How does kidney develop during gestation ?

The students of renal pathology, medicine, nephrology and urology would always like to imbibe knowledge about the origin and development of kidney to understand the pathogenesis of developmental kidney diseases. The urogenital system is derived and developed from the intermediate mesoderm and the primitive urogenital sinus of the cloaca. The ureteral bud (UB) develops from the Wolffian duct (WD) at approximately 28 days of gestation. The ureteral bud (UB) initiates the epithelialization/tubulogenesis of the metanephric mesenchyme (MM) while itself undergoes branching to form and adult kidney. Much knowledge about the development of kidney could be gathered from the experimental studies using mouse embryo. In the mouse the ureteral bud (UB) invaginates from the caudal end of the Wolffian duct (WD) and grows out into the adjacent metanephric mesenchyme cells.

The metanephric mesenchyme cells comprise of tubule precursors, endothelial precursors and stromal cells. These loose metanephric mesenchyme cells aggregate to form "pre tubular aggregate" which undergoes structural change to form a 'tear-drop' like structure called renal vesicle (RV). The renal vesicle rapidly undergoes mesenchymal-epithelial transformation (MET) to form a comma-shaped structure. The comma-shaped structure formed by the mesenchymal-epithelial transformation of RV undergoes series of tightly controlled transformations and form a very complex S-shaped body. The lower part of the "S" (of S-shaped body) gives rise to podocytes and Bowman's capsule. The upper part of the "S" (of S-shaped body) forms the distal convoluted tubule of the nephron. The middle segment of the "S" (of S-shaped body) gives rise to the proximal convoluted tubule and the loop of Henle of the nephron. Each tip of the ureteral bud gives rise to a nephron. After 20-22 weeks of gestation in humans, the ureteral bud stops branching but the nephron induction continues for other 8 to10 weeks, leading to arcade formation wherein each tip of the ureteral bud has 9-11 nephrons attached to it. The arcade formation is considered as the last step of the nephron induction in humans. However, in mice the process of nephron induction continues for about two weeks after birth. The mouse kidney has single papilla and carries around 35,000 nephrons/kidney. Human kidneys roughly contain 6x10⁵ to 1.1x10⁶ nephrons/kidney.

The knowledge of developmental stages of kidney is important to understand the pathogenesis of developmental cystic kidney diseases like renal agenesis (no kidney developed), renal hypoplasia (under developed kidneys) and renal dysplasia (abnormally developed kidneys). Renal hypoplasia (reduction in total number of nephrons), renal dysplasia (abnormally developed kidney due to failure of UB to induce formation of nephrons) and segmental hypoplasia are the major developmental cystic kidney diseases. Simple hypoplasia leads to very small sized kidney called miniature kidney. Miniature kidney would represent reduction in renal calyces with glomerular disarray and reduction of tubules, medulla & cortex. Segmental hypoplasia presents during the late childhood with renal insufficiency associated with hypertension and recurrent urinary tract infection (UTI). Patients with segmental hypoplasia have small sized kidney (s) with a transverse groove on the capsular surface at the upper pole, overlying an area of marked parenchymal thinning. Areas of segmental hypoplasia represented by scarred zones with no glomeruli, atrophic tubules and thick walled blood vessels could be revealed under light microscopy of histological sections.

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)

End Stage Renal Disease: Management Issues

The patents with end stage renal disease (ESRD) need regular hemodialysis or renal replacement (kidney transplantation) for survival. Both the hemodialysis and kidney transplantation are very costly procedures for the patients and their families. The patients with chronic kidney disease (CKD) are at high risk of developing end stage renal disease (ESRD). Chronic kidney disease (CKD) is diagnosed on the basis of persistently high level of serum creatinine (more than 1.8 mg/dl). As a rough estimate one person in every 150 people may be suffering from CKD and around 3% of CKD cases are sure to develop ESRD. In a country with 500 million population there could be more than 100,000 patients with ESRD and around 3.5 million patients with CKD. Half of the projected figures could be annual incidence.

It has been worked out that the cost of annual dialysis is much more than the renal replacement therapy (RRT). Though the renal transplantation (kidney transplantation) is the more effective and sustainable therapy but the economic factors, availability of kidney and facilities retard its scope. The annual cost of dialysis may range from US$5000 to 10,000 depending on condition of the patient; whereas the one-time cost of renal transplantation at government funded hospitals in most of the developing countries ranges from US$1500 to US$2000 and annual cost of immunosuppressive therapy would be around US$3000 to 4000. As compared to patients on dialysis, the quality of life for the patients of renal transplantation is extremely better. A renal transplantation at an optimum time minimizes the graft maintenance costs and maximizes the graft survival. The patient can return to productive life within a year after renal transplantation. My friend AB, who got renal transplantation around 10 year ago, is living a normal life.

