RENAL TUBULAR ACIDOSIS.pptx

Renal tubular acidosis

1. RENAL TUBULAR ACIDOSIS DR MOHAMMED H. E 29.06.2022 1

2. OUTLINE INTRODUCTION DEFINITION OF TERMS PATHOPHYSIOLOGY CLINICAL FEATURES WORK UP MANAGEMENT CONCLUSION REFERENCES 2

3. INTRODUCTION M etabolic acidosis is a clinical disturbance characterized by an increase in plasma acidity, low blood pH (<7.35) I t occurs when the body produces excessive quantities of acid or when the kidneys are not removing enough acid from the body (increased production of hydrogen ions or the inability of the body to form bicarbonate (HCO3) in the kidney I f unchecked, leads to acidemia with varying consequences 3

4. INTRODUCTION U sually, is a sign of an underlying disease process and identification of this underlying condition is essential to initiate appropriate therapy C auses are diverse Consequences can be serious including coma and death U nderstanding the regulation of acid-base balance requires appreciation of the fundamental definitions 4

5. DEFINITION OF TERMS An acid is a substance that can donate hydrogen ions (H+) A base is a substance that can accept H+ B uffers P revent sudden and large swings in pH , resist pH changes C onsist of a weak base and acid C hemical buffers- P hosphate buffer, bicarbonate buffer, ammonia buffer A cidemia refers to a pH < 7.35 (normal range 7.35-7.45) 5

6. RENAL PHYSIOLOGY K idneys regulate plasma osmolarity by modulating the amount of water, solutes, and electrolytes in the blood T hey ensure long term acid-base balance N ormally the kidneys secrete H+ into the urine which are lost from the body during urination I f blood is too acidic, more H+ are lost and vice versa if too basic M echanism of urine formation- Glomerular filtration, tubular reabsorption and tubular secretion 6

7. ACIDIFICATION OF URINE U rine acidification and bicarbonate reabsorption take place in several segments of the nephron; proximal tubule, loop of Henle, distal tubule, and collecting ducts where most acidification occurs K idneys normally maintain acid-base balance by excreting the acid ions and reabsorbing the bicarbonate ions (base) which serves to neutralize the acid produced by the body D uring the elaboration of an acid urine, the distal nephron (DCT and Collecting duct) reabsorb that portion of the filtered HCO3 escaping proximal reabsorption, titrtate luminal buffers and lower urine pH T he secretion of H+ occurs by a primary active mechanism which involves the extrusion of H+ across the luminal cell membrane by an electrogenic H+ pump driven by the hydrolysis of ATP 7

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9. ANION GAP Na + Unmeasured cations = Cl + HCO3 + Unmeasured anions A nion gap is the quantity of anions not balanced by cations U sually due to negatively charged plasma proteins as the charges of the other unmeasured cations and anions tend to balance out 9

10. CAUSES OF METABOLIC ACIDOSIS 4 main causes; I ncrease in the generation of H+ from endogenous and exogenous acids (Lactate, ketones) or exogenous acids (salicylate, methanol, ethylene glycol) I nability of the kidneys to excrete the hydrogen from dietary protein intake (type 1 and 4 R enal tubular acidosis) T he loss of bicarbonate due to wasting through the kidneys (type 2 RTA) or through the GIT (diarrhoea) T he kidneys response to alkalosis 10

11. HIGH ANION GAP H igh AG if over 12mEq/L C auses ; L actic acidosis K etoacidosis CKD Ingestions; Salicylte, methanol, ethylene glycol, propylene, paraldehyde, metformin, phenformin M assive rhabdomyolysis 11

12. NORMAL ANION GAP T he number of bicarbonate ions decrease T o compensate the amount of lost bicarbonate ions, the body absorbs chloride ions A s a result, the anion gap remains normal but the amount of chloride ions increases A lso known as hyperchloremic acidosis H yperchloremic acidosis occurs basically due to these conditions; S evere diarrhoea R enal tubular acidosis R arer causes; uterosigmoid or pancreatic fistulas, acetazolamide use, Addison‘s disease 12

