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The Fivefold Life पर ण प न सवयमव वय न द न वतत सम The Fivefold Life पर ण प न सवयमव वय न द न वतत सम न पर ण , व कत भदत भवतयस भद त सवरण सल लम व ప ర ణ ప న వ య న ద న సమ న భవత యస ప ర ణ స వయమ వ వ త త భ ద త , వ క త భ ద త స వర ణ సల లమ వ பர ண ப ந வய ன த ந பர ணஃ ஸம ன பவதயஸ

The Life – Praana – Apana – Vyana – Udaana (Motor, Sensory) – Samaana The Life – Praana – Apana – Vyana – Udaana (Motor, Sensory) – Samaana Respiration Digestion and UT (excretory) Circulation (CVS) Nervous System Equilibrium (Metabolic) These five are the five different life functions in us. They are so differentiated due to the structural (anatomical) and functional (physiological) differences. Together, they

Polyuria How to Evaluate ? Dr R V S N Sarma M. D. , Polyuria How to Evaluate ? Dr R V S N Sarma M. D. , M. Sc. , (Canada) Consultant Physician and Chest Specialist www. drsarma. in, sarma. [email protected] com

DEDICATION Prof. Dr Peter AGRE, M. D. , et al Medical Doctor, John Hopkins DEDICATION Prof. Dr Peter AGRE, M. D. , et al Medical Doctor, John Hopkins Discoverer of Water Channels

Aquaporin (AQP) Prof. Dr. Peter AGRE Nobel Laureate Nobel Prize in Chemistry 2003 Aquaporin (AQP) Prof. Dr. Peter AGRE Nobel Laureate Nobel Prize in Chemistry 2003

The Body Compartments Body Water (35 L) Extra Cellular (60%) Plasma (2. 5 L) The Body Compartments Body Water (35 L) Extra Cellular (60%) Plasma (2. 5 L) Interstitial Intracellul ar Cytoplasm

Daily Water Balance Source Qty. in liters Approximate Input per day 2. 4 Water Daily Water Balance Source Qty. in liters Approximate Input per day 2. 4 Water drunk as fluid 1. 5 Water content of food we eat 0. 5 Water from biological oxidation 0. 4 Approximate Output per day 2. 4 Urine 1. 5 Perspiration 0. 4 Loss in breath 0. 4 Fecal loss 0. 1

The Terminology 1. Solute – substance dissolved: Nacl, Glucose 2. Solvent – Liquid in The Terminology 1. Solute – substance dissolved: Nacl, Glucose 2. Solvent – Liquid in which dissolved - Water 3. Milli Osmoles/ Kilogram (m. Osm/kg) of Solvent - referred to as Osmolality 4. Milli Osmoles/ liter (m. Osm/L) of Solution referred to as Osmolarity

Osmolality • Depends on the # of particles in solution • Maintained within very Osmolality • Depends on the # of particles in solution • Maintained within very narrow ranges • Sodium is the principal determinant • 2(Na + K) + (Glucose /18) + (BUN /2. 8) • 2(132 + 4) + (108/18) + (14/2. 8) = • (2 x 136) + 6 + 5 = 272 + 11 = 283

Hypothalamic – Pituitary – Endocrine Axis Hypothalamic – Pituitary – Endocrine Axis

Vasopressin (AVP) • Anti Diuretic Hormone (ADH) / Vasopressin • AVP is Arginine Vasopressin Vasopressin (AVP) • Anti Diuretic Hormone (ADH) / Vasopressin • AVP is Arginine Vasopressin – In pigs, it is lysine vasopressin • Synthesized & Secreted by the Neurohypophysis – Includes nuclei in the hypothalamus which terminate in the pituitary

Plasma Osmolality - ADH Plasma Osmolality - ADH

Renal Excretion Primary Urine • GFR of 120 ml/mt x 60 min x 24 Renal Excretion Primary Urine • GFR of 120 ml/mt x 60 min x 24 hrs = 170 L Final Urine • Only 1. 5 to 2. 5 liters/day • 99% of the filtered water is reabsorbed • Only 1% is finally excreted • 70% H 20 is reabsorbed in PCT by AQP 1 • Rest 29% by AQP 2, 3 and 4 • Reabsorption of H 20 in CT – ADH mediated

