patient is suffering from Diabetes Insipidus

A 23-year-old male was seen in the emergency department after suffering a concussion and head trauma from a motor vehicle accident. The patient was stabilized in the emergency department and transferred to the intensive care unit (ICU) for observation. The patient had computed tomography(CT) scan of the head that revealed a small amount of cerebral edema but was otherwise normal. During the second day in the ICU, the nurse informed that the patient had a large amount of urine output in the last 24 hours. The nursing records reported his urine output over the previous 24 hours to be 5000 cc. He had not been given any diuretic medications. A urine osmolality was ordered and was found to be low. His physician remarked that the kidneys were not concentrating urine normally.

What is the most likely diagnosis for the increasing dilute urine output?

Which biochemical mediator is responsible for this disorder ?

Case details The patient is suffering from Diabetes Insipidus.  Excessive excretion of diluted urine with a low osmolarity and history of head injury are all suggestive of diabetes Insipidus. Head trauma is one of the most common causes of diabetes Insipidus, particularly if the posterior pituitary stalk is disrupted. 

Polyuria, Polydipsia,high plasma osmolarity and a low urinary osmolarity are hall marks of diabetes Insipidus. Diabetes Insipidus is not the same as diabetes mellitus (“sugar” diabetes).  Diabetes Insipidus resembles diabetes mellitus because the symptoms of both diseases are increased urination and thirst.  However, in every other respect, including the causes and treatment of the disorders, the diseases are completely unrelated.   Sometimes diabetes Insipidus is referred to as”water” diabetes to distinguish it from the more common diabetes mellitus or “sugar” diabetes.

Pathophysiology           

The regulation of urine production occur in the hypothalamus, which produces ADH in the supraoptic and Para ventricularnuclei. After synthesis, the hormone is transported in neuro secretory granules down the axon of the hypothalamic neuron to the posterior lobe of the pituitargland where it is stored for later release. In addition, the hypothalamus regulates the sensation of thirst in the ventromedial nucleus by sensing increases in serum osmolarity and relaying this information to the cortex.

The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubule, specifically it acts on proteinscalled aquaporins which open to allow water into the collecting duct cells.This increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine.

Signs and symptoms

Excessive urination and extreme thirst are typical for DI. Symptoms of diabetes Insipidus are quite similar to those of untreated diabetes mellitus, with the distinction that the urine does not contain glucose and there is no hyperglycemia. Signs of dehydration may also appear in some individuals since the body cannot conserve much of the water it takes in.

The extreme urination continues throughout the day and the night. In children, DI can interfere with appetite, eating,weight gain, and growth as well. They may present with fever, vomiting, ordiarrhea. Adults with untreated DI may remain healthy for decades as long as enough water is consumed to off set the urinary losses. However, there is a continuous risk of dehydration and loss of potassium.

Biochemical defect -Diabetes Insipidus is divided into four types, each of which has a different cause and must be treated differently. 

1) Central or neurogenic DI- The most common type of DI is caused by a lack of vasopressin, a hormone that normally acts upon the kidney to reduce urine output by increasing the concentration of the urine.  This type of DI isusually due to the destruction of the “posterior” part of the pituitary gland where vasopressin is normally produced.  Hence, it is commonly called pituitaryDI.   

The posterior pituitary can be destroyed by a variety of underlying diseases including tumors, infections, head injuries(As in the given patient), infiltrations, and various inheritable defects. The latter can be recognized by the onset of the DI in early childhood and a family history of parents, siblings or other relatives with the same disorder.  Nearly half the time, however, pituitary DI is”idiopathic” (that is, no cause can be found despite a thorough search including magnetic resonance imaging or MRI of the brain) and the underlying cause(s) is (are) still unknown.  

2) Gestagenic or gestational DI -Occasionally,a lack of vasopressin can also develop during pregnancy if the pituitary is slightly damaged and/or the placenta destroys the hormone too rapidly. 

3) Nephrogenic DI -The third type of DI is caused by an inability of the kidneys to respond to the “antidiuretic effect” of normal amounts of vasopressin.  The kidneys’ ability to respond to ADH can be impaired bydrugs—like lithium, for example—and by chronic disorders including polycystic kidney disease, sickle-cell disease, kidney failure, partial blockage of the ureters, and inherited genetic disorders.

