Nephritic Syndrome and Urine Examination

Examination of fresh urine as part of routine physical examination may show the presence of protein, blood or pus cells in the patients affected by nephritic syndrome. In many cases the renal disease is occult and is often detected during the routine physical examination. It is important to understand that acute nephritis, nephrotic syndrome and renal failure may occur either as a result of intrinsic disease of the kidneys or in association with a systemic disease. Metabolic and functional disturbances such as hypertension, uremia (elevated level of urea in blood), or anemia may cause occult renal disease.

Hypertension along with mild edema (swelling), apparently as suborbital puffy eyes is characteristic clinical feature of nephritic syndrome. Hematuria (blood in urine) with or without proteinuria (protein in urine), oliguria (low urinary output) and impaired excretory function are other characteristic features. The urine may be red or brownish to smoky brown in color in patients affected by nephritic syndrome. Microscopic examination of fresh urinary sediment in these patients may reveal very high count of dysmorphic red blood cells (dysmorphic RBCs). The detection of RBCs in the urinary casts signifies that the hematuria comes from the kidneys (renal parenchyma). Proteinuria may vary from 0.3g to 3.0g daily. Urinary sodium level (Na⁺ level) tends to be low due to sodium retention as a result of impaired excretory function by the kidneys. Retention of sodium and water in these patients lead to increased circulatory blood volume and cause hypertension. The uncontrolled hypertension may lead to cardiomegaly along with mild renal pain. Patients affected by nephritic syndrome need renal biopsy examination and specialized treatment under the supervision of a nephrologist.

Diagnosis and Type of Kidney Disease – Investigations and interpretations

Correlation of clinical and laboratory features is must for an accurate diagnosis and type of a kidney disease (renal disease) or glomerulonephritis. An experienced nephrologist can make a diagnosis of glomerulonephritis from thorough history, physical examination, urine examination and microscopy of urinary sediment. The assessment of presenting features of the patient, such as nephritic or nephrotic syndrome is important. However, the decision on the type of glomerulonephritis can not be based on the clinical and laboratory features; as the nephrotic syndrome may occur with any histological glomerulonephritis, and nephritic syndrome is the outcome of proliferative glomerulonephritis. So the ultimate diagnostic tool is renal biopsy and its light and fluorescent microscopy as well as ultrastructural study by electron microscope.

The interpretation of clinical features in the light of histological diagnosis of renal biopsy helps the clinician to detect any systemic disease associated with the renal disease (kidney disease). Majority of the patients with suspected glomerulonephritis need renal biopsy evaluation. However, in children with nephrotic syndrome; if there is no microscopic hematuria (blood in urine) and red cells' or granular casts, renal biopsy procedure may be avoided initially. In patients, who do not respond to steroid therapy; renal biopsy investigation is must. There are around one million glomeruli (1x10⁶ glomeruli) in each kidney and at least 5 glomeruli should be included in the renal biopsy evaluated histologically to achieve a diagnosis of glomerulonephritis.

Radiological and laboratory investigations in glomerulonephritis:

The clinical presentation, urine-analysis and microscopy findings, and presence of a normal upper & lower urinary tract on intravenous pyelography (IVP: a radiological investigation) or ultrasonography without any renal scarring could be indicative of glomerulonephritis, but there could be a need for renal biopsy.

Immune system associated investigations:

Our body is equipped with a multitasking immune system composed on lymphocytes, antibodies and complement system. The immune system always defends our body internally against a variety of infections and pathological conditions; and assessment of its components and abnormal products produced by it helps in diagnostic conclusions. Complement system of our body is composed of 9-components and boosts the body defense in association with cellular components. The blood level of complement components C3, C4 and C1q may be reduced or normal in some renal diseases. Low total serum complement, C3, C4 and C1q levels are observed in glomerulonephritis associated with circulatory immune complex disorders like systemic-lupus erythematosis (SLE), bacterial endocarditis and serum sickness. Normal levels of C4 and C1q but decreased level of C3 is generally observed in membranoproliferative glomerulonephritis (MPGN) and dense deposit disease of the kidney.

Following investigations are considered important to ascertain the diagnosis and type of glomerulonephritis:

Investigations for likely diagnosis of glomerulonephritis:

• Clinical presentation
• Urine analysis (proteinuria, hematuria and electrophoresis)
• Microscopy of urinary sediment
• Intravenous pyelography (IVP: Radiological investigation)
• Abdominal ultrasonography.

