DISCUSSION

CHRONIC KIDNEY DISEASE

CHRONIC KIDNEY DISEASE (CKD)

encompasses a spectrum of different

pathophysiologic processes associated with abnormal kidney function and a progressive decline in glomerular filtration rate (GFR).

RISK FACTORS hypertension, diabetes mellitus, autoimmune disease, older age, African ancestry, a family history of renal disease, a previous episode of acute kidney injury, and the presence of proteinuria, abnormal urinary sediment, or structural abnormalities of the urinary tract.

CHRONIC RENAL FAILURE

applies to the process of continuing significant irreversible reduction in nephron number and typically corresponds to CKD stages 35

END-STAGE RENAL DISEASE

represents a stage of CKD where the

accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome. leads to death unless the toxins are removed by renal replacement therapy, using dialysis or kidney transplantation

PATHOPHYSIOLOGY OF CKD
involves two broad sets of mechanisms of damage (1) initiating mechanisms specific to the underlying etiology (e.g., genetically determined abnormalities in kidney development or integrity, immune complex deposition and inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium)

PATHOPHYSIOLOGY OF CKD
and (2) a set of progressive mechanisms,

involving hyperfiltration and hypertrophy of the remaining viable nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology

Staging of CKD
In order to stage CKD, it is necessary to

estimate the GFR.

CHRONIC KIDNEY DISEASE (CKD)

The normal annual mean decline in GFR with

age from the peak GFR (120 mL/min per 1.73 m2) attained during the third decade of life is 1 mL/min per year per 1.73 m2 70 mL/min per 1.73 m2 at age 70. The mean GFR is lower in women than in men.

CHRONIC KIDNEY DISEASE (CKD)

Measurement of albuminuria is also helpful

for monitoring nephron injury and the response to therapy 24-h urine collection is the criterion standard for measurement of albuminuria Persistence in the urine of >17 mg of albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage

CHRONIC KIDNEY DISEASE (CKD)

Microalbuminuria refers to the excretion of

amounts of albumin too small to detect by urinary dipstick or conventional measures of urine protein
a good screening test for early detection of renal

disease, and may be a marker for the presence of microvascular disease in general

CHRONIC KIDNEY DISEASE (CKD)

Stages 1 and 2 CKD are usually not associated with any

symptoms arising from the decrement in GFR. there may be symptoms from the underlying renal disease itself even with well-preserved GFR
edema in patients with nephrotic syndrome signs of hypertension secondary to the renal parenchymal

disease in patients with polycystic kidney disease, some forms of glomerulonephritis, and many other parenchymal and vascular renal diseases

Most evident complications:

anemia and associated easy fatigability; decreasing appetite with

progressive malnutrition; abnormalities in calcium, phosphorus, and mineral-regulating hormones, such as 1,25(OH)2D3 (calcitriol), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23); and abnormalities in sodium, potassium, water, and acid-base homeostasis.

CHRONIC KIDNEY DISEASE (CKD)

Many patients, especially the elderly, will have GFR

values compatible with stage 2 or 3 CKD (majority of these patients will show no further deterioration of renal function) If there is evidence of decline of GFR and uncontrolled hypertension or proteinuria, referral to a nephrologist is appropriate. If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually experience a marked disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome.

 The most frequent cause of CKD in North America and Europe is diabetic nephropathy, most often secondary to type 2 diabetes mellitus. Patients with newly diagnosed CKD often also present with hypertension. When no overt evidence for a primary glomerular or tubulointerstitial kidney disease process is present, CKD is often attributed to hypertension.

Cardiovascular Abnormalities
Cardiovascular disease is the leading cause

of morbidity and mortality in patients at every stage of CKD.

Ischemic Vascular Disease

The presence of any stage of CKD is a major risk

factor for ischemic cardiovascular disease The increased prevalence of vascular disease in CKD patients derives from both traditional ("classic") and nontraditional (CKD-related) risk factors.
Traditional risk factors include hypertension,

hypervolemia, dyslipidemia, sympathetic overactivity, and hyperhomocysteinemia. CKD-related risk factors comprise anemia, hyperphosphatemia, hyperparathyroidism, sleep apnea, and generalized inflammation.