4) DipsogenicDI -The fourth form of DI occurs when vasopressin is suppressed by excessive intake of fluids.  The latter is usually referred to as primary polydipsia and is most often caused by an abnormality in the part of the brain that regulates thirst.  This subtype is difficult to differentiate from pituitary DI particularly since the two disorders can result form  many of the same brain diseases. 

Diagnosis

Diagnosis is based on a series of tests,including urinalysis and a fluid deprivation test.

Urine analysis -The urine of a person with DI will be less concentrated.
A fluid deprivation test helps determine whether DI is caused by one of the following:

• excessive intake of fluid
• a defect in ADH production
• a defect in the kidneys’ response to ADH

This test measures changes in body weight,urine output, and urine composition when fluids are withheld. Sometimes measuring blood levels of ADH during this test is also necessary.

Desmopressin stimulation Test -To distinguish between the main forms,desmopressin stimulation is also used; desmopressin can be taken by injection,a nasal spray, or a tablet. While taking desmopressin, a patient should drink fluids or water only when thirsty and not at other times, as this can lead to sudden fluid accumulation in the central nervous system. If desmopressin reduces urine output and increases osmolarity, the pituitary production of ADH is deficient, and the kidney responds normally. If the DI is due to renal pathology, desmopressin does not change either urine output or osmolarity.
In order to distinguish DI from other causes of excess urination, blood glucose levels, bicarbonate levels, and calcium levels need to be tested. Measurement of blood electrolytes can reveal a high sodium level (hypernatremia as dehydration develops).
In some patients, a magnetic resonance imaging (MRI) of the brain may be necessary as well.

Treatment

Central DI and gestational DI respond todesmopressin, a synthetic analogue of ADH. Gestational DI tends to abate on itsown 4 to 6 weeks following labor, though some women may develop it again in subsequent pregnancies. In dipsogenic DI, desmopressin is not usually an option.

Desmopressin is ineffective in nephrogenic DI. 
Again, adequate hydration is important for patients with DI, as they may become dehydrated easily.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Hypercalcemia

A 35 year -oid female reported to emergency with severe pain in the left flank region, which was radiating towards lower leg and back. The patient was in acute distress and agony. History revealed that she frequently suffered from urinary tract infections and had several such episodes of pain.She further reported that she constantly felt weakness, fatigue and bone pains from the previous few months. There was no history of fever and there was no personal or family history of medical problems.

Her physical examination was normal except for tenderness in the left renal region.

The attending physician ordered for complete blood count, electrolytes and a complete urinalysis.

The laboratory investigation report revealed a normal complete blood count (CBC), and significantly elevated calcium level and low phosphorus level. Urine was cloudy and had plenty of pus cells. The patient was admitted and treated for renal colic.

What is the underlying cause for repeated episodes of renal colic?

What is the most likely diagnosis?

What is the relationship of bone pains and frequent urinary tract infections in this patient?

What is the cause for high serum calcium and low phosphorus level in this patient?

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Hypercalcemia

A 35 year -oid female reported to emergency with severe pain in the left flank region, which was radiating towards lower leg and back. The patient was in acute distress and agony. History revealed that she frequently suffered from urinary tract infections and had several such episodes of pain. She further reported that she constantly felt weakness, fatigue and bone pains from the previous few months.

There was no history of fever and there was no personal or family history of medical problems.

Her physical examination was normal except for tenderness in the left renal region.The attending physician ordered for complete blood count, electrolytes and a complete urinalysis.

The laboratory investigation report revealed a normal complete blood count (CBC), and significantly elevated calcium level and low phosphorus level.Urine was cloudy and had plenty of pus cells. The patient was admitted and treated for renal colic.

What is the underlying cause for repeated episodes of renal colic?

What is the most likely diagnosis?

What is the relationship of bone pains and frequent urinary tract infections in this patient?

What is the cause for high serum calcium and low phosphorus level in this patient?

