Coagulation Disorders

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) are often not optimally diagnosed by many physicians. These are serious but preventable medical conditions. Deep Vein Thrombosis (DVT) is a medical condition which occurs when a blood clot forms in deep vein. These clots usually could develop in the lower leg, thigh, or pelvis. These can also occur in arm. One should have knowledge about DVT, because it can happen to anybody and can cause serious illness, disability and morbidity. DVT is preventable and treatable if detected early.

Pulmonary Embolism (PE) is also referred to as complication of DVT. It happens when part of the clot breaks off and travels through the blood stream to the lungs, causing a blockage called Pulmonary Embolism (PE). If the clot is small; with appropriate treatment, people can recover from PE. However, there could be some damage to the lungs. If the clot is large, it could stop the blood reaching lungs and can be fatal.

Risk Factors that could cause DVT

Anybody can have a DVT. However, the factors listed below could increase the chance if having DVT. The chance increases for someone who has more than one of these factors at the same time.

·         Hospitalization and some major surgery.

·         Being bedridden for long time due to illness.

·         Travelling for extended time beyond four hours in continuity.

·         Older age.

·         Overweight or obese

·         Family history of Venous Thromboembolism (VTE.)

·         During and just after pregnancy.

·         Hormonal contraceptive medication (Estrogen based medication).

·         Hormonal Replacement Therapy (HRT).

·         Trauma due to injury.

Preventing tips for DVT

Following tips could help prevent DVT:

·         Move around as soon as possible after having confined to the bed, after illness, injury, or surgery.

·         If you are at risk of DVT talk to your Physician/Surgeon for appropriate medication.

·         When sitting for long periods of time such as travelling for more than 4 hours; get up and walk around after 1 to 2 hours.

·         Raising and lowering your heels while keeping your toes on floor.

·         Raising and lowering your toes while keeping your heels on the floor.

Symptoms of DVT

Most of the people with DVT have no symptoms at all. The following are the most common symptoms of DVT that could occur in affected part of the body:

·         Swelling

·         Pain

·         Redness of the skin

·         Tenderness

If you have any doubt of having DVT consult your doctor as soon as possible.

Pulmonary Embolism (PE)

One can have Pulmonary Embolism (PE) without any symptoms of a DVT. Signs and symptoms of PE could be:

·         Difficulty in breathing

·         Faster than normal or irregular heartbeat.

·         Uneasiness

Coagulation Mechanisms of our Body

Our blood is a very complex tissue of our body, in the form of a fluid. It plays a variety of roles for homoeostasis. Our blood has cellular and noncellular components uniformly suspended in liquid phase. Blood plays multiple roles in our body for sustain life and longevity. There are three types of cells in our blood:

·         Red Blood Cells (RBCs) or Erythrocytes

·         White Blood Cells (WBCs) or Leucocytes

·         Platelets

Red Blood Cells (RBCs) or Erythrocytes provide red color to our blood. RBCs carry oxygen from lungs to various organs and parts of our body. White Blood Cells (WBCs) provide us natural and acquired immunity. Platelets along with other soluble coagulation factors (CFs) take part in coagulation of blood to safeguard us from internal of external bleeding. There are ‘XIII’ coagulation factors (CFs) in our blood. We know the chemistry and role of all the coagulation factors. Coagulation of Blood occurs through two mechanisms:

·         Intrinsic Pathway and

·         Extrinsic Pathway

Both the coagulation mechanisms involve various coagulation factors and finally lead to activation of factor ‘X’. Factor ‘X’ along with certain factors leads to formation of Thrombin from Prothrombin. Thrombin is central in clotting process, and it converts Fibrinogen to Fibrin; activates factor ‘V’, ‘VIII’ and ‘XI’, leading to generation of more Thrombin and stimulation of Platelets. Further by activating factor ‘XIII’, thrombin favors the formation of cross-linked bonds among Fibrin molecules, thus stabilizing the clot.

This determines that direct inhibition of Thrombin is a highly desirable target for prophylaxis and therapy of various Coagulation Disorders (CDs). Thrombin  has 3-sites for target activation:

Sites 1 and 2 are called Exosites and site-3 is called an active site. Exosite-1 is the Fibrin binding site of Thrombin and Exosite-2 serves as the Heparin-Binding Domain. The clotting pathway has traditionally been inhibited by using Heparin and Warfarin for treatment and prophylaxis of Coagulation Disorders (CDs).

