An organic nephropathy is almost always characterized by the presence of proteinuria, which, in many cases, is the earliest sign of renal impairment. Most of the proteins present in the urine are of plasma origin; however, if proteinuria originates from renal parenchymal lesions, secondary to ischemic, hypoxic, or toxic insults, proteinuria may also be represented by tissue proteins of the kidney and urinary tract. Of particular interest is the Tamm–Horsfall protein (THP), or uromodulin, a glycoprotein with immunosuppressive action secreted by the ascending tract of Henle’s loop: its average urinary excretion value is around 20–200 mg/day. THP has a MW of 85 kDa and is found in the urine in polymerized form, in aggregated subunits; it has an important role in the formation of urinary cylinders and shows antiviral activities, but, due to the high content in carbohydrates, it escapes the common methods used for the measurement of total urinary proteins. Recently, the role of THP in CKD and hypertension has been reevaluated, especially as a risk factor. It has also been shown that high THP concentrations reflect good renal reserve and are inversely correlated with the risk of GFR decay and AKI. Other urinary proteins of renal origin are protein 1, or Clara cell protein (CC16; PM = 15.8 kDa), and tissue enzymes, such as urokinase, an enzyme with antifibrinolytic activity, as well as other enzymes, such as alanine aminopeptidase (AAP; E.C. 3.4.11.2) and N-acetyl-β-D glucosaminidase (NAG; E.C. 3.2.1.30), whose increase in urine is of particular interest in the diagnosis of toxic nephropathy and, more generally, of tubulointerstitial nephritis. From a general point of view, proteinuria can be classified into physiological, transitory (intermittent or functional), and associated with nephropathies. There is a general agreement in defining “physiological” a content of urinary proteins in healthy adults not higher than 150–200 mg/ die/1.73 m2 of body surface (about 100–150 mg/L). Transient proteinuria is the nonconstant presence of protein in the urine. This type of proteinuria is also defined as functional, and it is essentially related to transient hemodynamic alterations (renal blood flow), which affect the reversible increase in glomerular permeability both in certain physiological situations, such as prolonged physical activity or heavy exertion, pregnancy, and intense cold, and in pathologies involving extrarenal organs and apparatuses, such as fever and hyperthermia, emotional stress, noradrenaline infusion, heart failure, and prolonged hyperlordotic posture, typically characteristic of orthostatic proteinuria. When the concentration of proteinuria stably exceed (at least three successive determinations) the threshold of physiological proteinuria, we talk about pathological or overt proteinuria. In the presence of proteinuria, it is absolutely necessary to establish its entity and composition. According to its composition, proteinuria can be classified into glomerular, tubular, mixed, and overflow proteinuria.

Glomerular proteinuria consists mainly of plasma proteins of PM >60 kDa. The term “selective proteinuria” indicates a glomerular proteinuria consisting almost exclusively of proteins with a MW between 60 and 150 kDa. The selectivity of glomerular proteinuria positively correlates with the ability of the glomerular filter to retain proteins with high and very high MWs (>150 kDa), distinguishing them from those with lower MWs. “Non- nephrotic glomerular proteinuria” refers to the excretion that does not exceed 3.5 g/day; above this limit, we talk about “nephrotic proteinuria,” which is usually accompanied by the clinical and humoral manifestations of the nephrotic syndrome: edemas, hypoalbuminemia, and increased globulins with the simultaneous presence of hypogammaglobulinemia. In these cases, protein loss can be marked (5–10 g/day), even reaching massive levels (more than 40 g/day). Tubular proteinuria consists of plasma proteins of low MW or microglobulins (MW ≤50 kDa). Mixed proteinuria results from the presence of high- and low-MW plasma proteins and proteins and enzymes of renal origin. It is predominantly found in conditions of impaired glomerular and tubular function. Finally, proteinuria due to overload, also called extrarenal proteinuria, is constituted by low-MW plasma proteins that are not normally present in the circulation or at most are present in low concentrations. In this case, the presence of extrarenal pathologies characterized by specific pathological mechanisms affecting organs and tissues (proliferation, cytolysis, etc.) causes an abnormal increase of proteins in the plasma and in the ultrafiltrate; this increase quickly saturates the tubular reabsorption mechanisms, causing their appearance in the urine. Typical examples include myoglobin, and immunoglobulin free light chains.

The approach to the study of proteinuria is developed through three phases: research, measurement, and characterization of the composition of proteinuria. The presence of proteinuria must be ascertained in all cases of suspected nephropathy or, in the absence of signs and/or symptoms, in all cases of hematuria, urinary tract infection, etc. If the presence of proteinuria is ascertained, it should always be measured to ascertain its extent. Finally, the characterization of the composition of proteinuria is an important evaluation criterion for the diagnosis and clinical classification of renal pathology. For these reasons, the methods can be schematically divided into qualitative and quantitative methods. Qualitative methods, such as dry chemistry methods (dip stick, see the section “Standard Urine Test”) and electrophoretic separative methods (solid support or liquid phase, namely capillary), allow the detection and characterization of proteinuria. Separative electrophoretic methods are the only ones able to highlight the morphology of the free light chains, allowing the diagnosis of Bence Jones proteinuria in the case of monoclonality. Quantitative methods allow deter mining the concentration of total proteins and of the main urinary specific proteins. In particular, the determination of total proteins in urine has several critical issues that have not yet been resolved, mainly due to the poor standardization of methods and numerous analytical interferences. The direct colorimetric methods constantly show, even if in a pronounced form, a limitation given by the different affinity of the dye for the different protein structures. It follows that in a urine sample, the prevalence of a certain type of protein structure rather than another (globulins rather than albumin, or vice versa, etc.) inevitably leads to overestimates or under estimates of the real protein content, with poor accuracy of the determination. To overcome this serious problem, the use of sodium dodecyl sulfate (SDS) was introduced, to be added in a defined amount to the reaction mixture containing the dye. The use of SDS increases the linearity range of the colorimetric method. To date, there is no definitive consensus on the choice of reference method for the determination of total urinary proteins: one of the few recommended methods for urinary proteins is the biuret colorimetric method after gel filtration, identified as the selected method. However, other recommended methods are affected, to a greater or lesser extent, by pitfalls related to interferences, protein pattern composition, etc. However, it is desirable that a good method can achieve wide ranges of linearity, allowing accurate measurements of protein concentrations between about 0.025 and 4.0 g/L.

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مواضيع ذات صلة

Water Balance

Albuminuria

rheumatoid factor (RF)

reticulocyte count (Retic count)

red blood cell indices (RBC indices, Blood indices)

NGAL

Biomarkers of Tubulo-Interstitial Injury

Low-Molecular-Weight Plasma Proteins

Immunofluorescence Assay (IFA)

Enzyme-Linked Fluorescent Assay (ELFA)

Diagnostic Evaluation of Lyme disease

red blood cell count (RBC count, Erythrocyte count)