by Dr. Fabio Ruben Acosta

Hematuria

Hematuria refers to the presence of blood in the urine, macroscopic or microscopic, which can come from any part of the urinary tract and can be a sign of serious underlying disease , including cancer. The literature supports the concept that the presence of macroscopic hematuria, which is a sign that usually leads the patient to consult, justifies a diagnostic evaluation.

Microscopic hematuria is generally an incidental finding. No organization currently recommends screening for microscopic hematuria in asymptomatic adults, although bladder cancer is the most commonly detected malignant lesion in these patients. However, urinalysis remains an important component of any medical "checkup." Hematuria can be measured quantitatively by determining the number of erythrocytes per milliliter of excreted urine or by the microscopic count of the centrifuged urine sediment.

Definition

It is defined as the evident presence of blood in the urine. It may be accompanied by clots. Microscopic hematuria is the presence of 3 or more erythrocytes per field of high magnification in the microscopic evaluation of the urinary sediment in 2 or 3 suitably collected urinary specimens. In the study of intermittent positive tests for hematuria with more than 3 erythrocytes in 2 or 3 specimens properly collected, this finding should be considered as microhematuria and should be adequately evaluated.

High-risk patients should be considered for complete urological evaluation when 3 or more erythrocytes have been found in a high-magnification field. Macroscopic hematuria should be profuse to determine a change in urine coloration, and on microscopic examination, red blood cells show no or minimal morphological changes. Hematuria involving the renal glomerulus is almost always accompanied by blood cylinders, and erythrocytes exhibit a distortion in their shape, called dysmorphic cells. Proteinuria can accompany hematuria of local origin, if it is severe, but it is always detected in hematuria secondary to diffuse kidney disease.

High-risk factors

• Age over 40 years.
• Cigarette.
• Abuse of pain relievers.
• Pelvic irradiation.
• Schistosoma hematobium.
• Cyclophosphamide.
• Exposure to dyes and rubber compounds.
• Industrial (benzene, aromatic amines).
• History of urological disease.
• History of irritative disorders of urination.
• Hemorrhagic diseases.
• Anticoagulant overdose.
• Renal embolism.
• Acute glomerulonephritis.
• Trauma.

Hematuria evaluation

Laboratory:

• Coagulation studies, with periodic monitoring.
• Uroanalysis: inspection of urine. Glomerular disease is accompanied by proteinuria, blood cylinders, abnormal red blood cell morphology. Proteinuria has been described with severe hematuria in the distal urinary tract and erythrocytes in interstitial nephritis, diabetic nephropathy, renal embolism, renal vein thrombosis, and exercise. The presence of leukocytes or pyocytes suggests inflammation or infection of the urinary tract, but they can also accompany an inflammatory response in glomerulonephritis. Urinary eosinophils can be seen in acute interstitial nephritis. Urinary erythrocytes of various sizes, shapes and hemoglobin contents (dysmorphic) indicate a glomerular process and those with a uniform character (isomorphic) a non-glomerular process. The presence of both populations is not specific.

Test of the three glasses of Guyon:

It is used to approximately locate the topography of gross hematuria. It consists of urinating the patient and trying to distribute the urination in three glasses, with which it is possible to observe:

1. the urine of the three glasses is red (all the urine is stained red). It is a total hematuria and the location of the bleeding is the kidney and the initial part of the ureter.
2. the urine of the first glass is reddish while that of the second and third is amber yellow (at first it comes out red and then it is normal in color). It is an initial hematuria and the location of the bleeding is the lower part of the bladder and the membranous and prostatic urethra.
3. The urine of the first two vessels is normal (amber yellow) and that of the third vessel is red or dark brown in color. It is a terminal or final hematuria and the bleeding site is at the back or background of the bladder.

Table (1) shows the multiple causes of hematuria depending on the site of bleeding from the urinary tract.