Case details Hypercalcemia, hypophosphatemia, recurrent urinary tract infections, renal stones and bone pains all signify underlying hyperparathyroidism. (Cloudy urine and pus cells are indicative of urinary tract infection).

Hyperparathyroidism is over activity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). The parathyroid hormone regulates calcium and phosphate levels.  

Hyperparathyroidism is classified in three categories-

1) Primary hyperparathyroidism-Primary hyperparathyroidism results from a hyper function of the parathyroid glands themselves. There is over secretion of PTH due to adenoma, hyperplasia or,rarely, carcinoma of the parathyroid glands.

2) Secondary hyperparathyroidism-Secondary hyperparathyroidism is the reaction of the parathyroid glands to a hypocalcaemia caused by something other than a parathyroid pathology, e.g.chronic renal failure or vitamin D deficiency.

3)Tertiary hyperparathyroidism- Tertiary hyperparathyroidism results from hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. In cases of long-standing secondary hyperparathyroidism, the hypertrophied parathyroid glands can become autonomously functioning and continue to secrete PTH independent of whether the original stimuli to secrete PTH are still present.

In all cases, the raised PTH levels are harmful to bone, and treatment is often needed.

Serum calcium- In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium (Hypercalcemia) due to:

1. increased bone resorption, allowing flow of calcium from bone to blood
2. reduced renal clearance of calcium
3. increased intestinal calcium absorption

By contrast, in secondary hyperparathyroidism effectiveness of PTH is reduced.

Serum phosphate

In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased renal tubular phosphate reabsorption. However, this is only present in about 50% of cases.This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of renal disease.

Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement is due to either deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients,repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. 

Nephrocalcinosis may also cause decreased renal function and phosphate retention.

There are great variations in the manifestations. Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers,mental changes, and, less frequently, extensive bone resorption.

Treatment and monitoring Treatment depends upon the severity and cause of the condition. If there is mildly increased calcium levels due to primary hyperparathyroidism and no symptoms, just regular check ups are needed. If symptoms are present or calcium level is very high, surgery may be needed to remove the parathyroid gland that is overproducing the hormone. Treatment of secondary hyperparathyroidism depends on the underlying cause.Vitamin D and Phosphorus supplementation can also be done. 

Calcimimetics

A Calcimimetics (cinacalcet) is a new type of drug for people with primary and secondary hyperparathyroidism on dialysis. It mimics the effect of calcium in tissues. This reduces PTH release from parathyroid glands, leading to lower calcium and phosphorus levels in blood. 

Surgery for hyperparathyroidism may lead to low blood calcium levels, which causes tingling and muscle twitching. This requires immediate treatment.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Diabetic ketoacidosis

A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is distinctive smell from her breath

What is the most likely diagnosis?

What is the biochemical basis for all the presenting symptoms?

Which laboratory test would you request?

Case discussion The patient is most probably suffering from diabetic ketoacidosis. She is a known diabetic and the presenting symptoms like abdominal pain, vomiting, rapid breathing and distinctive smell of breath, all indicate associated ketoacidosis.

Basic concept Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood.  It is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in type 1 diabetes mellitus, but it can also occur in type 2 diabetes mellitus under certain circumstances.

Causes- DKA occurs most frequently in knownDiabetics. It may also be the first presentation in patients who had not been previously diagnosed as diabetics. There is often a particular underlying problem that has led to DKA episode. This may be-

1) Inter current illness such as Pneumonia,Influenza, Gastroenteritis, Urinary tract infection or pregnancy.

2) Inadequate Insulin administration may be due to defective insulin pen device or in young patient intentional missing of dose due to fear of weight gain.

3) Associated myocardial infarction, stroke or use of cocaine

4) Inadequate food intake- may be due to anorexia associated with infective process or due to eating disorder in children. 

Diabetic keto acidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity,strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labelled ”ketosis-prone type 2 diabetes”.

Pathophysiology

DKA results from relative or absolute insulin deficiency combined with counter regulatory hormone excess (Glucagon, Catecholamines, cortisol, and growth hormone). The decreased ratio of insulin to Glucagon promotes Gluconeogenesis,glycogenolysis, and Ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver. 

a) Cause of hyperglycemia Uncontrolled IDDM leads to increased hepatic glucose output.First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle,insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues.

Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism. In addition, the level of hepatic Glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin(primarily through covalent modifications). The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels.

b) Cause of kenosis One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipose storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. 

The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy.Free fatty acids are also taken up by the liver. Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyl Transferase I, the enzyme required for the transport of fatty acyl-CoA’s into the mitochondria where they are subject to oxidation for energy production.

Thus, in the absence of insulin,malonyl-CoA levels fall and transport of fatty acyl-CoA’s into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majorityof the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetoacetate and β-hydroxybutyrate.  TCA cycle is in a state of suppression due to non availability of oxaloacetate which is channeled towards pathway of gluconeogenesis in the absence of Insulin. 

These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of Acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.

c) Causes of Acidosis and hyperventilationThe ketone bodies, however, have a low pH and therefore turn the blood acidic(metabolic acidosis). The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration. Ketones, too,participate in osmotic diuresis and lead to further electrolyte losses. As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 ml/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/l or 250 mg/dl. 

Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase triglyceride and VLDL production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Most commonly, DKA is precipitated by increased insulin requirements, as might occur during a concurrent illness. Occasionally, complete omission of insulin by the patient with type 1 DM precipitates DKA.

Clinical manifestations- The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst,excessive urine production and abdominal pain that may be severe.

Hyperglycemia is always present .In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as “Kussmaul respiration”). The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.  

Coffee ground vomiting(vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosions of the esophagus. In severe DKA, there may be confusion, lethargy, stupor or even coma(a marked decrease in the level of consciousness).

On physical examination -there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a ”ketotic”odor is present, which is often described as “fruity”. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.

Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.7–1.0% of children with DKA, and has been described in young adults, but is  very rare in adults. It carries 20–50% mortality. 

figure showing causes and consequences of DKADiagnosis

Investigations-  Diabetic Ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated.

Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery.

In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes.

Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured.

Given the need to exclude infection, chest radiography and urinalysis are usually performed.If cerebral edema is suspected because of confusion, recurrent vomiting or other symptoms, computed tomography may be performed to assess its severity and to exclude other causes such as stroke.

Management

 The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin.

a) Fluid replacement The amount of fluid depends on the estimated degree of dehydration. If dehydration is sosevere, rapid infusion of saline is recommended to restore circulating volume.

 b) Insulin is usually given continuously.

c) Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. Serum potassium levels are initially often mildly raised even though total body potassium is depleted. Hypokalemia often follows treatment. This increases the risk of irregularities in the heart rate. Therefore, continuous observation of the heart rate is recommended, as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l. If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia.

d) Bicarbonate- Sodium bicarbonate solution is administered to rapidly improve the acid levels in the blood.

Cerebral edema- administration of fluids is slowed; intravenous Mannitol and hypertonic saline (3%) are used.

Prognosis

 With appropriate therapy, the mortality of DKA is low (<5%) and is related more to the underlying or precipitating event, such as infection or myocardial infarction. The major non metabolic complication of DKA therapy is cerebral edema,which most often develops in children as DKA is resolving.

The etiology of and optimal therapy for cerebral edema are not well established, but over replacement of free water should be avoided. The other known complications of DKA therapy are, Hypoglycemia,hypokalemia and hypophosphatemia.Venous thrombosis, upper gastrointestinal bleeding, and acute respiratory distress syndrome occasionally complicate DKA.

Prevention of DKA

Following treatment, the physician and patient should review the sequence of events that led to DKA to prevent future recurrences. Foremost is patient education about the symptoms of DKA, its precipitating factors, and the management of diabetes during a concurrent illness.

During illness or when oral intake is compromised,patients should:

(1) frequently measure the capillary blood glucose;

(2) measure urinary ketones when the serum glucose > 16.5 mmol/L (300 mg/dL);

(3) drink fluids to maintain hydration;

(4) continue or increase insulin; and

(5) seek medical attention if dehydration, persistent vomiting, or uncontrolled hyperglycemia develop. Using these strategies, early DKA can be prevented or detected and treated appropriately on an outpatient basis.

