Nephrology Lecture 6 PDF

FACULTY of MEDICINE in ENGLISH LECTURE 6 CHRONIC KIDNEY DISEASE (CKD) Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 08th of January 2025...

FACULTY of MEDICINE in ENGLISH LECTURE 6 CHRONIC KIDNEY DISEASE (CKD) Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 08th of January 2025 Pentru uz intern Este interzisă copierea și distribuirea neautorizată a acestui material. At the end of this lecture, participants will be able to: - IDENTIFY PATIENTS WITH CHRONIC KIDNEY DISEASE; - DIFFERENTIATE THE ETIOLOGY OF CHRONIC KIDNEY DISEASE; - DISCOVER AND THREAT THE COMPLICATIONS OF CHRONIC KIDNEY DISEASE.  Definition CHRONIC KIDNEY DISEASE (CKD) - CKD is defined as abnormalities of the structure or function of the kidney, which persist for more than 3 months and influence the health status of the patients; Medicina 2021, 57, x FOR PEER REVIEW 2 of 12 - The complex of clinical Medicina 2021, 57, 422 and biological manifestations occurring as a result of guidelines are emphasizing the need for effective preventative measures, early detection, 2 of 13 progressive and irreversible and treatmentdestruction of CKD [3,7]. of nephrons. Chronic Kidney Disease Temporal criteria over 3 months Functional criteria Structural criteria eGFR < 60 mL/min/1.73m2 kidney damage Mihai Ciprian Stoica, Zsolt Gall, Mirela Liana Gliga, Carmen Denise Căldăraru, Orsolya Szekely. Oral1. Figure Figure anticoagulant 1.Diagnostic Diagnostictreatment in forpatients criteriafor criteria CKD. with atrial fibrilation and chronic kidney disease. CKD. Medicina 2021;57(5):422 Table1.1.The Table Thestages stagesofofchronic chronickidney disease1.1. kidneydisease eGFR (mL/min/1.73 CKD CKD eGFR (mL/min/1.73 m2 ) A1 > 300 A3 300 mg/g mg/g 3 m2) Stage 1 Stage 1 >90 >90 A0 A0 A1 A1 A2 A2 Stage 2 60–89 A0 A1 A2 Stage 2 60–89 A0 A1 A2 Stage 3a 45–59 A1 A2 A3 Stage 3a 45–59 A1 A2 A3 Stage 3b 30–44 A2 A3 A3  Plate 10-9 HEMODIALYSIS Indications Metabolic acidosis that is refractory to medical treatm Electrolyte abnormalities, such as hyperkalemia, tha Intoxication with dialysable drugs (e.g., salicylates, l Volume overload that is refractory to diuretics Uremia and its complications (encephalopathy, peri END STAGE KIDNEY DISEASE (ESKD) In patients with chronic kidney disease: Glomerular filtration rate !10–15 mL/min/1.73m2 Weight loss, anorexia, loss of appetite HEMODIALYSIS, PERITONEAL Any of the sequelae of impaired renal function listed DIALYSIS, AND CONTINUOUS THERAPIES Normal saline - The late stage of chronic renal failure When kidney dysfunction is severe enough to cause homeostatic abnormalities that cannot be corrected Hollow fiber machine or flu dialyzer cartridge in which, without replacement with diet or medications, dialysis is performed to arti- ficially replace the kidney’s major functions. The major goals of dialysis are to support the elimination of treatment of renal function or renal nitrogenous waste products, restore fluid and electro- lyte homeostasis, and restore normal plasma pH. The transplantation, survival the patient is major indications are listed in the plate. impossible. PRINCIPLES OF DIALYSIS Dialysis employs a semipermeable membrane to alter - Such patients the ofhave the membrane,glomerular composition of blood. Blood is located on one side whereas a wash solution, known as the dialysate, is on the opposite side. The objective is Dialysate bath filtration rate (GFR) below to the blood15andml/min. for the desirable electrolytes to move from the dialysate for the undesirable electrolytes to Structure of move in the opposite direction. The movement of fluid The Netter Collection of Medical Ilustrations: Urinary System, Vascular access, and solutes across the membrane depends on two physi- Volume 5, Elsevier, Second Edition, 2012. preferably via cal forces: diffusion and convection. arteriovenous In diffusion, solute transport is directly dependent on Dialysate exits fistula the concentration gradient of the solute, diffusivity of the solute, permeability of the membrane, and surface area across the membrane. The smaller the molecule, the more rapidly it will diffuse. Molecules continue Fluid and larg Direction of blood flow Direction of dialysate flow to move across the membrane until equilibrium is molecules achieved. ultrafiltered In convection, solutes are dragged across a mem- into dialysate brane in the solvent that contains them. An analogy would be an ocean wave (the solvent) pushing sea shells Small molecu (the solute) onto the shore. The solvent carrying these exchanged solutes crosses the membrane in a process known as between bloo and dialysate ultrafiltration, which depends on the pressure gradients because of across the membrane. Diffusion is more efficient at clearing small molecu- 4 diffusion lar weight substances (less than 500 Da), such as elec- K+, Pi, trolytes. In contrast, convection is more efficient at nitrogenous  CHRONIC KIDNEY DISEASE (CKD) Indicators of kidney damage - albuminuria > 30 mg/day (proteinuria > 150 mg/day); - urinary sediment abnormalities (red blood cells, red blood cell casts); - electrolyte, acid-base, metabolic anomalies due to the dysfunction of the renal tubes; - histological lesions of the kidney (kidney biopsy); - structural lesions of the kidney diagnosed by imaging examinations (morphological asymmetry, hyperechogenicity, nephrocalcinosis, contour irregularities, cystic diseases, hydronephrosis); - history of kidney transplantation. 