Warung Bebas

Saturday, 30 October 2010

Idiopathic thrombocytopenic purpura


Patient asks to mbah dukun: "Mbah, my name is Painem, im from Belgia, i have a problem. my son's legs frequently bruising, red spots appear, these has been about 6 months, intermittent, sometimes accompanied by fever, DHF-like disease. Would you tell me what is that?
Mbah Dukun anwers:

ITP, primary immune thrombocytopenia (also called immune (idiopathic) thrombocytopenic purpura), is an autoimmune disease. In autoimmune diseases, the body mounts an immune attack toward one or more seemingly normal organ systems. In ITP, platelets are the target. They are marked as foreign by the immune system and eliminated in the spleen and sometimes, the liver. In addition to increased platelet destruction, some people with ITP also have impaired platelet production.

Thrombocytopenic "means the blood does not have enough red blood cells (platelets). "Purpura" means a person has a lot of bruises (excessive).
ITP occurs when immune system cells (specialized lymphocytes) produce antibodies that cause the destruction of platelets in the spleen and other organs. As such, ITP historically has been considered a disease of platelet destruction. However, recent data also suggest that low platelet counts in the blood may be caused by the inability of the body’s natural processes to produce platelets. Therefore, increasing the rate of platelet production may help address low platelet counts associated with ITP.
There are 2 types of ITP. The first type usually attacks young children, while other types of attacking adults. Children aged 2 to 4 years who generally suffer from this disease. While the ITP for adults, mostly experienced by young women, but can also occur in anyone. ITP is not a hereditary disease.


Patient asks to mbah dukun:What are cause ITP, mbah?
Mbah Dukun anwers:

The specific cause of ITP is unknown. In some cases, ITP has appeared following a viral or bacterial infection, immunizations, exposure to a toxin, or in association with another illness such as lupus or the human immunodeficiency virus (HIV).
Platelets, also called thrombocytes, are specialized blood cells needed to prevent bleeding. Low platelet counts leave adult patients with ITP at risk for bleeding events. The risk of a serious bleeding event increases when platelet counts drop to less than 30,000 platelets per microliter of blood. In extreme cases, death can occur due to an intracerebral hemorrhage (bleeding into the brain).
Normal platelet counts range from 150,000 to 400,000 per microliter of blood. People with platelet counts under 10,000 are more prone to bleed. For many, a count of 30,000 is sufficient to prevent a catastrophic bleed. Individual reactions to low platelet counts differ.


Autoimmune disease, with anti-platelet antibody formation (usually specific for the platelet GPIIbIIIa receptor) and peripheral platelet destruction. Acute ITP usually occurs in children, follows an acute viral infection or recent live virus immunization, and usually undergoes a spontaneous remission within two months. Chronic ITP is more common in adults, shows an insidious presentation, and lasts > 6 months. The pathogenesis is complex and multifactorial, including a failure of self-antigen recognition and tolerance, altered cytokine secretion, impaired megakarypoiesis, and impaired cellmediated cytotoxicity.


Patients asks: What are the symptoms of ITP?
Mbah Dukun answers: 

People with ITP often have bruises or small purple spots on their skin (petechiae) where their blood has escaped from their veins or capillaries. Spontaneous bleeding can also occur in the mucus membranes on the inside of the mouth or in the gastrointestinal tract. It is possible, with a decreased number of platelets, to have a spontaneous cerebral hemorrhage.   

In children, signs of serious injury or internal head bleeding include: dizziness, headache that doesn’t go away or gets worse, vomiting, confusion, unusual sleepiness, slurred speech, weakness, numbness or tingling in hands or feet, stiff neck, seizures, eyes not moving together, or inability see. Call your doctor or hospital immediately if your child falls resulting in hitting their head or for any event that causes your child to lose consciousness.
Call your doctor or other healthcare provider immediately if you hit your head or have a serious accident. Watch for a large number of bruises and petechiae, or other signs of severe bleeding, which can indicate a very low platelet count. Signs of bleeding in the brain include: a headache that won’t go away, dizziness, vomiting, unusual sleepiness, confusion, slurring of speech, eyes not moving together, weakness on one side of the body, stiff neck or back, seizures, and inability to see or hear. Notify your doctor about nosebleeds, bleeding gums, or blood in urine, stool or vomit. Even when ITP patients are in remission they should watch for these symptoms so that they can contact their healthcare provider immediately if any of these occur.