13. URINE ANION GAP I n severe diarrhoea, bicarbonate is lost in the stool, reducing the amount of anions, resulting in acidity GI and renal losses can be distinguished via urinary anion gap analysis; Urine AG = Urine Na + Urine K – Urine Cl A positive value suggests a low urinary NH4+, and indicates renal bicarbonate loss (RTA) N egative values suggests a high urinary NH4+, found with GI causes (diarrhoea) 13

14. HYPERCHLOREMIC ACIDOSIS L oss of bicarbonate stores through diarrhoea or renal tubular wasting leads to a metabolic acidosis state characterized by increased plasma chloride concentration and decreased plasma bicarbonate concentration 14

15. RENAL TUBULAR ACIDOSIS RTA is a condition that results from the kidneys being unable to appropriately acidify the urine resulting in the accumulation of acid in the body A metabolic acidosis occuring secondary to decreased renal acid secretion in the absence of marked decreases in GFR, and characterized by a normal AG are collectively referred to as Renal Tubular Acidoses R esults in growth retardation, kidney stones, bone disease, CKD T ypes; RTA type 1- Distal RTA RTA type 2- Proximal RTA RTA type 3- Combined Proximal and Distal RTA RTA type 4- Hyperkalemic 15

16. TYPE 1 (DISTAL RTA) I n the distal nephron, primarily the collecting duct, the urine pH reaches its lowest values D istal tubule is responsible for generating new bicarbonate under influence of aldosterone D amage to alpha-intercalated cells of distal tubule causes no new generation of bicarbonate and thus, no hydrogen ions T his raises the urine pH due to inadequate acid secretion I t is associated with hypokalaemia due to failure of H+/ATPase A lso known as the classic type T he deficiency is secondary to 2 main pathophysiologic mechanisms; A secretory defect A permeability defect W hen secretory defect predominates, the decreased secretion of protons (H+) fails to maximally decrease the urinary pH 16

17. TYPE 1 O ther mechanisms include decreased functioning of H+/ATPase, increased leak of protons from the tubules back into the lumen as seen in amphotericin B toxicity C auses (Inherited); A utosomal dominant; mutations of SLC4A1 gene A utosomal recessive with deafness; mutations in the gene ATP6V1B expressed in alpha=intercalated cells of distal tubule and cochlear, having distal RTA and sensorineural deafness A utosomal recessive without deafness; mutations in ATP6V0A4 17

18. TYPE 1(Causes-Acquired) A utoimmune diseases are the commonest cause in adults; SLE, Sjogren syndrome, RA, SSc, thyroiditis, hepatitis and PBC G enetic association; Marfan‘s syndrome, Ehler Danlos syndrome, sickle cell disease, congenital obstruction of the urinry tract N ephrocalcinosis; chronic hypercalcemia, medullary sponge kidney T ubulointerstitial diseases; chronic pyelonephritis, chronic interstitial nephritis, obstructive uropathy, renal transplant ejection H ypergammaglobulinemic states; monoclonal gammopathy, multiple myeloma, amyloidosis, crryoglobulinemia, CLD D rugs; lithium , amphotericin B, NSAIDs, lead, antiviirals M iscellaneous; diopathic, familial hypercalciuria, glue sniffing (inhalation of recreation drug) 18

19. TYPE 2 (PROXIMAL) N ormally, 85% to 95% of bicarbonate is reabsorbed at the proximal tubule and only 10% absorbed at the distal tubule D ue to a bicarbonate leak , impaired proximal HCO3 reabsorption in proximal tubule results in excess HCO3 in urine leading to metabolic acidosis O ften associated with Fanconi syndrome and is rarer than type 1 H ypokalaemia is common due to osmotic diuresis because of decreased HCO3 reabsorption causing increased flow rate to the tubules and causing increased K+ excretions C arbonic anhydrase inhibitors impair proximal bicarbonate reabsorption, tenofovir, ifosfamide can cause Fanconi syndrome G enetic causes; autosomal recessive, autosomal dominant 19