5  - Diabetes CHRONIC KIDNEY DISEASE (CKD) - Hypertension - Cardiovascular diseases - Systemic diseases that can affect the kidney (systemic lupus erythematosus) Conditions associated with an - Structural diseases of the kidney, lithiasis, increased risk of CKD prostate hypertrophy - History of AKI - Weight under 2.5 kg at birth - First degree relatives under replacement treatment of renal function or with hereditary kidney diseases - Chronic exposure to nephrotoxic drugs (NSAIDs) 6  Prevalence of CKD CKD has an elevated global prevalence, consistently estimated at between 11% and 15%, with the majority at stage 3. At least 1 person in 10 suffers from CKD. CKD is a public health problem, along with its main causes: diabetes and hypertension. CKD stage Age in years (% of population affected) 300 mg/24 hr) and hypertension after 20 weeks of gestation in a previously normotensive woman. normal blood pressure Ada of p Prac hemodynamic effect, reduce CKD progression and improve cardiovascular Preeclampsia superimposed on chronic hypertension is defined as the appearance of proteinuria after 20 of O Gyn prognosis. weeks of gestation. If both hypertension and proteinuria Potential mechanism of disease pathogenesis exist before 20 weeks of gestation, preeclampsia is defined as a worsening of the hypertension to systolic - The ACEI and ARB association does not significantly improve renal or blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg or more after 20 weeks of gestation. cardiovascular risk and is burdened by the increased risk of adverse effects In most cases, preeclampsia occurs in the third tri- mester, although it may occur earlier in a patient with (hyperkalemia and AKI). underlying renal disease. It is classified as either “mild” or “severe”; criteria for upstaging to severe preeclamp- sia are listed in the figure. PATHOPHYSIOLOGY Release of sFlt-1 Despite intense research, the pathogenesis of pre- 26 eclampsia remains poorly understood. Current evi- dence, however, suggests there is abnormal remodeling  Plate 4-58 CLINICAL DEFINITION AND POTENTIAL MECHANISM OF PATHOGENES PREECLAMPSIA Clinical definition Pre-e The Netter “sev In normal pregnancy, blood pressure declines in the are a MANAGEMENT OF CKD first trimester because of a drop in peripheral vascular resistance, despite a marked increase in blood volume Collection of Medical SB and cardiac output. Hypertension during pregnancy, Ilustrations: tw Urinary defined as systolic blood pressure ≥140 mm Hg or dia- ap System, ! stolic pressure ≥90 mm Hg, is a major complication Volume 5, ur associated with a mortality rate of nearly 20% world- Renoprotection - Blood pressure wide. It may be due to: Chronic, preexisting hypertension Elsevier, Second O sa p and proteinuria control Gestational hypertension, which occurs after 20 weeks of pregnancy in a previously normotensive Edition, 2012. Hypertension Proteinuria C Pu woman SBP !140 or ! 300 mg of protein Ep DBP ! 90 after qu Preeclampsia or eclampsia excreted per 24 hours Tr Preeclampsia superimposed on chronic twenty weeks after twenty weeks of of pregnancy n - The treatment starts with the minimum dose, which can be gradually hypertension Preeclampsia, a severe complication that occurs in in a woman with previously pregnancy Th Fe increased, under control 7 days after initiation or dose change (serum 5% of pregnancies, is defined as the development of proteinuria (> 300 mg/24 hr) and hypertension after 20 normal blood pressure Adapte of pree creatinine, ionogram). weeks of gestation in a previously normotensive woman. Preeclampsia superimposed on chronic hypertension Practice of Obst is defined as the appearance of proteinuria after 20 Gyneco - In advanced stages of CKD, those dually metabolized (both by the kidneys and weeks of gestation. If both hypertension and proteinuria Potential mechanism of disease pathogenesis exist before 20 weeks of gestation, preeclampsia is the liver), fosinopril, trandalopril can be used. defined as a worsening of the hypertension to systolic blood pressure ≥160 mm Hg or diastolic blood pressure - Patients should be instructed to temporarily stop (2-3 days) ACEI/ARB in ≥110 mm Hg or more after 20 weeks of gestation. In most cases, preeclampsia occurs in the third tri- clinical situations with a risk of dehydration (fever, diarrhea, vomiting, mester, although it may occur earlier in a patient with underlying renal disease. It is classified as either “mild” enema/laxative preparation for colonoscopy) or before examinations with or “severe”; criteria for upstaging to severe preeclamp- sia are listed in the figure. contrast substances. PATHOPHYSIOLOGY Release of sFlt-1 Despite intense research, the pathogenesis of pre- eclampsia remains poorly understood. Current evi- dence, however, suggests there is abnormal remodeling of the uterine spiral arteries, and that the resulting placental ischemia triggers release of antiangiogenic substances that increase blood pressure and cause 27 diffuse endothelial dysfunction. In the glomerulus, endothelial dysfunction leads to proteinuria.  