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Chronic renal disease (CRD) (Chronic kidney disease)

A general term for heterogeneous disorders affecting the structure and function of the kidneys.

Chronic kidney disease (CKD)—or chronic renal failure (CRF), are terms that encompasses all degrees of decreased renal function, from damaged–at risk through mild, moderate, and severe chronic kidney failure.

In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes.

The prevalence of chronic kidney disease is higher in women (11·8%) than men (10·4%), although chronic kidney disease could be overestimated in women in part by assuming the same body surface area for both sexes in kidney function equations.

Autoimmune disease and infection (ie, pyelonephritis) are more common causes of chronic kidney disease in women than men, hypertension and diabetes prevail among men.

Pregnancy, as in the case of stroke, is a specific risk factor for women, as hypertensive disorders of pregnancy predispose women for developing chronic kidney disease later in life.

 In men with chronic kidney disease, testosterone deficiency is common, which increases men’s risk of cachexia and frailty.

Approximately 800,000 Americans have CRD as manifested by a serum creatinine level of 2.0 mg/dL or greater and more than 6.2 million are estimated the have a creatinine of greater  than 1.5 mg/dL.

Approximately 850 million people worldwide have chronic kidney disease, and almost 4 million receive renal replacement therapy.

Approximately 37 million people in the US  have chronic kidney disease.

Affects between 8-16% of the worldwide population, and is often under recognized.

1 in 10 American adults has some level of chronic kidney disease (CKD).

Kidney disease is the ninth leading cause of death in the United States.

Chronic kidney disease is the ninth leading cause of death (1·8% of deaths) for women, but is not among the ten leading causes of death for men.

The incidence of recognized CKD in people aged 20-64 years in the United States is less than 0.5%.

In contrast, the incidence of recognized CKD in people aged 65 years or older is approximately 4.3%.

The US prevalence of CKD increases dramatically with age- 4% at age 29-39 y; 47% at age >70 y.

CKD affects more than 10% of the worlds population and more than half of adults older than seventy years.

Autoimmune disease and infection (ie, pyelonephritis) are more common causes of chronic kidney disease in women than men, hypertension and diabetes prevail among men.

More than 520,000 Americans are undergoing dialysis, and fewer than 225,000 have a functioning kidney transplant.

Globally it is most commonly attributed to diabetes and or hypertension, but other causes such as glomerulonephritis, infection, and environmental exposures may contribute.

Less than 2% of patients with chronic kidney disease process progress to end-stage renal disease, as most patients with chronic kidney disease die of a cardiovascular event before they progress on to end-stage renal disease.

The prevalence of cardiovascular disease is markedly higher in patients with CKD compared to those without CKD: 65% of Medicare patients with CKD had cardiovascular disease compared to 32% without CKD.

The presence of CKD is associated with worse cardiovascular outcomes.

Estimated that 6-8% of non-institutionalized adults in the US have a GFR less than 60 mL/minute per 1.73 m² and nearly 10% of albuminuria.

Black individuals are 2-4 times more likely than others to progress to kidney failure and are less likely to receive optimal therapy including kidney transplants.

Sickle cell trait is not associated with diabetic or nondiabetic ESRD in a large sample of black patients.

Sickle cell trait, occurs in approximately 8% of African-Americans is associated with increased risk of kidney disease.
Compared with noncarriers of the sickle cell trait, they have a 1.8 odds for  the incident chronic kidney disease, a1..3 fold odds of GFR decline greater than 3 mL per minute per 1.73 m² and a 1.9 fold odds of albuminuria.

Glomerular disease is much more common among nonwhite persons.

Men have a more rapid decline in renal function and a greater risk to progression to end stage renal disease than women.

Focal segmental glomerular sclerosis is more common among Hispanic Americans and black persons, as is the risk of nephropathy with diabetes or with hypertension;

IgA nephropathy is rare in black individuals and more common among those with Asian ancestry.

Defined by reduced glomerular filtration rate of less than 60 mL per minute /1.73 m² or kidney damage usually detected by high albuminuria with greater than 30 mg of albumin per g of creatinine.

CKD defined as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months.