Heparin inhibits free Thrombin by binding simultaneously to Exosites on Thrombin and Antithrombin, forming a Heparin-Thrombin-Antithrombin Complex. But Heparin cannot inhibit Fibrin bound Thrombin. Heparin can bind independently to Fibrin and Thrombin to form Fibrin-Heparin-Thrombin bridge.

It has been documented that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are associated with variable anticoagulant effect and heparin induced thrombocytopenia (HIT) in around 3% cases. Warfarin acts as a Vitamin-K antagonist to inhibit formation of clotting factors (II, VII, IX, X). Vitamin-K antagonists have a number of shortcomings, including a delayed onset of action and interindividual variability in anticoagulant effect. Other drugs and foods have also been reported to alter anticoagulant effect of Vitamin-K antagonists. Anticoagulant treatment requires regular and frequent monitoring.

The effectiveness of heparin and warfarin in prophylaxis and treatment of various thromboembolitic disorders has been well established.  Effective use of these drugs comes with a steep cost of various side effects and problems like bleeding tendencies and immune thrombocytopenia. Parenteral administration needs hospitalization and constant monitoring during therapy.

Happy New Year - 2018

Dr. CS Rayat wishes his Followers & Friends “A Very Happy & Prosperous New Year-2018”.

“May every ray of the Sun fill your life with Success and Ultimate Happiness in 2018”

CS Rayat

Tuberculosis of Kidneys and Genital Glands

The tuberculosis of kidneys, testicles or ovaries (genital glands) is always secondary to primary lesion in the lungs, lymph glands or bones. The tuberculosis of kidneys may occur in early adult life. In the beginning it is commonly confined to one kidney but can spread to second kidney if chemotherapy is delayed. If the disease is not detected and treated well in time, it may spread to urinary bladder. In addition to low grade fever in the evening, feeling of general weakness and loss of appetite, it has three additional symptoms: increased frequency of urination, painless hematuria or passage of red blood cells or blood in the urine and a feeling of dull pain in the lower back or region of loin. The 'tubercular toxemia' is there. The treatment with anti-tubercular drugs is must to avoid surgical nephrectomy.

The tuberculosis of testicles or ovaries (genital glands) is also a serious manifestation of pulmonary tuberculosis. Initially there is swelling of one testicle in the male patient which can be easily felt. Later on it may transform into 'cold abscess' and a sinus is produced. Such patients show highly reactive 'tuberculin test'. The diagnosis is not difficult in a case of 'tuberculosis of ovary'. The swelling of the ovary can be palpated by experienced gynaecologist or can be detected by abdominal ultrasonography. The diagnosis can be confirmed easily by 'fine needle aspiration cytology' (FNAC). The signs and symptoms of 'tubercular toxemia' are there as stated in the case of tuberculosis of kidneys. The treatment with anti-tubercular drugs is must to avoid surgical removal of testicle or ovary.

The treatment begins with active anti-tubercular therapy by the use of at least three drugs and a longer course of treatment may be required in these cases. Surgical treatment will be required if the medical treatment alone is not capable of controlling the disease. If the disease is unilateral in one kidney or one testicle and there is no arrest of the disease with medical treatment, these organs would have to be removed surgically with informed consent of the patient.

To read more about ‘tuberculosis of lymph glands’ just click the following link: http://ntips4u.blogspot.in/2014/03/tuberculosis-of-lymph-glands-common.html

Dialysis Technology: Application of dialysis in acute renal failure !

Our kidneys are destined to perform excretory as well as regulatory function to maintain a state of homoeostasis in our body. Acute renal failure (ARF) is a syndrome defined as sudden or rapid loss of renal function (kidney function) leading to accumulation of urea and creatinine (nitrogenous waste compounds). If hyperbolic relationship between plasma creatinine or urea and glomerular filtration rate (GFR) is observed after investigations, the diagnosis is established as ARF. The early clinical signs of ARF/uremia are anorexia, nausea, vomiting, and sometimes pericarditis also. The ARF is an implication of loss of more than 50% of renal function. Dialysis should be instituted whenever early signs of uremia (elevated levels of urea in the blood) are present. Cases of metabolic acidosis as well as electrolyte and fluid imbalance also need dialysis for the reversal of hemodyanmics to normal.