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTITI MANAGEMENT NEPHRITIS OF CKD Major causes The Netter Renoprotection - Blood pressure and Tubulointerstitial nephritis can be divided into acute Collection of Medical proteinuria control and chronic forms. Acute interstitial nephritis (AIN, Ilustrations : Urinary see Plate 4-28) is typically associated with more severeSystem, insults, which cause a rapid decline in renal function - Diuretics are usually needed because water and Volume 5, Elsevier, and significant tubulointerstitial inflammation. Second salt retention is common in CKD and contributes to In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. high blood pressure. or more commonly, a milder renal injury that takes a Toxic Abnorma more indolent course. Instead of inflammation, there is Analgesics Lithium Hypokal tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA Cadmium - Thiazide diuretics are indicated as the second therapeutic line after ACEI/ARB, rioration of renal function. Although both acute and Lead Aristolochic Hyperox when the GFR is > 30 ml/min. Indapamide is preferred over thiazides because acid it is chronic forms have overlapping causes, they can be considered separate renal diseases because of their metabolically neutral. unique pathophysiologies. Between 10% to 20% of cases of end-stage renal disease (ESRD) worldwide result from primary CTIN, Loop diuretics (furosemide, torasemide) are of choice when eGFR is < 30 ml/min, a number that continues to grow as an increasing number of causes are identified. but in high doses (120-200 mg for eGFR < 10-15 ml/min). In case of resistance, their action can be potentiated by association with thiazides, PATHOPHYSIOLOGY especially when Neoplastic Heredi eGFR is > 15 ml/min. CTIN can occur as either a primary or secondary phe- Tubulointerstitial amyloidosis Multiple myeloma Pol nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanisms thickening often develop. One possible mechanism to 28 Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in in the kidneys  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTITI Major causes NEPHRITIS MANAGEMENT OF CKD The Netter Collection Tubulointerstitial nephritis can be divided into acute of Medical Ilustrations and chronic forms. Acute interstitial nephritis (AIN, : Urinary see Plate 4-28) is typically associated with more severe Renoprotection - Blood pressure and insults, which cause a rapid decline in renal function System, Volume 5, proteinuria control and significant tubulointerstitial inflammation. Elsevier, Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. or more commonly, a milder renal injury that takes a Toxic Abnorma more indolent course. Instead of inflammation, there is Analgesics Lithium Hypokal - Aldosterone antagonists (spironolactone and eplerenone) tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA have anti- Cadmium Hyperox rioration of renal function. Although both acute and hypertensive, anti-proteinuric, anti-fibrosing action chronic forms have overlapping causes, they can be and limit vascularacid and Lead Aristolochic ventricular remodeling (by antagonizing the tissue effects of aldosterone). considered separate renal diseases because of their unique pathophysiologies. - There is a risk of hyperkalemia, which occurs more frequently when eGFR is Between 10% to 20% of cases of end-stage renal below 30 ml/min. disease (ESRD) worldwide result from primary CTIN, a number that continues to grow as an increasing -Anti-aldosterones should be administered in small doses (25 mg/day) and with number of causes are identified. caution when the eGFR is lower than 60 ml/min and are formally contraindicated PATHOPHYSIOLOGY Neoplastic Heredi at values lower than 30 ml/min. CTIN can occur as either a primary or secondary phe- Tubulointerstitial amyloidosis Pol Multiple myeloma nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanisms thickening often develop. One possible mechanism to 29 Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in in the kidneys  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTI Major causes NEPHRITIS The Netter MANAGEMENT OFcanCKD Collection Tubulointerstitial nephritis be divided into acute of Medical Ilustrations and chronic forms. Acute interstitial nephritis (AIN, : Urinary see Plate 4-28) is typically associated with more severe Renoprotection - Blood pressure and insults, which cause a rapid decline in renal function System, Volume 5, proteinuria control and significant tubulointerstitial inflammation. Elsevier, Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. or more commonly, a milder renal injury that takes a Toxic - Ca channel blockers. Both dihydropyridines (nifedipine, amlodipine) Analgesics and non- Abnorm more indolent course. Instead of inflammation, there is Lithium Hypok tubulointerstitial fibrosis and scarring, with a slow dete- dihydropyridines (verapamil, diltiazem) are effective 5-ASA vasodilatory Cadmium rioration of renal function. Although both acute and Lead Aristolochic Hypero antihypertensives. Non-dihydropyridines in combination with ACEI additionally chronic forms have overlapping causes, they can be acid considered separate renal diseases because of their reduce proteinuria from diabetic nephropathy and have a cardiodepressant unique pathophysiologies. Between 10% to 20% of cases of end-stage renal effect. disease (ESRD) worldwide result from primary CTIN, a number that