The Fivefold Life

2. The Fivefold Life प्राणापान व्यानोदान समाना भवत्यसौ प्राणः स्वयमेव वृत्ति भेदत्, विकृति भेदात् सुवर्ण सलिलमिव ప్రాణాపాన వ్యానోదాన సమానా భవత్యసౌ ప్రాణః స్వయమేవ వృత్తి భేదాత్, వికృతి భేదాత్ సువర్ణ సలిలమివ ப்ராணாபாந வ்யானோதாந ஸமானா பவத்யஸௌ ப்ராணஃ ஸ்வயமேவ வ்ட்ற்த்தி பேதாத், விக்ட்ற்தி பேதாத் ஸுவர்ண ஸலிலமிவ

3. The Life • Praana Respiration • Apana Digestion and UT (excretory) • Vyana Circulation (CVS) • Udaana Nervous System (Motor, Sensory) • Samaana 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 all constitute life, just as the gold is same, though different apparently, in various ornaments.

4. Polyuria How to Evaluate ? Dr R V S N Sarma M.D., M.Sc., (Canada) Consultant Physician and Chest Specialist www.drsarma.in, sarma.rvsn@gmail.com

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

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

7. The Body Compartments

8. Daily Water Balance

9. The Terminology • Solute – substance dissolved: Nacl, Glucose • Solvent – Liquid in which dissolved - Water • Milli Osmoles/ Kilogram (mOsm/kg) of Solvent - referred to as Osmolality • Milli Osmoles/ liter (mOsm/L) of Solution - referred to as Osmolarity

10. 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

11. Hypothalamic – Pituitary – Endocrine Axis

12. 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

13. Plasma Osmolality - ADH

14. 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% H20 is reabsorbed in PCT by AQP1 • Rest 29% by AQP 2, 3 and 4 • Reabsorption of H20 in CT – ADH mediated

15. 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

16. Water Metabolism

17. Renal FunctionCounter Current Multiplier

18. The Bowman’s Capsule

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

20. In the Collecting Duct

21. 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)

22. 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

23. 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 - < 3L] • 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

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

25. 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

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

27. 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

28. 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

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

30. 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

31. 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

32. AVP - V2 Receptor Protein Schrier, R. W. J Am Soc Nephrol 2006;17:1820-1832

33. Nephrogenic Diabetes Insipidus NDI – Congenital and Acquired V2 Vasopressin Receptor Mutations 180+ Mutations are documented In Chromosome region Xq28 Protein misfolding – V2 Receptor Not Translocated BLM of CT 90% of NDI is genetic 10% Acquired – see next slide

34. 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)

35. 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.

36. 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

37. 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 mOsm/kg of water Urine Specific Gravity <1.010 PD is water intake of > 100 ml/kg per day Measure Plasma Sodium on that day

38. Diagnostic Algorithm

39. Diagnostic Algorithm contd..

40. Diagnostic Algorithm contd..

41. 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

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

43. 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)

44. 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

45. 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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