Investigations for likely type of glomerulonephritis:

• Estimation of serum complement components' level
• Detection of circulating immune complexes
• Detection of auto-antibodies such as anti-nuclear antibodies (ANA), anti-DNA antibodies and anti-glomerular basement membrane antibodies (anti-GBM antibodies)
• Renal biopsy

Investigations for assessing the implications of glomerulonephritis and monitoring the effect of therapy:

• Determination of 24 hour urinary protein
• Determination of level of serum proteins
• Determination of serum cholesterol and/or lipid profile
• Determination of serum creatinine, blood urea and serum electrolytes.

Nephrotic Syndrome and its Serious Effects

Urine examination shows critical abnormalities in nephrotic syndrome. The urine may froth if passed in a container or if shaken in a test tube. The dipstick test always shows extensive excretion of protein in urine. Total excretion of protein per day should be measured in 24-hour's collection of urine. The nephrotic syndrome is the consequence of prolonged massive proteinuria (excretion of protein in urine). The proteinuria exceeds 3.5 g/24-hours in adults or 50 mg/kg body-weight in children. Nephrotic syndrome is characterized by proteinuria, hematuria (blood in urine), hypertension (high blood pressure), oliguria (low output of urine per day), edema (swelling: apparently suborbital puffy eyes) and diminished renal function. Urine may be brown or red. Sodium (Na⁺) retention, increased circulating blood volume and hypertension (high blood pressure) may lead to cardiomegaly (enlargement of heart). Nephrotic syndrome is usually characterized by insidious onset of massive edema, proteinuria, hypoalbuminemia (low level of albumin in blood) and hyperlipidemia (high level of cholesterol in blood). There could be massive retention of sodium (Na⁺) and a tendency to excessive potassium (K⁺) loss. Serious ill effect of the nephrotic syndrome could be a tendency towards hypercoagulability (blood clotting disorder) which may lead to venous or arterial thrombosis and embolism. Susceptibility to chest (lung) infections may increase due to decreased immunoglobulins' level in blood. Serum calcium (Ca⁺⁺) level could be low as this is related to the level of albumin in blood. Dysfunction of proximal tubules of kidneys may cause glycosuria (excretion of glucose/sugar in urine) or aminoaciduria.

Therapy and Management of Glomerulonephritis

In my other articles you must have got ample information regarding classes or types of glomerulonephritis (GN). Primary glomerulonephritis accounts for about 30% patients requiring dialysis (a medical procedure of purifying blood with by passing through artificial kidney) and hospitalization. The yearly prevalence of primary GN is 0.002% that means 2 new patients per 100,000 population in a year. There are a variety of causes of primary GN with identical histopathological features. It is worth to mention here that there may be many immunopathological reasons in membranous glomerulonephritis (MGN). The character and severity of GN varies with the status of altered immune status of an individual. The understanding of pathogenesis of GN is must before initiating any therapy.

Regular follow-up in a clinic/renal clinic is must for the patient diagnosed of having a renal disease or glomerulonephritis. The follow-up provides an opportunity to the patient to learn about the complications of persistent GN and/or chronic renal failure. It has been observed that hypertension often develops coincidental with progression of renal disease. The hypertension needs to be kept under control in patients affected by persistent GN. The renal function deterioration causes edema in patients with glomerulonephritis. Though restriction in salt and water intake may cure the edema to some extent but diuretic drugs are preferred to treat the edema. Dietary management of progression of renal disease demands moderate reduction in protein intake (recommended: 0.8-1.0 g/kg body weight/day, during edema) to reduce the nephrotic overload and correction of proteinuria. Effective measures to reduce proteinuria are must to speed-up healing of renal lesions.

Corticosteroids, cyclophosphamide, chlorambucil and cyclosporin are the drugs of choice for the treatment of GN. About 95% of children generally respond to the first course of steroids within 8 weeks of commencement of treatment, whereas in adults it may take up-to 16 weeks and the percentage responding to the therapy could be around 80%. Oral prednisolone in single daily dose of 1mg/kg body weight is generally administered in adults. In children somewhat higher dose is required with reference to their body weights. Treatment of glomerulonephritis should never be tried as self help protocol as it needs regular follow-up. Parameters like body weight, blood pressure, 24 hour urinary protein, blood cells' count, blood urea and creatinine need to be worked out periodically to taper down the dose of steroids. Remission can also be achieved with cyclophosphamide, chlorambucil, cyclosporin and azathioprine. About 20-25% of patients are permanently cured with single course of treatment and around 50% may have relapse and need a repeat course of steroid treatment in combination with other immunosuppressive drugs. The dietary advice of nephrologist, controlled blood pressure and a treatment regimen for a sufficient time period may help a patient to keep a check on the complications of glomerulonephritis.

