Nephrology.docx

NEPHROLOGY **[1-Introduction to nephrology, kidney function and pathological renal diseases]** **[Clinical case]** Antonio is 70 years old, works as a bank clerk and he has been well until a few months ago. When asked, he remembered that on a few occasions, in the past years, he was found with hi...

NEPHROLOGY **[1-Introduction to nephrology, kidney function and pathological renal diseases]** **[Clinical case]** Antonio is 70 years old, works as a bank clerk and he has been well until a few months ago. When asked, he remembered that on a few occasions, in the past years, he was found with high blood pressure and had taken an anti-hypertensive drug for a while. Then he never checked his blood pressure again. In the last few months, he noticed frequent urination at night and has suffered headaches. If the patient doesn't take large doses of diuretics, **nocturia is the first sign of renal dysfunction, because the first ability lost is the one of concentrating urine**. Now the patient feels very tired, with lack of appetite and nausea. His doctor finds him pale, with edema in the lower limbs and with high blood pressure (210/110 mmHg). Therefore, he prescribes him some lab tests.  The results of the blood tests are: - Na 133 mmol/L (nv 136-145) → the sodium is low - K 5.8 mmol/L (nv 3.5-5.3) → the potassium is high - NaHCO3 16 mmol/L (nv 23-27) → bicarbonate is low - Hb 9.6 g/dl (nv 12-16) → he's anemic - Urea 190 mg/dl (nv 22-46) - S. creatinine 8.2 mg/dl (nv 0.5-1.0) - Uric acid 9.1mg/dl (nv 25-8) - Ca 7.8 mg/dl (nv 8.8-10.2) → calcium is low - P 6.5 mg/dl (nv 2.5-4.5) → phosphorus is high - Urinalysis: pH 6; protein 3+; Hb 1+ → altered: presence of proteinuria and hemoglobin Two tests are particularly important for the kidney function: **urea and serum creatinine**, both very high in this case. **Uric acid** is high too and that is also an expression of kidney function but can be altered also for other reasons, while urea and serum creatinine are strongly associated with renal function. These clinical features indicate a **severe renal dysfunction**. **[MAIN FUNCTIONS OF THE KIDNEY]** 1\) Kidneys act as **filters,** as they clear the body from wastes and toxic substances and return vitamins, amino acids, glucose, hormones and other vital substances into the bloodstream. In particular, serum creatinine, urea and uric acid are the wastes that should be eliminated and the fact that the patient has high levels indicates that the kidneys are not working properly.\ 2) They **monitor blood pressure** through the juxtaglomerular apparatus and if it falls due, for example, to a bleeding, renin is produced to raise it, through the increase of angiotensin II production. However, in Antonio's situation, this didn't happen, probably due to a change in the functioning of the juxtaglomerular apparatus.\ 3) Kidneys produce another hormone: **erythropoietin**, that stimulates the bone marrow to produce red blood cells. Nowadays we have synthetic erythropoietin and this is a revolution for patients undergoing dialysis and with renal insufficiency, because in the past they needed blood transfusions every two/four weeks. A decrease in hemoglobin is what makes the patient always feel tired. Athletes use this drug to increase their number of red blood cells, increasing the oxygenation of the body and so being able to sustain more efforts with less fatigue. Our patient is anemic, because his production of erythropoietin is altered.\ 4)  Kidneys **monitor and manage the concentration of water and salts** (Na and K) and respond to two hormones: antidiuretic hormone and aldosterone. From Antonio's lab tests we know that his Na was low and K was high, showing that also this function of the kidneys is impaired.\ 5)  They **convert vitamin D to the active form**, increasing calcium levels in bone, uptaking it from the intestine. In our patient's case, he has low calcium levels, due to the fact that his kidneys don't convert vitamin D to its active form.  **Serum creatinine and urea** **in blood** reflect waste excretion, because these two products are present and produced in the body and we know their normal values. When their levels are high in the blood, besides a few exceptions, it means that the **kidneys are not clearing well**. In particular serum creatinine is a specific test to identify kidney diseases and to assess the **glomerular filtration rate**. In addition, the presence of **proteins and hemoglobin in Antonio's urinalysis**, since they have a too high molecular weight to pass through the glomerular basement membrane, shows that there is an alteration there too. Therefore, **not only the clearing system is impaired, but also there is a change in the barrier**.  **[EVALUATION OF RENAL FUNCTION]** The best test to evaluate renal function is the evaluation of the glomerular filtration rate. The **glomerular filtration rate (GFR)** or renal clearance is expressed as the **volume of plasma that can be completely cleared from a substance in a unit of time**: mL/min.  An ideal substance to evaluate the GFR needs some specific characteristics: 1\) Appear endogenously in the plasma at constant rate  2\) Be briefly filtered by the glomerulus 3\) Be neither reabsorbed nor secreted by the renal tubule  4\) Undergo no extra-renal elimination The ideal substance is **inulin**, but it is not produced by the body, so we would have to inject it. Instead we use **serum creatinine** because it has many of the characteristics reported before: even though small amounts are secreted from the tubules, it is very easy to measure, it is very cheap and it can be measured even in underdeveloped countries in small hospitals. Therefore, through serum creatinine we can calculate the glomerular filtration rate.  The **normal range of GFR is 90-120 ml/min**, even though the levels of serum creatinine is different in males (0.6-1.2 mg/dl) and females (0.5-1.1 mg/dl), because it is produced by muscles.  