There are no specific tests for ITP; ITP can only be diagnosed by excluding other causes of a low
platelet count. Doctors call this a 'diagnosis of exclusion’. This situation is different from many other diseases. For example, a strep throat is diagnosed with certainty by a positive throat culture for the streptococcus germ, and most cancers are diagnosed with certainty by a positive biopsy. ITP has been defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia. Isolated thrombocytopenia means that the other components of the blood counts (the red and white blood cells) are normal. The phrase 'clinically apparent’ means that there is no obvious evidence of other disease causing thrombocytopenia even though there might be abnormalities of laboratory tests that suggest another condition. For example, a positive test for antinuclear antibodies (ANA) can be associated with lupus, but when there are no signs or symptoms of another disease (such as lupus) then ITP remains the appropriate diagnosis. On the other hand, if a patient has clinically apparent lupus, with features such as rash, arthritis, kidney disease, and other abnormalities, then ITP is not an appropriate diagnosis because the patient's problems and management will be determined by the course of the lupus, not just by the low platelet count. Although it may seem difficult to make a diagnosis in the absence of a specific, defining 'gold standard’ laboratory test, the diagnostic evaluation for ITP is usually quite simple and straightforward. It most often includes only the basic examination, including a medical history, physical examination, and blood counts with examination of the blood smear. If these are compatible with the diagnosis of ITP and do not suggest other causes for the low platelet count, then the diagnosis is established. Specifically, tests for antibodies against platelets are not required and do not influence treatment decisions (even though antibodies against platelets are the cause of ITP). The indications for doing a bone marrow examination when evaluating a patient for ITP are controversial. In children, it has been recommended that a bone marrow examination is important before treatment with prednisone is begun. This rule was established because prednisone alone may be partially effective in treating for the type of leukemia which is most common in young children, acute lymphocytic leukemia. There is concern that prednisone treatment may thus temporarily mask the presence of leukemia and delay definitive treatment. In practice, however, many pediatric hematologists begin prednisone without doing a bone marrow examination. In older adults, other bone marrow disorders such as myelodysplasia may affect platelet production and a low platelet count may initially be the only abnormality. So in these older patients, a bone marrow examination may be appropriate. A bone marrow examination may also be performed in patients, either children or adults, who do not respond appropriately to treatment. Drug-induced thrombocytopenia, in which an allergic reaction to a drug can cause a low platelet count, is initially indistinguishable from ITP.
Laboratory studies are more valuable in the exclusion of other diseases than in providing definitive evidence of ITP. Variable thrombocytopenia with a normal white blood count and erythrocytic indices (in the absence of severe hemorrhage). Peripheral blood smear examination reveals thrombocytopenia with normal leukocytic and erythrocytic morphology. Coagulation assays are within normal limits. Bone marrow evaluation reveals normal to increased megakaryocytes with normal morphology. Assays for platelet-associated immunoglobulin by ELISA or flow cytometry may be positive, but these assays are presently considered unreliable. Pseudothrombocytopenia must be excluded by peripheral smear examination for platelet clumping. The exclusion of other causes of thrombocytopenia should include other laboratory assays, especially a CBC, Ddimer and FDP assay, LDH, viral serology (especially for HIV), anti-nuclear antibody, rheumatoid factor studies, and ESR, liver function studies, and pregnancy


Patient asks to mbah dukun: So  What are the main treatments available for ITP?
 Mbah Dukun answers: 