Nephrotic Syndrome and Associated Renal Lesions

Nephrotic syndrome may occur in any type of primary or secondary glomerulonephritis. Around two dozen histopathological categories or subcategories of glomerulonephritis are now recognized and etiological factors are largely determined. However, prevention and treatment of glomerulonephritis needs momentum to curb the development of irreversible renal failure. The main diagnostic feature of nephrotic syndrome is massive proteinuria (excretion of protein in urine) exceeding 3 g/24 hour. The other features of nephrotic syndrome, such as, hypoproteinemia (decreased level of proteins in blood), edema (swelling) and hyperlipidemia (elevated levels of lipids in blood) are consequential due to excretion of proteins in urine. Clinically the patient does not bother to consult a nephrologist or general physician until edema becomes evident. With the fall in the plasma osmotic pressure due to loss of the plasma proteins in urine the fluid from blood would leak into the interstitial space resulting in a reduction in circulating blood volume, but the kidneys try to maintain blood volume by retaining salts and water.

In children around 80% cases of nephrotic syndrome are due to minimal change disease(MCD) and in adults the dominance of MCD is lost. In adults the cause of nephrotic syndrome may be minimal change disease, membranous glomerulonephritis (MGN), focal glomerulosclerosis, mesangial proliferative glomerulonephritis or membranoproliferative glomerulonephritis (MPGN). Metabolic disorders like diabetes mellitus could also be a cause of nephrotic syndrome. Secondary amyloidosis is also known to cause renal lesions associated with nephrotic syndrome. Immunological disorders like systemic lupus erythematosis and vasculitis may also be a cause of glomerulonephritis. Renal biopsy evaluation by light microscopy (LM), immunofluorescence microscopy (IFM) and electron microscopy (EM) is must for an accurate diagnosis of type of glomerulonephritis in a patient of nephrotic syndrome. Minimal change disease, membranous glomerulonephritis (MGN), focal glomerulosclerosis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis (MPGN) and diffuse endocapillary glomerulonephritis are the common and primary causes of nephrotic syndrome. Focal segmental proliferative glomerulonephritis and diffuse proliferative glomerulonephritis with crescents are considered as uncommon-primary causes of nephrotic syndrome. Glomerulonephritis due to metabolic disorders, immunological disorders, toxemia of pregnancy or malignant conditions of kidney are labeled as secondary causes of nephrotic syndrome.

Kidney Biopsy Evaluation and Clinicopathological Understanding

Kidney biopsy evaluation is must to understand the renal lesions in association with clinical picture. An adequate kidney biopsy should contain five to ten glomeruli and corresponding tubules and cortical tissue. The adequacy of needle biopsy of kidney depends on the expertise of nephrologist, performing the biopsy technique. Pathologist performs a methodic approach in the microscopic evaluation of kidney biopsy (renal biopsy). Patient may find microscopic description of glomeruli, tubules, blood vessels and interstitial tissue in the surgical pathology (histopathology) report of kidney biopsy. There are several categories of kidney diseases in which histomorphologic features obtained from renal biopsy may prove clinically helpful. Some such conditions are:

1. Nephritic syndrome and acute renal failure (Sudden impairment of renal function).
2. Nephrotic syndrome (Clinical picture characterized by marked edema, massive albuminuria, hypoproteinemia together with high blood cholesterol, normal blood pressure and absence of signs of renal failure)
3. Systemic diseases with associated renal disorders.
4. Evaluation of asymptomatic patients in whom routine laboratory examination has disclosed proteinuria (protein in urine) and/or microscopic hematuria (blood in urine).
5. Evaluation of prospective kidney donors, to be sure that they did not have any occult renal disease.
6. Assessment of renal microstructure of patients with renal transplant.
7. Evaluation of siblings of patients with hereditary renal disorders like Alport's syndrome.

The biopsies are classified by combining the clinical presentation, the histopathology, the immunopathology and ultrastructural pathology. There are several defined patterns of renal lesions and syndromes and these would be discussed separately.