Chronic Kidney Disease Pathophysiological and clinical considerations 腎臟科 CBL教材

OUTLINES I. INTRODUCTION: II. Definition of CKD(CRD) and ESRD III. Pathophysiology of Chronic Renal Disease IV. Stages of Chronic Renal Disease V. Pathophysiology and Biochemistry of Uremia VI. Clinical and Laboratory Manifestations of Chronic Renal Failure and Uremia 1). Fluid, Electrolyte, and Acid-Base Disorders: 2). Endocrine-Metabolic Disturbances 3). Neuromuscular Disturbances 4). Cardiovascular and Pulmonary Disturbances 5). Dermatologic Disturbances 6). Gastrointestinal Disturbances 7). Hematologic and Immunologic Disturbances VII. Evaluation and Management of Patients with Chronic Renal Disease

Introduction-1 由於國人飲食習慣與生活習慣不當、不當用藥、馬兜鈴酸、重金屬以及各種有毒物質的影響，加上人口老化、健康照護改善，高齡人口目逐年增加，以致於目前有超過五萬名尿毒症患者接受透析治療。而值得注意的是，目前這些已接受治療的尿毒症患者只是冰山之一角，據臨床經驗與資料顯示，粗估國人目前約有二百萬人已罹患慢性腎臟病。 腎臟病是一個隱形殺手，往往到了末期才產生明顯症狀，因此許多民眾已罹患“慢性腎臟病”卻渾然不知。慢性腎臟病(CKD)分為五期，前二期除了尿液及抽血檢驗外，臨床上並無明顯症狀， 進入慢性腎臟病(CKD)第三、四期的病患，再不注意健康維護，下一階段就是進入第五期的末期腎衰竭需洗腎階段，因此提醒您應該隨時注意自己是否已有「準尿毒症狀態」，所謂「準尿毒症狀態」的臨床表現，簡單來講就是「泡水高貧倦」-泡泡尿(蛋白尿)、水腫、高血壓、貧血與倦怠等五症狀，如果發現有上述五項症狀，而且原因不明，應該立即找腎臟專科醫師，進行詳細的腎臟功能檢查。

Introduction-2 另外，針對洗腎的六大高危險群-糖尿病、高血壓、老年人(>65歲)、蛋白尿、有腎臟病家族史、長期服用藥物者，如果現在還沒有腎臟功能不良的警訊出現，也應該「每三個月檢查尿液，血壓及血肌酐酸等三項」我們簡稱為「護腎檢查三三制」，可以提早發現問題，確保健康。 至於腎臟保健方面，飲食應該三少：少糖、少鹽、少油，同時要三多：多吃蔬菜、纖維、常喝水，生活習慣要四不一沒有：不熬夜、不憋尿、不隨便服來路不明的藥物、不抽菸，同時避免鮪魚肚，因為鮪魚肚代表可能罹患糖尿病，糖尿病又是引發尿毒症的主要原因之一。國內尿毒症發生率居高不下，可能與社會進步、糖尿病人口增加，及國人愛吃藥習慣有關，長期服用止痛藥或服用含有馬兜鈴酸的中藥，都會引發腎病變造成尿毒症。 隨著醫療的進步，新藥的研發，目前已知有藥物可以延緩慢性腎臟病之進程。如果你是六大腎臟病高危險群﹙糖尿病、高血壓、老年人、蛋白尿、有腎臟病家族史、長期服用藥物者﹚的朋友，若是能夠早期發現腎功能的變化，並提早做治療，可以避免步向「洗腎(透析治療)」之路，希望預防勝於治療的腎臟保健觀念，真正落實於我們的生活之中。

「泡水高屏見」 在初期腎功能喪失不多時，病患本身不會有任何不適，甚至抽血檢驗腎功能（肌酸酐）也不見得有異常，因此早期發現腎臟的疾病可藉由尿液檢查。如果小便有泡沫且久久不能散去，尿液常規證實有蛋白尿時即可診斷腎臟疾病，除了蛋白尿外，常見腎臟疾病的症狀有： 水腫：以下肢、眼瞼水腫為主，甚至全身浮腫也有可能，體重在短時間內急遽增加，小便量可能會減少。 高血壓：百分之三十的早期腎功能衰竭的病人有高血壓的症狀，所以高血壓的病人一定要檢查腎功能及蛋白尿以排除腎性高血壓。 貧血：腎功能衰退至正常的三分之一時，輕度貧血就會出現，若衰退至正常的四分之一時，嚴重貧血即可導致食慾不振、疲倦、無力等症狀。 疲倦：大多數疲倦的病人都以為是肝臟機能不佳而求診肝膽腸胃科，經過肝臟超音波、胃鏡、大腸鏡、抽血檢驗肝指數均正常，最後才診斷是慢性腎衰竭、貧血而轉診至腎臟內科醫師。 總之，慢性腎衰竭的症狀千奇百怪，但民眾可以記住一口訣：泡（蛋白尿）、水（水腫）、高（高血壓）、屏（貧血）、見（倦，疲倦），亦即「泡水高屏見」，就可以掌握腎臟是否出了問題，以期盡早診斷和治療。

Definition of CKD Definition: CKD is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function and frequently leading to end-stage renal disease (ESRD). ESRD: an irreversible loss of endogenous renal function, patient permanently depends upon renal replacement therapy [ dialysis（HD and PD) or transplantation], to avoid life-threatening uremia.