The estimated prevalence of CKD by stage is:

Stage 1: 5.7%

Stage 2: 5.4%

Stage 3: 5.4%

Stage 4: 0.4%

Stage 5: 0.4%

The US incidence of end-stage renal disease (ESRD)

Is approximately 350 per 1 million population.

The incident rate of ESRD cases at the initiation of hemodialysis is higher for males, with 415.1 per million population compared with 256.6 for females.

The percentage of patients older than 65 years has been the most rapidly growing segment of the ESRD population, having increased from 5% to 37% for this group.

Smokers tend to reach ESRD earlier than nonsmokers.

In patients with CKD stages 2-4 and subclinical hypothyroidism, thyroid hormone replacement therapy (THRT) with L-thyroxine delayed the rate of decline in kidney function to end-stage renal disease.

The incidence rate of ESRD among blacks in the United States is nearly 4 times that for whites.

Once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR.

With renal injury the kidney has the ability to maintain GFR, despite progressive destruction of nephrons, as the remaining nephrons manifest hyperfiltration and compensatory hypertrophy allowing for continued normal clearance of plasma solutes.

Generally, disturbances become clinically manifest with CKD stages 4-5 (GFR < 30 mL/min/1.73 m²).

With aging juxtamedullary glomeruli see a shunting of blood from afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla, contributing to an age-related decrease in renal blood flow.

Altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging.

Patients with tubulointerstitial disease, cystic diseases, nephrotic syndrome, and other conditions associated with symptoms like polyuria, hematuria, edema are more likely to develop signs of disease at earlier stages.

With age there is a wide variation in the rate of GFR decline reported because of race, gender, genetics and other risk factors for renal dysfunction.

The increased risk of CKD is contributed to by the non-white race, lower education, low income, and food insecurity.
African Americans and Pacific Islanders have substantially greater risk of end-stage kidney disease, due to increased prevalence of hypertension, diabetes, and obesity.

Genetic risk factors contribute to CRD risk: sickle cell trait in the presence of 2 APOL1 risk alleles, both coming in people of African dissent but not European ancestry, may double the risk of chronic kidney disease.In CKD extracellular volume expansion and total-body volume overload results from failure of sodium and free-water excretion when the GFR falls to less than 10-15 mL/min/1.73 m², when compensatory mechanisms have become exhausted.

At a higher GFR, excess sodium and water intake could result if the ingested amounts of sodium and water exceed the available potential for compensatory excretion.

Tubulointerstitial renal diseases represent the minority of cases of CKD, and such processes often cause fluid loss rather than overload.

Despite moderate or severe reductions in GFR, tubulointerstitial renal diseases may manifest first as polyuria and volume depletion, with inability to concentrate the urine.

Sodium retention and extracellular volume expansion lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension.

Paradoxically hyperfiltration and hypertrophy of residual nephrons has been hypothesized to represent a major cause of progressive renal dysfunction as the increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental and global glomerulosclerosis.

Inflammation and hemostasis are antecedent pathways for CKD.

Factors other than the underlying disease and glomerular hypertension that may cause progressive renal injury include: systemic hypertension, NSAIDs, intravenous contrast media, decreased perfusion from severe dehydration or shock, proteinuria, hyperlipidemia, hyperphosphatemia with calcium phosphate deposition, smoking, and diabetes.

Plasma levels of urea and creatinine show measurable increases only after total GFR has decreased to 50%.

The plasma creatinine value approximately doubles with a 50% reduction in GFR.

In children, the GFR increases to adult levels by d 2-3 years.

Early diagnosis and treatment of the underlying cause and/or institution of preventive measures is required care in patients with CKD as it may slow, or possibly halt, progression of the disease.

A normal kidney contains approximately 1 million nephrons, each of which contributes to the total glomerular filtration rate (GFR).

A doubling of serum creatinine concentration from baseline corresponds to a 57% reduction in estimated GFR and is used to document chronic kidney disease progression, but it is a late event requires a long follow-up and large sample sizes.

Not a functionally static prices but a potentially progressive one that may result in end-stage renal disease.

One year change in estimated GFR is strongly related to ESRD.