continues to grow as an increasing number of causes are identified. Other antihypertensives. When blood pressure control is not achieved with RAAS inhibitors, diuretics and calcium PATHOPHYSIOLOGYblockers, central adrenergics (rilmeridine, Neoplastic Here Tubulointerstitial amyloidosis P clonidine, methyl-dopa), beta-blockers CTIN can occur as either(the metabolically a primary or secondary phe- neutral Multiple carvedilol, myeloma nomenon. In primary CTIN, the initial injury affects nebivolol are preferable) or peripheral anti-adrenergics the tubulointerstitium (prazosin,Analgesic without glomerular or vascular doxazosin). nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanism thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in 30 in the kidneys decreased proximal reabsorption of electrolytes, which leads to a high solute load at the macula densa and resul-  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTI Major causes NEPHRITIS The Netter MANAGEMENT OF CKD Tubulointerstitial nephritis can be divided into acute Collection of Medical Ilustrations and chronic forms. Acute interstitial nephritis (AIN, : Urinary see Plate 4-28) is typically associated with more severeSystem, Other measures to limit the progression of CKD insults, which cause a rapid decline in renal function Volume 5, Elsevier, and significant tubulointerstitial inflammation. Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. or more commonly, a milder renal injury that takes a Toxic Abnorm more indolent course. Instead of inflammation, there is Analgesics Lithium Hypok tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA Cadmium Hypero rioration of renal function. Although both acute and Lead Aristolochic - Controlling dyslipidemia reduces cardiovascular risk and chronic forms have overlapping causes, they can be considered separate renal diseases because of their can contribute acid to reducing renal risk. unique pathophysiologies. Between 10% to 20% of cases of end-stage renal - Statins are recommended (possibly in combination with ezetimibe). disease (ESRD) worldwide result from primary CTIN, - Fibrates can be useful, especially in patients with diabetic nephropathy and a number that continues to grow as an increasing number of causes are identified. hypertriglyceridemia, because they reduce proteinuria. PATHOPHYSIOLOGY Neoplastic Here Tubulointerstitial amyloidosis P CTIN can occur as either a primary or secondary phe- Multiple myeloma nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanism thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in 31 in the kidneys decreased proximal reabsorption of electrolytes, which leads to a high solute load at the macula densa and resul-  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERST Major causes NEPHRITIS MANAGEMENT OF CKD nephritis can be divided into acute The Netter Tubulointerstitial Collection of and chronic forms. Acute interstitial nephritis Medical (AIN, Ilustrations: see Plate 4-28) is typically associated with more severe insults, which cause a rapid decline in renal Urinary functionSystem, Specific measures - treatment of causative nephropathy and significant tubulointerstitial inflammation.Volume 5, In contrast, primary chronic tubulointerstitial Elsevier, Second nephritis (CTIN) results either from untreated Edition, AIN2012. or more commonly, a milder renal injury that takes a Toxic Abnor more indolent course. Instead of inflammation, there is - Intensive glycaemic control improves the macro and microvascular tubulointerstitial fibrosis and scarring, with a slow dete- Analgesics 5-ASA Lithium Cadmium Hypo Hyper rioration of renal function. Although both acute and Lead Aristolochic complications of diabetes, but has been associated with an increased risk of chronic forms have overlapping causes, they can be considered separate renal diseases because of their acid hypoglycaemia in CKD patients. The goal of treatment is to maintain HbA1c unique pathophysiologies. Between 10% to 20% of cases of end-stage renal around 7%. disease (ESRD) worldwide result from primary CTIN, a number that continues to grow as an increasing number of causes are identified. PATHOPHYSIOLOGY Neoplastic Here - The first line of treatment for patients CTIN can occur with as either atype primary or2 diabetes secondary phe- and CKD is Tubulointerstitial amyloidosis Multiple myeloma P nomenon. In primary CTIN, the initial injury affects represented by Meformin, if the eGFR isthe greater than tubulointerstitium 30glomerular without ml/min. or vascular involvement. As the tubulointerstitial damage pro- Analgesic nephropathy gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanism thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. - If the desired glycemic control is not achieved, the second-line drug, which can In tubuloglomerular feedback, tubular damage results in toxic metabolites in the kidneys decreased proximal reabsorption of electrolytes, which be associated with Metformin, is SGLT2i (dapaglifozin, canaglifozin, empaglifozin), leads to a high solute load at the macula densa and resul- tant vasoconstriction of the afferent arteriole. This recommended for patients with eGFR over 30 ml/min. vasoconstriction causes glomerular ischemia that, if per- Phenacetin sistent, can result in glomerulosclerosis. Another expla- nation