1、Zhi-Qing Zhao, Ph.D.趙志青趙志青Department of Basic Biomedical SciencesMercer University School of Medicine1250 East 66th StreetSavannah, GA 31404, USAEmail: zhao_Renal Diseases, Renal Failureand Acid-Base Imbalance腎病，腎衰和酸堿平衡紊亂Consequences of Renal DiseasesAcute renal failureChronic renal failu

2、reDialysisKidney transplantationAcid-Base disorderPerfusion:Blood flowBlood pressure(prerenal)Obstruction:Kidney stoneProstateCancer(postrenal) Filtr/absorb:Glomerular/Tubulo-interstitial Diseases (intrarenal)Learning Objectives* Classification of renal diseases* Differentiation of nephrotic syndrom

3、e vs. nephritic syndrome * Pathogenesis of acute renal failure * Development of chronic renal failure, dialysis, and kidney transplantation* Regulation of acid-base balance * Acid-base imbalance (i.e., acidosis and alkalosis) Cause and Classification of Renal DiseasesC. Stone in ureters, bladderIII.

4、 Postrenal (urinary tract obstruction)(25% of cases) (5% of cases) (70% of cases) * The two major causes of reduced renal perfusion: Volume depletion (reduced volume of blood to the glomeruli) and/or relative hypotension* Prerenal disease is most commonly associated with an acute time course. * Howe

5、ver, among patients with chronic kidney disease, the addition of a prerenal process may result in acute renal dysfunctionPrerenal DiseasesRegulation of blood pressure by kidney(prerenal mechanism)GFR Mechanisms of Glomerulonephritis (intrarenal)ResolutionPersistent inflammationExit of anti-inflammat

6、ory molecules and leukocytesOn-offswitchScarringAntibody depositionCell-mediated immune mechanismsComplement activationInflux of circulating leukocytesGenetic factorCytokine or growth factor synthesisGenetic factorsGlomerulonephritisActivation of resident cellsChange in matrixHemodynamic alteration

7、Classification of Glomerular Nephropathy (GN）I） Primary G.N (the disease affects kidney only): Minimal change glomerular disease (Lipoid nephrosis) 類脂性腎病Acute diffuse proliferative GN Post-streptococcal GN 鏈球菌所導致的GNNon-post-streptococcal GN 非鏈球菌感染后腎小球腎炎Rapidly progressive GNMembraneous GN 膜性腎病Membra

8、noproliferative GN 增生性腎小球腎炎Chronic GNII） Secondary G.N (the disease affects kidney and other organs):Systemic lupus erythematosus (SLE) 全身性紅斑狼瘡Polyarteritis nodosa (PAN) 結(jié)節(jié)性多動脈炎Wegener granulomatosis 韋格納肉芽腫病Diabetes mellitus (diabeteic nephropathy) 糖尿病Goodpasture syndrome 肺出血腎炎綜合征Amyloidosis 淀粉樣變性8*

9、 Causes: Idiopathic and Secondary: neoplasia, autoimmune disease, drugs, infections. * Two general patterns (with considerable overlap in some diseases) are seen: Nephrotic pattern: Not associated with inflammation on histological examination: Proteinuria (moderate to severe . Most cases heavy prote

10、inuria). An inactive urine sediment with few RBCs &WBCs cells or casts. Nephritic pattern: Associated with inflammation on histological examination: active urine sediment with RBCs, WBCs, granular, red cell & other cellular casts Variable degree of proteinuria (mild to moderate in most cases

11、).Glomerular Diseases (intrrenal)Clinical Features of Glomerular Diseases (Nephrotic)Nephrotic syndrome（腎病綜合癥）（腎病綜合癥）Definition: Increased permeability of the glomerulus leading to loss of proteins into the tubules Etiology* Idiopathic nephrotic syndrome (90 %) - Minimal-change disease (75 %) - Foca