People with impaired renal function are 5.5 times more likely to die than those with normal renal function.

Causes of chronic kidney disease (CKD) include the following:

Diabetic kidney disease

Hypertension

Vascular disease

Glomerular disease (primary or secondary)

Cystic kidney diseases

Tubulointerstitial disease

Urinary tract obstruction or dysfunction

Recurrent kidney stone disease

Congenital (birth) defects of the kidney or bladder

Unrecovered acute kidney injury

Vascular diseases that can cause CKD include:

Renal artery stenosis

Cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)–positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides

ANCA-negative vasculitides

Atheroemboli

Hypertensive nephrosclerosis

Renal vein thrombosis

Primary glomerular diseases include the following:

Membranous nephropathy

Alport syndrome

Immunoglobulin A (IgA) nephropathy

Focal and segmental glomerulosclerosis (FSGS)

Minimal change disease

Membranoproliferative glomerulonephritis (MPGN)

Complement-related diseases (eg, atypical hemolytic-uremic syndrome [HUS], dense deposit disease)

Rapidly progressive (crescentic) glomerulonephritis

Secondary causes of glomerular disease include the following:

Diabetes mellitus

Systemic lupus erythematosus

Rheumatoid arthritis

Mixed connective tissue disease

Scleroderma

Wegener granulomatosis

Mixed cryoglobulinemia

Endocarditis

Hepatitis B and C

Syphilis

Human immunodeficiency virus (HIV)

Parasitic infection

Heroin use

Gold

Penicillamine

Amyloidosis

Light-chain deposition disease

Neoplasia

Thrombotic thrombocytopenic purpura (TTP)

Shiga-toxin or Streptococcus pneumoniae – related HUS

Henoch-Schönlein purpura

Reflux nephropathy

Causes of tubulointerstitial disease include the following:

Drugs such as sulfonamides, allopurinol.

Infection of viral, bacterial, or parasitic type.

Sjögren syndrome

Tubulointerstitial nephritis and uveitis (TINU) syndrome

Chronic hypokalemia

Chronic hypercalcemia

Sarcoidosis

Multiple myeloma nephropathy

Heavy metals

Radiation nephritis

Polycystic kidneys

Cystinosis and other inherited diseases

Urinary tract obstruction may result from:

Benign prostatic hypertrophy

Urolithiasis

Urethral stricture

Tumors

Neurogenic bladder

Congenital defects of the kidney or bladder

Retroperitoneal fibrosis

Associated with elevated homocysteine.

Commonly associated with thyroid dysfunction.

Adverse drug events and inappropriate prescribing of drugs related to renal function are estimated to occur in 20-46% of patients with impaired kidney function, yet 91% of these instances may be preventable.

Low estimated GFR and high albuminuria are independently associated with mortality and end-stage real disease regardless of age, across a wide range of populations.

Guidelines recommend the inclusion of estimated GFR and albuminuria levels when evaluating risks for overall mortality, cardiovascular disease, end-stage kidney failure, acute kidney injury, and the progression of CKD.

A strong association exists between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in hospitalized patients with diabetes mellitus.

Hemoglobin A-1C levels that are significantly lower or higher when associated with chronic kidney disease are associated with increased mortality.

Decreased glomerular filtration rate (GFR) is associated with an increased risk of obstructive sleep apnea.

Any AKI versus no AKI is a risk factor for stage 4 CKD, and each additional AKI episode doubles that risk.

One of the fastest growing health conditions in older people.

Puberty is often delayed among males and females with significant CKD.

Female patients with advanced renal insufficiency commonly develop menstrual irregularities.

Female gender is associated with a better renal prognosis in patients with chronic renal disease.

Women with ESRD are typically amenorrheic and infertile.

If pregnancy occurs with renal disease it can be associated with accelerated renal decline, including in women with a kidney transplant.

PPI’s associated with 20-50% increased risk of chronic kidney disease, the same was not found for the use of histamine2 receptor antagonists.

Approximately 30% of individuals older than 70 years have CKD.

The number of deaths from chronic renal disease has doubled between 1990 and 2010.

Disproportionately affects Hispanics, blacks, and Native Americans.