of the secondary glomerular damage seen in primary CTIN is “renal ablation nephropathy,” a theory Lack of redu which speculates that glomerulosclerosis results from a in the papill loss of renal mass caused by interstitial scarring. flow and oxy In secondary CTIN, in contrast, tubulointerstitial 32 are low; pro induced vas damage occurs in the setting of a primary glomerular or vascular insult. The tubular disease is thought to  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTE Major causes NEPHRITIS The Netter Collection MANAGEMENT OF nephritis Tubulointerstitial CKD can be divided into acute of Medical and chronic forms. Acute interstitial nephritis (AIN, Ilustrations : Urinary see Plate 4-28) is typically associated with more severeSystem, insults, which cause a rapid decline in renal function Specific measures - treatment of causative glomerulopathy Volume 5, and significant tubulointerstitial inflammation. Elsevier, Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. Immunosuppressive treatment or more commonly, a milder renal injury that takes a Toxic Ab more indolent course. Instead of inflammation, there is Analgesics Lithium Hy tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA Cadmium Hy rioration of renal function. Although both acute and Lead Aristolochic chronic forms have overlapping causes, they can be acid considered separate renal diseases because of their - It is recommended for stopping the immunological-inflammatory mechanism unique pathophysiologies. Between 10% to 20% of cases of end-stage renal and reducing proteinuria through specific pathogenic intervention in CKD disease (ESRD) worldwide result from primary CTIN, a number that continues to grow as an increasing caused by primary or secondary glomerular diseases. number of causes are identified. - Currently recommended: corticosteroids (methylprednisolone, prednisone), cyclophosphamide, cyclosporine, azathioprine, rituximab. PATHOPHYSIOLOGY Neoplastic H CTIN can occur as either a primary or secondary phe- Tubulointerstitial amyloidosis Multiple myeloma nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechan thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in 33 in the kidneys decreased proximal reabsorption of electrolytes, which leads to a high solute load at the macula densa and resul-  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTI Major causes NEPHRITIS The Netter MANAGEMENT OF CKD Tubulointerstitial nephritis can be divided into acute Collection of Medical Ilustrations and chronic forms. Acute interstitial nephritis (AIN, : Urinary see Plate 4-28) is typically associated with more severeSystem, insults, which cause a rapid decline in renal function Specific measures - treatment of causative nephropathy Volume 5, Elsevier, and significant tubulointerstitial inflammation. Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. Therapy to reduce the development of cysts or more commonly, a milder renal injury that takes a Toxic Abnorm more indolent course. Instead of inflammation, there is Analgesics Lithium Hypok tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA Cadmium Hypero rioration of renal function. Although both acute and Lead Aristolochic chronic forms have overlapping causes, they can be acid - The administration of a selective vasopressin V2 receptor antagonist considered separate renal diseases because of their (tolvaptan) is recommended in adults with ADPKD. The drug effectively inhibits unique pathophysiologies. Between 10% to 20% of cases of end-stage renal the growth of cysts and can delay the deterioration of kidney function. disease (ESRD) worldwide result from primary CTIN, a number that continues to grow as an increasing number of causes are identified. The treatment is recommended for patients with a tendency PATHOPHYSIOLOGY Neoplastic of rapid Here progression and eGFR > 30 CTIN ml/min. can occur as either a primary or secondary phe- Tubulointerstitial amyloidosis Multiple myeloma P nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanism thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in in the kidneys34 decreased proximal reabsorption of electrolytes, which leads to a high solute load at the macula densa and resul-  Plate 4-30 CHRONIC TUBULOINTERSTITIAL CHRONIC TUBULOINTERSTI Major causes NEPHRITIS The Netter MANAGEMENT OF CKD Tubulointerstitial nephritis can be divided into acute Collection of Medical Ilustrations and chronic forms. Acute interstitial nephritis (AIN, : Urinary see Plate 4-28) is typically associated with more severeSystem, insults, which cause a rapid decline in renal function Specific measures - treatment of causative nephropathy Volume 5, Elsevier, and significant tubulointerstitial inflammation. Second In contrast, primary chronic tubulointerstitial Edition, nephritis (CTIN) results either from untreated AIN 2012. Therapy to reduce the development of cysts or more commonly, a milder renal injury that takes a Toxic Abnorm more indolent course. Instead of inflammation, there is Analgesics Lithium Hypok tubulointerstitial fibrosis and scarring, with a slow dete- 5-ASA Cadmium Hypero rioration of renal function. Although both acute and Lead Aristolochic - loss of more than 2.5 ml/min annually chronic forms have overlapping causes, they can be for a period acid considered separate renal diseases because