Pathophysiology of CKD Initiating mechanisms to the underlying etiology  long term reduction of renal mass  causes structural and functional hypertrophy of surviving nephrons  mediated by vasoactive molecules, cytokines, and growth factors  initially to adaptive hyperfiltration  mediated by in glomerular capillary pressure and flow  maladaptive  predispose to sclerosis of the remaining viable nephron population

Pathophysiology of CKD Increased intra-renal activity of the renin-angiotensin axis plays an important role on the pathophysiology of CRD. Definition of CRD: pathophysiologic process described above last more than 3 months. Factors that increase the risk for CRD: family history of heritable renal disease, hypertension, diabetes, autoimmune disease, older age, past episode of acute renal failure, and current evidence of kidney damage with normal or even increased GFR

Pathophysiology of CKD Albuminuria: a key adjunctive tool for monitoring nephron injury and response to therapy in many forms of CRD. Measurement of albumin-to-creatinine ratio in a spot first morning urine sample: Persistence of > 17 mg albumin per gram of creatinine (alb./Cr:>17mg/gm) in adult males and 25 mg albumin per gram of creatinine (alb./Cr:>25mg/gm) in adult females usually signifies chronic renal damage.

CCr = Cr (U) x urine amount(one day) 1440 x Cr (P)

Pathophysiology of CKD Stages 3 and 4 of CRD: anemia, loss of energy, decreasing appetite, disturbances in nutritional status, abnormalities in calcium and phosphate metabolism accompanied by metabolic bone disease, abnormalities in sodium, water, potassium, and acid-base homeostasis. Stage 5(GFR<15 mL/min): severe disturbances in their daily activities, sense of well-being, nutritional status, water and electrolyte homeostatis

Pathophysiology and Biochemistry of Uremia Azotemia: retention of nitrogenous waste products Uremia: more advanced stages of CRD when the complex, multiorgan system derangements become clinically manifest. Middle molecules: a molecular mass of 500~12000 Da; are believed to contribute to mortality and morbidity in uremic subjects.

Pathophysiology and Biochemistry of Uremia Uremic syndrome: two sets of abnormalities: The accumulation of products of protein metabolism. The loss of other renal functions, such as fluid and electrolyte homeostasis and hormonal abnormalities.

Causes of chronic kidney diseases

Laboratory investigations of CKD

Clinical and Laboratory Manifestations of CRF and Uremia Fluid, Electrolyte, and Acid-Base disorders: Endocrine-metabolic disturbances: Neuromuscular disturbances: Cardiovascular and pulmonary disturbances: Dermatologic disturbances: Gastrointestinal disturbances: Hematologic and Immunologic disturbances:

Fluid, Electrolyte, and Acid-Base disorders: Volume expansion and contraction Hypernatremia and hyponatremia Hyperkalemia and hypokalemia Metabolic acidosis Hyperphosphatemia Hypocalcemia

Hyperkalemia Clinical situations cause hyperkalemia: Constipation Augmented dietary intake Protein catabolism Hemolysis Hemorrhage Transfusion of stored red blood cells Metabolic acidosis Following the exposure to a variety of medications that inhibit K+ entry into cells or K+ secretion in the distal nephron(beta-blockers, ACEI, ARB, NSAID, K+-sparing diuretics, etc)

Hematologic and Immunologic disturbances: Anemia Lymphocytopenia Bleeding diathesis Increased susceptibility to infection Splenomegaly and hypersplenism Leukopenia Hypocomplementemia

Evaluation of Patients with CKD Initial approach: History and Physical Examination Laboratory Investigations Imaging Studies Renal Biopsy Establishing the Diagnosis and Etiology of CKD

Management of Patients with CKD

Slowing the progression of CKD

Strategies to slowing down the progression of CKD A: Education: No smoking, no alcohol On low salt, low protein diet Avoid nephrotoxic agents and unnecessary drugs Obesity reduce body weight: close to IBW B: Medication: Use of ACEI, ARB etc Control BP Control sugar Control dyslipidemia Pentoxifyllin use[slow down(prevent) renal fibrosis] Ketosteril use(reduce urea production, reduce urea to kidney burden, improve nutrition status, and improve immunity) Kremezin (Spherical Adsorptive Carbon)

Managing Other Complications of CKD Uremic Symptomatology Medication Dose Adjustment Preparation for Renal Replacement Therapy Patient Education and Adjustment