Water Conservation • Volume – Renin secretion Angiotensin formation – Angiotensin II is a Water Conservation • Volume – Renin secretion Angiotensin formation – Angiotensin II is a dipsinogen – Angiotensin promotes AVP release • Osmolality – AVP is released – AVP leads to less urine produced – Without AVP, we will have a water diuresis

Water Metabolism Water Metabolism

Renal Function Counter Current Multiplier Renal Function Counter Current Multiplier

The Bowman’s Capsule The Bowman’s Capsule

Transporter Sites in the Nephron Schrier, R. W. J Am Soc Nephrol 2006; 17: Transporter Sites in the Nephron Schrier, R. W. J Am Soc Nephrol 2006; 17: 1820 -1832

In the Collecting Duct In the Collecting Duct

Water Balance § Complex interactions among § Plasma Osmolality § Plasma Volume § The Water Balance § Complex interactions among § Plasma Osmolality § Plasma Volume § The Thirst Center § The Kidney § The Posterior Pituitary (Neurohypophysis) § The Hypothalamus. § Dysfunction in any of these areas results in Polyuria (PU) and Polydipsia (PD)

Clinical Disorders of Water Imbalance • • Cardiac Failure Cirrhosis, Renal failure Hyper and Clinical Disorders of Water Imbalance • • Cardiac Failure Cirrhosis, Renal failure Hyper and Hypothyroidism Addison’s Disease Central Diabetes Insipidus (CDI) Nephrogenic Diabetes Insipidus (NDI) Psychogenic Polydipsia (PPD or CWD) Pregnancy

What is Polyuria ? • PU – Passage of Excessive quantity of urine – What is Polyuria ? • PU – Passage of Excessive quantity of urine – PU implies water or solute diuresis – At least more than 2. 5 to 3. 0 L /day – Or Urine of > 40 ml/kg/day [stress, exercise, summer / Winter - < 3 L] • Polyuria usually associated with Polydipsia • Polydipsia or PD – – Water intake of more than 100 ml/kg/d (6 L /d) • Frequency of urine – Frequent passage of small amounts of urine – Many causes – UTIs, BPH, UT Stones, Urinary Incontinence

How does Polyuria occur ? Four mechanisms 1. Increased intake of fluids – Psychogenic, How does Polyuria occur ? Four mechanisms 1. Increased intake of fluids – Psychogenic, stress, anxiety 2. Increased Glomerular Filtration Rate – Hyperthyroidism, Fever, Hyper metabolism 3. Increased output of solutes – DM, Hyperthyroidism, Hyperparathyroidism – Diuretics – increase the solute at the DCT 4. Inability of the kidney to reabsorb water in DCT – CDI, NDI, Drugs, CRF

History in a case of Polyuria • Is it increased volume or frequency ? History in a case of Polyuria • Is it increased volume or frequency ? • Is there associated Polydipsia ? • Weight loss – DM, Underlying malignancy • Family history – DM, DI • Past history – Neurosurgery, Meningitis, Head injury, Psychiatric illness – CWD • Drugs – Diuretics, Lithium, Analgesic abuse, Vitamin D – hypercalcemia, Nephrotoxic drugs • Recurrent Infections - DM • H/o HT, CKD, Hypercalcemia, UTO, PKD

Polyuria - Classification 1. Endocrine – DM, CDI, Cushing's syndrome 2. Renal – CRF, Polyuria - Classification 1. Endocrine – DM, CDI, Cushing's syndrome 2. Renal – CRF, Relief of UT obstruction, CPN, NDI, Fanconi 3. Iatrogenic – Diuretic therapy, Alcohol, Lithium, Tetracyclines 4. Metabolic – Hypercalcemia, Potassium depletion 5. Psychological – PPD or CWD 6. Other causes: Sickle-cell Anemia, PSVT