The inflammatory state appears to accelerate

vascular occlusive disease

Heart Failure
Abnormal cardiac function secondary to

myocardial ischemia, left ventricular hypertrophy, and frank cardiomyopathy, in combination with the salt and water retention that can be seen with CKD, often results in heart failure or even episodes of pulmonary edema.

Hypertension and Left Ventricular Hypertrophy

Hypertension is one of the most common

complications of CKD(usually develops early during the course of CKD and is associated with adverse outcomes) Left ventricular hypertrophy and dilated cardiomyopathy are among the strongest risk factors for cardiovascular morbidity and mortality in patients with CKD

Treatment: Cardiovascular Abnormalities

Management of Hypertension Two overall goals of therapy for hypertension
to slow the progression of the kidney disease itself to prevent the extrarenal complications of high blood

pressure, such as cardiovascular disease and stroke.

In all patients with CKD, blood pressure should be

controlled to levels recommended by national guideline panels. In CKD patients with diabetes or proteinuria >1 g per 24 h, blood pressure should be reduced to 125/75, if achievable without prohibitive adverse effects.

Treatment: Cardiovascular Abnormalities

When volume management alone is not

sufficient, the choice of antihypertensive agent is similar to that in the general population.
The ACE inhibitors and ARBs slow the rate of

decline of kidney function, but occasionally can precipitate an episode of acute kidney injury, especially when used in patients with ischemic renovascular disease.

Treatment: Cardiovascular Abnormalities

Management of Cardiovascular Disease There are many strategies available to treat the traditional and nontraditional risk factors in CKD patients. While these have been proved effective in the general population, there is little evidence for their benefit in patients with advanced CKD, especially those on dialysis hypertension, elevated serum levels of homocysteine, and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD.

Treatment: Cardiovascular Abnormalities

Modulation of traditional risk factors may be the

only weapon in the therapeutic armamentarium for these patients until the nature of inflammation in CKD and its treatment are better understood. Lifestyle changes, including regular exercise, should be advocated but are not often implemented. Hyperlipidemia in patients with CKD should be managed according to national guidelines. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD

Initial Approach History and Physical Examination

Symptoms and overt signs of kidney disease are often

subtle or absent until renal failure supervenes. History of:

hypertension (which can cause CKD or more commonly be a

consequence of CKD) diabetes mellitus abnormal urinalyses problems with pregnancy such as preeclampsia or early pregnancy loss.

Drug history: nonsteroidal anti-inflammatory agents, gold,

penicillamine, antimicrobials, chemotherapeutic agents, antiretroviral agents, proton pump inhibitors, phosphatecontaining bowel cathartics, and lithium, exposure to medical imaging radiocontrast agents

Initial Approach History and Physical Examination

In evaluating uremic syndrome: appetite, weight loss, nausea, hiccups, peripheral edema,

muscle cramps, pruritus, and restless legs Family history of kidney disease assessment of manifestations in other organ systems such as auditory, visual, integumentary and others, may lead to the diagnosis of a heritable form of CKD (e.g., Alport or Fabry syndrome, cystinuria, among others) or shared environmental exposure to nephrotoxic agents (e.g., heavy metals, aristolochic acid)

Initial Approach History and Physical Examination

The physical examination should focus on blood pressure and target organ damage from

hypertension. Funduscopy (diabetic retinopathy) and precordial examination (left ventricular heave, a fourth heart sound) should be carried out Edema and sensory polyneuropathy. The finding of asterixis or a pericardial friction rub not attributable to other causes usually signifies the presence of the uremic syndrome.

Laboratory Investigation
Focus on a search for clues to underlying causative or aggravating disease process and on

the degree of renal damage and its consequences.

Serum and urine protein electrophoresis, looking for

multiple myeloma, should be obtained in all patients >35 years with unexplained CKD, especially if there is associated anemia and elevated, or even inappropriately normal, serum calcium concentration in the face of renal insufficiency. In the presence of glomerulonephritis, lupus and underlying infectious etiologies such as hepatitis B and C and HIV should be assessed.

Laboratory Investigation
Serial measurements of renal function should be obtained to determine the pace of renal

deterioration and ensure that the disease is truly chronic

Serum concentrations of calcium, phosphorus, vitamin

D, and PTH Hemoglobin concentration, iron, B12, and folate should also be evaluated. 24-h urine collection may be helpful, as protein excretion >300 mg may be an indication for therapy with ACE inhibitors or ARBs.