20. TYPE 2 RTA(Causes) F amilial or Sporadic D ysproteinemic states; Multiple myeloma, amyloidosis, cryoglobulinemia D rugs or toxic nephropathy; Lead, Cdmium, Mercury, Ifosfamide, Acetazolamide H ereditary disorders; Cystinosis, Wilson disease, Tyrosinemia, Lowe syndrome I nterstitial renal conditions; Sjogren syndrome, Medullary cystic disease M iscellaneous; Malignancies, Nephrotic syndrome 20

21. TYPE 3 (MIXED) R are M ostly affects children from Arabic, North African and Middle Eastern descent D ue to mutations of CA II resulting in carbonic anhydrase II deficiency 21

22. TYPE 4 (HYPERKALEMIC) A mmonium excretion requires the renal synthesis of ammonia and the secretion of hydrogen ions from the collecting tubular cells into the tubular lumen where they are trapped as ammonium (NH4+) H ypoaldesteronism causes hyperkalemia and metabolic acidosis H yperkalaemia impairs ammonia genesis in the proximal tubule and reduces the availability of NH3 to buffer urinary hydrogen ions and decreases hydrogen ion excretion in urine T he failure to acidify urine is due to inadequate amount rather than complete absence of NH3 available for buffering of protons E ven if only a few protons are secreted distally, urine pH would fall and this is why these patients have a urine pH < 5.5 22

23. TYPE 4 D eficiency of or resistance to aldosterone is the most common cause of hyperkalaemic dRTA Most common cause of type 4 RTA in adults is hyporeninemic hypoaldosteronism which is frequently observed among patients with mild to moderate CKD, especially if due to diabetic nephropathy R esistance to the action of aldosterone is observed in patients with a chronic tubulointerstitial disease, those on potassium-sparing diuretics and rare congenital disorder called pseudohypoaldosteronism A ddison disease, bilateral adrenalectomy, certain enzymatic defects, NSAID use, HIV, Renal transplant 23

24. CLINICAL FEATURES Symptoms of metabolic acidosis are not specific T he respiratory centre in the brainstem is stimulated and hyperventilation develops in an effort to compensate for the acidosis A s a result; varying degrees of dyspnoea C hest pain, headache, confusion, generalized weakness, and bone pain N ausea, vomiting and loss of appetite 24

25. I mportant points in the history.. A ge of onset, family history may point toward inherited disorders which usually start in childhood V isual symptoms, including dimming, photophobia, scotomata- methanol ingestion R enal stones- RTA or chronic diarrhoea T innitus, blurred vision, and vertigo- Salicylate poisoning 25

26. I mportant points in the history.. D iarrhoea- GI losses of HCO H istory of DM, alcoholism, starvation- accumulation of ketoacids P olyuria, increased thirst, epigastric pain, vomiting- DKA N octuria, pruritus, polyuria, anorexia, decline in urine output- Renal failure I ngestion of toxins or drugs- Salicylates, acetazolamide,cyclosporine, ethylene glycol, methanol, metformin, topiramate 26

27. SIGNS T he best recognized sign of metabolic acidosis is kussmaul respirations, a form of hyperventilation that serves to increase minute ventilatory volume. C haracterized by an increase in tidal volume rather than respiratory rate. A ppreciated as deliberate, slow and deep breathing C hronic metabolic acidosis in children stunted growth and rickets C oma and hypotension in acute severe metabolic acidosis 27

28. SIGNS N on specific; and depend on the underlying cause S ome examples; xerosis, scratch marks, pallor, drowsiness, fetor, asterixis, pericardial rub for renal failure, dry mucous membranes and fruity smell for DKA 28

29. HISTORY AND PHYSICAL FOR THE RTAs T ype 1 Distal; rickets, growth failure, osteomalacia H ypercalciuria, hypocitaturia (citrate is reabsorbed as a buffer for hydrogen ions) A lkaline urine N ephrocalcinosis (calcium phosphate stones) R ecurrent UTIs ESRD M uscle weakness, arrhythmia from hypokalaemia 29

