Chronic Renal Failure
Department of Nephrology, The First Affiliated Hospital of Sun Yat-Sen University
Jiang Zongpei
CONTANT DEFINITIONS
ETIOLOGY
PATHOPHYSIOLOGY OF CKD
PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA
CLINICAL MANIFESTATIONS OF CHRONIC RENAL
FAILURE
EVALUATION AND MANAGEMENT OF PATIENTS WITH
CKD
TREATMENT
DEFINITIONS • Chronic Kidney disease (CKD) :
CKD is a pathophysiologic process with multiple etiologies, resulting in the irreversible attrition of nephron number and function, frequently leading to end stage renal disease (ESRD).
• ESRD
represents a clinical state or condition in which there has been an irreversible loss of renal function, and these patients usually need to accept renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia.
• Uremia
Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure.
Major causes of chronic renal failure • Glomerulopathies Primary glomerular diseases: 1. Focal and segmental glomerulosclerosis(FSGS) 2. Membranoproliferative glomerulonephritis(MPGN) 3. IgA nephropathy(IgAN) 4. Membranous nephropathy(MN)
Secondary glomerular diseases: 1.Diabetic nephropathy 2.Lupus nephropathy 3. Post-infectious glomerulonephritis 4. Amyloidosis 5.HIV-associated nephropathy 6.Collagen-vascular diseases 7.Sickle cell nephropathy 8. HIV associated membranoprolifer
ative glomerulonephritis
• Tubulointerstitial nephritis1. Drug hypersensitivity2. Heavy metals3. Analgesic nephropathy4. Reflux/chronic pyelonephritis5. Idiopathic• Hereditary diseases1. Polycystic kidney disease2. Medullary cystic disease3. Alport’s syndrome• Obstructive nephropathies1. Prostatic disease2. Nephrolithiasis3. Retroperitoneal fibrosis/tumor4. Congenital• Vascular diseases1. Hypertensive nephrosclerosis2. Renal artery stenosis
ETIOLOGY
The leading underlying etiologies of both CKD and ESRD in China.
• Glomerulonephritis 60%• Diabetic nephropathy 20%• Lupus nephropahty 5-10%• Hypertensive nephrosclerosis 5-10%• Others 5-10%
PATHOPHYSIOLOGY OF CKD The pathophysiology that why CKD progress to ESRD is unclearly now.
vasoactive moleculesCytokines
growth factorsRenin-angiotensin axis
glomerular hyperperfusion,Hypertensionhyperfiltration
glomerular hypertrophy
sclerosis
nephron population decrease and reduction of renal mass.
Such reduction of renal mass causes structural and functional hypertrophy of surviving ne
phrons
1
Renal pathologic change in CRF
Normal Sclerosis
Stages of chronic kidney disease: A clinical action plan
Stage Description GFR Action symptom
1 Kidney damage with normal of ↑GFR
≥90 Diagnosis and treatment.
Treatment of basic diseases.
Slowing of progression. Cardiovascular disease risk reduction.
patients often remain free of symptom
2 Kidney damage with mildly↓GFR
60-89 Estimating progression
3 Moderately↓GFR 30-59 Evaluating and treating complications
clinical and laboratory complications of CKD become progressive4 Severely↓GFR 15-29 Preparation for kidney repl
acement therapy.
5 Kidney failure <15 Replacement (if uremia is present)
Uremic symptoms become prominent and usually the patients need to accept renal replacement therapy
PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA
• Which toxin is responsible for uremic symptoms remain unclear.
• Urea may contribute to some of the clinical abnormalities, including
anorexia, malaise, vomiting, and headache.
• Nitrogenous excretory products (guanido compounds, urates and s
o on) and nitrogenous compounds (so-called middle molecules tox
ins) are associated with neuromuscular abnormalities and believed
to contribute to morbidity and mortality in uremic subjects.
PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA
• A host of metabolic and endocrine functions normally subserved
by the kidney are also impaired, resulting in anemia; malnutritio
n; impaired metabolism of carbohydrates, fats, and proteins and
metabolic bone disease.
• The endocrine hormone involved in ESRD patients are PTH, ins
ulin, erythropoietin (EPO) and so on.
CLINICAL MANIFESTATIONS OF CHRONIC
RENAL FAILURE
• Uremia leads to disturbances in the function of every organ system.
• The symptoms of chronic renal failure often develop slowly and are nonspecific.
• Individuals can remain asymptomatic until renal failure is far-advanced (GFR<10-15 ml/min).
CLINICAL MANIFESTATIONS OF CHRONIC RENAL FAILURE
• FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS
• BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM
• CARDIOVASCULAR ABNORMALITIES
• HEMATOLOGIC ABNORMALITIES
• NEUROMUSCULAR ABNORMALITIES
• GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES
• ENDOCRINE METABOLIC DISTURBANCES
FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS
Sodium And Water Homeostasis
• In most patients with stable CKD, the total body contents of Na+ and H2
O are increased modestly, and will cause edema and hypertention.
Glomerulo-tubular balance impaired and promote Na+ retention
Na+ retention may lead to cumulative positive Na+ balance and cause ext
racellular fluid volume (ECFV) expansion.
• Patients with CKD also have impaired renal mechanisms for conserving
Na+ and H2O. And these patients are easy to appear volume depletion.
FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS
Potassium Homeostasis In CKD
hyperkalemia is common in CKD patients dietary intake, protein catabolism, hemorrhage, transfusion of stored
red blood cells, metabolic acidosis ACE inhibitors and angiotensin receptor blockers(ARB), and some di
uretics
Hypokalemia is uncommon in CKD usually caused by markedly reduced dietary K+ intake Or association with excessive diuretic therapy or gastrointestinal loss
es. And also be seen in tubulointerstitial diseases, such as Fanconi’s syn
drome, renal tubular acidosis
FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS
Metabolic Acidosis is a common disturbance during the advanced stage
s of CKD
Reduced ability to produce ammonia.
Hyperkalemia further depresses urinary ammonium excretion.
BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM
The disorders of calcium, phosphorus, and bone diseases i
s common in CKD.
The major disorders of bone disease can be classified into:
1. high bone turnover with high PTH levels (including osteitis f
ibrosa)
2. low bone turnover with low or normal PTH levels (osteomal
acia and adynamic bone disease).
BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM
• The most common disorder is osteitis fibrosa.
As GFR decreases below 25% of normal
phosphorus excretion is impaired
Hyperphosphatemia
hypocalcemia
stimulating secretion of PTH
“secondary hyperparathyroidism”
high bone turnover with osteitis fibrosa.
Decreased renalFunction
Decreased 1.25(oh)2D3
A13+ IntoxicationAccumulation ofβ2 microglobulinHyperphosphatemia
Decreased ionizedCa2+
HyperparathyroidismDecreasedexpressionof calcium-
sensingreceptor
HyperplasiaOf the
parathyroidglands
Osteitis fibrosa cystica(high-turnover bone disease)
Osteomalacia Adynamic bonedisease
Dialysis-relatedamyloidosis
Metabolic acidosis Excess Ca and vit D,PD,diabetes
CARDIOVASCULAR ABNORMALITIES
• Cardiovascular disease is the leading cause of morbidity and mortality in patients with CKD at all stages.
Ischemic Cardiovascular Disease
Congestive Heart Failure
Hypertension And Left Ventricular Hypertrophy
Pericarditis
Ischemic Cardiovascular Disease • CKD is a major risk factor for ischemic cardiovascular disease, inclu
ding coronary heart, cerebrovascular, and peripheral vascular diseases
• Ischemic cardiovascular disease in CKD caused by both traditional risk factors and CKD-related risk factors
The traditional risk factors include hypertension, hypervolemia, dyslipidemia, and so on.