Kidney Diseases caused by Plasma Cell and B-Cell Disorders

A wide spectrum of clinical manifestations may result from the renal involvement with disorders of B-cells (B lymphocytes) and plasma cells. B lymphocytes and plasma cells are responsible cells for providing acquired and active immunity to our body through production of antibodies (immunoglobulins) against infectious organisms. But the disorders related to the function and number of B-cells and plasma cells lead to excessive or incomplete production of immunoglobulin molecules leading to deposition of immunoglobulins or their components in the kidneys. Deposition of immunoglobulins or their light or heavy chains cause a variety of renal disorders affecting glomeruli, extraglomerular blood vessels, tubules and interstitium. Two major classes of such diseases are as under:

A) Glomerular and vascular diseases

Glomerular and vascular diseases caused by B-cell and plasma cell disorders include amyloidosis (AL, AH and AHL type), light chain deposition disease (LCDD), heavy chain deposition disease (HCDD), light & heavy chain deposition disease (LHCDD), cryoglobulinemic glomerulonephritis (type I & II), monoclonal immunotactoid glomerulopathy and proliferative glomerulonephritis with monoclonal IgG deposits.

B) Tubulointerstitial diseases

Cast nephropathy and light chain proximal tubulopathy are the tubulointerstitial diseases caused due to renal involvement in multiple myeloma (Plasma cell disorder).

Important Investigations

Routine urine examination along with microscopy, blood biochemistry to ascertain renal functions and kidney biopsy evaluation by light, fluorescence and electron microscopy is required to establish an accurate diagnosis of renal disorder in patients affected by B-cell and plasma cell disorders.

The Role of Lymphatic System in Cellular Nutrition and Immunity

Every single cell in our body tissues and organs needs nutrition and clearing away of its waste products for survival and vital functioning. Lymphatic system plays a vital role in the circulation and regulation of interstitial fluid or tissue fluid. As the blood passes through blood capillaries in the tissues; plasma or tissue fluid oozes out through the porous walls of blood capillaries. The tissue fluid or the interstitial fluid fills the spaces or interstices between the cells of different tissues and organs. The blood circulates only through the blood vessels but the tissue fluid circulates through the actual tissue and carries food, oxygen and water from the blood stream to each individual cell and carries away its waste products like carbon dioxide, water and urea and pours out all these in the blood stream for final disposal. Lymphatic system is pump less system and runs parallel to the circulatory system and is comprised of following components.

Components of the Lymphatic System:

1. Lymphatic capillaries: These are hair like fine vessels in the spaces in the tissues and gather up excess fluid from the tissues. Lymphatic capillaries unite to form lymphatic vessels.
2. Lymphatic vessels: These are similar to veins in structure but carry lymph instead of blood. They are finer and more in number than the veins and are provided with unidirectional valves, to prevent the back flow of lymph or the tissue fluid. Lymphatic vessels are present in all tissues except the central nervous system. These run in the subcutaneous tissue and pass through one or more lymphatic nodes.
3. Lymph nodes or lymphatic nodes: Lymph nodes are numerous in number and vary in size from a pinhead to an almond. Lymphatic vessels which bring lymph to them are called afferent vessels. afferent vessels divide up within the node and discharge the lymph into the mesh of the lymph node. The lymph is collected again into a fresh vessel known as efferent vessel, which ultimately empties into a lymph duct. Lymph nodes consist of cells similar to white blood cells and are encapsulated by connective tissue. Lymph nodes filter out bacteria, provide fresh lymphocytes for the circulation and also produce some antibodies and antitoxins and boost up immunity.
4. Lymphatic ducts: These are major lymph channels. There are two lymphatic ducts, the thoracic duct and the right lymphatic duct. The thoracic duct is larger and all the lymphatic vessels from the lower limbs, and abdominal and pelvic organs empty into it. The thoracic duct empties into the left subclavian vein. The right lymphatic duct is comparatively small vessel formed by union of lymphatic vessels from the right side of the head, thorax and the right upper limb at the root of the neck. The right lymphatic duct is about one centimeter long and empties into the right subclavian vein.
5. Spleen, the master lymphatic organ: The spleen is the largest nodule of the lymphoid tissue. It is deep purplish red in color and lies high up at the back of the abdomen, on the left side behind the stomach and is enclosed in a capsule of connective tissue. It is composed of fibrous meshwork filled with pulp like material known as splenic pulp. It is a source of fresh lymphocytes for the blood stream, an area for the destruction of worn red blood cells (RBCs) and a legendary organ for fighting out circulatory infections.

Functions of Lymphatic System:

1. Restoration of constant stream of fresh interstitial fluid or lymph in the interstitial spaces as depicted in the diagram given below:

2. Regulation excess proteins in the tissue fluid and passing that back to the blood stream.
3. The lymph nodes filter out the bacterial infection and harmful substances from the lymph before pouring it back into the blood stream.
4. Lymphatic vessels in the abdominal organs assist in the absorption of digested fat.
5. Lymph nodes also produce fresh lymphocytes for the circulation.