PHAR2006 Pathophysiology 1: Acid-Base & Renal Disorders PDF

PHAR2006 PATHOPHYSIOLOGY 1 GARSHA McCALLA, Ph.D. Physiology Section, BMS, FMS, UWI, Mona [email protected] PATHOPHYSIOLOGY OF ACID-BASE & RENAL DISORDERS  Aim & Objectives AIM  To explore the pathophysiology of acid-base and renal disorders...

PHAR2006 PATHOPHYSIOLOGY 1 GARSHA McCALLA, Ph.D. Physiology Section, BMS, FMS, UWI, Mona [email protected] PATHOPHYSIOLOGY OF ACID-BASE & RENAL DISORDERS  Aim & Objectives AIM  To explore the pathophysiology of acid-base and renal disorders in humans Objectives  To identify types of acid-base and renal disorders  To identify causes of acid-base and renal disorders  To identify primary signs and symptoms of acid-base and renal disorders  To explain the pathophysiology of acid-base and selected renal disorders in humans  To distinguish between acute and chronic renal failure  PATHOPHYSIOLOGY OF ACID-BASE DISORDERS  Acid-base disorders - group of conditions characterized by changes in hydrogen ion (H+) or bicarbonate (HCO3-) levels, leading to pH changes in arterial blood  Efficient respiratory and renal homeostatic mechanisms are used to regulate acid-base balance Acid-base Disorders  Respiratory acidosis (Primary Carbonic Acid/CO2 Excess)  Respiratory alkalosis (Primary Carbonic Acid/CO2 Deficiency)  Metabolic acidosis (Primary Bicarbonate Deficiency)  Metabolic alkalosis (Primary Bicarbonate Excess)  PATHOPHYSIOLOGY OF ACID-BASE DISORDERS Lungs Respiratory acidosis Respiratory alkalosis Mechanism Alveolar hypoventilation → CO2 retention ↑ In respiratory rate and/or tidal volume → alveolar hyperventilation >>> >>>> → CO2 washout Common causes Airway obstruction: COPD Pain, anxiety, panic attacks exacerbation or bronchial asthma Pregnancy Respiratory muscle weakness High altitude CNS depression: due to Drug toxicity (progesterone, * head trauma salicylate) * post-ictal state (altered state of Hyperventilation while on mechanical consciousness after an epileptic ventilation seizure) * drug toxicity (opiates, barbiturates, and benzodiazepines) pH* (N=7.35-7.45) ↓ ↑ pCO2 (N=4.5-6 kPa) ↑ ↓ - HCO3 (N=22-29 mmol/L) ↑ (compensation) ↓ (compensation) *pH values may be within the reference range in the case of complete compensation. However, it still is referred to as compensated alkalosis or acidosis. https://www.amboss.com/us/knowledge/Acid-base_disorders  PATHOPHYSIOLOGY OF ACID-BASE DISORDERS Kidneys Metabolic acidosis Metabolic alkalosis ↑ Production/ingestion of H or loss of HCO3- + + Mechanism Loss of H or ↑ production/ingestion of - HCO3 Common causes High anion gap metabolic acidosis Chloride-responsive Lactic acidosis: severe tissue hypoxia, (urinary chloride normal [< 25 mmol/L]) liver failure, metformin use Vomiting or nasogastric suction Ketoacidosis: diabetes mellitus, Hypovolaemia (contraction starvation, alcoholism alkalosis) Renal insufficiency, uraemia Loop or thiazide diuretics Accumulation of exogenous organic Chloride-resistant acids (methanol, ethylene glycol, (urinary chloride elevated [> 40 mmol/L]) toluene, salicylate toxicity) Hyperaldosteronism Normal anion gap metabolic acidosis Cushing syndrome Renal tubular acidosis GI loss of HCO3- (e.g., diarrhoea) pH* (N=7.35-7.45) ↓ ↑ pCO2 (N=4.5-6 kPa) ↓ (compensation) ↑ (compensation) - (N=22-29 mol/L) HCO3 ↓ ↑ The anion gap is the difference between primary measured cations (sodium, Na + and potassium, K+) and the primary measured anions (chloride, Cl- and bicarbonate, HCO3-) in serum. https://emedicine.medscape.com/article/2087291-overview *pH values may be within the reference range in the case of complete compensation. However, it still is referred to as compensated alkalosis or acidosis. https://www.amboss.com/us/knowledge/Acid-base_disorders Symptoms of Acid-base Disorders (insensibility) (RA); Rapid breathing (MA)  PATHOPHYSIOLOGY OF RENAL DISORDERS  Hyperuricaemia  Renal failure Hyperuricaemia  Elevated blood uric acid (>6.8 mg/dL)  Uric acid is derived from purine nucleotides: AMP, GMP (necessary for normal nucleic acid synthesis)  Uric acid mostly occurs in its ion form as urate The blood urate concentration is dependent on the amount of purines:  Consumed  Synthesized  Excreted CAUSES OF HYPERURICAEMIA  Diet  Iron overload  Excess alcoholic beverages Meat, organs, fish, beans,  Chronic