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Chapter 18. Renal Failure. Section I . Introduction. Kidneys are the principal excretive organs. Not only excrete waste metabolic products to remove various harmful substances,. But also regulate a variety of material in plasma
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Chapter 18 Renal Failure
Section I . Introduction
Kidneys are the principal excretive organs Not only excretewaste metabolic products to remove various harmful substances, But also regulate a variety of material in plasma to maintain the homeostasis of internal environment (osmolality and acid-base balance) Besides, kidneys also producesome bioactive substances renin, prostaglandins (regulation of blood pressure) erythropoietin (formation of matured RBCs) active vitamin D (metabolism of calcium and phosphorus)
Kidneys are the principal excretive organs Not onlyexcretewaste metabolic products to remove various harmful substances, But alsoregulate a variety of material in plasma to maintain the homeostasis of internal environment (osmolality and acid-base balance) Besides, kidneys alsoproducesome bioactive substances renin, prostaglandins (regulation of blood pressure) erythropoietin (formation of matured RBCs) active vitamin D (metabolism of calcium and phosphorus)
The following pathologic process is termed ''renal failure'': Various causes Glomerular filteration rate↓ Retention of metabolic wastes, Disturbanc of internal environment Severely impair renal function a serial of clinical manifestations Renal Failure Acute renal failure (ARF) (CRF) Cronic renal failure Uremia
1. Causes of renal dysfunction (1) Primary renal disease (2) Renal injury secondary to systemic diseases.
1. Causes of renal dysfunction (1) Primary renal disease (2) Renal injury secondary to systemic diseases. 1)Glomerular disease 2)Renal tubular disease 3)Interstitial nephritis 4) Others: glomerulonephritis; nephrotic syndrome renal glucosuria; aminoaciduria, renal tubular acidosis acute or chronic interstitialinflammation renal injury, tumor, calculus; obstructive nephropathy; vascular nephropathy
1. Causes of renal dysfunction (1) Primary renal disease (2) Renal injury secondary to systemic diseases . 1) Circulatory systemdiseases: 2) Auto-immune and connective tissue diseases: 3) Metabolic diseases: 4) Hematological diseases: 5) Others: Shock, AS, thrombosis, etc. Lupus nephritis, renal injury by rheumatoid arthritis, etc Nephropathy caused by amyloidosis, diabetic or hyperuricemia Renal injury by plasmacyte disease, multiple myeloma or leukemia Heart failure, hepatic disease, endocrine disease and malignant tumors
2. The basic manifestation of RF The anatomic and functional unit of kidney is nephron, which consists of glomerulus and renal tubule. Each human kidney has approximately 1 million nephrons. The glomerular function is to form original urine by filtration, while the tubule perform reabsorption and secretion. The basic presentation of RF include: (l) Dysfunction of glomerule (2) Dysfunction of renal tubules (3) Dysfunction of renal endocrine
(l) Dysfunction of glomerule Renal blood flow Effective filtration pressure of the glomerule Kf (LPA, permeabilityandtotal filtration area) 20% of CI GFR Alteration of urinary quantity 125ml/min 180L/day Permeability (of glomerular filtration membrane) 99% Abnormality of urinary quality (hematuria & proteinuria) 1.5L/day
(2) Dysfunction of renal tubules The secretion and reabsorption function are very important for maintain the homeostasis of internal environment l ) Principal influencing factors ① Renal tubular EC (may impaired by ischemia, hypoxia, infection and toxins) ② Neuro-humoral factors (Aldosterone, ADH, ANP, PTH etc.) ③ Concentration and flow rate of the initial urine (ANP: atrium natriuretic peptide; PTH: parathyroid hormone) 180L/d 99% 1.5L/d