When using serum creatinine levels we also have to consider that there are **factors that can influence GFR**, such as aging, diet and muscle mass. Indeed, with aging, also in healthy people, there is a reduction after 50 years of the GFR and in particular after the age of 65, the decline is more rapid in women than in men. The muscle mass has to do with the amount of serum creatinine produced, that can again mildly change remaining in physiological levels. Patients with reduced muscle mass, despite normal serum creatinine, will have a reduced GFR, while patients with abundant muscle mass will have high levels of serum creatinine and normal GFR. For example in a woman with rheumatoid arthritis after a long treatment with corticosteroids, the muscle mass is particularly reduced: in this case there is normal serum creatinine, but the GFR is low. Diet is important too, because a lot of amino acids and proteins tend to improve GFR and decrease serum creatinine, while excessive meat consumption on the long term is not beneficial for the kidneys, because you increase the amount of waste they have to clear.  We are born with two kidneys and each kidney has one million nephrons, so **a single healthy kidney is able to sustain normal renal function**. This is why, when a young patient is in dialysis, we can ask their relatives to donate a kidney, maintaining their normal renal function throughout life.\ **Normally renal diseases are bilateral**, in particular glomerulo-nephritis, acute and chronic renal diseases, or they can start with one kidney and then also involve the other.  A healthy individual has **2 million nephrons, 120 ml/min of creatinine clearance and 1mg/dl of serum creatinine.** However, if serum creatinine increases from 1 to 2 mg/dl, the creatinine clearance is reduced to 70 ml/min, so the correlation is not direct. We can also observe that at this point we would have lost half of our nephrons, remaining with one million. Therefore, the change from 1 to 2 is very significant and the following changes cause a less severe change in GFR, even though the kidney function is reduced to half. Going back to Antonio, his serum creatinine was 8.2 mg/dl, meaning that his creatinine clearance would be less than 15 ml/min. **[HOW TO CALCULATE CREATININE CLEARANCE]** We need the **serum creatinine** of our patient, the **urinary volume** (ml) **over 24 hours** and **creatinine in urine**. You should also take into consideration the **weight** of the patient and their **sex** to calculate creatinine clearance. It is not easy nor practical, because there is the possibility of errors and not all patients are able to collect urine properly through the 24 hours: **urinary creatinine (mg/ml) x urinary volume (ml) / serum creatinine (mg/dl)**. Other methods, always based on serum creatinine, have been assessed: Crockcroft-Gault (140-age) x body weight (Kg)/ (72 x serum creatinine): for female, multiply result by 0.85, MDRD and CKD-EPI, which is the mostly used. In the case of Antonio, we calculate creatinine clearance using the three main methods used nowadays. With the Cockcroft and Gault method, the GFR is 8 ml/min, which is below 15 ml/min. With the MDRD formula, the result is 6.9 mil/ min, which is a little bit lower, but in this case it doesn't matter, all the **values are low and the patient needs dialysis** rapidly to improve his clinical situation. Finally, CKD-EPI gives the result of 5.9 ml/min, so the lowest. **Based on the GFR you can evaluate the stage of kidney dysfunction**: - G1: normal or high: GFR\>90 ml/min/1.73m2 - G2: mildly decreased: GFR 60-89 ml/min/1.73m2 - G3a: mildly to moderately decreased: GFR 45-59 ml/min/1.73m2 - G3b: moderately to severely decreased: GFR 30-44 ml/min/1.73m2 - G4: severely decreased: GFR 15-20 ml/min/1.73m2 - G5: kidney failure: GFR \ or equal to 3L in patients consuming a typical Western diet. It's characteristic of CKD. - **Anuria**= defined as \300 mOsm/kg H2O it suggests an osmotic diuresis or renal concentrating defect (as in uncontrolled diabetes), while urine osmolality \5.1 mmol/L**).  Hyperkalemia is very unusual in healthy individuals, so probably something else is going on. Two mechanisms may be associated to the develop of hyperkalemia:  - increased release from the cells (main causes: metabolic acidosis, insulin deficiency, use of beta blockers; exercise) - reduced urinary potassium excretion (reduced aldosterone secretion; reduced response to aldosterone; oliguria; acute and chronic kidney disease; selective impairment in potassium secretion) Reduced response to aldosterone is caused by mineralocorticoid receptor antagonists (so potassium sparing diuretics), but also angiotensin converting enzyme inhibitors (because they interfere with the renin-angiotensin-aldosterone system). A diagram of a plant Description automatically generated with medium confidence If a smaller amount of water and sodium arrives in the distal tubule, the exchange between sodium and potassium is impaired. [The more sodium arrives in the distal tubule], for example due to the action of thiazide diuretics, [the more the exchange between sodium and potassium is increased], so [the patient tends to develop hypokalemia]. If the patient produces a small amount of urine, with low sodium and low water content, the exchange is inhibited and potassium is retained. This is the reason why [GFR is reduced in the case of problems with potassium elimination.]  **Signs and symptoms:** Also in this case, symptoms are [muscle weakness or paralysis] and [cardiac arrhythmias]. Usually these manifestations arise when serum potassium concentration is equal or greater than 6.5-7.0 mmol/L. In the following image, we notice the changes in cardiac conduction typical of hyperkalemia:  - peaked T waves; - progressively disappearing P wave; - prolonged QRS complex; - atrial standstill pattern (in this case, there is no atrial activity); - sinusoidal wave pattern (associated with a very high risk of mortality). We can also have blocks in the conduction pathway of the heart. Due to its serious impairment of cardiac activity, hyperkalemia is considered a medical emergency. [Hyperkalemic emergencies] **muscle weakness or paralysis, cardiac conduction abnormalities or arrhythmias, serum K \>6.5 mmol/L, serum K\>5.5 mmol/L+kidney impairment+ongoing K increase** **Approach:** The [first question] in the approach to hyperkalemia is [whether the patient is safe or not]. In our clinical case, the patient was not stable. [We need to immediately treat him to stabilize him, then we can work to understand the causes of his hyperkalemia]. In the presence of symptoms, of high levels of potassium independently from symptoms, and of increasing levels of potassium we need to immediately treat the patient. **Treatment:** First treatment that we can give to the patient is **calcium gluconate**, which cannot reduce serum potassium concentration, but is [able to antagonize potassium effects on the heart], taking away potassium from heart receptors and [stabilizing the cardiac rhythm]. So, calcium gluconate does not treat hyperkalemia directly, but it stabilizes the patient. Then, to [actually reduce potassium levels], we can [shift potassium back into cells] by giving the patient **insulin** or **beta2-adrenergic agonists** or **sodium bicarbonate** (the latter creates [alkalosis], which is important for potassium shift inside the cells). Finally, we can try to [remove potassium from the body] using  **resins** which [bind potassium] in the gut and eliminate it with the stools, but this process occurs slowly and cannot be used in an emergency setting. For potassium removal we can also use **loop diuretics** or, if the patient has also severe kidney injury, **hemodialysis**, which is a kidney replacement therapy. When we choose to use a specific drug, we need to remember that all drugs have a time of [onset] and a period of [duration]. The onset of calcium gluconate, which stabilizes the patient, is very fast; while the potassium binders take some hours to activate. A close-up of a list of medication Description automatically generated **Possible causes:** The main causes of hyperkalemia are **potassium shift outside the cells** (for instance, due to insulin deficiency), **drugs interfering with potassium balance**, and **kidney injury**. Our patient is close to kidney failure (he has ischemic cardiopathy, low blood pressure, diarrhea, hypovolemia). He is also taking drugs which interfere with potassium balance: spironolactone (aldosterone antagonist) and ramipril (ACE inhibitor). There are also conditions of chronic kidney disease in which we must also consider [chronic potassium management through diet counseling] and the use of binders.  *There is a mistake in this summary: hyperkalemia is unusual in healthy patients.* Calcium and phosphorus Calcium and phosphorus are almost completely stored in bones. Calcium is mainly an intracellular ion too. **Parathyroid hormone** is the **main calcium regulator**. When we have [low serum calcium concentration], calcium is sensed by parathyroid gland cells, which produce the parathyroid hormone. First effect of PTH is on the kidneys: it increases [alpha-hydroxylase activity], which is responsible for activating vitamin D in the kidneys (active vitamin D is called calcitriol). [Calcitriol] favors intestinal calcium and phosphorus reabsorption. Then, in the kidneys, PTH has a direct effect on the tubule and it favors calcium reabsorption and phosphorus elimination. Finally, PTH increases [bone turnover] and favors calcium and phosphorus release by bones. After PTH secretion by parathyroid glands, serum calcium level is increased, while serum phosphorus level is constant. Instead, **calcitonin** is another hormone involved in calcium regulation which counteracts the effects of PTH.  The inactive form of vitamin D (called [cholecalciferol or calcidiol]) is produced by exposure to UV radiation. The active form is called calcitriol. Vitamin D deficiency is widespread all over the world, particularly in Northern nations. [We administer inactive vitamin D to patients with vitamin D deficiency], because it can enter the normal regulatory system and be converted into active form only when needed. Instead, if we gave them active vitamin D, it would have a biological effect without feedback control, leading to hypercalcemia. Hypocalcemia Hypocalcemia means [low serum calcium concentrations], both low [total] calcium levels (takes into consideration also the inactive calcium) and low [ionized] calcium levels (takes into consideration only the biologically active calcium). In case of hypoalbuminemia (low albumin levels), total calcium is artificially low, but ionized calcium is normal: this phenomenon is called false hypocalcemia. If we want to assess the true calcium levels, we need to measure the total calcium together with albumin, adjusting it for the levels of albumin, or the ionized calcium. In arterial blood gas analysis we measure the ionized calcium. **Symptoms:** **Hypocalcemia is associated with tetany**, which is neuromuscular irritability, whereas **hypercalcemia is associated with muscle weakness**. [Seizures, hypotension and psychiatric manifestations] are other symptoms of hypocalcemia. Trousseau's sign and Chvostek's sign are two indicators of tetany. A diagram of a person\'s body Description automatically generated **Possible causes:** In the case of hypocalcemia, we expect [high PTH]. If we have [low PTH] in case of hypocalcemia, the problem is in the parathyroid gland, which is unable to produce PTH, thus calcium cannot be regulated. It could be due to [genetic, autoimmune or iatrogenic diseases] (for example following thyroidectomy or radiotherapy for the thyroid gland). If PTH is high, hypocalcemia is due to other causes: vitamin D deficiency, reduced gastrointestinal reabsorption, chronic kidney disease (impaired vitamin D activation and calcium reabsorption), bisphosphonates use (drugs used in osteoporosis to improve bone mineralisation), hypomagnesemia. **Approach:** To treat hypocalcemia, we need to consider albumin and PTH levels.  **Treatment:** Both intravenous and oral calcium are administered depending on the severity of the symptoms. In case of severe muscle symptoms, we choose intravenous calcium, such as calcium gluconate (as used in hyperkalemia). If the problem is PTH, we must give the patients supplements of vitamin D. A yellow and black text on a yellow background Description automatically generated **Hypercalcemia** This clinical case regards Edna, a 50-years old woman. Her husband brought her to the E.D. because it has been two days since she was confused and weak. He also said that she started urinating more frequently than usual. She has a history of breast cancer, with negative follow-up. There is family history for breast cancer (mother) and myocardial infarction (father and uncle). She is an ex-smoker. Her vitals are the following: BP 95/60 mmHg, HR 56 bpm, SpO2 98%. She is confused and asthenic. Physical examination is normal, there are just signs of dehydration and hypovolemia. Low heart rate is not consistent with her condition of hypovolemia and dehydration. The following tests show us that she is in a condition of kidney failure. In addition, she has severe hypercalcemia. Hypercalcemia is defined by these values of serum calcium concentration: - total calcium \> 2.6 mmol/L (10.5 mg/dL) - ionized calcium  \> 1.3 mmol/L (5.2 mg/dL) **Signs and symptoms:** Symptoms of a patient with hypercalcemia are muscle weakness, polyuria, polydipsia, dehydration, nausea, anorexia, changes in sensorium (symptoms that Edna has too). **Approach and treatment:** First question to treat hypercalcemia is whether the patient is symptomatic. In case of a positive answer, we treat the patient first and understand the causes after, because it is a medical emergency. First treatment is **intravenous hydration with isotonic saline** and glucose (our patient had hypovolemia, which further worsens hypercalcemia), which is the only solution available in hospitals which also does not contain calcium. Then, **subcutaneous** **calcitonin** is administered to lower serum calcium concentration (not available in Italy). In addition, **bisphosphonates** are given to the patient. Also in this situation we must consider the onset and duration of action of these drugs. Isotonic saline takes hours; bisphosphonates take a lot of hours. One of the side effects of loop diuretics is hypocalcemia, because they eliminate sodium and calcium, so they can also be used to treat hypercalcemia. Instead, thiazide diuretics are not useful because they favor calcium reabsorption (they are hypocalciuric). **Glucocorticoids** (decrease intestinal calcium absorption) and **dialysis** may be useful too. [In the hospital, we normally use the following treatments in this order: saline infusion, bisphosphonates, loop diuretics, and sometimes glucocorticoids.] There are factors which aggravate hypercalcemia: - thiazide diuretics - lithium carbonate - volume depletion - prolonged bed rest or inactivity - a high-calcium diet (\>1000 mg/day) - calcium supplements - vitamin D supplements in excess of 800 international units/day - multivitamins containing calcium. **Possible causes:** When the patient is stabilized, we need to [measure the parathyroid hormone]. We expect to have [low PTH] in hypercalcemia. If [PTH is high], **primary hyperparathyroidism**, maybe due to a [tumor (adenoma) of the parathyroid gland], is the likely cause, so a situation in which the parathyroid gland autonomously produces PTH (high calcium levels are not able to induce feedback in the parathyroid gland). If PTH is low, the patient has either a tumor (**bone** **metastases**, for instance due to multiple myeloma, induce calcium release) or a **paraneoplastic syndrome** which may alter calcium levels or produce the PTH-related peptide, similar to the normal PTH. Sometimes we need to consider [vitamin D intoxication] as the cause of hypercalcemia, when the patient takes too many vitamin D supplements. Also [granulomatous diseases (sarcoidosis and TBC)] may cause hypercalcemia, because granulomas are able to activate a sort of vitamin D.   **[3-Disorders of water balance]** Dysnatremias are disorders of water homeostasis and not disorders of sodium. This is because sodium concentration does not give us information about the total content of sodium in our body. Our bodies are mainly constituted by water. About 60% of our body weight (for man) and 50% (for woman) is composed by water, which is divided in 2 compartments: 2/3 correspond to the intracellular fluid (ICF) while the remaining 1/3 corresponds to the extracellular fluid (ECF). Of the extracellular fluid, 1⁄4 is the plasma and the rest is interstitial fluid. This is very important to remember because when we lose or gain fluids, they are lost and gained in these proportions. Differently from potassium and calcium, sodium is almost all present in the extracellular fluid, with a concentration of 140 mmol/L. This explains why sodium is important for two different regulations: blood pressure and blood volume. On the other hand, potassium is the most relevant electrolyte present in the intracellular fluid as it is present with a concentration of 135 mmol/L. The system that regulates the amount of sodium present in the body is the RAAS, which is thus indirectly responsible for regulation of blood volume and pressure. If we have a reduction in body pressure and/or in fluid volume, there is an activation of the RAAS that causes production of angiotensin, release of aldosterone, and finally reabsorption of sodium and water. The regulation of effective circulating volume is achieved largely by controlling the sodium content of the body. **Sodium concentration** *Sodium concentration* is completely different. It is the ratio between the sodium content and water in the ECF and what mainly affects this ratio is the water content, which is why disorders of sodium (dysnatremias) are mainly due to water imbalances and just sometimes disorders of sodium balance. The osmolarity is mainly regulated by vasopressin, whose action is to regulate water reabsorption at the collecting duct. \[Na^+^\] is essential in maintaining osmotic equilibrium. Normal osmolarity is usually 285-295 mOsm/kg, 140 of which are constituted by sodium. The normal value for sodium is 140, potassium is very low in plasma and we can ignore it, so the first term of the equation can be approximated to 280; urea is usually around 25-30, which divided by 3 goes around 10; glucose is around 80-90, divided by 18 will be around 5. This means that we can approximate osmolality by just doubling the value of sodium, making the value of osmolality in a normal situation around 285-298 mOsm/kg. A black text on a white background Description automatically generated **Osmolarity and sodium concentration are not a matter or sodium amount but depend on water balance.