1. Antibiotics
An ITP diagnosis is sometimes associated with an infection and antibiotics can raise the platelet count. There has been considerable research on the success of antibiotics used to treat H-pylori in those diagnosed with ITP. The eradication of other infections can also raise the platelet count.
2. Anti-D
Used to achieve a temporary elevation of the platelet count, the treatment can be repeated for a more extended remedy. The shorter infusion time and often lower cost is an advantage over IVIg. Win Rho SDF and Rhophylac are approved for the treatment of ITP in the US.
3. B-cell depletion
B-cell depletion by a monoclonal antibody (anti-CD20, rituximab) has not been approved by the FDA to treat ITP, although it has become a widely used treatment choice. It works by disabling and changing B-cells, a type of white blood cell. Other anti-CD20 options are in clinical trials.
4. Chemotherapy
Various chemotherapy drugs have been used as a second or third-line treatment choice for chronic ITP patients. Each has a slightly different side effect profile. They have been effective in a small percentage of cases and can be quite toxic. They have not been approved by the FDA to treat ITP.
5. Corticosteroids
Often the first-line treatment for ITP, the dose of corticosteroids (ex. Prednisone) is initially quite high then gradually tapered. Sometimes the platelets remain elevated but in most cases the platelet count recedes as the dose is reduced. An alternate method of administering corticosteroids is an extremely high dose for a few days with no taper. The side effects of corticosteroids can be uncomfortable and grow in severity if the treatment is continued for a long time. While the FDA mentions this as a first-line treatment, it has not been officially approved for the treatment of ITP.
6. Immunoglobulins
An IV drip of immunoglobulin, a type of antibody, is also referred to as IVIg, IGG or IGIV. This treatment is a temporary measure and is not expected to result in a sustained, elevated platelet count, although in some rare cases this does happen. It can be repeated for longer lasting results. IVIg is manufactured by several companies, some of which have received FDA approval for its use in the treatment of ITP.
7. Immunosuppressants
This class of drugs disables parts of the immune system and is often used to prevent the rejection of transplanted organs. These are second and third-line treatments for ITP and have been used to treat other autoimmune diseases such as MS and lupus. None have been approved by the FDA to treat ITP.
8. Modified Testosterone
A synthetic androgen (male sex hormone) is sometimes used to treat ITP when other treatments have failed. It disrupts the action of the pituitary gland, reduces estrogen, halts menses and can cause masculine features for women.
9. Platelet Growth Factors
The newest treatment approach for ITP is the use of platelet growth factors. These agents increase platelets by stimulating the bone marrow to produce more of them. Once thought to be only a disease of platelet destruction, recent research has shown that many people with ITP also have a platelet production problem. Nplate and Promacta have been approved for the treatment of ITP in this category.
10. Splenectomy
This is a surgical procedure where the spleen is removed. The spleen is a large blood filter which, for many people, removes antibody-coated platelets. Theoretically, if the spleen is removed, the platelets will remain in circulation. However, there are other ways the body removes platelets, so this treatment sometimes fails to have a lasting effect.Treatment for ITP is most often coordinated by a hematologist (doctor who specializes in blood disorders). The goals of ITP treatment are to ensure a safe platelet count, prevent bleeding complications, and minimize treatment side effects.

All of these treatments have their own benefits and risks. Side effects have been reported for each of the drugs and treatments for ITP. These side effects will vary from one person to another. You may experience all, some, or none of the side effects. Here are the side effects for frequently used treatments.

 Patient says: thank you mbah for explain, 6 million dollars, I give to mbah Dukun as dowry

1. http://www.pdsa.org
2. http://www.pathology.vcu.edu/clinical/coag/ITP.pdf
3. http://www.amgen.com/pdfs/misc/Fact_Sheet_ITP.pdf
4. http://www.ohiohealth.com
5. http://www.hoslink.com

Thursday, 21 October 2010

Chronic Myelogenous Leukemia

Chronic Myelocytic leukemia (mieloid, mielogenous, granulocytic, CML) is a disease in which a cell in the bone marrow turn into malignant and produce a large number of granulocytes (a type of white blood cells) are abnormal . When this happens, infectious anemia, or bleeding easily occurs. CML seldom attack individuals under the age of 20 years, but the incidence increases with age.

