Podocytes and Podocytopathies

Kidneys play a vital role in excretion and water/fluid volume regulation. Glomeruli are the filtration units of nephrons in the kidneys and these contain cellular and non cellular components in addition to capillary space and urinary space. Podocytes (cells with pedicles or feet) are post-mitotic epithelial cells resting in the urinary space of glomeruli. The number, size and morphology of podocytes are influenced by biochemical, immunological, therapeutic and genetic factors. According to the old classification of renal disorders, the patients having nephrotic syndrome can be grouped into two groups: (1) Non-immune complex mediated nephrotic syndrome, and (2) Immune complex mediated nephrotic syndrome. Now, patients with non-immune complex mediated nephrotic syndrome may have three possible diagnoses:

1. Minimal change disease: Wherein morphologic evaluation of the renal biopsy (kidney biopsy) by light microscopy does not exhibit any glomerular damage. However, extensive effacement of foot processes of podocytes can be revealed by electron microscopy.
2. Focal segmental glomerulosclerosis (FSGS): Wherein segmental sclerosis/solidification of the glomerular tuft, along with hyalinosis and adhesion of tuft to the Bowman's capsule is exhibited on the renal biopsy (kidney biopsy) evaluation by light microscopy. In these cases, variable degree of foot process effacement can be revealed by electron microscopy.
3. Collapsing glomerulopathy: FSGS associated with the rapid deterioration of renal function was described as "Malignant FSGS" in 1978. During HIV pandemic in 1980's the associated nephropathy showing collapse of glomerular capillary wall along with increased cellularity in the urinary space was termed as HIV associated nephropathy (HIV-AN). Collapsing glomerulopathy was first time described in non-HIV patients in 1986 by Weiss and associates.

Now we know that podocyte number and effacement of their foot processes due to genetic or biological factors are very much associated with the primary nephrotic syndrome or proteinuric renal disorders. The etiology and pathogenic mechanisms are known to influence the morphologic diagnosis of podocytopathies. Podocytopathies are proteinuric renal disorders caused due to intrinsic or extrinsic podocyte injury exhibited by variable degree of foot process effacement and altered genotypic and/or phenotypic expression. Podocytes may reorganize their foot processes (altered cell morphology without change in cell count/number). There may be decreased number of podocytes (podocytopenia) if the injured podocytes die. There may be podocyte developmental arrest as seen in congenital nephrotic syndrome of Finnish type (CNF). Podocytes may dedifferentiate and proliferate under genetic, immunological, viral or therapeutic insult and re-enter the cell cycle despite the fact that podocytes are post-mitotic cells. Two electron micrographs are exhibited below to illustrate the normal (Figure-1) and increased number(Figure-2) podocytes in the urinary space of glomeruli from different cases.

Figure-1: Electron micrograph through a portion of glomerulus from a case of minimal change disease showing normal number of podocytes. (GBM: glomerular basement membrane, CL: capillary lumen, EnC: Endothelial cell, US: urinary space and Pc: podocyte)

Figure-2: Electron micrograph through a portion of glomerulus from a case of podocytopathy showing increased number of podocytes. (GBM: glomerular basement membrane, CL: capillary lumen, US: urinary space and Pc: podocytes)

Acute Glomerulonephritis

The term acute glomerulonephritis is used by clinicians as well as pathologists to describe the sudden onset of kidney disease. Irrespective of the cause, there would be enlargement of a kidney or kidneys and the capsule around the kidney is strained and stretched. Ultrasonography is always helpful to ascertain the size of kidneys. Histological examination of kidney biopsy would present densely cellular glomerular tuft with polymorphonuclear cells (a type of white blood cells) in the glomerular capillaries. Accumulation of leukocytes (white blood cells) in the glomerular capillaries with swelling and proliferation of the vascular endothelium (inner lining of capillaries) is rapidly followed by edema (swelling) and mesangial proliferation (enlargement of inner stalk of a cluster of glomerular capillaries)leading to capillary ischemia (poor blood supply).