12、l sclerosis (10 %) - Mesangial proliferation (5 %)* Membranous nephropathy & Membranoproliferative glomerulonephritis (10 %) Characters and causes of pathological changesMassive proteinuria 蛋白尿 (= or 3.5g/24h)Hypoalbuminemia 低白蛋白血癥 (10mmol/L) Electron MicroscopyCapillary lumenElectron microscopy

13、 of a podocyte with its nucleus (red arrow) and foot Processes interdigitating with those of the adjacent podocyte.Membranes (毛細血管膜毛細血管膜)Here is a normal glomerulus with the membranes outlined even better than with PAS stain; this is stained with a type of silver stain used on renal biopsies。Here is

14、 a glomerulus with markedly thickened membranes, outlined and highlighted by that type of silver stain. This is from a case of membranous glomerulopathy. Here is a normal glomerulus stained with PAS, which outlines the membranes of the capillary loops better than the routine H&E stain.Here is a

15、glomerulus with thickened Membranes (think membranous glomerulopathy).Membranes (毛細血管膜毛細血管膜)Sclerosis (硬化硬化)Segmental sclerosis like this is most often due to the group of diseases called focal segmental glomerulo- sclerosis.Here is another example of segmental glomerulosclerosis (again just so happ

16、ening to involve the lower part of the glomerulus). Glomerular diseases Pathogenesis of Nephrotic syndrome Clinical Features of Glomerular Diseases (Nephritic) Nephritic syndrome （腎炎綜合癥）（腎炎綜合癥）Definition: Immune complex deposition by an infection in epithelial membrane or GBM that allow blood into t

17、he tubule.EtiologyIgA Nephropathy (Bergers disease)Post-infectious glomerulonephritisRapidly progressive glomerulonephritisProliferative glomerulonephritisSecondary glomerulonephritisGoodpasture syndromeCharacters and causes of pathological changesHematuria 血尿Oliguria 少尿Azotemia 氮血癥Hypertension 高血壓L

18、ocal immune pathways in glomerulonephritis (Nephritic)18Normal GlomerulusSize and Charge-selective barrierIn basement membrane and podocytic epitheliumHere is a glomerulus with a normalnumber of cells in it (normal cellularity)Here is a hypercellular glomerulus, with neutrophils infiltrating (acute

19、post-streptococcal glomerulonephritis):Cellularity (細胞性細胞性)Crescents (新月體新月體)Here are the crescents as outlined and seen in rapidly progressive glomerulonephritisElectron microscopy close-up of some foot processes, with red arrow to a slit diaphragmand the epithelial side of the basement membrane in

20、 the bottom part of the image.Here is a granular pattern of immuno- fluorescence; this is the most common pattern and is seen in multiple types of glomerular disease.Here is a linear pattern of immuno- fluorescence; this is seen in Goodpasture syndrome.Immunofluorescence (免疫熒光免疫熒光)This is a mesangia

21、l distribution of deposits, unlike the more common distribution in the capillary loops; mesangial distribution is seen in IgA nephropathy.Immunofluorescence (免疫熒光免疫熒光) Glomerular diseases Pathogenesis of Nephritic syndrome a.Cytotoxic complement factorsb.Chemotactic factorsc.Ischemia of glomeruliCla

22、ssification of Glomerular Diseases According to the EtiologyO nephroticI - nephriticTubulointerstitial DiseasesTubulointerstitial diseases may present as acute renal failure (ARF) and acute tubular necrosis (ATN) is, in fact, the most common cause of intrinsic ARF in adults. Tubular injury is charac

23、terized by abnormalities of solute transport. Tubulointerstitial disease may also progress insidiously and present in the late stages as chronic renal failure. During chronic progression to renal failure, the patient may manifest findings (sometimes subtle).TubulesTubulointerstitial DiseasesClinical

24、 manifestations: Acute tubular necrosis Acute pyelonephritis 急性腎盂腎炎 Chronic pyelonephritis Drug-induced interstitial nephritisCauses: Drugs, heavy metals, obstructive uropathy, nephrolithiasis, immunologic diseases, neoplasia, atherosclerotic kidney disease (ischemic), metabolic diseases, genetics.