Imaging Studies
Renal ultrasound
most useful imaging study can verify the presence of two kidneys, determine if

they are symmetric, provide an estimate of kidney size, and rule out renal masses and evidence of obstruction. bilaterally small kidneys supports the diagnosis of CKD of long-standing duration, with an irreversible component of scarring. If the kidney size is normal, it is possible that the renal disease is acute or subacute. The exceptions are diabetic nephropathy, amyloidosis, and HIV nephropathy, where kidney size may be normal in the face of CKD.

Imaging Studies
The diagnosis of renovascular disease can be undertaken with different techniques, including

Doppler sonography, nuclear medicine studies, or CT or MRI studies. Radiographic contrast imaging studies are not particularly helpful in the investigation of CKD. Intravenous or intraarterial dye should be avoided where possible in the CKD patient, especially with diabetic nephropathy, because of the risk of radiographic contrast dyeinduced renal failure.

Renal Biopsy
In the patient with bilaterally small kidneys, renal biopsy is not advised because:
it is technically difficult and has a greater likelihood of

causing bleeding and other adverse consequences there is usually so much scarring that the underlying disease may not be apparent the window of opportunity to render disease-specific therapy has passed.

Other contraindications to renal biopsy include uncontrolled hypertension, active urinary tract infection, bleeding diathesis (including ongoing

anticoagulation), and severe obesity.

Renal Biopsy
Ultrasound-guided percutaneous biopsy is

the favored approach, but a surgical or laparoscopic approach can be considered, especially in the patient with a single kidney where direct visualization and control of bleeding are crucial. Bleeding time should be measured, and, if increased, desmopressin should be administered immediately prior to the procedure.

Establishing the Diagnosis and Etiology of CKD

The most important initial diagnostic step of a patient

presenting with elevated serum creatinine is to distinguish newly diagnosed CKD from acute or subacute renal failure Previous measurements of serum creatinine concentration are particularly helpful Elevated serum creatinine concentration in the past suggests that the renal disease represents the progression of a chronic process. Evidence of metabolic bone disease with hyperphosphatemia, hypocalcemia, and elevated PTH and bone alkaline phosphatase levels suggests chronicity.

Establishing the Diagnosis and Etiology of CKD

Normochromic, normocytic anemia suggests

that the process has been ongoing for some time. The finding of bilaterally reduced kidney size (<8.5 cm in all but the smallest adults) favors CKD. In the absence of a clinical diagnosis, renal biopsy may be the only recourse to establish an etiology in early-stage CKD.

Treatment: Chronic Kidney Disease

Optimized glucose control in diabetes mellitus Immunomodulatory agents for glomerulonephritis Emerging specific therapies to retard cytogenesis in polycystic

kidney disease.
The optimal timing of both specific and nonspecific therapy is

usually well before there has been a measurable decline in GFR and certainly before CKD is established

Treatment: Chronic Kidney Disease

It is helpful to sequentially measure and plot

the rate of decline of GFR in all patients Any acceleration in the rate of decline should prompt a search for superimposed acute or subacute processes that may be reversible. (ECFV depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to nephrotoxic agents)

Reducing Intraglomerular Hypertension and Proteinuria

Increased intraglomerular filtration pressures and glomerular hypertrophy develop as a

response to loss of nephron number from different kidney diseases. promotes the ongoing decline of kidney function

Control of systemic and glomerular hypertension is important in slowing the progression of CKD( Antihypertensive therapy ) 125/75 mmHg as the target blood pressure in proteinuric CKD patients.

Reducing Intraglomerular Hypertension and Proteinuria

ACE inhibitors and ARBs inhibit the

angiotensin-induced vasoconstriction of the efferent arterioles of the glomerular microcirculation

effective in slowing the progression of renal failure

in patients with advanced stages of both diabetic and nondiabetic CKD.