DKA IN PREGNANCY-   DKA in pregnancy is of special concern. It tends to occur at lower plasma glucose levels and more rapidly than in non-pregnant patients and usually occurs in the second and third trimesters because of increasing insulin resistance. Fetal mortality rates have previously been reported as high as 30% rising to over 60% in DKA with coma. However with improvements in diabetic care the figure for fetal loss has been reported as low as 9% in some countries. Prevention, early recognition and aggressive management are vitally important to minimize fetal mortality.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Renal clearance

Renal clearance is a measurement to determine the functional status of the kidney. By definition clearance is the volume of plasma from which a substance is completely removed through excretion by the kidney in a given amount of time (usually a minute). For example, the  urea is 75 ml/min. This means that the kidney removes all of the urea in 75ml of plasma in one minute. 

Every minute approximately 625 ml of plasma flows to the kidney. This is the renal plasma flow. Some of the fluid leaves the kidney in the plasma while some leaves the kidney as urine. There are only two ways for a substance to end up in the urine: either it is filtered at the glomerulus and then not reabsorbed from the tubules, or the substance is not filtered but is secreted by the peritubular capillaries into the tubules. In either instance, the substance ends up in the collecting duct and is excreted into the urine.

Figure- showing the structure and function of a nephron

Of the 625 ml/min of plasma that goes to the glomerulus, 125 ml/min is filtered into Bowman’s capsule forming the filtrate (The rate of filtration is known as the Glomerular filtration rate- GFR). The remaining 500 ml/min enters into the peritubular capillaries. Of the 125ml/min filtered, almost all of the water in this fluid is reabsorbed back into the blood. The composition of the filtrate in Bowman’s capsule is identical to the composition of the plasma except that the filtrate has no or very little amount of proteins.

Any substance, which is freely filtered by the glomerulus and is neither reabsorbed nor secreted, ends up in the urine.Thus all the plasma that gets filtered is cleared of that substance(that is, all the substance in the filtrate gets excreted) while the substance that that is not filtered (and thus remains in the plasma) is not excreted.Since clearance is defined as the volume of plasma ‘cleared’ of a substance in1 min, the clearance for that substance would be 125 ml/min. This means that out of the 625 ml of plasma that come to the kidney in one minute, 125 ml (the fraction that is filtered) has all of the substance removed from it in that minute, the other 500 ml (the fraction that is not filtered) keeps it as there is no way for the substance get into the urine as it is not secreted.

The GFR is typically recorded in units of volume per time, e.g., millilitres per minute ml/min. 

The compound inulin is cleared in the same way as mentioned above. All of the plasma that is filtered is cleared of inulin so that if one has to measure the clearance of inulin, it would be equal the amount of plasma filtered in a minute, the glomerular filtration rate.Therefore, the clearance of inulin is equal to the glomerular filtration rate, the volume of plasma filtered in one minute. Inulin is not a normal metabolite of the body; it is in fact administered to determine the functional status of the kidney

The clearance of any other substance is not similar to clearance of inulin. For example-Glucose, like inulin, is freely filtered. Thus glucose is present in Bowman’s Capsule. However, glucose does not appear in urine because glucose is completely reabsorbed as it passes through the tubules. Inulin is not reabsorbed. This means all of the glucose that comes to the kidney is saved and leaves the kidney in the plasma and that no glucose is excreted into the urine. The clearance of glucose is therefore 0ml/min as no plasma has its glucose removed as it passes through the kidney.This would be true for any substance that is completely reabsorbed. Hence if the clearance of Tryptophan (an amino acid) is 0 ml/min, it can be inferred that Tryptophan must be completely reabsorbed (as long as it is freely filtered).

Taking the example of another substance, Paraamino Hippuric acid (PAH), It is freely filtered, not reabsorbed and is completely secreted by the kidney. Thus all of the PAH entering the kidney ends up in the urine, both the PAH that is filtered and that that is not filtered.This means that all the plasma entering the kidneys would be cleared of PAH. Since the renal plasma flow is about 625 ml/min in a ‘normal’ kidney, the clearance of PAH must be 625 ml/min. Therefore, the PAH clearance is equal to the renal plasma flow. PAH clearance is used to determine whether the kidneys have an adequate plasma flow.