Dialysis is a procedure for artificially purifying the blood of a patient through meticulous surgical intervention and electromechanical equipment. No specific elevated value of plasma creatinine or urea could be regarded as critical. The fluid intake and nutritional requirements are taken into consideration for deciding the timing and mode of dialysis. Cases of ARF should be put on dialysis without much delay for the successful recovery of their renal function. However, cases of chronic renal failure (CRF) may be kept in waiting. The dialysis procedure is of two types: i)  Hemodialysis (where patient's blood is passed through artificial kidney in conjunction with dialysis solution) and ii)  Peritoneal dialysis (where dialysis fluid is passed through the abdominal peritoneal cavity of the patient). The technique of dialysis was established long back in USA by Dr. Alan P Kendal, who also patented a 'suitcase kidney' in 1978.

Conventional hemodialysis remains the preferred and the best mode of dialysis. The hemodialysis is ideal for non-hypotensive and hemodynamically stable patients. Peritoneal dialysis is probably less effective in patients with hypercatabolic disorder and/or with undiagnosed abdominal disease. Peritoneal dialysis should be avoided in patients with recent abdominal surgery. The surgical intervention for hemodialysis can be in the following ways: i)  Continuous arteriovenous hemofiltration (CAVH), ii)  Continuous arteriovenous hemofiltration with/without concomitant dialysis (CAVHD), iii)  Continuous veno-venous filtration (CVVHD). These hemodialysis techniques are simpler, safe and very effective. The biochemical recovery is monitored during the dialysis for needful correction of fluid and electrolytes. After successive dialysis sessions the patient would return to normal health.

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.

Disseminated Intravascular Coagulation: Pathophysiology and Diagnosis

Disseminated intravascular coagulation (DIC) should be recognized as consumptive coagulopathy since it is not a primary disease. It is always a complication of an underlying disease that not only triggers it but also fuels it. Disease or trauma associated tissue injury with a release of thromboplastic material into the circulation is the major cause of DIC. The clotting system as well as the fibrinolytic system (bleeding system) are involved in the pathophysiology of disseminated intravascular coagulation. Clinically, coagulopathy could be recognized as acute hemorrhagic DIC and subacute or chronic DIC. A third type of consumptive coagulopathy could be recognized with fibrinolysis. Disseminated intravascular coagulation is an acquired coagulation disorder in which formation of microthrombi, consumption of coagulation factors, activation of fibrinolysis and a bleeding tendency may occur consecutively or simultaneously. In brief, it is a systemic pathologic process characterized by a disseminated (generalized) activation of clotting and/or fibrinolytic systems in the circulatory system of the patient. The common pathway of all inciting causes (independent of etiologies) is the formation of thrombin and plasmin (fibrinolysin).

Thrombin plays a vital role in DIC. The alterations of coagulation system detected in the laboratory during DIC reflect the multiple actions of thrombin. Thrombin cleaves fibrinogen to release fibrinopeptide-A (FPA) and fibrinopeptide-B (FPB). Subsequently the remaining fibrin monomers may combine with fibrinogen and circulate as soluble fibrin monomer complexes (SFMC) or polymerize to form fibrin microthrombi. Thrombin also activates factor XIII (fibrin stabilizing factor) to form factor XIIIa, and the factor XIIIa creates bridges, linking any two adjacent monomers of fibrin. Thrombin activates procoagulant cofactors, factors VIII and V, to participate in the process of its own generation. Thrombin also plays a regulatory role by activating protein-C, which acts as an anticoagulant to inactivate factors VIIIa and Va. In brief, thrombin alone accounts for decreased levels of fibrinogen and factors II, V, VIII & XIII and decreased count of platelets in patients with DIC.

Screening tests for DIC are: Prothrombin time (PT), Partial thromboplastin time (PTT), Fibrinogen assay and Platelet count. Platelet count, PT, Fibrinogen assay and Determination of Antithrombin-III (AT-III) should always be done to diagnose consumptive DIC.

Confirmatory tests for DIC are: Fibrin monomer assay (it measures thrombin cleaved fibrinogen), Detection of fibrin split products (i.e. detection of plasmin-cleaved fibrinogen or fibrin) and Detection of D-dimer (i.e. detection of plasmin-cleaved cross-linked fibrin). Activation of coagulation could be assessed by the detection of soluble fibrin monomer complexes(SFMC). Detection of fibrinogen degradation products (FDPs) is indicative of reactive fibrinolysis.