Defined by National Kidney Foundation as kidney damage of at least 3 months duration with damage defined as functional or structural abnormalities of the kidney with or without decreased GFR, and manifested as either pathologic abnormalities or markers of kidney damage.

The U.S. Renal data System reports that in 2006, the adjusted incidence of end-stage renal diseae increased to 360 cases per million people.

Chronic renal disease (CRD)-National Kidney Foundation staging system for CRD

Stage 1-kidney damage with normal or increased GFR-≥90mL/min/1.73m2.

Stage 2-kidney damage with mildly decreased GFR-60-89mL/min/1.73m2.

Stage 3-moderately decreased GFR 30-59mL/min/1.73m2.

Stage 4-severely decreased GFR- 15-29mL/min/1.73m2

Stage 5-kidney failure GFR <15mL/min/1.73m2

Estimated GFR can be derived from a single serum creatinine measurement, combined with age, sex, and race.

GFR undergoes an annual mean decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years.

Creatinine is derived from muscle and, therefore children and smaller individuals have lower creatinine levels independent of the GFR.

Labs should supply appropriate pediatric normal ranges, and results for individuals who have low muscle mass due to malnutrition, cachexia, or amputation.

CKD during childhood is rare and is usually the result of congenital defects, such posterior urethral valves or dysplastic kidney malformations.

Genetic kidney diseases are also frequently manifested in childhood CKD.

Most cases are acquired rather than inherited.

CKD in a child is more likely to have a genetic or inherited cause.

Genetic syndromes associated with CKD include autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome, single-gene or few-gene mutations associated with CKD include Dent disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS).

Black patients with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk for hypertension-attributable ESRD and FSGS.

Elevated FGF-23 gene levels are an independent risk factor for ESRD.

6 SNPs are associated with reduced GFR, located in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80.

SLC47A1 SNP is associated with decreased GFR in nondiabetic individuals,

SNPs located in the DNAJC16 and CDK12 genes are associated with decreased GFR in individuals younger than 65 years.

Polymorphisms in genes involving the renin-angiotensin system (RAS) have also been implicated in predisposition to CKD.

Testosterone can increase oxidative stress, activate the renin angiotensin system, and aggravate renal fibrosis.

Estrogens inhibit these pathological processes in the diseased kidney.

CKD patients are significantly more likely to have the A2350G polymorphism in the ACE gene.

Estimated GFR lower than 60 ml/ min/1.73 m² indicates moderate to severe kidney disease.

Stage 1 CKD is associated with other evidence of damage to the kidneys, such as albuminuria.

The first two stages of chronic kidney disease are a warning that one should be concerned about preventing future renal damage.

In preventing ESRD in older patients with CKD, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have only marginal benefit.

The use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers is recommended in diabetic kidney disease with or without proteinuria.

In nondiabetic kidney disease, these agents are effective in retarding the progression of disease among patients with proteinuria of more than 500 mg/day.

A low-protein diet may slow the GFR decline in patients with the most rapidly declining GFR and reduce proteinuria, but the magnitude of the effect is relatively weak.

Protein restriction early in chronic kidney disease to delay a decline in the glomerular filtration rate is controversial.

Additional dietary restrictions may also be indicated:

Phosphate restriction starting early in CKD

Potassium restriction

Sodium and water restriction as needed to avoid volume overload

Fruits and vegetables that increasing the amount of alkali in the diet may help to reduce kidney injury.

As a patient approaches CKD stage 5, protein restriction is recommended in adults, but not in children, to delay the onset of uremic symptoms.

Patients with chronic renal disease are predisposed to becoming malnourished and are at higher risk for malnutrition with overly aggressive protein restriction.

Reduction in salt intake may slow the progression of diabetic kidney disease by lowering blood pressure.

Aggressive blood pressure control can help to delay the decline in renal function in patients with CKD, and systolic blood pressure (SBP) control is considered more important than diastolic blood pressure control.

In the first two stages improved blood pressure control, improved glycemia in diabetes, reduced use of nonsteroidal anti-inflammatory drugs and frequent screening for albuminuria are indicated.

Stage 3 chronic kidney disease comprises the largest category of chronic kidney disease.