** **Blood Volume** -\> depends on sodium content (regulated by RAAS and baroreceptors) Hypovolemia: sodium depletion -\> decreased blood volume -\> typical symptoms: low blood pressure, dry mouth, reduced refill capillary time, dry skin.\ Hypervolemia (edema): sodium increase -\> increased blood volume -\> typical symptoms: high blood pressure, increased jugular vein pressure. **Sodium concentration** -\> depends on water balance (regulated by ADH and thirst) Hyponatremia: water excess\ Hypernatremia: water deficit (dehydration) **Dysnatremias (derangement of \[Na^+^\]) are always disorders of water balance** (and just sometimes disorders of sodium balance). EXAMPLE: Nephrotic syndrome is a condition in which the patient loses a great amount of proteins in the urine and as a consequence also in the blood. This loss of proteins determines a reduction in the colloid osmotic pressure, activation of RAAS and consequently massive edemas. -\> HYPERVOLEMIC (high sodium amount). On the other hand, sodium concentration will be low (hyponatremia). HIGH SODIUM AMOUNT BUT LOW SODIUM CONCENTRATION -\> EXAMPLE of how sodium concentration doesn't give any information about sodium amount. **Hyponatremia - condition in which** \[Na^+^\] \< 135 mmol/L Is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It occurs in 1-2% of hospitalised patients and in up to 30% of patients in intensive care units. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening. A prompt recognition is mandatory since it's an independent risk factor that increases in-hospital mortality by 40%. Hyponatremia is of clinical significance only when it reflects corresponding plasma hypoosmolality. because in this case water would flow from the extracellular fluid to the intracellular one (by osmosis), causing **cell swelling**.   Total osmolality is not always equivalent to "effective" osmolality, referred to as tonicity. Hyponatremia and hypoosmolality are usually synonymous, except in the case of pseudohyponatremia or marked hyperglycemia. **Pseudohyponatremia** Low sodium concentration is an artefact due to accumulation of other plasma constituents such as triglycerides and proteins. It is usually associated with a measured normal serum osmolality. It is an asymptomatic condition (tonicity is normal). This condition is due to the fact that when we analyse blood, before examining the sample, the machine dilutes it. If the solid phase is increased and so we have a higher number of triglycerides and proteins, once they are diluted, we also have a dilution of sodium, which will result hyponatraemic. When you find hyponatremia, you have to exclude pseudohyponatremia by measuring triglycerides or proteins or measuring the sodium through blood gas analyzer which directly measures sodium concentration without diluting the sample. **Marked hyperglycemia** High concentrations of effective solutes other than sodium can cause a relative decrease in sodium concentration despite an unchanged plasma osmolality. The main solute that causes this effect is glucose. In order to have a correct diagnosis, we have to measure plasma osmolality and correct sodium concentration by 1.6 mmol/L for each 100 mg/dL increase in blood glucose concentration greater than 100 mg/dL. **Definition based on biochemical severity (European guidelines)** [Mild] -\> biochemical finding of a serum sodium concentration **between 130 and 135 mmol/L** as measured by ion specific electrode [Moderate] -\> biochemical finding of a serum sodium concentration **between 125 and 129 mmol/L** as measured by ion specific electrode [Profound] -\> biochemical finding of a serum sodium concentration **lower than 125 mmol/L** as measured by ion specific electrode **Definition based on time of development** [Acute] -\> hyponatremia documented to exist for **less than 48 hours** [Chronic] -\> hyponatremia documented to exist for at least 48 hours If hyponatremia cannot be classified, we consider it being chronic, unless there is clinical or amnestic evidence of the contrary. Since it is very dangerous to correct improperly chronic hyponatremia, if we don't know if it is acute or chronic, it is better to consider it always chronic. **Hyponatremia symptoms** Hyponatremia symptoms are the expression of central nervous system dysfunction caused by brain cells swelling in response to water movement from the extracellular to the intracellular compartment (difference in effective osmolality between brain and plasma). Acute hyponatremia -\> clinical presentation: cerebral oedema + increased intracranial pressure -\> **hyponatremic encephalopathy -\> reversible** (except in advanced cases) if a proper therapy is established.  