Medical conditions which may lead to 'Acute Hemorrhagic DIC':

• Infections: Typhoid fever, Gram-positive and Gram-negative septicemia, viremia, parasites etc.
• Tissue injury: Renal allograft rejection, snake bite, heat stroke, brain injury, crush injury, necrotizing enterocolitis, hemolytic transfusion reaction etc.
• Malignancy: Acute promyelocytic leukemia.
• Obstetric: Amniotic fluid embolism, eclampsia, abruptio placentae, hypertonic saline abortion.
• Other causes: Severe liver disease.

Medical conditions which may lead to 'Subacute Chronic DIC':

• Vascular: Chronic renal disease, connective tissue disorders, venous thrombosis, arterial embolization, pulmonary embolus etc
• Obstetric: Retained dead fetus.
• Malignancy: Mucin-producing adenocarcinomas.

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.

Diabetic Renal Disease

Diabetes is a multidisciplinary disease, as many systems may need medical care. Optimal control of blood glucose level is essential to prevent diabetic complications like neuropathy, diabetic renal disease (diabetic nephropathy) and diabetic disease of eyes (diabetic retinopathy). There may also vascular and cardiac complications associated with diabetes in some patients. Diabetes may be insulin dependent (type-I) or non-insulin dependent diabetes mellitus (NIDDM or type-II diabetes). Diabetic patients develop progressive thickening of glomerular basement membrane (GBM) of glomerular capillaries along with widening of mesangium in majority of glomeruli of their kidneys. The unusual thickening of GBM and widening of mesangial area of the bundles of glomerular capillaries lead to narrowing down of functional lumen of these capillaries, there by causing pathophysiological change in the glomerular function affecting the glomerular filtration rate (GFR). Ultrastructural features of glomerulus affected by diabetes have been illustrated in Figure-1b below in comparison to normal features depicted in Figure-1a at the same magnification.

Figure-1a: Electron micrograph of a portion of the tuft of a normal glomerulus depicting normal GBM: glomerular basement membrane, Mes: mesangial area, EpC: epithelial cells or podocytes, CL: capillary lumen and US: urinary space.

Figure-1b: Electron micrograph of a portion of the tuft of a glomerulus affected by diabetes, depicting thickened GBM: glomerular basement membrane, Mes: mesangial area (widened), EpC: epithelial cell or podocyte, CL: capillary lumen (narrowed down) and US: urinary space. Note: Just compare the feature with the electron micrograph shown in figure-1a.

Uncontrolled diabetes may lead to global sclerosis of glomeruli resulting in 'end stage renal disease' (ESRD) or renal failure. Retinopathy, neuropathy and vascular and/or cardiac disease accompanying ESRD may complicate the management of prospective patients. So, diabetic patients are advised to comply sincerely with the advice of general physician or diabetologist to avoid diabetes associated complications, otherwise they may require the consultation of a nephrologist, ophthalmologist and cardiologist to manage the complications. The treatment of diabetes associated renal disease should ideally be introduced when 'traces of albumin in urine' (microalbuminuria) and polyuria (increased urine output) are detected in diabetic patients. Optimal control of diabetes by insulin and/or diet and exercise is must to avoid complications. Once massive proteinuria (excretion of >3.5 g protein per 24 hours) is developed in diabetic patients, the cost of reversal of complications may be many times higher. Just be health conscious and stay healthy & live-long.

Various Causes of Acute Renal Failure

The cause and/or precipitating factor of acute renal failure (ARF) is always responsible for the effectiveness of therapy and supportive care techniques including hemodialysis. A rapid loss of renal function is exhibited through elevated levels of serum creatinine and blood urea due to fall in the clearance of these nitrogenous wastes by the kidneys in all cases of ARF. It has been observed that a loss of 50% of glomerular filtration rate (GFR) leads to significant elevation of the level of creatinine in the blood with a decrease in the urine output (oliguria). There could be three types of causes and implicating factors of acute renal failure: 1) Pre-renal, 2) Renal and 3) Post-renal. In pre-renal type ARF causes are the physiological factors or conditions which lead to poor renal perfusion and severe impairment of renal function. Hemorrhage in gastrointestinal tract (stomach and intestines) and other internal spaces, sepsis, hepatic failure (liver failure), over compliance of antihypertensive drugs or non-steroidal anti-inflammatory drugs (NSAID), arterial or venous thrombosis and intra-vascular hemolysis due to transfusion reactions, are the major pre-renal causes of ARF.