Physical Examination • Wasting / Cachexia – DM, DI, Malignancy • Skin manifestations – Physical Examination • Wasting / Cachexia – DM, DI, Malignancy • Skin manifestations – Ca, DM • Nails – Clubbing, CKD nails, Ca Bronchus • Anemia – CKD, Malignancy • Lymph adenopathy – Infiltrative, Malignancy • Fundus exam – DM, HT, Papilledema

Diabetes Insipidus (DI) • Diabetes Insipidus refers to an abnormal state of water and Diabetes Insipidus (DI) • Diabetes Insipidus refers to an abnormal state of water and not osmotic diuresis • DI can be an early sign of serious underlying disease - a brain tumor. • Abrupt onset of Polyuria and preference for extremely cold or iced water – suggests CDI • Dx of DI is missed - sometimes for years • DI has FOUR main types, namely – CDI, NDI, PDDI, GDI

The Four Types of DI 1. Central DI (Neurogenic) – of the ADH or The Four Types of DI 1. Central DI (Neurogenic) – of the ADH or AVP 2. Nephrogenic DI, Non response of kidneys to ADH 3. Primary Polydipsic DI - suppression of ADH by excessive fluid intake - Dipsogenic, Psychogenic or Iatrogenic DI – excessive water drinking as Rx. 4. Gestagenic DI, during pregnancy due to ADH destruction by vasopressinase from placenta.

Central DI (CDI) Neurogenic • Acquired - Brain tumors; Head trauma; Granulomatous diseases; Autoimmunity; Central DI (CDI) Neurogenic • Acquired - Brain tumors; Head trauma; Granulomatous diseases; Autoimmunity; • Inherited - Genetic Mutation of Vasopressin Gene - Autosomal Dominant or Recessive or X-linked Recessive • Idiopathic

Central Diabetes Insipidus (CDI) • Lack of AVP production and or secretion • May Central Diabetes Insipidus (CDI) • Lack of AVP production and or secretion • May be partial or complete • Usually the urine volume is very high > 8 -10 L • Polydipsia is usually a feature -very troublesome • Any disturbance or injury of the hypothalamus & or pituitary is a potential cause – Idiopathic, Trauma, Neoplasia, Cysts, Inflammation

AVP - V 2 Receptor Protein Schrier, R. W. J Am Soc Nephrol 2006; AVP - V 2 Receptor Protein Schrier, R. W. J Am Soc Nephrol 2006; 17: 1820 -1832

Nephrogenic Diabetes Insipidus • NDI – Congenital and Acquired • V 2 Vasopressin Receptor Nephrogenic Diabetes Insipidus • NDI – Congenital and Acquired • V 2 Vasopressin Receptor Mutations • 180+ Mutations are documented • In Chromosome region Xq 28 • Protein misfolding – V 2 Receptor • Not Translocated BLM of CT • 90% of NDI is genetic • 10% Acquired – see next slide

Acquired NDI • Hypokalemia and hypercalcemia • Bilateral urinary tract obstruction • Lithium therapy Acquired NDI • Hypokalemia and hypercalcemia • Bilateral urinary tract obstruction • Lithium therapy • Acute renal failure • Advanced chronic renal failure • The Polyuria of Acquired NDI is of a moderate degree (3 to 4 L / 24 h)

Nephrogenic Diabetes Insipidus • Nephrogenic DI commonly occurs at birth • Urinary frequency, Nocturia, Nephrogenic Diabetes Insipidus • Nephrogenic DI commonly occurs at birth • Urinary frequency, Nocturia, Enuresis, and frequent or constant thirst – suspect NDI. • Thirst and Polyuria can not be verbalized • Inconsolable crying, unusually wet diapers, frequent need to nurse, dry skin with cool extremities, and failure to thrive.