CML clinical picture similar to the AML, but milder symptoms, namely: In the early stages, CML may not cause symptoms. But some patients may experience fatigue and weakness, loss of appetite, weight loss, fever or sweating at night, full feeling in his stomach (because of an enlarged spleen). Most of the granulocytes leukemic produced in the bone marrow, but some are made in the spleen and liver. In CML, the cells consist of cells that are very young to a mature cell, while the LMA is only found in young cells.
Leukemic Granulocytes tend to shift the normal cells in the bone marrow and often led to the formation of large amounts of fibrous tissue that normal bone marrow depend on During the course of the disease, more and more young granulocytes that enter the bloodstream and bone marrow (acceleration phase). In these phases, anemia and thrombocytopenia (decreased platelet count) and the proportion of young white blood cells (blast cells) increased dramatically. Sometimes granulocytes leukemik experience more change and evolve into blast crisis disease. In blast crisis, the malignant stem cells only produce young granulocytes only, a sign that the disease is getting worse.


According to Smeltzer and Bare (2001), although the cause of leukemia is unknown, presdiposistion of genetic and environmental factors seem to play a role. Environmental factors in the form of high-dose radiation exposure pergion accompanied by manifestations of leukemia that arose many years later. Chemicals (eg benzene, arsenic, pesticides, chloramphenicol, fenilbutazone, and antineoplastil agent) is associated with an increased frequency especially alkyl agents.
The cause of most types of leukemia is unknown.
Viruses cause some of leukemia in animals. Virus HTLV-I (human T-cell lymphotropic virus type I), which resemble the virus that causes AIDS, is thought to cause a rare type of leukemia in humans, namely  adult T-cell leukemia .Exposure against radiation (radiation) and certain chemicals ( such as benzene) and the use of anticancer drugs, increases the risk of leukemia. People who have certain genetic abnormalities (eg Down syndrome and Fanconi's syndrome), are also more susceptible to leukemia..

In Kenya, China, and India, the CML of patients aged 20-40 years. This disease can be about all age groups, both men and women, but rarely found in children aged less than 10 years.


In normal circumstances, white blood cells serve as our defense to infection. These cells normally develop in accordance with instructions, can be controlled according to the needs of our bodies. Leukemia increase production of white blood cells in bone marrow that is more than normal. They look different from normal blood cells and does not function as usual. Tues leukemia block production of normal white blood cells, impairing the ability of the body against infection. Tues leukemia also damages other blood cell production in bone marrow, including red blood cells where the cell's function is to supply oxygen to the tissues .

According to Smeltzer and Bare (2001) analysis cytogenic generate a lot of knowledge about the chromosomal aberrations found in patients with leukemia,. Changes may include changes in chromosome numbers, which add or remove an entire chromosome, or changes in the structure, which includes this translocation, two or more chromosomes alter the genetic material, with the development of genes that change is considered cause onset of abnormal cell proliferation.
Chromosomal disorders occur in Ph chromosome (Philadelphia), namely the loss of some long arm of chromosome 22 andtranslocate Darim with the long arm of chromosome 9. So there is a merger between the genes that exist in the long arm of chromosome 9 that ABL with BCR gene located on the long arm of chromosome 22 as look in the picture. Because of this translocation, there was an excessive proliferation of pluripotent stem cells in the system hematopoiesis. In addition to excessive proliferation, white blood cells produced more of survival than normal cells because the gene is anti-apoptotic BCR_ABL. The impact of these two mechanisms, the formation of abnormal clones that finally urged hemopoesis other systems. Eventually these cells control bone marrow and replace the place of cells that produce blood cells are normal. This cancer can also infiltrate into other organs, including liver, spleen, lymph nodes, kidneys and brain.

Signs and symptoms of clinical

CML is divided into 3 phases, namely chronic phase, accelerated phase and blast crisis. Generally, when enforced, the patient still in chronic phase, diagnosis is often discovered accidentally at the time of preoperative preparation, which found great leukocytosis without symptoms of infection.
In the chronic phase, patients often complain of an enlarged spleen or feeling full quickly because of the insistence spleen against the hull. Sometimes there is pain like perur squeezed in the upper right. Other complaints are not specific, among others, feeling tired, weak body, which is not very high fever, night sweats. Weight loss occurred after a prolonged illness. All the complaints above is an illustration of hipermetabolism caused proliferation of leukemia cells.
After 2-3 years, some patients will get worse progressively . Characteristic acceleration phase is a difficult leukocytosis mielosupresif controlled by medication, mieloblast in peripheral 15-30%, promielocyte> 30% and platelets <100.000/mm3. The main complaint of severe anemia, resulting petekie, ekimosis, if accompanied by fever, usually no infection. Fever, enlarged lymph nodes and the formation of lumps of skin that are filled with granulocytes leukemik (kloroma) is a bad omen.