Acute tubular necrosis (ATN), rapidly progressive glomerulonephritis (RPGN), post infection glomerulonephritis and interstitial nephritis are some major renal causes of ARF. Pre-renal factors and use of nephrotoxic drugs may also be associated cause of ATN. Some viral infections, drugs, multiple myeloma, lymphoma and granuloma may cause interstitial nephritis leading to renal type ARF.

Post-renal type ARF is caused by intra-tubular obstruction due to fibrosis, stones or tumors. Every case of acute renal failure needs urgent investigations to establish the cause and efficient mode of supportive care and line of treatment. A comprehensive physical examination is required to look for possible causes of ARF and planning the investigations to classify the type of ARF. By timely diagnosis and treatment, renal function could be restored in majority of cases of pre-renal type acute renal failure.

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.

Amyloidosis: Causes and Detection

Amyloidosis or deposition of amyloid in vital organs could be labeled as chronic pathological state. Amyloid is an abnormal protein derivative and amyloidosis is characterized by extracellular accumulation of this abnormal protein, which could be detected with Congo-Red staining during histological examination of biopsies/tissues. Genesis of amyloid is associated with B-cell (B Lymphocytes) and Plasma-cell disorders or chronic infections like tuberculosis. Renal (kidney) involvement in amyloidosis may affect all compartments of kidneys. Renal glomeruli, extraglomerular blood vessels, uriniferous tubules and even interstitium could be severely affected leading to impairment of renal function and can cause renal failure. Amyloid could be composed of one or more proteins out of around two dozen different monotypic polypeptides, including immunoglobulin light chains (AL type amyloid), immunoglobulin heavy chains (AH type amyloid), amyloid-A-protein (AA type amyloid), prealbumin, b-2 microglobulin, b-amyloid protein, islet amyloid polypeptide, procalcitonin, cystatin-C, apolipoprotein A-1 or A-2, gelsolin, lysozymes etc. Immunoglobulin light chains type (AL type) and amyloid-A-protein (AA type) amyloid mostly affect the kidneys. Almost all the patients with amyloidosis of kidneys have proteinuria (excretion of proteins in urine; >3g/day) and around 70% also have diminished renal function. On electron microscopy amyloid could be resolved as approximately 10 nm thick non branching and randomly arranged fibrils as illustrated in Figure-1.

Figure-1: Electron micrograph showing randomly arranged non-branching fibrils of amyloid in the mesangial area of a renal glomerulus. Original magnification 36000x.

Amyloid-A-protein type (AA type) amyloidosis is most often associated with chronic inflammatory diseases like tuberculosis, osteoarthritis, or rheumatoid arthritis. Some viral infections can also boost amyloidosis. Production of amyloidogenic light chains is associated with B-cell lymphoma, multiple myeloma or plasma-cell dyscrasia. AL and AA type amyloid have identical physicochemical properties. On renal biopsy evaluation we find acidophilic deposits which stain weakly with Periodic acid Schiff's stain or Silver stain. Amyloid stains bright red with Congo-Red stain and shows apple green birefringence by polarized light microscopy. Amyloid deposits could be revealed in the mesangium and peripheral capillary wall of renal glomerulus depending on the chronicity of the disease process. In advanced stages of amyloidosis, the amyloid deposits could be detected in arteries and interstitial tissue of kidneys in addition to glomeruli, by conventional methods and electron microscopy.

IgA Nephropathy as a cause of End Stage Renal Disease

There are a variety of causes of end stage renal disease (ESRD) in teenagers and adults. Immunoglobulin-A (IgA) nephropathy could be a cause of end stage renal disease (ESRD) in around 25% of cases. There are five types of immunoglobulins in our body for protection against microorganisms and IgA provides defence at mucous membranes. Colostrum and breast milk are rich sources of IgA and protect us during infancy through breast-feeding. However, later in life, chronic mucosal inflammation (inflammation of respiratory, oral, or gastrointestinal mucous membranes) may lead to IgA-nephropathy (IgAN). Viral (including HIV), bacterial, yeast and parasitic infections have been found to be associated with IgAN. Environmental and food antigens have also been implicated in IgAN as these may mimic molecular structure of microbial antigens and lead to excessive IgA production, aggregation and breakdown of mucosal barrier. Patients affected by IgAN may present with hematuria (blood in urine) and/or proteinuria (protein in urine) with or without rise in serum creatinine. The most common initial symptom in children is microscopic hematuria. Some adults may present with acute or chronic renal failure.