Polydipsic DI Polydipsic • Acquired • Idiopathic (mostly) • Chronic meningitis; Granulomatous Diseases; Multiple Polydipsic DI Polydipsic • Acquired • Idiopathic (mostly) • Chronic meningitis; Granulomatous Diseases; Multiple Sclerosis or other diffuse pathology of the brain • Psychiatric illness (CWD or PPD) Gestagenic – Placental Vasopressinase

24 hr urine collection • Clean, 5 liter, plastic container with 10 ml of 24 hr urine collection • Clean, 5 liter, plastic container with 10 ml of acetic acid during normal fluid & food intake • PU is > 40 ml/kg body weight per day • Urine Osmolality < 300 m. Osm/kg of water • Urine Specific Gravity <1. 010 • PD is water intake of > 100 ml/kg per day • Measure Plasma Sodium on that day

Diagnostic Algorithm 24 Hour Urine Volume (fluids ad libitum) Less than 3 L More Diagnostic Algorithm 24 Hour Urine Volume (fluids ad libitum) Less than 3 L More than 3 L Measure Urine Osmolality if urine volume is > 3 L < 300 m. Osm/Kg > 300 m. Osm/Kg If Urine Osmolality is > 300 m. Osm/Kg (Solute ) DM Evaluation CKD Evaluation

Diagnostic Algorithm contd. . Urine Osmolality < 300 - Fluid Deprivation 12 hrs > Diagnostic Algorithm contd. . Urine Osmolality < 300 - Fluid Deprivation 12 hrs > 750 m. Osm/Kg < 750 m. Osm/Kg Osmolality > 750 m. Osm/Kg – Serum ADH, RF, Na and ADH, RF - N CWD (PPD) Osmolality > 750 m. Osm/Kg – Serum ADH, RF, Na N - Na, ADH, RF - Abn CKD / Renal / Cal

Diagnostic Algorithm contd. . Osmolality but < 750 m. Osm/Kg – Formal WDT No Diagnostic Algorithm contd. . Osmolality but < 750 m. Osm/Kg – Formal WDT No Response Positive Response No Response to WDT Nephrogenic (NDI) Genetic / Acquired Positive Response to WDT Central (CDI) MRI, evaluate causes

Hare-Hickey Test (WDT) • Indication – Evaluation of Diabetes Insipidus • Technique – Complete Hare-Hickey Test (WDT) • Indication – Evaluation of Diabetes Insipidus • Technique – Complete Fluid Deprivation or Inj. Hypertonic Nacl – Injection of DDAVP exogenously • Measure ADH to Serum Osmolality ratio – Interpretation of ADH to Serum Osmolality ratio – Decreased ratio in Central Diabetes Insipidus – Increased ratio in Nephrogenic Diabetes Insipidus

DDAVP, AVP and Oxytocin Desmopressin (1 -desamino-8 -D-Arginine Vasopressin) DDAVP, AVP and Oxytocin Desmopressin (1 -desamino-8 -D-Arginine Vasopressin)

DDAVP • Several formulations are available • Intranasal solution - 100 mcg/ml • Intranasal DDAVP • Several formulations are available • Intranasal solution - 100 mcg/ml • Intranasal spray (10 mcg/spray) • Parenteral (i. v or i. m) - 4 mcg/ml - used rarely • Oral - 200 mcg tablets (roughly 10 mcg intranasal = 200 mcg oral)

Nocturnal Polyuria (NP) • Circadian Rhythm disorder of AVP • Increase in ANP and Nocturnal Polyuria (NP) • Circadian Rhythm disorder of AVP • Increase in ANP and BNP • Measurement of plasma AVP and urinary AVP • Urine AVP / Urine Cr ratio is good lab test to pick up NP due to defective AVP

Take Home • AVP or ADH from neuro hypophysis • ADH action on CT Take Home • AVP or ADH from neuro hypophysis • ADH action on CT and DCT – Water reabsorb. • Renal handling of water – homeostasis - AQP • Polyuria – multiple diseases cause it – DI imp. • CDI, NDI, PDI, GDI – Congenital, Acquired. • Algorithmic approach - 24 hr U, U Osmolality, • 12 hr fluid restriction and full WDT – DD of DI • DDAVP replacement in CDI and NDI

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