30. HISTORY AND PHYSICAL FOR THE RTAs T ype 2 Proximal O steomalacia H ypokalaemia H ypophosphatemic rickets L oss of glucose, urate, and amino acids in the urine T ype 3 Mixed Guibaud-Vainsel syndrome O steopetrosis C erebral calcification, M ental retardation F acial dysmorphism, conductive hearing loss, blindness due to nerve compression T ype 4 Hyperkalemic H yperkalaemia, metabolic acidosis 30

31. TESTS FOR METABOLIC ACIDOSIS A rterial blood gases pH, pO2, P CO2, HCO3 V enous blood samples Na, K, Cl, HCO3 G lucose S erum lactose M easured serum osmolarity S erum ketones U rine U rine pH, urine ketones 31

32. C alculations A nion gap O smolar gap A ppropriate P CO2 change based on serum bicarbonate 32

33. INTERPRETATION STEPS D etermine the main acid-base problem 1. D etermine the acid-base status (pH lower than 7.35) M etabolic or Respiratory 2. Bicarbonate < 20mEq/L M etabolic acidosis 3. C alculate anion gap Normal AG; 8 – 16mEq/L (5 -7 using newer lab analyzers) 4. A ssess if respiratory compensation is adequate 5. D etermine if patients history and physical fits the proposed diagnosis of type and causes of metabolic acidosis 33

34. URINE pH and AG dRTA – urinary pH > 5.5, urinary AG positive pRTA – urinary pH < 5.5, urinary AG positive T ype 4 RTA - urinary pH < 5.5, urinary AG positive D iarrhoea – urinary pH variable, urinary AG negative 34

35. WORK UP 1st clue to metabolic acidosis is a decreased serum bicarbonate concentration observed from an EUCr R emember that a decreased serum bicarbonate can be observed as a compensatory response to respiratory alkalosis B icarbonate of less than 15mEq/L almost always is due to at least in part, metabolic acidosis O nly definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases, whcih shows pH and PaCO to be low 35

36. A low serum HCO3 and pH of less than 7.40 upon ABG analysis confirms metabolic acidosis C alculate the anion gap (AG) to help with the differential diagnosis and diagnose mixed disorders I n general, a high-AG acidosis is present if AG is greater than 10-12mEq/L and a non-AG acidosis is present if the AG is less than or equal to 10-12 mEq/L. T he AG decreases by 2.5mEq for every 1g/dl decrease in serum albumin 36

37. O smolar gap (OG) = Measured serum osmolality - Calculated serum osmolality N ormal is about 10-15mOsm/kg C alculated plasma osmolality (P) = {2 X Na}+{Glucose in mg/dl}/18+{BUN in mg/dl}/2.8 I f AG is elevated, calculate osmolar gap OG > 15mOsm/kg indicates the presence of abnormal unmeasured os motically active molecules M ost common causes; ethanol, methanol, ethylene glycol, isopropanolol 37

38. EVALUATION OF RTAs (General) C onsider RTAs in any patient with an otherwise unexplained normal anion gap (hyperchloremic) metabolic acidosis M easure blood pH P lasma potassium; low in type 1 and type 2 and high in type 4 BUN/Cr; normal or near normal (rules out renal failure as the cause of acidosis) U rine anion gap (Na + K) – Cl (positive gap signifies low NH4Cl excretion which causes a decrease inchloride in urine along with hyperchloemic metabolic acidosis suggesting RTA 38

39. EVALUATION OF RTAs (Specific) A cid load test confirms diagnosis of distal RTA B icarbonate infusion test U rine Na; type 4 RTA presents with persistently high urine Na despite restricted Na diet because of aldosterone deficiency or resistance 39