Hematuria diagnosis

1. Questioning: Age can serve as a guide since glomerulonephritis and pyelonephritis are more frequent in childhood. In adulthood, lithiasis, pyelonephritis, glomerulonephritis and tuberculosis. After 50 years, kidney and bladder cancer and prostatic pathology (adenoma and carcinoma) predominate. You can also see lithiasis and urinary infections.
   The history can be important: A family history of kidney disease and deafness, sometimes with ocular changes (cataracts, keratoconus) orient Alport syndrome (glomerulopathy). Relatives of the patient in 1 or 2 who suffer from bleeding tendencies orient coagulopathy. Polycystic disease in one of the parents or grandparents is an important fact. Ingestion of medications can cause hematuria and should be investigated, especially pain relievers and / or anticoagulants.
   Some symptoms are guiding: for example a renal colic followed by hematuria or a lithiasis, but if in this context vermiform clots are removed, think of destructive kidney disease (TB, cancer). If in addition to hematuria there is fever and low back pain without colic, think of acute pyelonephritis and if anuria and removal of pieces of tissue in a diabetic are added to this symptom, think of necrotizing renal papillitis. A hypogastric pain that radiates to the penis, with tenesmus accompanying hematuria, leads to a bladder stone. A painless hematuria with a history of polydictor nocturia and dysuria leads to suspicion of prostate disease. A history of cardiac arrhythmia (atrial fibrillation) with hematuria, with or without low back pain leads to suspicion of renal embolism. The same if the patient is having a myocardial infarction. But if you receive heparin for a heart attack, it is necessary to differentiate iatrogenesis from embolism.
2. Physical Examination: A complete examination should be carried out and not only of the urinary system, since extra-urinary signs can provide valuable elements for the diagnosis. Thus we will have that in a patient with purpura and a history of other bleeding (epistaxis, gingivorrhagia, enterorrhagia or melena), it is possible to think of a hemorrhagic, spontaneous or anticoagulant-induced diathesis (history of receiving dicumarinics). If there is arthritis or arthralgias with bloody diarrhea and abdominal colic after an upper respiratory tract, anaphylactoid purpura from Schonlein Henoch may be suspected. If the patient has, in addition to hematuria, subcutaneous edema and high blood pressure, an acute or subacute nephritic syndrome may be considered, and if there are signs of heart failure with anorexia, nausea or vomiting and poor general condition, It is a chronic glomerulopathy with end-stage renal failure. In a female patient, hematuric, micro or macroscopic, with arthritis, fever and butterfly wing malar erythema, think of systemic lupus erythematosus.
   On examination of the urinary system, the kidneys will be palpated since a unilateral painless nephromegaly can lead to renal cancer, if it is bilateral, polycystic kidney disease, if it is painful and unilateral and preceded by colic rather corresponds to lithiasic uronephrosis. Positive fist percussion can target pyelonephritis, lithiasis, tuberculosis, renal infarction. The same goes for pain at the ureteral points. Palpation and percussion of the hypogastrium will provide us with information on bladder pathology and / or low urinary retention. Do not forget the rectal examination that will inform us of the prostate.
   Imaging evaluation: although Intravenous Urography is the best procedure for evaluating the anatomy of the upper urinary tract in patients with hematuria, its role has recently been questioned. Retrograde pyelography should be performed when urography does not visualize the entire urinary tract. Despite the fact that intravenous urography is easily accessible and inexpensive, its sensitivity is lower in detecting small renal masses. Some authors consider that a renal ultrasound can replace it with a minimal decrease in diagnostic capacity, but it fails to detect some ureteral stones and, most seriously, even in urothelial tumors of the collecting system. Such a strategy is preferable in the patient at high risk of contrast nephropathy. In this case, a Computerized Axial Tomography (CAT) is suggested due to its greater sensitivity to detect lesions smaller than 3 cm and those that do not directly deform the pyelocaliceal system. CT is the preferred modality for the detection of solid renal masses, and is comparable to Magnetic Resonance, but more accessible and less expensive. It is the best modality for detection of stones, kidney and perirenal infections, with a sensitivity of 94-98% for detection of kidney stones. Helical CT urography is an excellent complement.
3. Urethrocystoscopy: detects bladder cancer with a sensitivity of 87% (9). Cancers that can escape are carcinomas in situ. Cystoscopy should not be postponed, because an intermittent bleeding lesion may leak.
4. Urinary cytology: in large series, urinary cytology has had a sensitivity of 67% and a specificity of 96% in the detection of urothelial cancer, especially of the bladder. It should be done on a fresh urine sample, bladder washes, or endoscopic brushing. In carcinoma in situ of the bladder, cytology may be positive before being detected by cystoscopy.
5. Renal biopsy: there is no consensus on the indication for renal biopsy. Opponents believe that the biopsy results have not affected the treatment of those patients with hypertension, reduced creatinine clearance, or proteinuria. Others find that kidney biopsy changed therapy in some hematuria and proteinuria patients.