Patients with chronic kidney disease (CKD) stages 1-3 (glomerular filtration rate [GFR] >30 mL/min/1.73 m²) are frequently asymptomatic, and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements.

On CKD can cause altered salt and water processing may cause edema, pulmonary edema and hypertension.

Anemia, develops primarily as a result of decreased renal synthesis of erythropoietin, and also is associated with the development of cardiovascular disease, new onset of heart failure, more severe heart failure, and increased cardiovascular mortality.

BNP is often elevated  in patients  with reduced GFR, even in the absence of cardiovascular disease.

Chronic elevations of cardiac troponin occur in chronic kidney disease related to myocardial strain from altered hemodynamics, inflammation, endothelial dysfunction, subendocardial ischemia, and possibly reduced clearance.

Adults aged 50 years or above with an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 who are not being treated with long-term dialysis or kidney transplantation should be treated with a statin or a statin plus ezetimibe.

Patients aged 18-49 years with an estimated GFR of less than 60 mL/min/1.73 m2 who are not being treated with or kidney transplantation should be treated with statins if they have coronary disease, diabetes, prior ischemic stroke, or an estimated 10-year incidence of coronary death or nonfatal myocardial infarction exceeding 10%.

Patients aged 50 years or older with CKD and an estimated GFR of 60 mL/min/1.73 m2 or higher should be treated with a statin.

Treatment with statins or statin/ezetimibe should not be initiated in adults with dialysis-dependent CKD.

Patients already being treated with a statin at the time of dialysis should continue.

Adult kidney transplant patients should be treated with a statin because of an increased risk for coronary events.

Other manifestations of uremia in end-stage renal disease (ESRD):

Pericarditis

Encephalopathy

Peripheral neuropathy

Restless leg syndrome

Gastrointestinal symptoms: Anorexia, nausea, vomiting, diarrhea

Skin manifestations: Dry skin, pruritus, ecchymosis

Fatigue, increased somnolence, failure to thrive

Malnutrition

Erectile dysfunction, decreased libido, and amenorrhea

Platelet dysfunction with tendency to bleed

Forty-five percent of adult patients with CKD have depressive symptoms at initiation of dialysis therapy.

The differential diagnosis for CKD includes:

Systemic lupus erythematosus

Renal artery stenosis

Urinary obstruction

Wegener granulomatosis

Acute Kidney Injury

Alport Syndrome

Autosomal Dominant Polycystic Kidney Disease

Chronic Glomerulonephritis

Diabetic Nephropathy

Goodpasture Syndrome

Multiple Myeloma

Nephrolithiasis

Nephrosclerosis

Rapidly Progressive Glomerulonephritis

Clinical manifestations resulting from low kidney function typically appear in stages 4-5.

Many patients with chronic kidney disease stage do not die of renal causes, and do not develop end-stage kidney disease overtime: there is a disconnect between classification based on estimated GFR and the patient’s clinical course.

Using a Chronic Kidney Disease Epidemiology Collaboration equation resulting in 28% reduction in the classification of individuals in to stages 3 to 5.

Approximately 20 million people in the U.S. are at risk for CRD.

Mortality associated with chronic kidney disease is high, and is related to both baseline kidney function and the rate of progression of disease.

Patients with CKD generally experience progressive loss of kidney function.

The rate of progression depends on age, the underlying diagnosis, the success of preventive measures, and the individual patient.

Lower estimated glomerular filtration rate (GFR), higher albuminuria, younger age, and male sex pointed to a faster progression of kidney failure.

Biological sex probably contributes to the more rapid rate of chronic kidney disease progression in men than women.

Also, a lower serum albumin, calcium, and bicarbonate level and a higher serum phosphate level were found to predict an elevated risk of kidney failure.

Patients with hyperphosphatemia are treated with dietary phosphate binders and dietary phosphate restriction.

Management of abnormal mineral homeostasis in patients with CKD includes:

Lowering high serum phosphorus levels

Maintaining serum calcium levels

Lowering serum parathyroid hormone levels

Providing osteoporosis prophylaxis

The use of phosphate binders are been proposed as a means of reducing elevated phosphorus levels in patients with CKD.

