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Kidneys are bean shaped organs located on the posterior side of the abdomen one on each side of the vertebral column. The left kidney lies a little higher than the right one. Each kidney is enclosed with a transparent membrane called renal capsule and is divided into outer renal cortex and inner renal medulla. The capsule protects the kidneys against infections and trauma. The renal cortex is convex in shape whereas the renal medulla is concave. The outer cortex is surrounded by a tough fibrous capsule. A capsule called renal pelvis is attached on the indented side of the kidney. This capsule extends into the ureter. The primary function of the kidney is to regulate the electrolytes and maintain the pH balance of the body to create a stable environment for tissue and cell metabolism. The other important functions are excreting metabolic waste products, conserving nutrients and water transport.
The medulla is made up renal pyramids and its apex is known as papilla. It meets the calyx, a branch of the renal pelvis. The basal portion of the pyramid is elongated and grows towards the cortex and the space between the renal pyramids is known as renal columns.
The cortex of kidney is made up of two types of tissues
Labyrinth of Ludwig or cortical substance proper
The medulary rays are also known as 'Henle', which are cylindrical in shape and are aligned parallel to each other. The medullary rays are the extensions of the pyramidal structures and the cortical substance proper is interspaced between them. The 'labrynth of Ludwig' are made up of small structures known as glomeruli or Malphigian tubules.
Renal pelvis or artery
The renal artery enters the kidney the concave side through the hilum and branches out in the cortical portion. The artery branches out in right angles and these branches at the base of renal pelvis are known as major calyx and the others, which are away from the renal pelvis, are smaller in size known as minor calyx.
The region between the parts of the kidney is made up blood vessels, stroma and colleting tubules. These regions of the kidney appear like colloidal substance altogether.
These are small tubes, which are either straight or twisted. The tubules originate from sac-like structure present around the glomerulus known as the Bowman's capsule. The walls of the tubules are lined with epithelial cells, which are striated due to the presence of cylindrical objects called rods of Heiderihain.
These are the important units of kidney, which filter the blood, which helps to control and regulate the concentration of the substances, like water and sodium salts. The renal tubules excrete waste material and the renal corpuscles reabsorb the essential substances. These nephrons regulate blood pressure and blood volume. Two types of nephrons are present
Fig.1. Anatomy and Histology of Kidney
Kidney cancers caused due to smoking
Smoking causes two types of cancer in kidney
Renal Cell Carcinoma
Transitional Cell Carcinoma
Renal cell carcinoma
Smoking increases the risk of developing kidney cancer as the harmful chemicals in cigarettes are absorbed into the blood stream and the blood is filtered in the kidneys. Many of these chemicals are trapped and some of them cause damage to the cells and later becomes cancerous causing renal cell carcinoma. The cells usually affected are the tubular epithelial cells in the renal cortex region. These tumours are either cystic or solid and spread to other organs like the adrenal glands, spleen, colon and pancreas.
Fig.2. Renal Cell Carcinoma
Stages of Renal Cell Carcinoma
There are four stages in Renal Cell Carcinoma
In this stage, the tumour is about 7 cm in size and is confined to the Kidneys.
In this stage, the cancer extends to the fat tissue present around the kidney and the size is larger than 7cm.
There are three possible conditions in this stage
The cancer is confined to the kidney, but the cancerous cells enter the lymph system and also invade into the adjacent lymph node.
The cancer spreads to the fat tissue, fibrous tissue and adrenal glands, which are found in the kidney. The tumour may also be present in one of the lymph nodes.
The cancer extends to the renal vein, which carries clean blood from the kidneys.
This stage has are three possible situations
The cancer extends beyond the fibrous tissue surrounding the kidney.
Cancer cells are found in several lymph nodes.
The cancer spreads to adjacent organs like bowel, pancreas or lungs.
Fig.3. Stages of Renal Cell Carcinoma
Clear Renal cell carcinoma
It is the most common type of renal cell carcinoma caused due to smoking. The cancer cells originate from the mature renal tubular cells in the proximal tubule of the nephron. This type of cancer is caused due to the deletion or translocation of the short arm of chromosome 3. The cancer is confined only to the organ hence it is easy to treat this type of cancer.
Transitional cell carcinoma
The cancer cells originate from the "transitional cells" that lines the pelvis region of Kidneys and Ureters. The cancer cells differ from those of the renal cell carcinoma. The cancer cells spread through two ways:
By epithelial cells that line the organs and many passageways that exit the body
Through lymphatic system
Fig.4. Transitional Cell Carcinoma
Stages of Transitional Cell Carcinoma
There are five stages in the development of transitional cell carcinoma
Stage 0 (papillary carcinoma and carcinoma in Situ)
The abnormal cells are found in the tissue lining of the renal pelvis and these cells become cancerous and spread to the nearby normal tissue. This stage is divided into two depending on the type of tumour formed
Stage 0a - the tumours look like tiny mushrooms growing from the lining. It is also called non-invasive papillary carcinoma.