kidney disease sweetbreads, yeast, beer and sweetened soft drinks  Hypertension (with high fructose corn syrup)  Hypothyroidism  Insulin resistance  Diuretics (e.g. thiazides, loop diuretics)  Genetics (Inflammatory arthritis)  Obesity Pathophysiology of Hyperuricaemia  When solubility of urate exceeds its normal threshold (>6.8 mg/dL) monosodium urate (MSU) crystal deposition may occur and lead to gout  The aqueous solubility of uric acid is relatively low vs normal range of serum concentration, so a modest increase can elevate the risk of MSU crystal formation and precipitation, notably in the joints and urine (Chhana et al., 2015) Chhana, A., Lee, G., & Dalbeth, N. (2015). Factors influencing the crystallization of monosodium urate: A systematic literature review. BMC Musculoskeletal Disorders, 16, 296. https://doi.org/10.1186/s12891-015-0762-4 Pathophysiology of Hyperuricaemia  Inability of the body to handle the urate load will result in hyperuricaemia  Too much produced – overwhelms kidneys/GIT  Insufficient amount excreted or egested Result: heart disease, diabetes, and kidney disease  Signs & Symptoms of Hyperuricaemia ❖ Mostly asymptomatic ❖ 33% of patients experience symptoms:  Crystals predominantly form in and around joints and in kidneys  Inflammation and pain – due to WBCs attacking the crystals  Gout (gouty arthritis):  Redness and swelling (inflammation)  Joint stiffness  Severe joint pain  Difficulty moving affected joints  Mis-shapen joints  Tophaceous gout (clumps formed by uric acid crystals)  Hard lumps under the skin, around joints, and in the top ear curvature  RENAL (KIDNEY) DISEASES  The kidneys are a part of the urinary system  Main functions of the kidneys: 1. Produce, secrete, & concentrate urine  Regulates excretion of wastes  Regulates acid-base, fluid, & electrolyte balance 2. Synthesize & secrete erythropoietin (EPO)  Stimulates RBC production 3. Synthesize & secrete renin  Regulates blood pressure  RENAL (KIDNEY) DISEASES  The kidneys filter blood at the glomerulus  Volume of filtrate produced by both kidneys per min:  Known as the glomerular filtration rate (GFR)  GFR = 125 ml/min (180 L/day)  Most of the filtrate is reabsorbed leaving only about 1% (1-1.5 L) for excretion as urine  Kidney diseases can decrease the GFR and result in renal failure  RENAL FAILURE  An end-stage renal disease (ESRD) that can arise from a multiplicity of renal disorders, e.g., renal insufficiency  Encompasses all forms of reduced renal function  Diabetics, hypertensives, & obese persons are at greater risk for developing kidney disease & renal failure Renal failure may be categorized into 2 main categories:  Acute renal failure (ARF)  Chronic renal failure (CRF) Many kidney diseases may be categorized into acute or chronic renal failure  ACUTE RENAL FAILURE (ARF)  The kidneys abruptly stop functioning completely or almost completely but may possess the ability to recover close to normal function  Due to pre-renal, renal (intra-renal), or post- renal obstruction or problem  Causes of Acute Renal Failure Causes are classified as follows:  Pre-renal: due to reduced renal  Renal (Intra-renal): due to  Post-renal: due to obstruction blood flow kidney damage to outflow of urine  Severe and prolonged shock  Glomerulonephritis  Bladder, uterine, colon or (main cause) cervical tumour  Acute tubular necrosis  An infection  Blood clots  Large calculus (stone) in  Medications (aspirin, the renal pelvis  Cholesterol deposits ibuprofen, naproxen, or  Kidney stones COX-2 inhibitors, like  Medications such as:  Prostate gland disease or Celebrex)  NSAIDs like ibuprofen cancer  Blood pressure medications and naproxen  Enlarged prostate  Liver failure  Chemotherapy  Blood clots in your urinary  Heart failure  Antibiotics tract  Severe burns or dehydration  Nerve damage in your bladder  Blood or fluid loss  PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE  An infection normally causes the release Pre-renal Failure of chemicals to fight it. If there is  Obstruction leads to hypoperfusion of imbalance in the body’s response to these the kidneys chemicals (sepsis), many organs may be damaged.  