of their Rapid of 5 years or more than 5 ml/min in one year; unique pathophysiologies. Between 10% to 20% of cases of end-stage renal progression disease (ESRD) worldwide result from primary CTIN, in ADPKD is a number that continues to grow as an increasing number of causes are identified. defined by: - thePATHOPHYSIOLOGY increase in the total volume of the kidneys Neoplastic Here (assessed byoccur CTIN can CTasand either MRI) a primaryby more than or secondary phe- 5% per year. Tubulointerstitial amyloidosis Multiple myeloma P nomenon. In primary CTIN, the initial injury affects the tubulointerstitium without glomerular or vascular Analgesic nephropathy involvement. As the tubulointerstitial damage pro- gresses, however, glomerular sclerosis and arteriolar Possible pathogenetic mechanism thickening often develop. One possible mechanism to Accumulation of explain this phenomenon is tubuloglomerular feedback. toxic metabolites In tubuloglomerular feedback, tubular damage results in in the kidneys35 decreased proximal reabsorption of electrolytes, which leads to a high solute load at the macula densa and resul-  thyroidism an 13 g/dL and 12 g/dL, further [HCO 3 !] ding a complete Metabolic The Netter COMPLICATIONSacidosis Collection of an assessmentAnaemia of OF CKD Medical Ilustrations: Urinary is common and System, ion of -red cells. [Pi] Volume 5, Elsevier, Anaemia in CKD impairs quality of life and wellbeing. Anemia Second the inflammatory [Ca""] Edition, 2012. secretion of hep- Hyperphosphatem - Erythropoietin deficiency - this is the most significant mechanism; rom the GI tract Hypocalcemia - Increased blood loss - there may be occult gastrointestinal bleeding, repeated blood sampling, blood loss during haemodialysis or platelet dysfunction; ting agents are A normochromic, - Bone marrow toxins - these are retained in CKD or there is of 11 to 12 g/dL. normocytic fibrosis secondary to hyperparathyroidism; anemia develops - Haematinic deficiency – there may be decreased iron, vitamin B12 /dL. In patients or folate; by a number of hould be assessed - Increased red cell destruction – red cells have a shortened mechanism: pparent erythro- lifespan in uraemia and haemodialysis itself may cause a ents, such as iron degree of haemolysis. monly given. If for cardiovascular disease, such as hypertension, diabe- ments because of tes mellitus, and hyperlipidemia. CKD itself, however, 36 nous iron prepa- also appears to be an independent risk factor for CVD,  MANAGEMENT OF ANAEMIA IN CKD - Administration of erythropoiesis stimulating agents is not recommended for all patients. - Treatment with Iron preparations is often necessary and correction of anaemia has been observed, without the need for the administration of erythropoiesis stimulating agents. The required dose varies between 200-1000mg and covers a period of 6 months. - The absolute deficiency is suggested by a serum ferritin < 100 ng/ml and the deficiency in the use of transferrin saturation < 20%; - The objective of treatment with Iron is to maintain serum ferritin between 200- 500 ng/ml and transferrin saturation between 20-50%; - It is recommended to administer Iron i.v. preparations, because the synthesis of hepcidin (an acute phase reactant produced by the liver in response to cytokines - IL-6) inhibits the gastrointestinal absorption of iron and sequesters iron in the liver. 37  !] 3 olic The Netter MANAGEMENT OF ANAEMIA IN CKD is Collection of Medical Ilustrations: Urinary System, - The administration of erythropoiesis stimulating agents Volume 5, Elsevier, [Pi](ESA) can be recommended in the following conditions: Anemia Second [Ca""] Edition, 2012. Hyperphosphatemia Hypocalcemia - ESAs (epoetin 𝛼, 𝛽, 𝜁, longer acting darbepoetin 𝛼) can be given subcutaneously or by i.v. injection. [K"] - Hypertension can be significantHyperkalemia side-effect in 30% of patients new of ESAs, blood pressure should be monitored in the first 6 months and treated Volumeif rising. - Peripheral resistance increases in all patients, owing Uremia to loss of hypoxic overload vasodilatation and to an increase blood viscosity. D uch as hypertension, diabe- analogues. It may affect the intimal layer, lead 38 mia. CKD itself, however, atherosclerotic plaques, and/or the medial layer, l  MANAGEMENT OF ANAEMIA IN CKD - The administration of erythropoiesis stimulating agents (ESA) can be recommended in the following conditions: - It is indicated if moderate-severe anaemia persists (Hb < 10 g/dL), after several determinations, after eliminating other causes (iron deficiency) and the patient has symptoms that can be induced by anaemia (worsening of heart failure or angina pectoris). - The objective of the treatment is to maintain Hb between 10-12 g/dL, without intentionally exceeding 13 g/dL. - Patients who fail to respond to ESA should be screened to exclude associated bleeding, malignancy, infection, inflammation or formation of anti-erythropoietin antibodies. 39  MANAGEMENT OF ANAEMIA IN CKD - Correcting anaemia with ESAs improves quality of life, exercise tolerance and sexual and cognitive function in dialysis patients. Also leads to regression of left ventricular hypertrophy; - By avoiding blood transfusion, the risk in minimized of sensitization to HLA antigens, which may complicate future renal transplantation; - Despite all these benefits, the randomized trials conducted to date have not found improvement in survival and reduction in cardiovascular morbidity after complete correction of CKD-associated anaemia with ESAs. - On the contrary, an increase in the number of vascular accidents and the reactivation of some neoplasms were reported. 