jones protein & micoproteins in urine. In negative dipsticks does not exclude. There should be detected by 3% sulphosalicylic acid. But dipsticks test is commonly used in clinical section. . In pregnant women, high protein levels in urine can be associated with precalmpsia (5). Dipsticks can not measure protein excretion accurately. And dipsticks more sensitive. To get idea about severerity & follow the process of proteinuria, get urin protein; creatinine ratio. The normal value of the protein ; creatinine ratio is <40mg/m mol in early morning urine sample (1).
Trace = 5-20 mg/dL
1+ = 30 mg/dL
2+ = 100 mg/dL
3+ = 300 mg/dL
4+ = Greater than 2000 mg/dL are the estimated protein concentration, with results (7)
For the determination whether there is persistent proteinuria or not, a 24-hour urine collection is wanted from the patient with proteinuria within two weeks of the febrile episode. Bacterial and viral respiratory infections is 30%, viral exanthemata is 4%, gastro-enteritis is 8%, infectious hepatitis is 5%, and viral stomatitis is 4% are the percentages after diagnosing (10).
Sulphosalicylic acid method is also can be used to diagnose.
Laboratory test
A complete blood count and serum electrolyte, serum creatinine and blood urea nitrogen measurements should be checked if someone assumes that patient has renal disease. It is suggested that impaired renal function is occur if there is an elevation in blood urea nitrogen or serum creatinine. Additional blood work should be ordered when specify by history, physical examination, or initial laboratory results .Hematuria which is caused by more serious renal diseases is a secondary disease to simple urinary tract infections (12).
Imagine studies
Ultrasonography of the urinary tract is done for anatomic abnormalities. It is a suitable noninvasive screening test. As well as patients with chronic kidney disease should be aware with this test. To detect renal scars a dimercaptosuccinic acid scan is the ideal study (12).
Renal biopsy
This is not an essential test which relevant to proteinuria. When proteinuria is associated with active urinary sediments, hypertension, persistent and gross hematuria, hypocomplementemia and renal insufficiency with depressed glomerular filtration rate which is less than 60 mL per minute per 1.73 m2 for more than three months should be done the renal biopsy. In some patients with nephritic syndrome and patients who can't response to corticosteroid treatment should get this treatment (12).
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Management
First we should make sure whether the proteinuria is transient or orthostatic. If the child is asymptomatic, there is no any doubt about hematuria, and the child is safe. As well as normal blood pressure and glomerular filtration rate can be expected. When significant proteinuria persist the child should get a physical examination, urinalysis, blood pressure measurement, and blood tests for creatinine and urea nitrogen levels every year or every 24 weeks. Specific limitation on diet or physical activity is not prescribed. If the child is sure, the tests can be done annually.
Patients who have idiopathic nephritic syndrome should be given a trial of prednisone thus 2 mg per kg per day, or 60 mg per m.per day to a maximum of 80 mg per day, in up to three divided doses for 4 to 6 weeks, followed by treatment on every other days for another 4 to 6 weeks. Some patients fail or intolerable of some adverse effects. If it is so the second-line therapy is wanted to the patient. Cyclophosphamide, cyclosporine (Sandimmune), chlorambucil (Leukeran) is given as the second line therapy. An adjunctive angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin-II receptor blocker are used to reduce proteinuria and to slow progression of renal disease in patients with renal dysfunction. For a perfect diagnosis or consideration of renal biopsy appointment to nephrologists is required.
Clinical features
With cause of hyperfiltration due to loss of nephrons history of vesicoureteric reflux or recurrent urinary tract infection appears as the clinical features. nephritic features recent upper respiratory tract infection, microscopic hematuria interspersed with episodes of macroscopic hematuria are occurs when IgA nephropathy is the cause for proteinuria. As the reason of Membranoproliferative glomerulonephritis Nephrotic and nephritic features history of chronic hepatitis B or C is associated with infections, rheumatologic disease, and malignancies showing clinical features.
As well as acute tubular necrosis cause to make medication historyaminoglycosides, cisplatin, amphotericin B, NSAIDs history of radiocontrast media. Hematuria, nephromegaly, hypertension, renal insufficiency, family history of the condition can be considered as clinical features in polycystic kidney disease. Within the cause of pyelonephritis fever, chills, hematuria, flank and costovertebral tenderness, irritative urinary symptoms may occur. In diabetes mellitus polyuria, polydipsia, polyphagia, weight loss can be identify as clinical features (12). Toxins which cause for proteinuria like copper, lead, mercury appear clinical features. Lead is caused for constipation, lead line along gum margin, cognitive or behavioral impairment. Mercury also can cause to dental amalgam filling, may have cognitive impairment and nephrotictype syndrome however clinical features help to diagnose and find the cause which affect on proteinuria.
Tubular proteinuria