2) Types of renal tubular dysfunction ① Dysfunction of reabsorption Proximal convoluted tubule: glucosuria, phosphuria, aminoaciduria, Na+ and H2O retention, renal tubular acidosis ② Dysfunction of concentration and dilution Henle’s (medullary) loop and collecting tubule: polyuria, Isosthenuria (isotonic), Hyposthenuria (hypotonic) ③ Acid-base Disturbances Proximal tubule (secrete H+, NH4+, NH3 ; reabsorb HCO3–); Medullary loop (reabsorb b HCO3– and NH3) Distal tubule (secrete H+)
(3) Dysfunction of renal endocrine ① Increased secretion of rennin Renin ② Declined Kallikrein-kinin system (KKS) Kinin ③ Increased secretion of endothelin ET ④ Inadequate synthesis of prostaglandins from arachidonic acid PGE2 , I2 Renal Hypertension
EPO ⑤ Decreased eryhropoietin ⑥ Decreased 1-a-hydroxylase ⑦ Weakened inactivation to PTH ⑧ Weakened inactivation to gastrin (90% formed in kidney) Renal aneamia 1,25-(OH)2- D3 PTH Renal osteodystrophy HCI Ulceration
Section 2. Acute Renal Failure
Variouscauses Rapidly and severely decline of GFR Kidneys fail to excretion and regulation in hours to days Oliguria or anuria Retention of nitrogenous wastes (azotemia) water/electrolyte acid-base disturbance Oliguria is usually emphasized in the past, but in some cases, patients have high level BUN (azotemia) while urine volume does not change. It is called non-oliguria ARF
l. Causes and classification Acute renal failure (ARF) may result from a wide variety of diseases (shock, heart failure, severe infection, hepatic diseases), trauma, surgical procedures, drugs, renal toxins and urinary tract obstruction. According to causes, ARF may be divided into three main categories: Prerenal Intrarenal acute renal failure Postrenal
( l ) Prerenal failure (functional RF or prerenal azotemia) (2) Intrarenal failure (parenchymal RF) (3) Postrenal failure (Obstructive RF, Postrenal azotemia) caused by any disorder external to the kidneys that rapidly and severely decreases the blood supply to the nephron. caused by disease of the renal tissue itself, affecting the blood vessels, glomeruli or tubules. caused by obstructive disorders (uretal or urethral) that can block or partially block urine flow, while the kidney's blood supply and other functions are initially normal.
( l ) Prerenal failure Hypovolemia, Acute heart failure Expanded vascular bed volume (Hepatorenal syndrome Anaphylactic shock, etc.) Renal vascular blockage or auto-regulation disturbances Sudden decrease of renal perfusion GFR↓ Na+, H2O reabsorption↑ Azotemia(urinary Cr/plasma Cr > 40 ) Oliguna (<400ml/day) Urinary Na+<20 mmol/L Urine gravity > 1.020 No RBC, WBC or cast in urine
(2) Intrarenal failure Causes:intrinsic (parenchymal) renal diseases 1. Renal tubular diseases 2. Glomerular diseases 3. Renal interstitial diseases 4. Renal blood vessel diseases Acute renal ischemia Acute renal poisoning Acute Tubular Necrosis (most common) Renal tubule blocked by Hb or Mb Glomerulonephritis, pye1onephritis, etc Severe infection, drug allergy, etc Thrombosis, DIC, etc
Clinical features: 1. Oliguria or Non-oliguria 2. Isothenuria the specific gravity of urine become fixed at 1.010 or 0.285 mOsm / L (equal to the osmotic concentration of plasma), implying an inability of the kidney to concentration or dilute the urine. 3. Urinary Na+ >40mmo l/L (ability to reabsorb Na +) 4. Hematuria. 5. Azotemia(urinary Cr/plasma Cr < 20)
(3) Postrenal failure Stone or tumor →Bilateral Obstruction Renal pelvises hydropsy increased renal interstitial pressure increased intracapsular pressure →GFR↓↓ suddenly anuria and azotemia
2. Pathogenesis There are three major factors may account for the development of ARF(ATN): 1. Renal hemodynamic factors 2. Nephronal factors 3. Filtration area and permeability 1. Alteration of renal hemodynamics 2.Renal tubule injury 3.Decreased ultrafiltration coefficient (Kf) of glomeruli
2. Pathogenesis 1. Alteration of renal hemodynamics 2.Renal tubule injury 3.Decreased ultrafiltration coefficient (Kf) of glomeruli
(l ) Alteration of renal hemodynamics The decreased renal perfusion caused by renal vasoconstriction is the principal pathogenesis of ARF. Effective filtration pressure, FF & Kf There are many factors may associated with renal vasoconstriction:. GFR Oliguria or anuria Renin-Angiotensin System Catecholamine Prostaglandins, etc.