Chronic hyponatremia -\> usually asymptomatic or paucisymptomatic A close-up of a medical chart Description automatically generated **Hyponatremia - Causes** In general, the patient can be in a situation of hypovolemia, euvolemia, or hypervolemia, which correspond respectively to a situation of total amount of sodium in the body that is low, normal, or increased. In all these conditions water levels are high. In order to have hyponatremia, we must have an unbalanced ratio of water to sodium. When we find a hyponatremic patient, and we exclude pseudohyponatremia and marked hyperglycemia, we can distinguish the causes of the disease by measuring the amount of sodium in the patient (volume status), which can be hypovolemic, euvolemic, or hypervolemic. Causes of [hypovolemic hyponatremia] are **extrarenal salt loss** (if sodium in the urine is \20 mmol/L), such as the ones caused by diuretics (especially thiazide), ACE inhibitors, nephropathies, mineralocorticoid deficiencies, cerebral sodium-wasting syndrome. The patient that results with [hypervolemic hyponatremia] is typically oedematous, and the main causes are heart failure, liver disease, nephrotic syndrome (rare), and advanced kidney disease. In this case, even if it is hyponatremic, the total amount of sodium that is present in the body can be very high. Main causes of patients with [euvolemic hyponatremia] may be hypothyroidism, psychogenic polydipsia, adrenocorticotropic deficiency, **SIADH** (syndrome of inappropriate ADH secretion), which is responsible for the presence of increased ADH and production of very concentrated urine. **SIADH:** Syndrome Of Inappropriate Antidiuretic Hormone Secretion. This syndrome is characterised by an excessive release of ADH from the posterior pituitary gland or from different sources, which causes the production of hyperconcentrated urine. Therefore the patient will present low blood osmolarity while high urine osmolarity.  SIADH is a very frequent disorder in clinical practice, in particular some of its possible causes are cancers, pulmonary disorders and nervous system disorders but also infections, traumas, after surgeries, and even by some viruses such as HIV. **Diagnostic criteria of SIADH: ** It is very important to recognize and to treat this syndrome. How to treat hyponatremia then? We started this lesson saying that these are not problems related with sodium, indeed both Hyponatrimia and Hypernatremia are disorders of water balance, therefore we have to keep this in mind for the treatment.   What would happen if we give normal saline to hyponatremic patients?  Hyponatremic patients are able to excrete very concentrated urine and at the same time to reabsorb water. So out of 1L of saline solution given, the patient will be able to excrete all the NaCl inside without using the whole litre of water; therefore the patient\'s sodium concentration would go down. **Approach to Hyponatremia** First of all we have to exclude hyperglycemia and other causes of non-hypotonic hyponatremia. Once we ensure hypotonic hyponatremia then we have to assess the severity of the symptoms.  A close-up of a medical chart Description automatically generated If the symptoms are [severe], we shall give an infusion of 150 mL of 3% hypertonic saline over 20 min. (3% saline: 3gr of NaCl in 1 L of solution; solution or a concentration of NaCl of 513 mmol/L). We chose a hypertonic solution so that the patient is not able to eliminate all the sodium therefore raising its concentration.  Other solutions that are used are 0.9% NaCl with a sodium osmolality of 154 mmol/L (isotonic saline or fisiologica) and 0.45% NaCl with a sodium osmolality of 77 mmol/L. **Osmotic demyelination syndrome** This syndrome occurs when we correct hyponatremia too rapidly. It is an irreversible neurological condition characterised by acute paralysis and neurocognitive disorders caused by damage to the myelin sheath. It may involve the central basis pontis, causing central pontine myelinolysis; or the thalamus, internal capsule, and deep cerebral cortex, causing extrapontine myelinolysis. In both cases, cerebral damages are not reversible. **Signs and symptoms** of osmotic demyelination syndrome are impairment in short-term memory, attention deficit, dysarthria, dysphagia, flaccid quadriparesis, oculomotor abnormalities, ataxia, mutism, parkinsonism, catatonia, dystonia, tremor, locked-in syndrome, seizures, coma.  1. Normal 1. Central pontine myelinolysis In order to avoid the development of this syndrome we should maintain a safe range through Safety sodiemia correction, which is: -Recommended \[Na+\] increase: 10 mmol/24 hr or 18 mmol/48 hr. There is a formula that helps us to calculate the estimated sodium concentration change upon infusion of the solution:A black text on a white background Description automatically generated Where TBW is the total body water (60% of weight for men and 50% for women). If we take a 70 kg patient with a severe hyponatremia of \[Na+\]=110 mmol/L and we administer 3x100 mL 3% hypertonic solution boli, we will have a change in \[Na+\]=(513-110)/42+1=9.94 mmol/L. Since we have to inject 300 mL, the sodium will be corrected to around 9.4/3.3=2.8 mmol. This value is theoretical though, it is never exactly this due to urination, sweating, etc. so while injecting the solution, the patient must be checked almost every hour for sodium values. **Diagnostic approach to hyponatremia** Now we know that if we are in an emergency setting, the hyponatremia is severe so we should immediately treat our patient with a hypertonic solution to stabilize him, although always within the safe range, therefore acting slowly.  If the patient is asymptomatic, it means that there is no urgency to treat the condition since it is not acute. We can thus focus on the etiology of the disease, trying to understand the causes behind the disease.  First of all, we check the volume status to understand if the patient is hypo-, eu-, or hypervolemic. This is done by checking the following parameters: orthostatic vital signs, peripheral oedema, internal jugular vein distension, hepatojugular reflux, lung auscultation, daily weight monitoring, brain natriuretic peptide (BNP), blood pressure, chest radiography, and inferior vena cava ultrasound.  