40. TREATMENT T reatment of GI causes of hyperchloremic acidosis is aimed at; A dministration of saline solutions to repair volume losses E arly administration of potassium T reatment of acidosis with bicarbonate-containing solutions is accompanied by potassium replacement to avoid severe hypokalemia G enerally, identify underlying disease entity, give specific therapy H owever therapy for hyperchloremic RTA still needed G oals of therapy; reduce rate of progression to CKD, neutralize metabolic bone disease and in children, improve growth 40

41. TREATMENT/ MANAGEMENT OF THE RTAs (Hypokalaemic dRTA) T reatment consists of long-term alkali administrationin amounts sufficient to counterbalance endogenous acid productionand any bicarbonaturia that may be present O ral bicarbonate replacement at 1-2 mEq/kg per day by sodium bicarbonate or potassium citrate P otassium citrate necessary for patients with hypokalaemia, nephrolithiasis or nephrocalcinosis S ought and treat underlying conditions M ost bicarbonate is absorbed in the proximal tubule so distal RTA is relatively easy to correct S pironolactone can be used to maintain normokalaemia 41

42. TREATMENT/ MANAGEMENT OF THE RTAs (Proximal RTA) H igh doses of bicarbonate greater than 5 to 15 mEq/kg per day are required to treat type 2 RTA R aising the serum bicarbonate concentration will increase the filtered bicarbonate load above the proximal tubule‘s reduced absorptive capacity, resulting in a marked bicarbonate diuresis so a larger amount of alkali is required to account for these urine losses I ncreased bicarbonate concentration in urine induced by alkali therapy also increases urinary potassium losses A dministration of potassium salts must accompany or precede as it minimizes the degree of hypokalemia associated with alkali therapy C an be dificult to treat because alkali administration results in prompt and marked bicarbonaturia and potassium wasting T hiazide diuretics cause extracellular volume depletion which will enhance bicarbonate reabsorption in type 2 RTA 42

43. TREATMENT/ MANAGEMENT OF THE RTAs (Hyperkalaemic dRTA) I dentify entities amenable to intervention such as obstructive uropathy M ost patients can be managed with a limitation of dietary potassium to 40 to 60 mEq per day A void foods and drugs that may contain high potassium content C ation exchange resins may be helpful in hyperkalaemia D istal sodium delivery is increased if patients increase ingestion of dietary salt F ludrocortisone 0.1mg per day is effective in managing hyperkalaemia associated with aldosterone deficiency. H owever it is not usually used due to hypertension, heart failure and oedema exacerbated in patients with renal insufficiency 43

44. H ypophosphatemia due to decreased proximal phosphate reabsorption and reduced activation of vitamin D also occurs in some patients and may be a major contributor to the development of bone disease T hus phosphate and vitamin D supplementation may be required to normalize the serum phosphate and reverse metabolic bone disease 44

45. PROGNOSIS Morbidity and mortality in metabolic acidosis are primarily related to the underlying condition and the acid-base derangement P rognosis is poor if the derangements are large and vitals are unstable 45

46. CONCLUSION M etabolic acidosis is a clinical disturbance characterized by an increase in plasma acidity (pH < 7.35 and a low HCO3 level) I t is usually a sign of an underlying disease process I dentify underlying and initiate appropriate therapy T reatment is case dependent and lab tests include; arterial blood gas, electrolytes, toxin levels T he overall prevalence in the population is uncertain 46

47. REFERENCES Roth KS, Chan JC. Renal tubular acidosis; a new look at an old problem. C lin Pediatr (Phila). 2001 Oct;40(10):533-43 (Pub Med) T repiccione F, Prosperi F, Hubner CA, Chambrey R. N ew findings on the Pathogenesis of Distal Renal Tubular Acidosis. K idney Dis (Basel). 2017 Dec;3(3):98-105 (Pub Med ) J ohnson RJ, Feehally J, Floege J, Marcello T. Comprehensive Clinical Nephrology. 5e. P hiladelphia, PA; Elsevier/Saunders 2015 Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison‘s Principles of Internal Medicine, 18e. New York; McGraw Hill; 2012. 47

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