According Mbah Dukun stated that investigation of leukemia are:
• A complete blood count showed normocytic, anemia normocytic
• Smear of peripheral blood: normochrom normositer, often found in the polichromate eritroblas asidosis or polikromatofil. Looks all levels of differentiation and maturation of granulocyte series, the percentage of cells increased metamielosit mielocyte and so does the percentage of eosinophils or basophils.
• Hemoglobin: normal or slightly decreased, to less than 10 g/100 ml
• reticulocyte count: the number is usually low
• Platelet count: probably very low (<50.000/mm)
• SDP: more than 50.000/cm with increasing SDP are immature (probably deviated to the left).
• PT / PTT: elongated
• LDH: may increase
• Uric acid serum / urine: may increase
• Copper serum: increased
• Zinc serum: increased
• Bone marrow biopsy: abnormal human resources is usually more than 50% or more of the SDP in the bone marrow. Often 60% - 90% of the blast, with precursor eritroid, mature cells, and megakariositis decline.
• Photos chest and lymph node biopsy: to indicate the degree of involvement.

Chronic Mielogenus  Leukemia Treatment

Most treatments do not cure the disease, but only slow the progression of the disease. Treatment is considered successful if the number of white blood cells can be reduced to less than 50.000/microliter blood. Even the best treatment that can not destroy all cells of leukemic. The only chance of healing is with bone marrow transplantation. Transplantation most effective if done at an early stage and less effective if done on the acceleration phase or blast crisis. . Indication of bone marrow transplantation: 1. Age not more than 60 years, 2. There is a suitable donor, 3. Includes low-risk groups according to the calculation of Sokal.
Drug alpha interferon can normalize bone marrow and cause remission. Hydroxyurea by mouth (swallowed) is the most widely used chemotherapy for this disease. Busulfan is also effective, but because it has serious side effects, then its use should not be too long. Radiation therapy to the spleen sometimes help reduce the number of leukemic cells . Sometimes the spleen must be surgically removed (splenectomy) to: reduce discomfort in the stomach, increasing the number of platelets, reducing the possibility of transfusion.

Hidroxyurea (Hydrea)
• It is elected for induction remission therapy hematologic on LGK.
• More effective than busulfan, melfalan (Alkeran), and Klorambusil.
• Effects mielosupresif still take several days to 1 week after treatment was stopped. Unlike busulfan can cause aplastic anemia and pulmonary fibrosis.
• 30mg/kgBB/day dose given as a single dose or divided into 2-3 doses. If leukocyte> 300.000/mm3, the dose may be raised until maksimal2, 5 grams / day.
• Its use was discontinued when leukocyte <8.000/mm3 or platelets <100.000/mm3
• Drug interactions can occur when used in conjunction with 5-FU, causes neurotoxicity.
• During use hydrea should be monitored Hb, leucocytes, platelets, kidney function, liver function.
Busulfan (myleran)
• Includes an alkyl group which is very strong.
• 4-8mg/dayper oral dose, can be increased up to 12mg/hari.
Should be discontinued if the leukocyte between 10-20.000/mm3, and only started again after leucocytes> 50.000/mm3.
• It should not be given to pregnant women.
• Drug interactions: acetaminophen, cyclophosphamide, and itrakonasol will increase the effect of busulfan, whereas phenytoin would reduce its effect.
• When leucocytes are very high, busulfan administration should be accompanied by either allopurinol and hydration.
• Can cause lung fibrosis and prolonged bone marrow suppression.