IgA nephropathy is a common nephropathy, which could be detected on renal (kidney) biopsy evaluation through light and fluorescence microscopy. However, electron microscopic study of renal biopsy acts as a diagnostic adjunct as the location of immune complexes in the renal glomerulus could be pronounced on electron micrographs. Figures 1 and 2 are the electron micrographs from a proven case of IgAN, illustrating mesangial deposits of IgA.

Figure-1: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 4600x.

Figure-2: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 6000x.

The pathology of IgAN may be variable depending on underlying cause. Mesangioproliferative glomerulonephritis is the most common pattern in many renal biopsies; however, glomeruli may appear normal on light microscopy in some of the cases. Renal biopsies in a few cases may also show crescent formation in occasional glomeruli. Diagnosis of IgA nephropathy is established by direct immunofluorescence technique on renal biopsies and the pattern may be dominant or co-dominant for IgA staining. The incidence of ESRD has been found to be high in patients presenting with >1g/day proteinuria with increased level of serum creatinine as compared to those having proteinuria <1g/day with increased level of serum creatinine. Pathogenesis of IgAN is very complex. A variety of underlying diseases including hepato-biliary disease can be associated with IgA nephropathy. Defective detection and clearance by liver of polymeric immune complexes of IgA (IgA1) due to abnormal galactosylation of O-linked glycans is probably the major cause of IgAN in addition to loss of mucosal barrier and chronic mucosal inflammation. Recurrent tonsillitis may also lead to IgA nephropathy and tonsillectomy may be helpful in these cases to remove the mucosal foci of infection. Optimal treatment of tonsillitis and other oromucosal infections with antibiotics along with conventional treatment of IgAN would be helpful to put brakes on the progression of IgA nephropathy. Patients with acute or chronic renal failure due to advanced stage of IgAN may need hemodialysis or renal transplantation. Use of anti-oxidants and fish oil as food supplements in some cases of IgA nephropathy have been found beneficial.

Urea Synthesis and Clearing: Role of Liver and Kidneys

The proteins we eat contain about 20% nitrogen. A person consuming around 100g proteins daily will excrete about 17g of nitrogen daily in the form of urea. In man and other vertebrate animals the major excretory product of protein metabolism is urea, and they are classified as ureotelic animals. Birds and reptiles excrete the waste nitrogen in the form of relatively insoluble uric acid as the end product of nitrogen metabolism and are called uricotelic animals. Urea is synthesized in liver and is released into the blood and cleared by kidneys in the urine.
Urea synthesis in the liver involves five enzymes: (1) Carbamoyl phosphate synthetase 2) Ornithine carbamoyl transferase (3) Argininosuccinate synthetase (4) Argininosuccinate lyase and (5) Arginase. Deficiency in any of these enzymes may lead to metabolic disorder. The sole function of urea cycle is to convert the ammonia to non-toxic compound urea. All metabolic disorders of urea synthesis cause ammonia intoxication. Catabolism of amino acids in the most of cells produces ammonia. Considerable quantity of ammonia is produced by intestinal bacteria from the dietary proteins and from the urea present in cellular fluids secreted into the gastrointestinal tract. The ammonia produced in the intestine is absorbed into the portal venous blood and is promptly removed by the liver, where urea is synthesized from the ammonia. At first step, carbamoyl phosphate is produced by condensation of one molecule each of ammonia, carbon dioxide and phosphate, under the action of intramitochondrial carbamoyl phosphate synthetase-1 (CPS-1) in the presence of Mg⁺⁺ and N-acetyl glutamate. Now citrulline is formed from the carbamoyl phosphate by union of carbamoyl phosphate and ornithine under the action of another intramitochondrial enzyme called ornithine carbamoyl transferase. The rest of the steps in the urea synthesis take place in cytosol. Citrulline diffuses out from the mitochondrial membrane into the cytosol, where it is linked with aspartate to form argininosuccinate under the action of enzyme argininosuccinate synthetase in the presence of Mg⁺⁺ ions and ATP. There after the cleavage of argininosuccinate to arginine and fumarate is catalyzed by argininosuccinate lyase. The final step in the urea synthesis is the hydrolysis of arginine to urea and ornithine. Ornithine from the cytosol enters the mitochondria and is recycled in urea synthesis. Though other body tissues also exhibit the presence of urea synthesis enzymes but the physiologic contribution of extrahepatic urea synthesis is very low. Urea produced by the hepatic cells enters the blood and is excreted in the urine by the kidneys. Low level of blood/plasma urea and respiratory alkalosis are indicative of urea cycle disorders. Free "Human Body Maps"