The CKD-related risks include anemia, hyperphosphatemia, high PTH level, and a state of “microinflammation” that can be found at all stages of CKD.
Hypertension And Left Ventricular
Hypertrophy • Hypertension is the most common complication of CKD and ESRD.
It may develop early during the course of CKD
Volume overload is the major cause of hypertension in uremia.
Rarely, Patients may develop malignant hypertension
• Left ventricular hypertrophy and dilated cardiomyopathy are the mos
t important risk factors for cardiovascular morbidity and mortality in p
atients with CKD and ESRD
thought to be related prolonged hypertension and ECFV overload.
anemia
Toxins in uremia
Congestive Heart Failure
Abnormal cardiac function
secondary to myocardial ischemic disease
and/or left ventricular hypertrophy
together with salt and water retention in uremia
often result in congestive heart failure and/or pulmonary edema.
These patients usually need to accept dialysis treatment
immediately.
Pericarditis
• Pericarditis is common in ESRD patients. And usually indicate the patients need accept hemodialysis immediately.
Pericardial pain with respiratory accentuation, accompanied by a friction rub, are the hallmarks of uremic pericarditis.
The finding of a multicomponent friction rub strongly supports the diagnosis.
Classic electrocardiographic and echocardiography is useful in diagnosis for pericarditis.
HEMATOLOGIC ABNORMALITIES
Anemia • Anemia in CKD is a normocytic, normochromic
• And will observed beginning at stage 3 CKD and is almost univ
ersal at stage 4.
• the anemia of CKD is associated with a number of physiologic
abnormalities
decreased tissue oxygen delivery and utilization
increased cardiac output
cardiac enlargement
ventricular hypertrophy
congestive heart failure
impaired body defense against infection.
HEMATOLOGIC ABNORMALITIES Anemia
The primary cause of anemia in patients with CKD
insufficient production of EPO by the diseased kidneys.
iron and folate deficiency
Severe PTH
acute and chronic inflammation
aluminum toxicity
shortened red cell survival.
NEUROMUSCULAR ABNORMALITIES
• Central, peripheral, and autonomic neuropathy, as well as abnorm
alities in muscle composition and function, are all common compli
cations in CKD.
• Retained nitrogenous metabolites and middle molecules toxins as
well as PTH , all contribute to the pathophysiology of neuromuscu
lar abnormalities.
• The “restless legs syndrome ” is characterized by illdefined sensat
ions of discomfort in the legs and legs and feet requiring frequentl
y movement.
GASTROINTESTINAL AND NUTRITIONAL
ABNORMALITIES
Gastrointestinal symptoms (abdominal pain, nausea, vomiting)
usually may the first symptom for ESRD patients.
Urimic toxins is associated with an unpleasant metallic taste s
ensation in ESRD patient.
Gastritis, peptic disease are common in ESRD patient.
Protein restriction is useful in diminishing the symptoms. But it
is sometimes easy to cause malnutrition.
ENDOCRINE-METABOLIC
DISTURBANCES
• Disturbances in parathyroid function
• Glucose metabolism impaired in CKD
Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects.
Many hypoglycemic drugs require dose reduction in renal failure
• The growth and sex hormone secretion is impaired in CKD ,
Sexual maturation is often in children with CKD.
EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD History Hypertension Diabetes systemic infectious Inflammatory metabolic diseases exposure to drugs and toxins a family history of renal and urologic disease.
In evaluating the uremic syndrome questions about appetite; diet; nausea; vomiting; edema;
weight change
Physical examination blood pressure examination of the abdomen for renal masses, examination for edema neurologic examination
EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Laboratory Investigations
Laboratory investigation should focus on to find evidence to unde
rlying disease process and its continued activity.
immunologic tests (SLE and vasculitis)
Serum and uriary protein electrophoresis.