Imatinib mesylate (Gleevec = Glyvec)
• Classified as menoklonal antibody designed to inhibit the tyrosine kinase activity of BCR-ABL fusion gene.
• aborted in either the gastric mucosa by oral administration.
• For the clonic phase, 400mg/hari dose after a meal. The dose may be increased to 600mg/hari if not achieve hematologic response after 3 months of delivery, or never achieve a good response but there was deterioration in hemotologik, the hemoglobin is low and / or leucocytes increases with / without a change in platelet counts.
• The dose should be reduced if there neutropeniaweight (<500/mm3) or thrombocytopenia weight (<50.000/mm3) or elevated SGOT / SGPT and bilirubin.
• For accelerate phase or blast crisis phase, can be given directly 800mg/day (400mg bid).
• hypersensitivity reactions can occur, although very rarely.
• It should not be given to pregnant women.
• Drug interactions: ketoconazole, simvastatin and venitoin will enhance the effect of imatinib mesilat.
• In addition to hematologic remission, these drugs can produce remission Cytogenetics characterized by the loss / reduction in Ph chromosome and biological remission was also characterized by reduced expression of BCR-ABL gene or the protein it produces.
• In contrast to imatinib mesilat, interferon can not produce biological remission can achieve remission despite Cytogenetics
• 5 million IU/m2/day subcutaneous dose to achieve remission Cytogenetics, usually after 12 months of therapy. Based on data from studies in Indonesia, which can be tolerated dose is 3 million IU/m2/day. It is now available pegylated interferon preparations, so that the injection once a week, do not need every day.
• Required premedication with analgesic and antipyretic before giving interferon to prevent / reduce the side effects of interferon in the form of flue-like syndrome.
• Drug interactions: theophylline, cimetidine, vinblastine and zidovudin interveron toxin can enhance the effect.
• Exercise caution when given at an advanced age, impaired liver function and kidney weight, patients with epilepsy.
Bone marrow transplant
• It is the definitive therapy for LGK. The data show that bone marrow transplantation (CST) to extend the period of remission up to> 9 years, especially in allogeneic CST.
• Not done on LGK with negative Ph chromosome or BCR-ABL negative.

Thursday, 7 October 2010


There is no definite definition of the notion Cardiorenal Syndrome (CRS). The National Heart, Lung, and Blood Institute defines the circumstances in which therapy to relieve symptoms of congestive heart failure is limited by the decline in kidney function. More broadly described as a state of moderate or high renal dysfunction, which appears in heart failure patients during therapy. Some say the CRS is the linkage of heart and kidney with the burden of excess fluid in which patients become resistant to diuretic therapy.

Based on the Studies of Left Ventricular Dysfunction (SOLVD), factors associated with decreased kidney function (defined by increased serum creatinine 0.3 mg / dL) were:

• Old age
• low ejection fraction
• Increased level of creatinine
• Low Pressure diastole
• DM
• Hypertension
• The use of antiplatelet, diuretic and β-blockers

Still little knowledge about the pathophysiology of CRS. Decrease in Cardiac Output (CO) in CHF that causes a decrease in renal perfusion, could be an easy explanation. But it has been shown that the decline in kidney function can also occur in ADHF. This contrasts with the statement that the decrease in ejection fraction will lead to renal hypoperfusion and then lead to kidney dysfunction. Thus giving the impression that the pathophysiology of renal dysfunction is more complex than simply decreasing CO.
The model of Guyton explains the relationship component of the heart-kidney, namely Renin-Angiotensin System (RAS), the balance of nitric oxide and reactive oxygen species (NO-ROS), inflammation, and sympathetic nervous system (Sympathetic Nervous System (SNS)) the fourth called Cardiorenal Connection (CRC).

Renin-Angiotensin System (RAS)
When heart failure, a decline in CO and mean arterial blood pressure and renal hypoperfusion and activation of RAS occurs. In kidney failure also occurs inappropriate activation of RAS. In addition to volume retention and vasoconstriction occurs, one of the action on the RAS of the most damaging is the activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) by Angiotensin II, led to the formation of ROS. NADPH-oxidase have been found elevated in end-stage heart failure.
Angiotensin II causes vascular inflammation via nuclear factor kappa B (NF-кB), which induces production and adhesion molecule kemotatik. RAS also increase sympathetic activity, the situation is found in renal failure.