Renal Transplantation and Immune Profiling

Organ transplantation is analogous to blood transfusion and we need to detect and match the tissue antigens of the donor and the recipient before transplantation of an organ, say kidney. Tissue antigens are known as human leucocyte antigens (HLA). There are four loci called A, B, C and D on the 6th chromosome, which govern these tissue antigens or HLA. We inherit one gene (each gene has sub-genes) each on each locus from our mother and father. There is antigenic polymorphism at each locus (A, B, C, and D). Unless the kidney donor and the recipient (patient) are identical twins, a 100% match of these HLA is not possible. There is 50% match of HLA amongst parents and children, and the siblings. Unrelated donor and recipient may also have 50% matching of tissue antigens or HLA. The participation of immune mechanisms in allogenic kidney transplant begins with the identification and appropriate reaction to the donor organ, by the recipient, depending on the degree of HLA mismatch. Immunosuppressive therapeutic protocols are prescribed for the adoption and survival of grafted/transplanted kidney. There is very complex immune pathway in our body involving antigen presenting cells and T & B cells (Lymphocytes), which get activated and lead to injury of the target cells. The intragraft cell trafficking and their effector mechanisms may have serious implications. Post transplant immune profiling is a way of monitoring the allograft function and to elucidate pathogenic mechanisms and molecular pathways causing tissue injury and disease.

Transplant tolerance could only be achieved through sincere compliance of immunosuppressive therapy. The immune system of the recipient following renal transplantation, though challenged by the exposure to donor antigens to initiate an early sub-clinical or acute rejection process, attempts to regulate the inflammatory processes or maintain homoeostasis in the body. The acute rejection may be cell or antibody mediated. The transplant tolerance is defined as maintenance of stable allograft function without clinical evidence of immunosuppression. There are many therapeutic approaches to achieve the transplant tolerance, however, the best one is donor specific transfusion or hematopoietic cell infusion. Almost all the transplant recipients have to depend on a variety of immunosuppressive protocols to ward of any chance of allograft rejection.

End Stage Renal Disease and Renal Transplantation

Chronic glomerulonephritis, diabetic nephropathy, chronic tubulointerstitial disease, benign nephrosclerosis and polycystic kidney disease are the major causes of end stage renal disease (ESRD) and renal failure. Patients with ESRD exhibit a variety of abnormalities in their autonomic functions. Precise mechanisms of evaluating autonomic functions have revealed abnormalities in efferent parasympathetic pathway and baroreceptor sensitivity in patients with end stage renal disease. An increase in expiration-inspiration, lying standing and valsalva ratios, and baroreceptor sensitivity slope have been well documented in ESRD. Uremic patients with ESRD respond poorly to antihypertensive drugs as compared to otherwise healthy controls. Renal involvement in multiple myeloma is an other cause of ESRD and renal failure. Dialysis is an adoptive procedure in patients having end stage renal disease and ultimate surgical measure is renal (kidney) transplantation. Adequate dialysis in patients with ESRD reverses the elevated levels of urea, creatinine and electrolytes in blood.

Though renal transplantation is must in patients with ESRD, but it needs a lot of medication and post transplantation care for the successful adoption and survival of renal allograft. Systemic fungal infections (cryptococcosis, mucuromycosis, candidiasis, aspergillosis and mixed infections) have been documented after renal transplantation. Though these infections are treatable but may complicate the post operative care as additional medication will be required in addition to immunosuppressive therapy. High incidence of tuberculosis has also been observed in recipients of renal transplant along with viral infections like BK virus and cytomegalovirus (CMV). Adverse impact of pre-transplant polyoma virus (BK virus) infection on the graft survival has also been documented. Molecular technology has been developed for the early detection and identification of these viruses from the time of renal transplantation onwards by using protocol biopsies from the grafted kidney.