25、Lab values: Eosinophilia (50% patients) 嗜伊紅血球過多 Urinalysis: (proteinuria, hematuria, casts, WBCs, eosinophils and crystals.Gross Pathology:1) Enlarged up to 30% over normal2) Pale cortex3) Congested medulla, especially at cortico- medullary junctionAcute Tubular NecrosisGranular eosinophilic cytopla

26、sm in normal tubulesBlebbing of luminal side cell membrane in tubules after ATNBlebbing of luminal side Acute Tubular Necrosis: Microscopic FindingsDiffuse edema of tubular cells (vacuolization of cytoplasm, early ischemic change)Loss of brush borders and flattening of epitheliumAcute Tubular Necros

27、is: Microscopic FindingsNecrosis & sloughing of epithelial cells mixing with castsCasts of acute tubular necrosis areflushed out and degenerate into pigmented, brownish granular castsAcute Tubular Necrosis: Microscopic FindingsAcute Renal Failure (ARF) Acute kidney injury (AKI) Acute tubular nec

28、rosis (ATN)- Define acute renal failure- Explain the causes of ARF- Differentiate between the three types of ARF- Identify the clinical stages of ARF- Discuss the clinical manifestations of ARF- List the complications of ARF- Develop a plan for managing ARFAcute Renal Failure (ARF)* Definition: Sudd

29、en deterioration in the ability of the kidneys to function (to maintain fluid, solute or electrolyte homeostasis). It occurs over hours or few days. * Characterized by: - A rapid decrease in GFR 10 mL/min or normal) levels.* Associated with: - Classic finding of oliguria (UO 400 ml/day); but may hav

30、e normal to increase UO. - Fluid, electrolyte and acid-base imbalances (metabolic acidosis)* Usually reversible with prompt treatmentCause and Location of ARF Acute renal failure is often classified according to location of the initial insult: Prerenal: (volume depletion, drug-induced: ACEI, Diureti

31、cs) - Before the kidneys; blood flow to kidneys - Occurs in about 55-60% of all ARF casesIntrarenal (inflammatory disease: vasculitis, glomerulonephritis, acute tubular necrosis, drug-induced) - Within the kidneys; actual damage to the filtering structures of the kidneys - Occurs in about 35-40% of

32、all ARF casesPostrenal (obstruction, cancer, congenital abnormalities) - After kidney, obstruction of urinary excretion - Occurs in about 5% of all ARF cases PrerenalIntrarenalPostrenalPrerenal ARF It occurs when renal blood flow is decreased before reaching the kidney, causing ischemia of nephrons.

33、 Renal perfusion = GFR leading to oliguriaCommon causes:Hypotension (severe and abrupt), Hypovolemia, Low cardiac output statesDiagnosis of Prerenal ARF:Urine sediment (usually normal, without cellular elements or abnormal casts, unless chronic kidney disease is present)Urine Na 20 in ATN)Urine/plas

34、ma creatinine 20 (15 in ATN)Fractional Excretion of Na (FeNa) 1% in ATN)Urine Na/K 20 is typical, BUN is not specific to prerenal ARFIntrarenal ARFIt occurs when there is actual damage to the renal tissue, resulting in malfunction of the nephrons.Acute tubular necrosis (ATN) Damage to the renal tubu

35、les characterized by varying degrees of cellular damage or death.- Ischemic: Renal trauma, massive hemorrhage or post-surgery- Nephrotoxic: i. v. contrast dyes, heavy metals or antibioticsTreatment: Immediate treatment to increase renal blood flow and minimize damage. Not always reversible; may lead

36、 to CRF.Ischemic Acute Renal Failure1) Definition: Onset of ARF in the aftermath ofrelatively modest hypotensive events2) Morphology Sporadic foci of tubular necrosis ( Tubular obstruction Renal vasoconstriction (2 obstruction)4) Course: Reversibility is its hallmarkPathogenesis of Ischemic Acute Re