In patients with CKD who have normal or near-normal serum phosphorus levels, these agents significantly reduce serum and urinary phosphorus and discourage secondary hyperparathyroidism progression.

Phosphate binders encourage vascular calcification.

Hypocalcemia is treated with calcium supplements with or without calcitriol.

Hyperparathyroidism is treated with calcitriol, vitamin D analogues, or calcimimetics.

The calcimimetic Cinacalcet mimics calcium at the parathyroid hormone (PTH) receptor and reduces PTH levels.

Cinacalcet directly lowers intact PTH levels by increasing the sensitivity to extracellular calcium of calcium-sensing receptors on chief cells of the parathyroid glands.

Cinacalcet is indicated for secondary hyperparathyroidism in patients with CKD on dialysis.

The major cause of mortality increase is cardiovascular disease, but there is also increased with mortality from cancer and infections among patients with chronic kidney disease.

Serum free light chains increased in CRD.

High levels of free light chains associated with increased mortality in patients with chronic renal disease.

Meta-analysis show an independent association between serum free light chain levels and progression to ESRD and mortality in patients with chronic kidney disease.

Less than 2% of patients with chronic kidney disease require renal replacement therapy, and this is explained partly by increased risk of death from cardiovascular disease before progression to end-stage renal disease.

Cardiovascular complications from kidney disease include: angina pectoris, myocardial infarction, heart failure, stroke, peripheral vascular disease, arrhythmias and sudden death (Pun PH).

Risk of cardiovascular complications from chronic kidney disease increases from early-stage to advance stage disease.

Following myocardial infarction patients with stage III or stage for chronic kidney disease have increased risk of death and poor outcomes probably related to the proximity of lesions to the coronary ostia (van Domburg RT and).

Chronic kidney disease is associated with sudden death and uremic cardiomyopathy is characterized by diastolic dysfunction heart failure and LVH.

For patients with stages 4-5 CKD, the adjusted mortality rate is 76% greater.

Mortality rates are consistently higher for men than for women, and for black persons than for white individuals and patients of other races.

For Medicare CKD patients aged 66 years and older, deaths per 1000 patient-years in 2009 were 75 for white patients and 83 for black patients.

The highest mortality rate is within the first 6 months of initiating dialysis.

Mortality then tends to improve over the next 6 months, before increasing gradually over the next 4 years.

At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a patient aged 60 years who is starting hemodialysis is closer to 4 years.

In older individuals serum cystatin C levels, an estimate of GFR, is linearly related to the risk of cardiovascular events, premature death, and decline in functional status.

Affects 11% of U.S. men and 15% of U.S. women.

Incidence increasing.

More than 20 million people in U.S. have stage 2,3,4 chronic kidney disease.

About half the patients with chronic kidney disease have stage 1 or 1 disease.

Longevity increases the risk of developing diabetes, hypertension, atherosclerosis vascular disease and exposure to nephrotoxic medications that can impair renal function.

Nephrotoxic drugs include: NSAIDs, antibiotics, chemotherapy drugs, proton pump inhibitors and radio contrast agents.

In chronic kidney disease drugs that are excreted or metabolized renally should be adjusted according to the residual glomerular filtration rate, and some drugs are contraindicated in moderate to severe renal impairment because of potentially serious effects from drug or metabolite accumulation.

More than 320,000 individuals have stage 5 disease, including those on dialysis, or have functioning renal transplant.

Patients with ESRD who undergo renal transplantation survive longer than those on long-term dialysis.

More frequent dialysis episodes than 3/week increases risk of vascular access problems.

Mortality in patients with CKD is 56% greater than that in patients without CKD.

End-stage renal patients account for more than a half a million hospitalizations per year with an average stay of 11 days.

Rates of hospitalization in the CKD population, are 3-5 times higher than those of patients without CKD.

Hemodialysis and peritoneal dialysis patients average 2 hospital admissions per year.

Patients who have a renal transplant average 1 hospital admission per year.

African-Americans have 2-3 times risk of Caucasians.

Black individuals have genetic susceptibility factors for CRD, have higher probably all CRD stages, more rapid progression of kidney disease than white people.