Now, if the clearance of a substance is 625ml/min, this would suggest that the kidney completely secretes this substance(that is, the kidney ‘treats’ this substance the same as PAH which is known to be completely secreted). Using similar logic, a clearance value of 125 would suggest that the kidney neither reabsorbs nor secretes the substance and a clearance value of 0 suggests that the kidney completely reabsorbs the substance (assuming that the substance is freely filterable in the glomerulus).

The urea clearance has been measured to be 75ml/min. What does the kidney ‘do’ with urea (does it reabsorb, secrete or neither)? Well if urea is completely reabsorbed, its clearance should be like that of glucose (0 ml/min) and if urea is not reabsorbed at all (and not secreted), its clearance should be 125 ml/min. Since the value of urea clearance is 75 ml/minute, which means urea is partially reabsorbed. Note that the common belief concerning kidney function is that it removes urea from the blood yet the nephron partially reabsorbs urea! Thus urea clearance is not a true predictor of Glomerular filtration rate as is Inulin clearance.

In clinical practice, however, creatinine clearance or estimates of creatinine clearance based on the serum creatinine level are used to measure GFR. Creatinine is produced naturally by the body (creatinine is a break-down product of creatine phosphate, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the peritubular capillaries in very small amounts such that creatinine clearance over estimates actual GFR by 10-20%. This margin of error is acceptable, considering the ease with which creatinine clearance is measured.Unlike precise GFR measurements involving constant infusions of inulin,creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome.

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------

Chemistry Of Proteins-3

1. Why are amino acids called as Amino acids?

(Since they have an amino group and an acid group i.e. Carboxyl group which is ionized at the physiological p H and behaves as a proton donor and is thus an acid)

 2- What is meant by primary amino acids?

(Those amino acids which have a genetic information on the DNA for their synthesis are called as Primary or standard amino acids)

3- What is the linkage between the amino acids in a peptide?

(The amino acids are linked together by a peptide bond which is an anhydrous linkage between the amino acids)

4- Name the amino acids which are derived or modified after translation but are not incorporated in to the tissue proteins.

 (Homocysteine, GABA, Argino succinic acid, Ornithine, Citrulline, etc)

5- Define Denaturation

 ( It is the loss of secondary , tertiary or quaternary structure( if present ) of a protein on exposure to heat, UV light, acids, alkalies, heavy metal salts or even by vigorous shaking, the primary structure is left intact)

6-What is meant by a complete protein, give an example of a complete protein?

( A Complete protein contains all the essential amino acids in an appropriate amount  required for growth, repair and maintenance of body weight.  Example -Egg protein)

7- Give an example of a protein with axial ratios >10:1

(Fibrinogen, keratin, collagen )

8-How many amino acids can be accommodated in one turn of alpha helix?

(3.4 amino acids)

 9- What are chaperones?

 (These are the proteins which participate in the proper folding of the proteins)

10- What is the defect in “transmissible spongiform encephalopathies’?

(These are included under the category of Prion’s diseases and are fatal neurodegenerative diseases characterized by spongiform changes, astrocytic gliomas, and neuronal loss resulting from the deposition of insoluble protein aggregates in neural cells. The protein aggregates are formed of misfolded proteins.)

11-What is the difference between a homodimer and a heterodimer?

(Homodimer contains two copies of the same polypeptide chain, while in a heterodimer the polypeptides differ)

12-What are amphipathic helices?

(The alpha helices having predominantly hydrophobic R groups on one side of the axis of the helix and predominantly hydrophilic ones on the other side are called amphipathic helices)

13-All the amino acids except——- have a chiral centre.

 (Glycine)

14-What is meant by isoelectric  p H ?

 ( It is the p H at which amino acid carries no net electrical charge)

15-Proteins contain only D-amino acids, for which a left handed alpha helix is by far the more stable,  thus only left-handed helices are present in proteins. True or false?