37、nal FailurePostrenal ARFOccurs as a result of conditions that block urine flow distal to kidneys, resulting in urine to backing-up into the kidneys.Caused by a bilateral obstruction of the ureters or a bladder outlet obstruction.- Calculi (stones)- Tumors or masses- Blood clots- Benign prostate hype

38、rtrophy (BPH) Oliguria or Anuria ( 100 ml/day). Treatment to correct cause, if not corrected, it may lead to permanent renal damage. Assessment of ARF* Morphologic Evaluation - Histology (renal biopsy) - Electron microscopy of the kidney* Urinalysis - Proteinuria - indicates glomerular damage - Glyc

39、osuria - indicates tubular damage - Urine volume and osmolarity - Urine pH, glucose, gravity - indicates tubular damage - Microscopic examination - casts, crystals, bacteria, etc.* Blood Chemistries - Creatinine and blood urea nitrogen (BUN) for GFR - Electrolytes - Ca, K, CI, Mg - Clearance of p-am

40、inohippuric acid for filtration and secretion Relationship between BUN or creatinine and % functional nephrons is a “rectangular hyperbola”- Large changes in GFR “early” in renal disease cause small changes in BUN or creatinine- Small changes in GFR late in renal disease cause big changes in BUN or

41、serum creatinineStaging System for Acute Kidney InjuryARF: Signs and SymptomsHyperkalemia 高血鉀Nausea/Vomiting 惡心/ 嘔吐HTN 高血壓Pulmonary edema 肺水腫Ascites 腹水Asterixis 撲翼樣震顫Encephalopathy 腦病Early Clinical Manifestations of ARF Symptoms depend on degree and cause of renal failure Initial Symptoms: Fatigue a

42、nd malaise - Loss of excretory capacity and accumulation of water, electrolytes and nitrogenous wastes- Prerenal azotemia: Elevated BUN/ creatinine (20-30:1) with normal creatinine- Urinalysis: No casts detected- Increased urinary osmolality depending upon the type of ARF from 350 to 1500 mOsm/L- Fr

43、actional urine Na excretion (99%)- pH, HCO3 and pCO2 lowPhases of Acute Renal Failure Clinical progression of reversible RF occurs in four phases:Initiation phase- Begins with initial insult and ends when oliguria developsOliguric phase - Accompanied by rise in serum concentrations of substances usu

44、ally excreted by kidneys (urea, creatinine, organic acids, intracellular cations K+ & Mg)- Urinary output tubular atrophy, interstitial fibrosis, and long-term CKD.* If ARF is massive or superimposed on CKD, injured tubules heal poorly and cause severe scarring with loss of peritubular capillari

45、es = salt-sensitive hypertension.* Hypertension = damages glomeruli* Episodes of ARF (usually acute tubular necrosis) often lead, eventually, to CRF * Over time, combinations of acute renal insults are additive and lead to CRF * The definition of CRF requires that at least 3 months of renal failure

46、have occurred * Causes of Acute Renal Failure (ARF) a. Prerenal azotemia - renal hypoperfusion, usually with acute tubular necrosis b. Intrinsic Renal Disease, usually glomerular disease c. Postrenal azotemia - obstruction of some type Etiology of CKDChronic Renal Failure (CRF)* Occurs when compensa

47、tory mechanisms of the diseased kidneys are no longer able to maintain the excretory, regulatory and endocrine functions of the kidneys.* Result in retention of nitrogenous solutes, derangements of fluid, electrolyte and acid-base balance and failure of hormone production.Etiology of Chronic Kidney

48、DiseasesDiabetes mellitusHypertensionGlomerulonephritis and polycystic kidney disease Use of analgesics AtherosclerosisObstruction of the urine flowChronic Kidney DiseasesChronic Renal Failure End-Stage Renal DiseaseTransplantationGlomerular Filtration Rate (GFR)- Best index of kidney function- Used