Black individuals develop stage 4 chronic kidney disease,on average 10-15 years earlier than whites.

Monoclonal gammopathy has emerge as important causes kidney injury is responsible for variety of glomerular, to below interstitial, and vascular lesions within the kidney-monoclonal gammopathy of renal significance.

Monoclonal gammopathy of renal significance describes a B-cell or plasma cell clonal disorder that does not fill the criteria for cancer, yet  produces a nephrotoxic monoclonal immunoglobin that leads to kidney injury or disease.

Approximately 17% of people older than 60 years have an estimated GFR less than 60 mL/min per 1.73m2.

Recommended that patients with reduced renal function with a serum creatinine > 1.7 mg/dL or glomerular filtration rate <30 mL/min should be referred to a nephrologists for evaluation and management.

85% of patients with impaired kidney function with a GFR lower than 55 mL/min/1.73m2 have progressive loss of kidney function of 4 mL/min/year.

Rising incidence and prevalence is a global trend.

Incidence of end stage renal disease increased 43% during the decade following 1991.

Increasing incidence related to the increasing prevalence of hypertension and diabetes.

Chronic renal disease in developed countries associated with old age, diabetes, hypertension, obesity, and cardiovascular disease.

Aging initiates various structural and functional changes within the kidney, as renal mass progressively declines with advancing age, and glomerulosclerosis leads to a decrease in renal weight.

There is a decrease in glomerular number of as much as 30-50% by age 70 years.

The GFR peaks during the third decade of life at approximately 120 mL/min/1.73 m2.

Diabetic glomerularosclerosis was characterized by slowly worsening of albuminuria, hypertension and progressive decline in GFR, sometimes with nephrotic syndrome.

In a study involving 4038 patients with diabetes, chronic kidney disease, and anemia were randomly assigned to darbepoetin to achieve a hemoglobin of approximately 13 g per deciliter compared to placebo and darbepoetin rescue when the hemoglobin was less than 9 g per deciliter: the use of darbepoetin for diabetic patients with chronic kidney disease and moderate anemia, who were not undergoing dialysis did not reduce death, or cardiovascular events, or renal events and was associated with an increased risk of stroke(Trial to Reduce Cardiovascular Events with Aranesp Therapy [TREAT}.

When the hemoglobin level is below 10 g/dL, treatment with erythropoiesis-stimulating agents (ESAs) such as epoetin alfa or darbepoetin alfa are considered.

Growth factors are used to treat anemia of CKD by stimulating red blood cell production.

Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells, and induces the release of reticulocytes from the bone marrow into the bloodstream.

With erythropoietin treatment, the goal is a hemoglobin level of 10-12 g/dL, as normalization of hemoglobin in patients with CKD stages 4-5 has been associated with an increased risk of adverse outcomes.

Iron supplementation is required in almost all erythropoietin treated patients since iron deficiency may result in hypo-responsiveness to EPO.

Iron deficiency in these patients is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the gastrointestinal tract.

Ferrous sulfate is used for hemoglobin synthesis in patients with anemia of CKD who are being treated with erythropoietin.

Other iron treatments include Iron dextran, Iron sucrose (Venofer), Ferric gluconate (Ferrlecit), Ferumoxytol (Feraheme)

In hemodialysis patients iron stores may be depleted from blood loss from numerous sources and total 1-4 g of iron per year.

In patients with chronic kidney disease iron stores should be evaluated and iron saturation should be maintained at 30-50% and ferritin at 200 to 500 ng/ milliliter.

Patients at increased risk for non cardiovascular morbidity and mortality including that caused by infection.

Bacteremia second leading cause of death with end stage renal disease requiring dialysis.

The prevalence in diabetes is 40%, and diabetes is the primary cause of kidney failure in 45% of patients receiving dialysis.

Diabetes and CKD are independent risk factors for cardiovascular disease events and progression to end-stage renal disease.

CKD with diabetes is associated with chronic inflammation and oxidative stress resulting in glomerular dysfunction, mesangial cell contraction, mesangial expansion, and decline in kidney function.