It should be added that in hematurias in which glomerular disease is suspected, in addition to the usual techniques of light microscopy, immunofluorescence is used to identify deposits of immune complexes in said structure, and electron microscopy to identify the exact location of said deposits in the glomerulus walls.

The most common findings are:

• proliferative glomerulonephritis, especially Ig A nephropathy.
• Diffuse proliferative glomerulonephritis, basement membrane disease.

Summary:

• Not all hematurias are of urinary cause.
• Hematuria accompanied by blood cylinders and proteinuria of 24 hours. greater than 1 g. and / or with deformed red cells in the sediment, it is probably of glomerular origin.
• The three-vessel test is useful in locating the origin of a macrohematuria.
• An anamnesis should be made regarding recent previous medications and concomitant symptoms when there are no urinary symptoms.
• The physical examination must be complete and not only of the urinary system.
• Ask for complementary studies that are cheaper, less invasive or less subject to toxic side effects and that provide more information. Example: routine analysis with excretory urography or bilateral renal vesicoprostatic ultrasound.
• In the elderly, the most frequent causes of hematuria are bladder cancer, kidney cancer, prostate disease, and lithiasis.

Finally, the figure shows an algorithm to follow in case of hematuria.

Proteinuria

Proteinuria is the presence of proteins in the urine, whether it is normal, the result of special physiological situations, or pathological. This last condition is usually simply called proteinuria.

Laboratory methods to determine proteinuria

There are different options to determine or quantify the presence of proteins in the urine. The dipstick or test strips have the advantage of being a quick and cheap method, however it offers many false positives. It is based on a colorimetric method and gives the results in ranges:

• Negative (0-10 mg / dL)
• Traces (10-20 mg / dL)
• + (30 mg/dL)
• ++ (100 mg/dL)
• +++ (300 mg/dL)
• ++++ (1000 mg/dL)

It is quite sensitive to albumin, but does not detect small proteins such as macro and micro globulins or Bence Jones proteins.

There is another method, which is used less and less, and is based on sulfosalicylic acid (SSA). It is a qualitative test based on comparative turbidity, it is more sensitive for low weight proteins and can detect levels from 4 mg / dl.

Normal proteinuria

An average of 80 ± 24 mg / day of protein is detected in the urine of healthy people; the normal limit is 150 mg / day in adults and 140 mg / m2 / day in children.

Under normal conditions, the glomerular capillary wall limits the filtering of plasma proteins in relation to their molecular size and their electrical charge. The large proteins practically do not appear in the glomerular filtration or do so in minimal quantity. Albumin filtration is very limited due to its medium size and anionic load, although due to its high plasma concentration and the large total volume of glomerular filtration, significant amounts pass into the urinary space. Low molecular weight proteins are easier to filter, and for some of the proteins in this heterogeneous group, the concentration in the filtrate is greater than 50% of the plasma concentration.

In an adult individual, (Figure 3) the daily filtered mass, that is, the product of the glomerular filtration rate by the concentration of proteins in the filtrate, is 5 g / day. Renal tubular reabsorption plays a very important role in preventing body protein depletion. Daily, the reabsorbed mass (filtered mass - excreted mass) is close to 4950 mg / d. Protein reabsorption occurs mainly in the proximal tubule, in the Sl and S2 portions. It is a reabsorption mediated by endocytosis. Tubular protein secretion occurs only in the ascending part of the Henle loop. The only protein described so far, secreted into the tubular lumen, is the Tamm-Horsfall protein.