40  COMPLICATIONS OF CKD Biochemical abnormalities - PO4, PTH, FGF-23 ↑ Mineral and bone disorder (MBD) - Ca, 1,25 (OH)2D ↓ Increased incidence of: fractures, cardiovascular events Vascular, valvular Bone abnormalities: calcifications Mortality, morbidity - osteitis fibrosa - osteomalacia - mixed bone lesions 41  MANAGEMENT OF CKD-MBD Reduction of phosphate and limiting of calcium load - Dietary restriction. Exclusion of foods with phosphate-based additives from the diet in patients with CKD stage G5/G5D. - Gut phosphate binders. Sevelamer carbonate, lathanum carbonate, calcium carbonate and calcium acetate all reduce phophate absorbtion and serum phosphate levels when taken with meals. 42  MANAGEMENT OF CKD-MBD Control of PTH and achievement of normal calcium - Calcitriol vitamin D analogues (alfa-calcidol or novel vitamin D metabolites - paricalcitol). These ar given orally to suppress PTH once the level is three times or more above the upper limit of normal. - Calcimimetic agents (cinacalcet) act by activating the calcium-sensing receptor. Calcium mimetics are indicated only for dialysis patients in monotherapy. - During the treatment of secondary hyperparathyroidism, calcium levels must be carefully monitored, which must be kept within normal limits. - For cases with severe increases (800-1000 pg/mL) of PTH, refractory to drug treatment, parathyroidectomy may be indicated. 43  COMPLICATIONS OF CKD Cardiovascular disease - In CKD, the cardiovascular risk is much higher than the renal one: the probability of death from a cardiovascular cause is 6-10 times higher than that of initiating renal replacement therapy and that of fatal cardiovascular events, substantially higher than in the general population. - Suden cardiac GFR ↓ death, myocardial infarction, cardiac failure, stroke and peripheral Proteinuria ↑ vascular disease 44  COMPLICATIONS OF CKD Cardiovascular disease Risk factors: Hypertension Diabetes mellitus Dyslipidaemia Smoking Male gender - Left ventricular hypertrophy, diastolic and systolic dysfunction are common in patients with CKD. These are the consequence of hemodynamic factors (pressure/volume overload - reduction of arteriolar compliance) and metabolic factors (uremic intoxication). Both left ventricular hypertrophy and systolic dysfunction are risk factors for premature death in patients with CKD. 45  COMPLICATIONS OF CKD Cardiovascular disease - Pericarditis Uremic pericarditis appears in stage G5, of kidney decompensation; Clinical: pericardial friction, irritating cough, precordial pain; Small amount of pericardial fluid, without hemodynamic consequences. Rarely, cardiac tamponade; It is one of the major indications for the initiation of renal Two replacement therapy. clinical settings: Dialysis pericarditis – intercurrent illness or surgery in patients receiving adequate dialysis. 46  COMPLICATIONS OF CKD Skin disease Pruritus (itching) is common and is caused by: accumulating nitrogenous waste products of protein catabolism (itching improves following dialysis); hypercalcaemia and hyperphosphatemia; hyperparathyroidism (even if calcium and phosphate levels are normal); iron deficiency. 47  COMPLICATIONS OF CKD Skin disease – Nephrogenic systemic fibrosis (NSF) - Systemic fibrosing skin disorder affect - patients with eGFR < 30 ml/min or under RRT; - Gadolinium-containing contrast agents – 95% - Diagnosis is based of cases of NSF (contrast agents are excreted on skin biopsy exclusively by the kidney); (proliferation of dermal fibrocytes - NSF is chronic and unremitting; with excessive - 30% of patients are dying; collagen deposition); - No therapy; - Prevention is the key!!! 48  36 1396 Kidney and urinary tract disease Tenapanor, a minimally absorbed, small-molecule inhibitor of Kumar COMPLICATIONS OF CKD the sodium/hydrogen exchanger isoform 3 (NHE3), inhibits both sodium and water transport locally in the gastrointestinal tract, and Clark¢s. as well as phosphate transport by indirectly inhibiting paracel- Clinical lular absorption of phosphate. It also downregulates intestinal Medicine Skin disease – Caciphylaxis phosphate transporters Na/Pi2b and reduces absorption direct- , Elsevier ly. Clinically, the role of inhibitors of phosphate absorption has publishin not yet been determined.! g house, 10th Control of PTH and achievement of normal calcium edition, - calcific uraemic arteriolopathy – rare vitamin Calcitriol (1,25-dihydroxycholecalciferol), butD ana- July 2020. logues such as alfacalcidol, or novel vitamin D metabolites life-threatening complication in CKD (22-oxacalcitriol, paricalcitol, doxercalciferol). These are given Fig. 36.48 Calciphylaxis. Characteristic arterial calcification of the skin microvasculature in the absence of vasculitic change (arrowed). orally to suppress PTH once the level is three times or more patients; above the upper limit of normal. Newer vitamin D analogues, such as paricalcitol (19-nor-1,25 dihydroxyvitamin D ), may be 2 Male gender – over-represented in patients with CKD. - clinical – painful skin patches, less likely ulcers, to lead to hypercalcaemia, non- but their usefulness over the conventional but less expensive calcitriol or alfacalcidol re- Also clustering with CKD, ventricular hypertrophy is common, as is systolic and diastolic dysfunction. Left ventricular hyper- healing eschars, panniculitis mains to be established. and dermal Calcimimetic agents (e.g. cinacalcet and etelcalcetide, trophy is a risk factor for early death in CKD, as in the general population. Systolic dysfunction is also a marker for early death. necrosis; calcium-sensing receptor agonists, see p. 645). These have also been tried in established secondary hyperparathyroidism Myocardial fibrosis, abnormal myocyte function, calcium overload and hyperparathyroidism, and carnitine and selenium deficiencies - histology – vascularwith calcification and small- successful suppression of PTH levels and lowering of cal- cium × phosphate product. Calcimimetics act by activating the all contribute to the systolic dysfunction seen with the uraemic cardiomyopathy. vessels thrombosis; calcium- sensing receptor, leading the parathyroid to respond as though serum calcium levels were high, reducing PTH synthesis Coronary artery and generalized vascular calcification - pathogenesis – reducing thehowever, synthesis a controlled trial toof and release. The long-term safety and efficacy of these agents have been confirmed; assess po- Traditional risk factors (e.g. smoking, diabetes) only partly explain Gla proteins, which are inhibitors of tential survival benefits on treatment was non-conclusive.! the increased cardiovascular risk in patients with CKD. Coronary artery calcification is more common in patients with ESKD than in Calciphylaxis arteriolar calcification. Also known as calcific uraemic arteriolopathy, this is a rare but seri- normal individuals and it is likely that this contributes to cardiovas- cular mortality. Peripheral vessel calcification increases vascular ous life-threatening complication in CKD patients. It presents as stiffness (reduced compliance), which manifests as increased painful skin patches, plaques and ulcers, with non-healing eschars, pulse pressure, increased pulse wave velocity, and an increased panniculitis and dermal necrosis. The characteristic feature on afterload with advancing left ventricular hypertrophy. Risk factors histology is vascular calcification and superimposed small-vessel related to calcification include: thrombosis (Fig. 36.48). Risk factors include hyperparathyroid- A raised (calcium × phosphate) product, which promotes cal- ism, elevated serum phosphate, morbid obesity and warfarin use cification. 49 (by inhibiting vitamin K-dependent carboxylation and activation of Hyperparathyroidism, which increases intracellular calcium. calcification inhibitor matrix gla protein). Control of hyperparathy- Uraemia, which leads to loss of constitutive inhibitors of calcifi-  36 1396 Kidney and urinary tract disease COMPLICATIONS OF CKD Tenapanor, a minimally absorbed, small-molecule inhibitor of Kumar the sodium/hydrogen exchanger isoform 3 (NHE3), inhibits both and sodium and water transport locally in the gastrointestinal tract, Clark¢s. as well as phosphate transport by indirectly inhibiting paracel- Clinical lular absorption of phosphate. It also downregulates intestinal Medicine Skin disease – Caciphylaxis phosphate transporters Na/Pi2b and reduces absorption direct- ly. Clinically, the role of inhibitors of phosphate absorption has , Elsevier publishin not yet been determined.! g house, 10th Control of PTH and achievement of normal calcium edition, Calcitriol (1,25-dihydroxycholecalciferol), vitamin D ana- July 2020. logues such as alfacalcidol, or novel vitamin D metabolites Fig. 36.48 Calciphylaxis. Characteristic arterial calcification of the (22-oxacalcitriol, paricalcitol, doxercalciferol). These are given skin microvasculature in the absence of vasculitic change (arrowed). orally to suppress PTH once the level is three times or more - Control hyperparathyroidism (calcimimetic agents or surgical treatment) above the upper limit of normal. Newer vitamin D analogues, Male gender – over-represented in patients with CKD. such as paricalcitol (19-nor-1,25 dihydroxyvitamin D2), may be → drop both calcium and phosphate to low normal Also range; less likely to lead to hypercalcaemia, but their usefulness over clustering with CKD, ventricular hypertrophy is common, the conventional but less expensive calcitriol or alfacalcidol re- as is systolic and diastolic dysfunction. Left ventricular hyper- - Sodium thiosulfate and bisphosphonates have mains to be established. been tried with variable trophy is a risk factor for early death in CKD, as in the general Calcimimetic agents (e.g. cinacalcet and etelcalcetide, population. Systolic dysfunction is also a marker for early death. success; calcium-sensing receptor agonists, see p. 645). These have Myocardial fibrosis, abnormal myocyte function, calcium overload also been tried in established secondary hyperparathyroidism and hyperparathyroidism, and carnitine and selenium deficiencies - Despite treatment, subsequent infection increases the risk and many die with successful suppression of PTH levels and lowering of cal- all contribute to the systolic dysfunction seen with the uraemic cium × phosphate pr