Slowing Progression of Diabetic Renal Disease

Diabetic nephropathy is now the leading

cause of CKD requiring renal replacement therapy in many parts of the world The prognosis of diabetic patients on dialysis is poor, with survival comparable to many forms of cancer

Control of Blood Glucose

Excellent glycemic control reduces the risk of

kidney disease and its progression in both type 1 and type 2 diabetes mellitus. It is recommended that plasma values for preprandial glucose be kept in the 90130 mg/dL range and hemoglobin A1C should be < 7%. As the GFR decreases with progressive nephropathy, the use and dose of oral hypoglycemics needs to be reevaluated

Control of Blood Pressure and Proteinuria

Hypertension is found in the majority of type 2

diabetic patients at diagnosis. Microalbuminuria, the finding of albumin in the urine not detectable by the urine dipstick, precedes the decline in GFR and heralds renal and cardiovascular complications. Testing for microalbumin is recommended in all diabetic patients, at least annually. If the patient already has established proteinuria, then testing for microalbumin is not necessary.

Control of Blood Pressure and Proteinuria

Antihypertensive treatment reduces

albuminuria and diminishes its progression even in normotensive diabetic patients. the use of ACE inhibitors and ARBs in particular is associated with additional renoprotection.

Protein Restriction
While protein restriction has been advocated

to reduce symptoms associated with uremia, it may also slow the rate of renal decline at earlier stages of renal disease. daily protein intake of between 0.60 and 0.75 g/kg per day, depending upon patient adherence, comorbid disease, presence of proteinuria, and nutritional status. at least 50% of the protein intake be of high biologic value.

Protein Restriction
As patients approach stage 5 CKD,

spontaneous protein intake tends to decrease, and patients may enter a state of protein-energy malnutrition hence protein intake of up to 0.90 g/kg per day might be recommended with emphasis on proteins of high biologic value. Sufficient energy intake is important to prevent protein-calorie malnutrition, and 35 kcal/kg is recommended.

Managing Other Complications of Chronic Kidney Disease

Medication Dose Adjustment For those agents in which >70% excretion is by a nonrenal route, such as hepatic elimination, dose adjustment may not be needed. Some drugs that should be avoided include metformin, meperidine, and oral hypoglycemics that are eliminated by the kidney. NSAIDs should be avoided Nephrotoxic medical imaging radiocontrast agents and gadolinium should be avoided or used according to strict guidelines when medically necessary as described above.

Managing Other Complications of Chronic Kidney Disease

Preparation for Renal Replacement Therapy Temporary relief of symptoms and signs of impending uremia may sometimes be achieved with protein restriction However, this carries a significant risk of protein-energy malnutrition thus plans for more long-term management should be in place.

Managing Other Complications of Chronic Kidney Disease

Clear indications for initiation of renal replacement therapy for patients with CKD include: uremic pericarditis Encephalopathy intractable muscle cramping Anorexia nausea not attributable to reversible causes such as peptic ulcer disease evidence of malnutrition fluid and electrolyte abnormalities, principally hyperkalemia or ECF volume overload, that are refractory to other measures.

Managing Other Complications of Chronic Kidney Disease

Because of the interindividual variability in the

severity of uremic symptoms and renal function, it is ill-advised to assign an arbitrary urea nitrogen or creatinine level to the need to start dialysis. On a practical level, advanced preparation may help to avoid problems with the dialysis process itself and thus preempt the morbidity associated with resorting to the insertion of temporary hemodialysis access with its attendant risks of sepsis, bleeding, and thrombosis.

Patient Education
Social, psychological, and physical preparation for the transition to renal replacement therapy

and the choice of the optimal initial modality are best accomplished with a gradual approach involving a multidisciplinary team. it is important to prepare patients with an intensive educational program, explaining the likelihood and timing of initiation of renal replacement therapy and the various forms of therapy available.

 The more knowledgeable that patients are about hemodialysis (both in-center and home-

based), peritoneal dialysis, and kidney transplantation, the easier and more appropriate will be their decisions. The educational programs should be commenced no later than stage 4 CKD so that the patient has sufficient time and cognitive function to learn the important concepts, to make informed choices, and implement preparatory measures for renal replacement therapy.

 Exploration of social service support is also

important. early education of family members Kidney transplantation offers the best potential for complete rehabilitation, because dialysis replaces only a small fraction of the kidneys' filtration function and none of the other renal functions, including endocrine and antiinflammatory effects.

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