1) Renin-angiotension system Toxin, Ischemia Impairing proximal convoluted tube and ascending limb of medullary lope vasoconstriction Reabsorption of Na+ Renal perfusion pressure Na+ in distal convoluted tube stimulating juxtaglomerular cells in afferent arteriole (T-G feedback) Stimulating macula densa of juxtaglomerular apparatus Activating RAS
Effective circulating blood flow↓ or toxin → excitation of sympathetic-adrenomedullary system → CA↑→vasoconstriction of renal cortex especially of afferent arteriole 2) Catecholamine (CA) 3) Prostaglandins (PG) 4) Endothelin (ET) 5) Others: Decreased synthesis of PG → PGI2/TXA2↓ → renal vasoconstriction Renal diseases may stimulate blood vessel EC to secrete ET. During ARF the level of plasma ET and the ability of ET-R to combine ET are all increased, which will directly or indirectly lead to renal vasoconstriction NO synthesis↓, ADH, PAF and TNF↑and ischemia- reperfusion injury → promote ATN All these go into a vicious circle and cause increasingly severe damage
(2) Renal tubule injury 1) Renal tubule obstruction Cast formation 2) Renal tubule backflow of original urine Loss of tubule integrity
Renal tubule injury Loss of tubule integrity Renal tubule EC necrosis Basement membrane broken down Dead and detached ECs Filtered protein (HB or MB) Backleak of original urine into renal interstitium Cast formation Interstitial edema formation Tubule obstruction Oppressing Oppression renal tubule renal capillary Intracapsular pressure Aggravate Aggravate tubule obstruction renal ischemia Effective filtration p GFR Oliguria
(3) Decreased ultrafiltration coefficient (Kf) of renal glomeruli Decreased filter area↓ structural destruction of filter membrane Ultrafiltration Coefficient↓
3. Clinical course and manifestation (l) Oliguria type of ARF (2) Nonoliguria type of ARF
(l) Oliguria type of ARF When various diseases lead to destruction of the tubular cells of the nephron (as typically occurs in cases of ATN), a characteristic response pattern is noted. It usually develops in three stages: Oliguria phase diuresis phase recovery phase
l) Oliguria phase Oliguria: Urine volume < 400 ml / day, or <50ml / day (anuria) It usually occurs in one day after renal damage and lasting l-2 weeks. The longer the time last, the worse the prognosis is A duration more than one month indicates that the necrosis of tubule is very severe.
As the urine formation rapidly diminished, the wastes of protein metabolism and water, electrolytes accumulate in extracellular fluid, which is often characterized by: 1. Azotemia Progressive elevation of NPN (Urea, creatinine, etc.) 2. Hyperkalemia May lead to ventricular fibrillation and cardiac arrest (No.1 cause of death) 3. Metabolic acidosis May depress CNS and heart, aggravate hyperkalemia 4. Retention of water and sodium Edema, hyponatremia and even water intoxication would occur if there is water and salts overload
2. Hyperkalemia 2. Hyperkalemia 3.Metabolic acidosis Death Triangle 4. Edema, hyponatremia and Water intoxication
Differences between functional and parenchymal ARF INDEXES F - ARF P - ARF Urine specific gravity > l .020 < l .0l 5 Urine osmolality > 500 mmol / L < 350 mmol / L Urine Na+< 20 mmol / L > 40 mmol / L Urine Cr / Plasma Cr > 40 < 20 Renal failure index (RFI) < l > 2 FENa < l >2 Urinary sediment Normal Proteins, cells, casts urine Na+ urine Na+ /serum Na+ urine Cr/plasma Cr; urine Cr/plasma Cr RFI = FENa =
2) Diuresis phase If the patient pass through the oliguria phase safely, the tubular EC may regenerate and the renal function would recover gradually. An increasing urine volume is a signal of renal EC healing, and suggests the start-up of diuresis phase if it is more than 400 ml per day. After then, the urine volume increasing doubly up to 3-5L/day and may last about one month.
The mechanisms for diuresis including: a) The RBF & GFR recovered gradually while the reabsorption function of regenerating immature tubules keep on abnormal. b) The high level of metabolic products retained during the oliguria phase resulted in a hyperosmolarity diuretic effect. c) The tubular integrity recovered, interstitial edema subsided, the casts to be washed out and the tubular obstruction relieved.