Moreover, a series of exams can be useful: creatinine, urea, electrolytes, uric acid, urinalysis, urine sodium, urine osmolality, thyroid function tests, and ACTH and cortisol. Once we have assessed the volume status we can proceed with specific treatments: A hypovolemic patient ***with extrarenal salt loss*** has both a water excess and a volume deficit, so a normal isotonic saline (0.9%) is sufficient for the treatment. In the case of ***hypovolemic with renal salt loss,*** we can use isotonic saline as well, but we must also discontinue the responsible drugs that the patient is taking. An ***euvolemic patient*** is treated with water restriction, because it is avidly retaining water in the kidneys, but, more importantly, we must treat the causes of the SIADH. In the meanwhile that the causes are treated, we may use Vaptans drugs, which are antagonists of the receptors for vasopressin, so they contrast the excess of ADH. These drugs are also used because it is not always easy to treat the causes as some of them can be chronic. A ***hypervolemic patient*** is treated with diuretics. **KEY POINTS on HYPONATREMIA: ** - Hyponatremia is clinically significant when reflects a hypotonic state - Always exclude non hypotonic hyponatremia - Hyponatremia is always a water problem, just sometimes a salt problem - Sodium concentration does NOT provide any information about total body salt or volume status - Severe symptomatic hyponatremia should be promptly and correctly corrected, avoiding overly rapid correction (risk of ODS) and carefully monitoring the patient - A correct etiologic diagnosis will drive a correct treatment **HYPERNATREMIA ** Hypernatremia results from a water deficit, which leads to a sodium concentration higher than 145 mmol/L. In most cases it is hard to develop hypernatremia, because if a person is alert and able to drink, it shouldn't normally develop it; indeed hypernatremia requires two things:  -Loss of water, -Failure to adequately replace the water loss. **Causes** As in the case of hyponatremia, we can have hypernatremia in patients that are hypovolemic, euvolemic, and hypervolemic. As before, the 3 cases related to the amount of sodium present in the body: low, normal, and high. In this case, there aren't situations similar to those of hyponatremia, indeed we can proceed with the treatment without worrying too much about developing complications such as the Osmotic demyelination syndrome.  **Diabetes insipidus** It is the opposite of SIADH, indeed Diabetes insipidus (DI) is characterized by polyuria and polydipsia and is caused by defects in ADH action. It is basically the opposite of SIADH, in this situation we have production of a large volume of diluted urine (polyuria).  It can be caused by several factors: Central DI: due to deficiency of ADH. It can be congenital, post-traumatic, iatrogenic (post- surgical), due to primary or secondary CNS tumours, infiltrative disorders (such as tuberculosis or sarcoidosis), haemorrhage, aneurysm, infection (meningitis or encephalitis), hypoxic encephalopathy. Nephrogenic DI: due to being unresponsive to ADH. It can be hereditary (x-linked recessive, defect of V2 receptors or aquaporins) or acquired (electrolyte disorders such as hypercalcemia and hypokalaemia, induced by drugs such as lithium, demeclocycline, amphotericin B, chronic intestinal kidney disease, malnutrition). Gestational DI: due to degradation of ADH. Caused by vasopressinase mediated (produced by the placenta) and occurs in the peripheral circulation. **SYMPTOMS:**  Signs and symptoms are mostly related to the CNS and include: - Altered mental status - Lethargy - Irritability - Restlessness - Muscle twitching - Hyperreflexia and spasticity - Seizures (usually in children) - Coma **TREATMENT:** Typical patient in a hospital that develops hypernatremia is an old individual with cognitive impairment. To treat this condition we need to proceed as follows: 1\. determine the volume status (sodium balance), 2\. calculate the free water deficit, 3\. choose a replacement fluid, 4\. determine the rate of depletion, 5\. estimate the ongoing sensible and insensible losses (urine, sweats\...).   Once assessed the **volume status (1)**, as previously described above...  **2. To calculate water deficit:** **Water deficit = TBW x (\[Na+\]s/140-1)** In this formula, TBW is the total body water, then we have sodium concentration in serum, and 140 represents the ideal value of sodium concentration we want to reach. So, if we have a male of 70 kg and with a \[Na+\] of 165 mmol/L, the water deficit will be of 7.5L. To replace it, we need to choose a solution that is hypotonic, such as 5% dextrose. **3. Choosing a replacement fluid:**  Enteral route for repletion of free water is the preferred option. We could also decide to give fluids to the patient, either through the mouth or through intravenous infusion (if we select this method we would have to choose an hypotonic solution, ex. Glucose solutions) **4. To determine rate of repletion**:  **Δ \[Na+\] = (\[Na+\]inf - \[Na+\]s) ÷ (TBW + 1)** -We use the same formula as for hyponatremia. Eg. Δ \[Na+\] = (0 -- 165 mmol/L) ÷ 43 L = - 3.8 mmol/L if 1 L of 5% glucose is administered. The recommended rate of correction is 0.5 mmol/L/h or a decrease of 10 to 12 mmol/L in a 24-hour period. Always consider **sensible and insensible losses (5)**, it is better to proceed slowly with the repletion process, although there is no side effect of osmotic demyelination syndrome as it happens in hyponatremia.  **HYPERNATREMIA KEY POINTS:** Hypernatremia always reflect a hyperosmolar state Hypernatremia is always a water problem, just sometimes a salt problem Patients must have a defect in thirst mechanism or limited access to free water for hypernatremia to persist Sodium concentration does not provide any information about total body salt or volume status Calculation of water deficit is useful, but represent only a snapshot Don't trust formulas too much, use the clinical judgement and carefully monitor the patient Consider sensible and insensible losses **[4-Approach to glomerular diseases]** Introduction What is the most simple lab test that is used to evaluate kidney functionality? *Serum creatinine*. It is the most cheap and simple test. What is the most accurate test to evaluate kidney function? Measurement of *glomerular filtration rate* through the *inulin clearance* test, which is not commonly used due its complexity. As a matter of fact, you need to inject it and wait for hours for the results. However, there are different, quicker and more simple methods to evaluate the GFR along with serum creatinine in order to assess the renal functionality.  