腎臟替代性療法 Renal replacement therapy 血液透析(Hemodialysis) 間歇性 Hemodialysis(HD)血液透析 Hemofiltration(HF)血液過濾 Hemodiafiltration(HDF)血液透析過濾 Hemoperfusion(HP)血液灌洗 混合型 Hybrid Extended daily dialysis (EDD) Sustained low-efficiency dialysis (SLED) Sustained low-efficiency daily diafiltration (SLEDD-f) 連續性(Continuous renal replacement therapy, CRRT) 腹膜透析(Peritoneal dialysis) 腎移植(Renal transplantation)

◎血液透析的原理 擴散作用 (Diffusion) 對流作用 (Convection) 超過濾作用 (Ultrafiltration)

擴散作用 擴散: a ionic transport driven by a difference of concentration

對流及超過濾作用 對流: a filtration issued from a pressure difference 水 +溶質

透析之溶質清除機制(1) 擴散作用 Diffusion 對流作用 Convection There are a number of key scientific principles used to accomplish the goals of CRRT. They are listed here and before we discuss the individual therapies, I would like to review them. Understanding the principles of diffusion, ultrafiltration, convection and adsorption will clarify which therapy will best produce the desired outcome whether used alone or in combination.

透析之溶質清除機制(2) 有些膜材料帶有吸附特性 As you can see with our cups, a semipermeable membrane separates a concentrated solution from a solution with no solute. In this diagram, very little solute actually passes through the membrane, instead, it adheres to the membrane. Movement of fluid is required for adsorption to occur. Not all membranes possess this adsorptive quality and it is necessary to identify specific properties of the membrane and target molecules in order to predict whether adsorption will play a role in the clearance of a specific substance. 有些膜材料帶有吸附特性

透析之液體清除機制 超過濾作用-Ultrafiltration This slide illustrates the process of ultrafiltration. We now have two cups of fluid. Each cup contains two compartments separated by a semipermeable membrane. The cup on the left illustrates how the exertion of a positive pressure on the left compartment will PUSH fluid from that compartment to the one on the right. Similarly, looking at the cup on the right side of the slide, a negative pressure applied to the right compartment will PULL fluid from the compartment on the left into that on the right. How does this work in continuous therapies? 因壓力梯度差造成的液體移動

分子尺寸 - 原理的考量 目標移除分子的大小: “大分子" “中分子" “小分子" 白蛋白 (Albumin) 球蛋白 (Globulin) 菊澱粉 (Insulin) 尿毒 (Ureic Toxics) Beta2-microglobulin “小分子" 水 (Water) 塩 (鈉, Chlore, 鉀 …) 對流作用 Convection 擴散作用 Diffusion

HD Order =Diagnosis □ESRD on regular HD，□Acute on Chronic renal failure，□Chronic renal failure in uremic stage□ARF with associated symptom/sign: uremic symptom，hyperkalemia，fluid overload，metabolic acidosis，oliguria =Frequency □QW135 □QW246 □QW15 □QW26 □_________ =Dialyzer □KF18C □FB170G □FB210G =Dialysate □No.8 □No.9 □No.10 □No.11 □K+ modification: meq =Duration □4hrs □2.5hrs × 1 then 3hrs × 2 then 4hrs =Access □Right □Left □Femoral □Neck □Double lumen catheter □AV Fistula □Gortex □Hickman catheter =Blood Flow rate □200〜250ml/min □150ml/min x 3 then 200〜250ml/min □150ml/min x 1 then 180ml/min x 2 then 200〜250ml/min =Ultrafiltration(UF) □Nature □ __〜 _Kg =Dry weight _______Kg =Mannitol □150ml IVF x 3 times =Transfusion □PRBC ____U □FFP____U □Primin □During H/D =Heparin □Free □Drained out □loading dose: ____ IU/hr，maintenance dose: ____ IU/hr; Fraxiparin: loading: _____ ml

本院目前使用的透析濃縮液品項 品名 Na K Ca Mg Cl CH3COO¯ HCO3¯ Dextrose NO.8 75.00 2.0 3.5 1 81.50 5 - 200 NO.9 2.5 80.50 100 NO.10 74.94 3.0 80.94 NO.11

AV Graft (Gortex)

AV Fistula (native)

Tunneled cuffed catheter (Hickman, Permcath)

Double lumen catheter

Peritoneal dialysis (Tenckhoff) catheter

腹膜透析液 Dianeal Physioneal Extraneal Nutrineal 電解質 Na(mmol/l) 132 Ca(mEq/l) 2.5/3.5 2.5 3.5 Mg(mmol/l) 0.25 Cl(mmol/l) 95 96 105 緩衝劑 Bicarbonate (mmol/l) 15 Lactate 40 25 pH 5.4 7.4 5.8 6.7 Glucose (%) 1.5/2.5/4.25 7.5% Icodextrin 1.1% Amino acid Osmolality (mOsmol/l) 346/396/485 284 365

Renal Transplant