Stage 0is - it is a flat tumour on the tissue lining of the renal pelvis and is called carcinoma in situ.
In this stage, the cancer spreads through the lining of the renal pelvis into the layer of connective tissues.
In this stage, the cancer spreads from the layer of connective tissue to the muscle layer of the renal pelvis.
The cancer spreads to the layer of fat outside the renal pelvis or into the wall of the kidney.
The cancer spreads to either
Fat layer of Kidney
One or more lymph nodes
Fig.5. Transitional cell carcinoma stages
There are three types of renal cell carcinoma
Conventional or clear cell renal cell carcinoma
Oncocytoma and chromophobe renal cell carcinoma
Collecting duct renal cell carcinoma
The study of different articles shows that primary compound in tobacco smoke, BPDE (benzo-alfa-pyrene dio epoxide) which is a major cause of kidney cancer (Renal cell carcinoma cancer). It induces mutation in chromosome 3p21.3 related to tumorigenesis of several neoplasms, including renal cell carcinoma. The degree of susceptibility to the mutation induced by BPDE in chromosome 3p has been proposed as a maker of individual predisposition to develop the disease.
Molecular mechanism of the development of renal cell carcinoma
In clear cell renal cell carcinoma, hypoxia inducible factor Î± (HIF Î±) transcription factor accumulates, resulting in the over expression of proteins that are normally inducible with hypoxia, such as transforming growth factor Î± and Î² (TGF-Î± and TGF-Î², respectively), vascular endothelial growth factor (VEGF), and platelet-derived growth factor Î² chain (PDGF-Î²). The over expressed VEGF, PDGF-B, and TGF-Î² act on neighbouring vascular cells to promote tumour angiogenesis. The process of tumour vasculature provides additional nutrient and oxygen to promote the growth of tumour cells. TGF Î± promotes the tumour cell proliferation and survival by signaling through the epidermal growth factor receptor. VHL (Von Lippel Lindau) protein plays an important role in Renal Cell Carcinoma by controlling HIF Î± transcription factor. Under normoxic condition, HIF Î± is hydroxylated on two proline residues by a proline hydroxylase and on an aspargin residue by aspargin hydroxylase. Hydroxylation (OH) by proline hydroxylase permits binding of HIF Î± to VHL protein, which promotes the ubiquitination (Ub) and destruction of HIF Î± by the proteasome pathway. Hydroxylation by asparagine hydroxylase blocks the interaction of HIF Î± with transcriptional coactivator p300. VHL protein, with elongin proteins C and B, binds cul2 protein (a member of the cullin family of ubiquitin ligase proteins). RING-box protein Rbx1 serves as the ubiquitin transferase for the VHL skp-cullin-F-box protein (SCF) complex. In the absence of wild-type VHL protein, hydroxylated HIF Î± accumulates and is able to heterodimerize with HIF-Î² and activate transcription at hypoxia-response elements (HREs), which are found in genes such as VEGF. In hypoxic conditions, HIF Î± is not hydroxylated and so cannot bind VHL protein.
Fig.6. Mechanism of Renal cell carcinoma
Promoter hypermethylation is also very much seen in current smokers. There are a lot of gene getting hypermethylated and includes VHL (P=0.048), RASSF1A (P=0.011), MGMT (P=0.045) and other genes whose hypermethylation is negatively affected by the hypermethylation of some other genes, which have a P- value lower than 0.05, such as p14ARF with RASSF1A, RARÎ²2 or p16INK4a, p16INK4a with APC or RARÎ²2; and RASSF1A with APC.
UNDERSTANDING IN THE GENETIC LEVEL
This gene codes for a protein which acts as a copper enzyme. This enzyme initiates the cross linking of collagen and elastin.
CHR 5 q22.2-q23.1
Allelic imbalance (LOH or amplification).
This gene codes for RAS effector proteins which are involved in cellular transformation.
CHR 3 p21.3
VHL( Von-Hippel-Lindau) tumour suppressor gene
This gene codes for the protein elongin B, elongin C and cullin 2 and posses the property of ubiquitination of E3 activity.
CHR 3 p26-p25
Somatic mutations at the sites 3G:C-A:T and 1A:T-G:C
NORE1A( also known as RASSF5)
This gene codes for a protein which is located in centrosomes, microtubules and is involved in the activation of RAS, RAP1 proteins.
CHR 1 q32.1
Chromosomal translocation between NORE1A gene on chromosome 1q32.1 and the LSAMP gene on chromosome 3q13.3.
TIMP3(smoking is a risk factor with 29.5% risk)
this gene encodes the protein which acts as inhibitors for metalloproteinase's
CHR 22 q12.3
-5'CpG island (nucleotide position, 581-1342)
(Obtained from MOLBIO tools).
This gene is a positive mediator of Gamma-induced programmed cell death.
This gene has a high content of cysteine residues and is involved in binding to heavy metals.