NO is important in the kidneys for the control of extracellular fluid volume and blood pressure by vasodilation, natriuresis and desensitasi tubuloglomerular feedback. In the CRS NO-ROS imbalance, namely increased production of ROS, decreased antioxidant and decreased NO. Impairment of antioxidants due to oxidative inactivation, decrease in antioxidant vitamins, and disposal of water-soluble antioxidants through dialysis membranes. Oxidative stress is the beginning of the inflammatory response by production (or activation) proinflammatory cytokines, particularly interleukin-1, interleukin-6, C-reactive protein and tumor necrosis factor-alpha (TNFα). These cytokines have an important role in the pathophysiology of atherosclerosis, the negative inotropic effect, cardiac remodeling and thrombotic complications. In vivo and in vitro in mice, oxidative stress increased preganglionic sympathetic nerve activity, increased Artrial Mean Pressure (MAP) and heart rate.
Although not yet completely resolved, oxidative damage in renal tubular or interstitial cells may be involved in the feedback system of the secretion of renin and angiotensin formation in the CRS. Constraints on the synthesis of NO causes chronic cardiac regulation ACE and angiotensin II receptor, which may mediate inflammatory.

It has been estimated to worsen inflammation of heart failure. In patients with heart failure, increased TNF-α and IL-6 found in plasma and myocardium and the nexus with disease progression. Interleukin-18 also terdapt in heart failure after mitral insufficiency. Role of activation of inflammatory cells certainly not very clear, but in CKD and heart failure are chronic inflammatory disorders.
Low-grade inflammation can cause ROS production by activation of leukocytes to remove Oxidative content.

The first SNS activation of heart failure by baroreflex to provide inotropic and maintain CO. However, excessive sympathetic activity can induce cardiomyocyte apoptosis, hypertrophy and focal myocardial necrosis. Hypertrophy in part due to direct action catecholamines, because some studies indicate noradrenaline induces hypertrophy in cultured cardiomyocyte. In chronic excessive sympathetic activity causes insensitive beta-adrenoreceptor in heart failure and kidney failure. This can cause disruption baroreceptors reflex, reduced heart rate variability decrease and increase state toward arrhythmia.
Sympathetic effects on the kidney to increase renin due to prolonged excessive sympathetic activity has growth-promoting effects on intrarenal vascular wall. This effect is often found mediated by ROS production. SNS can induce inflammation by producing cytokine-mediated noradrenaline from liver and heart, and beta-blockade.
SNS is also releasing neurohormon neuropeptide Y (NPY) involved in vasoconstriction associated with prolonged stress. NPY acts as a trigger of vascular growth, especially in neo-intima formation of blood vessels associated with atherosclerosis. NPY also affect the immune response that is changing the release of cytokines and immune cell function.
So fourth cardiorenal connectors can enlarge the effects of the damage between each other with cardiorenal syndrome as a result.

Until now there is no definitive medical management of heart failure in patients with kidney failure. Treatment is only based on clinical trials. So in this situation is more individualized therapy.

1. ACE inhibitors
ACE inhibitors are known to increase the survival rate in heart failure. However, this drug should be used with caution in renal insufficiency. The Cooperative North Scandinavian Enapril Survival Study (Consensus) shows patients with severe heart failure have increased serum creatinine (> 30%) when using ACE inhibitors. In most patients in which ACE inhibitor was stopped, creatinine levels returned to baseline. Consensus provides good evidence about the benefits of ACE inhibitors in patients with heart failure and renal insufficiency being. But the study did not include patients with severe renal insufficiency (GFR <30 mL / min per 1.73 m2), so that the efficacy and safety of ACE inhibitors in these patients is unknown.
To reduce the incidence of renal failure, ACE inhibitors should be started with low doses, but avoid dehydration and use of common NSAIDs. ACE inhibitors can be delayed if the serum creatinine +6 mg / dL, or GFR <20 mL / min or other contraindications to appear. ACE inhibitors can still be used as long as no worsening renal failure and severe hyperkalemia does not occur