There can be cases in which the two test results are not consistent, since creatinine is produced by our muscle cells. As a consequence, in case of hypertrophy the patient will have higher creatinine levels, whereas in case of atrophy lower creatinine levels. Elderly people are characterised by lower creatinine levels (due to physiological reduction of muscle mass) and lower GFR. Instead, in case of Rheumatoid Arthritis, due to prolonged use of corticosteroids,  the patient may have  a normal serum creatinine level but a low GFR (30-40 mL/min). [Remember that normal results range from 90 to 120 mL/min.] In case of altered kidney functionality, *urinalysis* should be performed as well. If both serum creatinine and urinalysis don't suggest any alteration, you can exclude any kidney functionality abnormality. On the contrary, in case they are both altered, it's most likely a kidney dysfunction, whereas if only one of them is not normal you need to perform further tests. Glomerular diseases Glomerular diseases may present in different clinical forms that can be called ***nephrological syndromes***. They can vary from *asymptomatic* forms (detectable only with  lab tests) to mild/severe clinical manifestations with *acute renal dysfunction*.  These different syndromes originate from ***variable combinations of serum creatinine, amount of proteinuria and alterations of the urinary sediment***.  Recognising the correct and specific nephrological syndrome is extremely important because different complications may arise and different treatments will be needed. Furthermore, some of them will be characterised by a better prognosis, others by a worse one.  During the last lecture we talked about three different types of acute renal dysfunction, among which one of them was characterised by glomerular nephritis. On that occasion we talked about pre-renal, renal and post-renal AKIs. In renal you can find tubulointerstitial diseases and glomerulonephritis. Specifically, the latter by definition is part of an acute kidney injury. However, if the glomerular disease is not treated it can progress to end stage kidney disease (your kidneys stop working completely and you require dialysis). As you can see from the image below, 15% of cases of end stage renal disease are due to untreated glomerulonephritis: Macroscopic hematuria Remember that even 1 mm of blood can make urine red, therefore it is hard for a macroscopic hematuria to cause anaemia, unless it lasts for a prolonged period of time.  The colour of the hematuria can be different and is a factor that needs to be taken in consideration. It can range between bright red and coke-like. The former (**blunt haematuria** or bright red) is an indicator of a considerable bleeding in progress, "**a wash of meat**" hematuria suggests a slight bleeding, whereas "**coke like**" hematuria is associated with previous bleeding or the presence of hemoglobinuria. Hematuria can be ***symptomatic***, as in the case of a urinary tract infection or kidney stones, or ***asymptomatic***. It can also be ***persistent or intermittent***, meaning that one time urination is characterised by blood and another time is not. It can also be classified in ***initial, total or terminal***. Initial haematuria means blood is present only at the beginning of urination and suggests a urethral damage, in terminal hematuria blood appears only at the end of urination and comes usually from the bladder (also prostate or trigonal area), whereas total hematuria is usually associated with kidney origin.  Red urine can also be caused by ***pseudo-hematuria***, due to the presence of *myoglobin*, high consumption of vegetables or use of drugs. In order to obtain the correct diagnosis and distinguish between macroscopic hematuria and pseudo-hematuria, a dipstick test should be done. It will be negative in case of presence of myoglobin or other substances, while it will be positive in case of presence of blood.  The *causes* of macroscopic hematuria not caused by glomerular bleeding are: ***inflammation of urinary bladder, urethra or prostate, urinary infections, acute pyelonephritis, presence of kidney stones, polycystic kidney diseases, blood clotting disorders, sickle cell diseases, cancer of kidneys, bladder or prostate or trauma***. On the other hand, the most frequent glomerular disease that presents with macroscopic hematuria is ***IgA nephropathy***. As a matter of fact, 30 to 40% of patients with IgA nephropathy display macroscopic hematuria occurring during or post an upper respiratory tract infection. Macroscopic hematuria can occur also in case of other glomerular diseases. In these latter cases hematuria is asymptomatic, total and persistent for a number of urinations, generally lasting three days or more. **Asymptomatic urinary abnormalities** As the name itself suggests, the patient doesn't show any symptoms. In this case serum creatinine, GFR and blood pressure are normal, so ***diagnosis is only obtained by urinalysis***.  As a matter of fact ***proteinuria*** will be higher than normal range (\>150 mg/day), but lower than 3g/day. Usually, there are also ***hematuria*** that can be detected by a dipstick test (more than 2 red blood cells per high power field) and *hyaline* or *hyaline-granular casts* (rarely erythrocytes casts). In case of microscopic hematuria it's important to differentiate between isomorphic erythrocytes, similar to those found in the blood, and dysmorphic erythrocytes, which are characterised by irregular shapes and contours due to the passage through gaps of the glomerular membrane.  Remember that ***several glomerular diseases are associated with asymptomatic urinary abnormalities***. **Nephrotic syndrome** Generally the main clinical manifestation of this syndrome is the presence of ***edema***. However, it is characterised by ***proteinuria higher than 3.5g/day*** associated with low serum protein and ***low albumin*** (\