Therefore, the normal protein composition of urine is represented by 10-20% albumin and 60-80% Tamm-Horsfall protein.

Abnormal proteinuria. Pathophysiological classification

If the measurement is adequate, proteinuria greater than 150 mg / 1.7 m2 / day is abnormal. There are certain circumstances in which in the absence of any type of alteration of the glomerulus, functional or structural,

significant amounts of protein appear in the urine.

Proteinuria in special situations

These forms of proteinuria are transitory and functional and their differential diagnosis consists precisely in demonstrating these two characteristics.

• Transient proteinuria: In certain situations, such as intense exercise, uncomplicated pregnancy, fever, seizures, infections and heart failure, proteinuria may appear that does not express glomerulo-tubular pathology, but rather special conditions of glomerular filtration, generally mediated by angiotensin II and norepinephrine.
• Orthostatic proteinuria:  It appears in adolescents and in people with hyperlordosis in prolonged orthostatic disease; normal proteinuria increases and disappears with decubitus. Its amount is usually less than 1 g / day. In most cases it does not involve  any disorder. If it is associated with high blood pressure or sediment disturbances, its prognosis is more uncertain. Sometimes it transforms into persistent proteinuria.

Pathological proteinuria

It is a persistent proteinuria (Fig. 4) and according to its characteristics and amount it is classified in two ways:

Microalbuminuria. Normal urinary albumin clearance is 5 to 30 mg / day. Persistent albuminurias between 30 and 300 mg / day are considered pathological and are called microalbuminuria. This degree of albuminuria is not detectable by conventional urine test strips. Ideally, 24-hour urine measurement should be performed using radioimmunoassay, radioimmunoassay technique (ELISA), or nephelometry. For simplicity, it has been suggested that it could be determined in urine of shorter periods or in samples in the early morning; It can also be measured in relation to the creatinine concentration in the same urine. In adults, 30 mg albumin / mg creatinine would be equivalent to 30 mg / day of microalbuminuria. This ratio depends on the usual daily excretion of creatinine. Positive cases should be confirmed in 24-hour urine. Fever, exercise, poor blood glucose control, and heart failure can cause transient microalbuminuria. Its detection is important in diabetes and arterial hypertension because it implies incipient glomerular involvement. It can be considered as a cardiovascular risk prediction factor.

Pathological or clinical proteinuria. It is characterized by persistent proteinuria greater than 300 mg / dl. The figures of pathological proteinuria have prognostic value and determine the diagnosis and treatment regimen. Protein lower than 2 g / day are considered mild, mean between 2 and 3.5 g / day; higher values ​​define the nephrotic syndrome.

The mechanisms of glomerular proteinuria are as follows: 1- Decreased negative charges on the glomerular capillary wall, 2- Structural changes of the basement membrane that increase pore size, and 3- Increased intraglomerular capillary pressure.

Regarding the qualitative classification of proteinuruia, they can be SELECTIVE (filters almost exclusively albumin) and NON-SELECTIVE (filters albumins, immunoglobulins and other proteins).

The aetiological classification of proteinuria is summarized as follows:

• Mild grade (<1gr./24 hs)
  • Benign nephroangiosclerosis
  • Incipient Diabetic Nephropathy
  • Polycystic kidney disease
  • Medullary cystic disease
  • Obstructive nephropathy
  • Glomerulonephritis
• Moderate Grade (1-3.5 gr./24 hs)
  • Primary Glomerular Nephropathies
  • Secondary Glomerular Nephropathies
  • Advanced kidney disease
• Severe degree (> 3.5 gr./24 hs)
  • Primary Nephrotic Syndrome (Minimal Change Nephropathy, Membranous Nephropathy, etc.)
  • Secondary Nephrotic Syndrome (Diabetes Mellitus, SLE, Amyloidosis, Cryoglobulinemia)

Physical exam

• Edema: eyelids, ankles, scrotals, areas of decline. More severe cases can have anasarca, pleural effusion and ascites.
• Diuresis: oliguria – normal.
• Manifestations of thrombotic complications of nephrotic syndrome
• Deposits of skin lipids (xanthomas)
• Lipiduria
• Hypertension or arterial hypotension.