Hypoperfusion leads to:  Ischaemia  The chemical and humoral mediators  Hypoxaemia released during sepsis contribute to a pro-  Azotaemia (excess blood inflammatory response and systemic nitrogenous wastes) in 40-80% of vasodilation. cases  This results in decreased systemic  Reduced GFR, leading to electrolyte pressure which stimulates the imbalance & metabolic acidosis sympathetic nervous system, resulting in:  Kidney damage  Renal artery constriction  Decreased filtration  Decreased excretion  PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE Intra-renal Failure Post-renal Failure  Intrinsic renal problems caused by  Obstruction to the outflow of urine (in glomerulonephritis, tubular necrosis, the urinary tract) results in: etc., can damage the glomerular  Azotaemia blood vessels, tiny tubules, etc., and affect renal blood flow  Build up of pressure in the kidney nephrons  Prolonged or severe lack of blood flow by ischaemia can produce:  If unrelieved, build up of wastes & pressure can:  Kidney damage  Prevent normal outflow of urine  Intrinsic renal azotaemia  Damage renal tissue  Shut down nephrons  Blood or fluid loss can lead to hypotension and ischaemia, leading to generation of toxic free radicals. The end result may be swelling, injury, and necrosis. CHRONIC RENAL FAILURE (CRF)  Progressive loss of nephron function, resulting in gradual diminution of kidney function  Irreversible damage to ~75% of the nephrons  Currently known as chronic kidney disease (CKD)  Onset usually slow and asymptomatic  Characterized by progressive reduction in glomerular filtration rate (GFR) to ~10% of normal function (~ 12.5 - 20 ml/min)  In ESRD, the GFR falls below 5% (~6.25-10 ml/min)  Classification of Chronic Kidney Disease Levey, A. S., Eckardt, K. U., Tsukamoto, Y., Levin, A., Coresh, J., Rossert, J., …Eknoyan, G. (2005). Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International, 67(6), 2089-2100.  Causes of Chronic Renal Failure Main Causes of End Stage % of ESRD Other causes Renal Disease (ESRD) Patients Diabetes mellitus 28  Autoimmune diseases, such as lupus and IgA nephropathy Hypertension 25  Genetic diseases such as Glomerulonephritis 21 hereditary nephritis (Alport syndrome) Polycystic kidney disease 4 (most prevalent genetic  Nephrotic syndrome cause – autosomal dominant form) Other/unknown 22  Urinary tract problems Guyton & Hall (1997). Human Physiology and Mechanisms of Diseases, 6th ed. Ch. 23, Regulation of acid-base balance; micturition; renal disease, pg 267.  Pathophysiology of Chronic Renal Failure  The pathophysiology of CRF is related mainly to specific initiating mechanisms. Over the course of time, adaptive physiology plays a role leading to compensatory hyperfiltration and hypertrophy of remaining viable nephrons. As insult continues, subsequentially histopathologic changes occur which include:  distortion of glomerular architecture  abnormal podocyte function  disruption of filtration leading to sclerosis (Almirall, 2016; Bindroo & Challa, 2019) Bindroo, S., & Challa, H. J. (2019). Renal failure. https://www.ncbi.nlm.nih.gov/books/NBK519012/ Almirall, J. (2016). Sodium excretion, cardiovascular disease, and chronic kidney disease. Journal of the American Medical Association, 316(10), 1112. doi:10.1001/jama.2016.11553  Pathophysiology of Chronic Renal Failure  Other changes include:  Sclerotic glomeruli eventually becoming non-functional  Markedly increased proteinuria  Worsened systemic hypertension  Adapted nephrons develop enhanced:  Ability to postpone uraemia  GFR  Tubular functions (to secrete ions)  Adaptation eventually results in destruction of the nephrons  Signs & Symptoms of Renal Failure ACUTE CHRONIC When symptomatic: When symptomatic: Onset asymptomatic End-stage renal failure:  Infrequent urination  Shortness of  Accumulation of  Very deep (Kussmaul’s) (less than normal) breath creatinine and urea respirations * Swelling of legs,  Nausea *   Nausea or  Nausea ankles, & feet (caused  Vomiting  Vomiting  Vomiting by fluid retention)  Pruritis  Pruritis (itching)  Pruritis  Joint pain, swelling  Anorexia *  Nosebleed  GI bleeding  Stomach & back pain  Hiccough  Muscle twitching  Anaemia  Chest pain or pressure  Muscle twitching  Seizures (in  Polyuria  Seizure  Loss of appetite severe cases) or  Acidosis  Confusion  Coma  Coma (in severe  Electrolyte imbalance  Drowsiness  Fever cases)  Hypertension * Occur as uraemia  Rash  Drowsiness or progresses feeling very tired