The glomerular basement membrane (GBM) is the other important component affected by acute glomerulonephritis. By electron microscopic study of kidney biopsy, electron dense deposits of antigen-antibody complexes could be revealed in and around the glomerular basement membrane. The ultrastructural features of normal GBM have been depicted in the figure-1 and the figure-2 is from a case affected by acute glomerulonephritis.

Figure-1: Electron micrograph of a capillary loop of glomerular tuft showing normal features; CL: capillary lumen, US; urinary space, En: endothelium, GBM: glomerular basement membrane, EpC: epithelial cell or podocyte.

Figure-2: Electron micrograph of a capillary loop of glomerular tuft from a case affected by acute glomerulonephritis is showing sub-epithelial deposits; CL: capillary lumen, US; urinary space, GBM: glomerular basement membrane, dep: deposits on sub-epithelial site of GBM.

The tubules in the kidney may show slight degenerative changes. The degree of degenerative changes in the tubules depends on the extent of the glomerular obstruction. The interstitial tissue and the blood vessels are observed to be normal on the histological study of kidney biopsy.

Renal Biopsy Procedure: Complications

Pathological lesions in affected kidneys of patients with renal disorder (kidney disease) could only be evaluated through histological, immunofluorescence and ultrastructural examination of renal biopsy. The renal biopsy (kidney biopsy) procedure as percutaneous needle biopsy was established long back in 1949 and has undergone a great refinement. At present, a large number of medical centers have been performing ultrasound guided percutaneous renal biopsy procedure for the diagnostic and prognostic evaluation of renal tissue. However, majority of the centers lack the facility of electron microscopy for ultrastructural examination of renal biopsies. Cases with microscopic hematuria (blood in urine) and hereditary nephropathies need ultrastructural examination of renal biopsy (kidney biopsy) for an accurate diagnosis. In expert hands the procedure is as safe as incision biopsy or percutaneous biopsy of liver, but post biopsy complications in rare cases could not be avoided. Hematuria (blood in urine) is a common complication and could rarely necessitate blood transfusion. There are 0.01 percent (1 in 10,000) chances of severe hemorrhage secondary to puncture leading to compulsive nephrectomy (surgical removal of kidney). Uncommon complications could be sepsis and hypertension due to perirenal hematoma. Renal biopsy (kidney biopsy) procedure is not advisable for patients with only one functional kidney.

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.

Kidney Biopsy and Its Diagnostic Relevance

The entire focus of the modern medicine is to find a rational treatment for various ailments. The accurate diagnosis is the key to specific therapy for a disease. Kidney biopsy evaluation is of paramount importance to assess the pathological lesions associated with the disordered renal function and for deciding the course of a particular treatment regimen. Percutaneous needle biopsy of kidney was introduced by Iversen in 1949. Kidney biopsy, need not to be performed in every case with symptoms of renal disease. For kidney biopsy procedure, the patients must be selected carefully, excluding cases with only one functional kidney. Patient is briefly hospitalized for taking kidney biopsy. The blood coagulation parameters of the patient must be within normal limits. Needle biopsy of kidney is performed by the Nephrologist under ultrasound guidance, preserved in the suitable fixatives and immediately rushed to the Pathology Laboratory for histological, immunofluorescence and ultrastructural examination. Composite study of the kidney biopsy by the three methods mentioned above is essential to establish an accurate diagnosis of renal disorder or kidney disease and evolution of a particular renal disorder. A renal biopsy (kidney biopsy) must contain glomeruli to be considered adequate for achieving a diagnosis. Generally, the specimen is considered adequate when atleast 5 glomeruli with corresponding tubules are present. Many pathologists believe that interpretation of renal biopsies is extremely difficult. Obviously it has become more complex over the years because of changing approaches to the classification of glomerular diseases. A thorough knowledge of normal histology and ultrastructure of renal components is essential to recognize any alteration in various components of the kidney. An accurate diagnosis could only be achieved through clinicopathological correlation and consideration of family history of patient in cases of congenital and hereditary glomerular diseases.