 (False –Proteins contain only L-amino acids, for which a right-handed alpha helix is by far the most stable, and only right-handed alpha helices are present in proteins)

16-Give examples of metalloproteins-

( Alcohol dehydrogenase, glutamate dehydrogenase, Xanthine oxidase  etc. are the examples of metalloproteins

17-Give examples of non standard amino acids which are incorporated in to tissue proteins.

( Hydroxy proline, hydroxy lysine )

18– What is meant by zwitterion ?

( It is the form of amino acid present at its isoelectric p H,  both positive  and negative charges are there but the net charge is zero)

19-Name an indole ring containing amino acid-

(Tryptophan

20- Name the peptides which act as gastro intestinal hormones-

( Secretin, pancreozymin and cholecystokinin)

21- Name the amide group containing amino acids

(Asparagine, Glutamine)

22- What are derived proteins ?

(Proteoses, peptones and peptides etc, the product of digestion and denaturation are called as derived proteins )

23- Give two examples of antibiotic peptides

(Polymyxin, Penicillin, etc )

24-What is the difference between cysteine and cystine ?

( Two cystine residues are joined together by a disulfide bridge to from cystine )

25- What are histones? 

( Histones are simple proteins which can bind with DNA to form nucleoproteins, generally they are rich in basic amino acids like Arginine and lysine )

26- Which amino acid disrupts the alpha helical structure of the proteins ?

( Proline and hydroxy proline )

27- Name the components of Glutathione

(Glutamic acid, cysteine and glycine )

28- Name two proteins with a quaternary structure

( Immuno globulins, Hemoglobin, CPK , LDH etc )

29- What are brain peptides ?

( Met encephalin and Leuencephalin)

30- Name a Phospho protein

(Casein, Ovovitellin)

31-What is the product formed after decarboxylation of an amino acid ?

( Amines are formed after decarboxylation of amino acids- like Tryptamine, histamine Tyramine etc)

32-Name the sulphur-containing amino acids-

(Cysteine, cystine and Methionine)

33-Choose the aromatic amino acid out of the following-

Arginine, Histidine, lysine and Tyrosine —— (Tyrosine)

34-Choose an amino acid that does not participate in the alpha helical formation-

Methionine, tryptophan, serine, cysteine——

( Tryptophan )

 35- Millon’s reaction is specific for——- ?        

( Tyrosine )

36- Out of the followings which amino acid is not present in the proteins?

β- Alanine, Histidine, Glycine                    

(β- Alanine)

 37- Name a peptide which acts as a smooth muscle relaxant

( Bradykinin)

38-   What is the nature of prosthetic group in Ceruloplasmin ?

(Copper- It is metalloprotein)

 39- What is a nutritionally poor protein ?Give an example-

( A protein which lacks many essential amino acids is called a poor protein, E.g.- Gelatin

 40- Which protein is abundantly present in hair?     

(Keratin )

41-What is the significance of Biuret test?

 ( It is for the detection of proteins and peptides. Dipeptides and amino acids do not give this test positive, more than two peptide bonds are required for this test to be positive )

42- What is the nature of casein, the milk protein?

( It is a Phospho protein- A conjugated protein)

 43- What is the axial ratio in fibrous proteins?

 ( > 10:1)

 44- In proteins the alpha helical and beta pleated sheet structures are examples of-

Primary, secondary or tertiary structure ?            

( Secondary)

 45- Name an Imidazole ring containing amino acid 

(Histidine)

46- Name a peptide  hormone which prevents diuresis –

( ADH)

47 What is the basis of using raw egg for heavy metal poisoning ?

( Egg protein binds with heavy metal to form metal proteinate complex, which is water-soluble and is excretable, else heavy protein binds with tissue proteins to cause damage)

48- The tertiary structure of a protein describes sequence of amino acids- true or false ?

( False- Tertiary structure describes the folding of the protein )

49- Give two examples of haemoproteins.

(Hemoglobin, Myoglobin, Cytochromes, Catalase, Peroxidase and Tryptophan Pyrrolase)

50-  In a protein the disulphide bridges can be broken by–

 ( Reduction )

------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------