During this stage, the excretion of urea and other nitrogenous compounds lags behind that of salt and water as reflected by the continual rise in the concentrations of these substances for several days after the onset of the diuresis. The reason is the incomplete recovery of GFR. Nevertheless, the tubular function also not well recovered, the kidney still work as a simple filter. Salt and water loss could occur and lead to dehydration, hypokalemia and hyponatremia.
Therefore, this stage is also considered to be a critical phase, and it has been pointed out that approximately 25 percent of the deaths in ARF occurred following the onset of the diuresis.
3) Recovery phase The improvement of renal function leads to a gradual reduction of BUN and correction of water, electrolytes and acid-base imbalance. The full recovery is depends on the healing of tubular ECs. This process may take up three months to one year. Unfortunately, not all individuals are restored to health and may become chronic renal failure due to serious damage of the renal tubular EC and the fibrosis of renal tissue.
(2) Nonoliguric type of ARF While oliguria is a hallmark of ARF, some patients will develop an acute lose of renal function without oliguria. The common cause of this type is renal toxic substances, especially the aminoglycoside antibiotics and radiography contrast agents. It is suggested that in such cases, GFR has not been reduced severely and might remain partial tubule function, but its ability of concentration is impaired. The urine volume may be more (about 400-1000ml / day) and the concentration of Na+ in urine may be lower, while azotemia is still existed.
The prognosis of which is better than that of oliguria type. It might be related to either a milder renal injury or fewer complications because of better water/ electrolyte and acid-base balance. However, both types may transform each other, the nonoliguria type will become oliguria type if having not pay attention and treat properly.
4. Principles of prevention and treatment (l) Etiologic treatment (shock, infection, DIC, kidney disease, recover renal perfusion, eliminate tubule obstruction, etc.) (2) Diuresis (osmolar diuretic: improving perfusion, excreting toxin and alleviating tubular obstruction) (3) Maintaining water and electrolytes balance, correcting hyperkalemia. (4) Dialysis (peritoneal dialysis or hemodialysis)
Summary for ARF Acute Renal Failure Intrarenal failure (parenchymal RF) Acute Tubular Necrosis Oliguria or anuria Retention of nitrogenous wastes (azotemia) water/electrolyte acid-base disturbance Acute Renal Failure Variouscauses Rapidly and severely decline of GFR Kidneys fail to excretion and regulation in hours to days Oliguria or anuria Retention of nitrogenous wastes (azotemia) water/electrolyte acid-base disturbance Acute Renal Failure Prerenal failure (functional RF) Intrarenal failure (parenchymal RF) Postrenal failure (Obstructive RF) Acute Tubular Necrosis
Summary for ARF Pathogenesis Toxin, Ischemia renal tubule injury Renal hemodynamic alteration Backleak of original urine into renal interstitium renal vasoconstriction Tubule obstruction renal perfusion effective filtration pressure Oliguria GFR glomerular Kf
Summary for ARF Clinical course and manifestation (l) Oliguria type of ARF phase phase phase diuresis recovery Oliguria hyperkalemia Metabolic acidosiswater intoxication Differences between functional and parenchymal ARF ( ) Urine specific gravity, osmolality, Na+, Cr , sediment (2) Nonoliguric type of ARF GFR has not been reduced severely and might remain partial tubule function, but its ability of concentration is impaired
Today’s question (l)What are the primary causes of death in oliguria type of ARF? Hyperkalemia;metabolic acidosis;water intoxication (2) How to differentiate the functional and parenchymal ARF INDEXES F - ARF P - ARF Urine specific gravity Urine Na+ Urine Cr / Plasma Cr Urinary sediment > l .020 < l .0l5 < 20 mmol / L > 40 mmol / L > 40 < 20 Normal Proteins, cells, casts
Section 3. Chronic Renal failure
CRF is characterized by progressive and irreversible loss of large numbers of functioning nephrons, which lead to a very significant reduction in GFR. The remnant nephron fail to excrete waste metabolic product and keep the constancy of internal environment. Various diseases(kidney or kidney-related diseases) progressive irreversible destruction of nephron Retention of waste metabolic products Water/electrolyte and acid-base imbalance Disturbance of renal endocrine CRF