49、 to establish stage of CRF- GFR is the amount of filtrate formed per minute based on total surface area available for filtration (number of functioning glomeruli)- Can be determined using injected isotope (inulin) measurement in urine- Can be calculated from serum creatinine using standard equations

50、Structural or functional abnormalities of the kidneys for 3 months, as manifested by either:1. Kidney damage as defined by- pathologic abnormalities- markers of kidney damage, including abnormalities in the composition of the blood or urine or in imaging tests2. GFR 60 ml/min/1.73 m2, with or withou

51、t kidney damageDefinition of CRFNephrons are destroyed and replaced with scar tissue; remaining nephrons become hypertrophied and eventually fail to function.GFR and Creatinine (Cr)* Chronic renal disease is found in person of all ages. * GFR is estimated by a serum creatinine value and reduces over

52、 age:- 25-year-old man in a 70-kg: Cr 1.2 mg/dl represents estimated GFR 74 ml/min 1.73 m2 - 80-year-old man in a 70-kg: Cr 1.2 mg/dl represents estimated GFR 58 ml/min 1.73 m2 Stage I(pre-failure)Stage II(mild failure)Stage III(moderate failure)Stage IV(severe failure)5* Staging criteria based on c

53、reatinine value (mg/dl) in CRF.Stages of CRFStage 1:- Reduced renal reserve, characterized by a loss of 40-75% of nephron function (GFR 90 mL/min/1.73 m2).- Usually asymptomatic; remaining function nephrons are able to maintain balance for Na, K, and water. Diagnosis is based on tests of blood and u

54、rine. Stage 2:- Renal insufficiency, characterized by a 75-90% loss of nephron function (GFR 60-89 mL/min/1.73 m2). - Clinical Manifestations:* Serum creatinine and BUN* Kidneys loose ability to concentrate urine* Client may report polyuria and nocturia.Stages of CRF Cont., Stage 3: End-Stage Renal

55、Disease (ESRD)- Final Stage: characterized by 90% loss of nephron function (GFR, 30-59 mL/min/1.73 m2).- Clinical manifestations: * Serum Creatinine & BUN * Electrolyte imbalances* Uremia affecting all body systemsStage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2) andpreparation for renal r

56、eplacement therapy.Stage 5:Established kidney failure (GFR 90Tx comorbid conditions. Slow progression. CVD risk reduction2. Mild decrease in GFR60-89Estimating progression3. Moderate decrease in GFR30-59Evaluating, treating complications4. Severe decrease in GFR15-29Prepare for kidney replacement tx

57、5. Kidney failure20:1100:1Prerenal (before the kidney)BUN reabsorption is increased. BUN is disproportionately elevated relative to creatinine in serum. Dehydration or hypoperfusion is suspected.10-20:140-100:1Normal or Postrenal (after the kidney)Normal range. Can also be postrenal disease. BUN rea

58、bsorption is within normal limits.10:1 160 mEq/L) occurs with decreased renal excretion of sodium in the end stages of renal disease. Hyperkalemia and HypokalemiaHyperkalemia(serum K 5.0 mM/L)Hypokalemia(serum K CO2 + H2O (HCO3- / CO2 in ECF)Oxidation of sulfhydryl groups - sulfuric acid methionine,

59、 cysteine - CO2 + H2O + urea + H2SO4 Hydrolysis of phosphoester acid - phosphoric acidOxidation of neutral dietary precursors - organic acids glucose - lactic acid, pyruvic acid triglycerides - acetoacetic acid, -OH butyric acid nucleoproteins - uric acidOxidation of organic cations yielding hydroge

60、n ions R-NH3+ - CO2 + H2O + urea + H+Oxidation of organic anions yielding bicarbonate / R-COO- + H2CO3 - CO2 + H2O + urea + HCO3-Hydrolysis of phosphoester salts yielding bicarbonateVolatile acid - can leave solution and enter the atmosphere (e.g. carbonic acid) - most important factor affecting pH of ECFCO2 + H2O H2CO3 H+ +