Urinalysis, a 24h urine collection for protein excretion
measurements of plasma creatinine and estimation of GFR.
to assess metabolic bone disease
hemoglobin.
EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Imaging Studies
The most useful imaging study is renal ultrasonography. Provide an estimate of kidney size and obstructive uropathy. The small kidneys usually supports the diagnosis of progressive
CKD is irreversible Normal kidney size usually suggests the possibility of an acute ra
ther than chronic process.
a vascular imaging procedure, such as doppler sonography of the renal arteries, radionuclide scintigraphy, magnetic resonance angiography (MRA)
EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Renal Biopsy
Renal biopsy should be reserved for patients with near normal kidney size, in whom a definitive diagnosis cannot be made yet.
Contraindications to renal biopsy include:
bilateral small kidneys
polycystic kidney disease
uncontrolled hypertension
urinary tract or perinephric infection
bleeding diathesis
respiratory distress
morbid obesity.
ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF CKD
The most important initial step in the evaluation of a patient presenting with renal failure is to distinguish newly diagnosed CKD from acute renal failure.
the demonstration of evidence of chronic renal failure
Hyperphosphatemia
Hypocalcemia
elevated PTH levels
normocytic and normochromic anemia
bilaterally reduced kidney size(<8.5 cm)
Reversible causes of renal failure
Reversible factors Diagnostic clues
Infection Urine culture and sensitivity tests
Obstruction Bladder catheterization, then renal ultrasound
Extracellular fluid volume depletion
Orthostatic blood pressure and pulse:↓blood pressure and ↑pulse upon sitting up from a supine position
Hypokalemia, hypercalcemia, and hyperuricemia(usually >15 mg/dL)
Serum electrolytes, calcium, phosphate
uric acid
Nephrotoxic agents Drug history
Hypertension Blood pressure, chest X-ray
Congestive heart failure Physical examination, chest X-ray
TREATMENT • SLOWING THE PROGRESSION OF CKD Protein Restriction Reducing Intraglomerular Hypertension And Proteinuria
• MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Disorders of Mineral Metabolism Hypertension Cardiovascular Disease Uremic Pericarditis Congestive Heart Failure Anemia Abnormal Hemostasis Renal replacement therapy
SLOWING THE PROGRESSION OF CKD Protein Restriction
• A major goal of protein restriction in CKD, is to slow the progression of nephron injury.
• Protein restriction should be carried out in the context of an overall dietary program that keeping nutritional status and avoids malnutrition.
• Metabolic and nutritional studies indicate that protein requirements for patients with CKD are in the range of 0.6-0.8 g/kg per day.
• And we need give patients enough essential amino acids and energy supply (35 kcal/kg per day).
SLOWING THE PROGRESSION OF CKD Reducin
g Intraglomerular Hypertension And Proteinuria • Progressive renal injury in CKD appears to be most closely related
to the height of intraglomerular pressure and/or the extent of glomerular hypertrophy.
• Antihypertensive therapy in patients with CKD also aims to slow the progression of nephron injury, by reduce intraglomerular hypertension and hypertrophy.
• ACE inhibitors(ACEI) and angiotensin receptor blockers (ARB) are now clearly established as effective, antiproteinuric and anti-intraglomerular hypertension agents.
• If patients present side effects of the use of ACEI/ARBthese (e.g. cough, hyperkalemia) . We may choice of calcium channel blockers (CCB) as a second line medicine.
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Disorders of Mineral Metabolism
• Treatment should begin with dietary phosphorus restriction to
<1000 mg/d. Oral phosphorus binding agents.
• Vitamin D or vitamin D analogs should be given when PTH level
is more than two to three times to normal
• It is particularly important to maintain the calcium-phosphate
product in the normal range to avoid metastatic calcification.
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Hypertension
• Volume control with salt restriction is the essential of therapy.
• The choice of antihypertensive agent is similar to that in the general population, ACE inhibitior, ARB, CCB, or combination.