2.  Diuretics
Use of diuretics in the CRS is still very controversial. Several studies have shown aggressive diuresis can worsen kidney function. High-dose diuretics were associated with increased mortality. Because diuretic therapy may worsen renal function and decreased kidney function causing poor results, then the diuretic resistance can be an indicator of poor prognosis of chronic renal failure. However because of lack of definitive data, patients with volume overload state should not barred from granting tiazid loop or diuretics to reduce symptoms.
Some of the factors that create resistance diuretics include: inadequate diuretic dose, excess sodium intake, the late drug absorption, decreased diuretic excretion in the urine and increased sodium reabsorption in the nephron that are not sensitive to the diuretic.
Overcoming resistance diuretic furosemide infusion can be given continuously, starting from 5 mg / h to 10 mg / hour, followed by intravenous thiazide diuretics (usually 250 mg or 500 mg of intravenous chlorothiazide).
When deciding dose diuretics in patients with refractory edema, should be considered in several ways. First, the effective dose should be determined. Also, patients who did not respond with 20 mg of furosemide may not be past the threshold, then the dose should be increased to 40 mg instead of giving the same dose 2 times. Second, patients should limit sodium intake, because high sodium can prevent discharge despite adequate diuretic has been given. Third, patients initially may be given intravenous diuretics for preventing poor oral bioavabilitas due to decreased perfusion and gut motility and mucosal edema also can decrease drug absorption. High dose intravenous diuretics should be given slowly, over 30-60 minutes, to avoid ototoxic.

3. Low-dose dopamine
 Often the effort to increase blood flow to the kidneys and urine output to reduce the incidence of renal failure used low-dose dopamine (approximately 1-3 g / kg / min) or called renal dose. Low-dose dopamine is a non-selective dopaminergic agonists. This can improve renal function by vasodilation (D1 and D2 receptors), saluresis (D1), increased CO (β) and increased renal perfusion (α).
In the experiment by the Australian and New Zealand Intensive Care Society of the effects of low dose dopamine (2 g / kg / min) in the kidneys which was conducted on 2 groups (dopamine group and the placebo group) concluded that no clinically significant protection of kidney failure.

4. Digoxin
Research from The Digitalis Investigation Group (DIG) showed digoxin does not affect life expectancy, but reduced heart failure hospitalizations by 28%. There has been no research on the effects of digoxin in renal failure. To use the safe in patients with heart failure and renal insufficiency, digoxin should be used without a loading dose and with low maintenance dose of 0125 mg.

5. Inotropic
If renal dysfunction in CRS mainly because of low CO, inotropic therapy experiments using dopamine or milrinon can be considered. But its use in CRS is still controversial. Until there is more meaningful data that this drug can be given at a low CO state for a brief period with the monitoring, because of possible risk of arrhythmia.

6. Nesiritide
B-Type natriuretic peptide (BNP) is synthesized in ventricular myocardium due to the response of the widening and overload. BNP mendilatasi arteries and veins, increase the excretion of sodium, and pressing RAS.3 Nesiritide is a synthetic form of BNP has been recognized Food and Drug Administration for the treatment of ADHF. Nesiritide has the effect of venous dilatation, and coronary arteries, reducing preload and afterload, increased CO without direct inotropic effects. causes natriuresis and dieresis, and suppress norepinephrine, endothelin-1, and aldosterone.
At CRS, nesiritide study showed no effect on GFR, renal plasma flow, urine output and sodium excretion. Even in some of the data actually increase the risk of renal insufficiency in patients with heart failure. Further research is needed to determine the role and safety of nesiritide.

7. Ultrafiltration
Ultrafiltration or dialysis is used in patients with chronic volume overload resistant to therapy. Improve kidney dialysis and cardiac hemodynamic responses, but usually used as a palliative in end-stage CRS and can not be given to long term.

By looking at the vagueness of CRS pathophysiology and therapy, these patients have a poor prognosis. Increased serum creatinine or decreased GFR is a poor prognosis. Prognosis worse if accompanied by oliguria, edema, hyponatremia, or resistant to diuretics.

Cardiorenal syndrome is a state of interrelations between the heart and kidneys which leads to fluid overload, diuretic resistance and further involve the various systems that bring clinical circumstances will be worse.
Cardiorenal syndrome have a unique and complex pathophysiology. Whatever the degree of renal insufficiency with a combination of heart failure is a challenge in the management of patients and is associated with poor prognosis.
 There are currently no selective therapy for cardiorenal directly affects the connection. Almost all of the current therapies have adverse effects on kidney function. Therefore, good clinical decision is needed in the management of patients.
Large-scale research is needed to determine the definite pathophysiology of cardiorenal syndrome and establish an effective therapy

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