• In all patients with CKD, blood pressure should be controlled to at least the level of 130/80 to 85mmHg.
• In CKD patients with diabetes or proteinuria > 1g per 24 h, blood pressure should be further reduced to 125/75 mmHg.
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Cardiovascular Disease
Risk factor Life-style changes
Hyperlipidemia
Hypertension
CKD related risk factor
Congestive Heart Failure Water and salt intake
Diuretics
Digoxin
ACE inhibitors ARB
Dialysis immediately
Uremic Pericarditis Dialysis immediately
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Anemia
• As insufficient production of EPO by the diseased kidneys,
recombinant human EPO is most important in treatment of
anemia caused by kidney diseases.
• The iron status of the patient with CKD must be assessed, and
adequate iron stores should be available before treatment with
EPO
Management guidelines for correction of anemia of chronic renal disease
Erythropoietin
Starting dosage: 50-150 units/kg per week IV or SC (once, twice, or three times per week )
Target hemoglobin(Hb): 11-12 g/dL
Optimal rate of correction Increase Hb by 1-2 g/dL over 4-week period
Darbepoetin alfa
Starting dosage: 0.45 ug/kg administered as a single IV or SC injection once weekly 0.75 ug/kg administered as a single IV or SC injection once every 2 Weeks
Target Hb: ≤12 g/dL
Optimal rate of correction Increase Hb by 1-2 g/dL over 4-week period
Iron
1. Monitor iron stores by percent transferrin saturation (TSat) and serum ferritin.
2. If patient is iron-deficient (Tsat <20%; serum ferritin<100 ug/L, administer iron, 50-100 mg IV twice per week for 5 weeks; if iron are still low, repeat the same course.)
3. If iron indices are normal yet Hb is still inadequate, administer IV iron as outlined above; monitor Hb, Tsat, and ferritin.
4. Withhold iron therapy when TSat >50% and/or ferritin >800 ng/mL(>800 ug/L).
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE RENAL REPLACEMENT THERAPY
• GFR is below 10 ml/min in CRF usually need to require renal replacement therapy.
• Absolute indications for dialysis include: severe volume overload, especially in heart failure severe hyperkalemia and/or acidosis encephalopathy not otherwise explained pericarditis or other serositis symptomatic uremia (e.g., anorexia, nausea, vomiting) protein energy malnutrition.
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE
Hemodialysis
• Hemodialysis requires a constant flow of blood along one side of a semipermeable membrane, and with dialysate solution along the other side. Diffusion and convection allow the dialysate to remove unwanted substances from the blood while adding back needed components.
• Most patients undergo dialysis thrice weekly, usually for 3-4 h.
Peritoneal dialysis is through a peritoneal catheter that allows infusion of a dialysate solution into the abdominal cavity, which allows transfer of solutes across the peritoneal membrane.
Patients generally have the choice of performing their own exchanges (2-3 L of dialysate, 4-5 times during daytime hours) or using an automated device at night. The most common complication of peritoneal dialysis is peritonitis.
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE
Peritoneal dialysis
Up to 50% of all patients with ESRD are su
itable for kidney transplantation.
The most common method for kidney trans
plantantion is put the graft in right side plev
ic cavity.
Two-thirds of kidney transplants come fro
m deceased donors, and the others from li
ving related or unrelated donors.
Immunosuppressive drugs developed very
fast in these years. (Cyclosporine, MMF, t
acrolimus and rapamycin.)
MANAGING COMPLICATIONS OF CHRONIC RENAL FAILUREkidney transplantation.
Conclusion DEFINITIONS
ETIOLOGY
PATHOPHYSIOLOGY OF CKD
PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA
CLINICAL MANIFESTATIONS OF CHRONIC RENAL
FAILURE
EVALUATION AND MANAGEMENT OF PATIENTS WITH
CKD
TREATMENT
Thanks for your attention!