In patients with chronic kidney disease, higher physical activity is associated with lower rates of estimated GFR decline and higher handgrip strength and gait speed is associated with the risk of death.

Targeting a hemoglobin A1c lower than 7% slows progression of diabetic kidney disease, including microalbuminuria and overt nephropathy.

Hemoglobin A1c levels higher than 9% in CKD is associated with a markedly worse clinical outcome in diabetics with excess mortality (Shurraw S et al).

Hemoglobin A1c levels within 6.5% in CKD is associated with excess mortality in diabetic patients (Shurraw S et al).

Increasing incidence of albuminuria.

Renal impairment is a risk factor for bleeding with all anticoagulants.

In patients with the creatinine clearance of less than 60 mL/ min bleeding rates were increased in patients receiving unfractionated heparin or low molecular weight heparin.

Progression to ESRD results in an eightfold reduction in lifespan.

Present in 25% of patients with small unilateral renal masses at the time of presentation, this is despite a normal contralateral kidney.

Fibroblast growth factor 23 (FGF 23) levels increase as renal function declines.

Highest levels of fibroblast growth factor 23 known to be present in patients with chronic kidney disease.

Levels of fibroblast growth factor 23 increase in chronic renal insufficiency as a response to maintain neutral phosphate balance and normal phosphate levels with renal imnpairment of phosphate excretion.

It is likely that preventing increased serum phosphate is beneficial in CKD as the risk of adverse renal and cardiovascular outcomes in association with hyperphosphatemia and even modest elevations in serum phosphate within the normal range.

Secondary hyperparathyroidism develops in CKD because of the following factors:

Hyperphosphatemia

Hypocalcemia

Decreased renal synthesis of 1,25-dihydroxycholecalciferol.

Alteration in the parathyroid glands, which gives rise to increased PTH secretion and increased parathyroid growth.

Skeletal resistance to PTH

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion.

Phosphate retention begins in early CKD.

When the GFR falls, less phosphate is filtered and excreted.

Because of increased PTH secretion, which increases renal excretion of phosphate serum levels do not rise initially.

As the GFR falls toward CKD stages 4-5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m².

Increased phosphate concentration effects PTH concentration by its direct effect on the parathyroid glands.

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels.

Hypocalcemia also results from increased calcium-phosphate binding, caused by elevated serum phosphate levels.

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all independently trigger PTH synthesis and secretion.

PTH secretion becomes maladaptive, and the parathyroid glands, which initially hypertrophy, become hyperplastic.

Persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.

Treatments for the pathologic manifestations of CKD include:

Hyperphosphatemia: Dietary phosphate binders and dietary phosphate restriction.

Calcium acetate is used for the treatment of hyperphosphatemia in end-stage renal disease (ESRD). .

Hypocalcemia: Calcium supplements and possibly calcitriol

Hyperparathyroidism: Calcitriol or vitamin D analogue

Calcium carbonate is used for the treatment of hyperphosphatemia, normalizing phosphate concentrations in patients, and can also be used as a calcium supplement in these patients.

Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces.

Vitamin D analogues are recommended in patients with CKD stages 3-5, who are not on dialysis and in whom the serum parathyroid hormone (PTH) level is elevated.

Vitamin D increases the absorption of calcium in the intestines and decreases secretion of calcium in the kidneys.

Increased calcium levels in serum, decreases phosphate and PTH levels, as well as bone resorption.

Calcitriol, 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3 is the potent active metabolite of vitamin D, can be used to suppress PTH production and secretion in secondary hyperparathyroidism.

Calcitriol can alleviate hypocalcemia in CKD by increasing intestinal calcium absorption and helping to prevent secretion of calcium in the kidneys.

Doxercalciferol is a vitamin D analogue, 1-alpha-hydroxyergocalciferol, that is indicated for the treatment of secondary hyperparathyroidism in patients with CKD.

Paricalcitol is a synthetic vitamin D analogue that binds and activates vitamin D receptors in the kidneys, parathyroid glands, intestines, and bones, and used for the prevention and treatment of secondary hyperparathyroidism associated with CKD stages 3-4 and stage 5 patients on hemodialysis or peritoneal dialysis.

Paricalcitol reduces PTH levels, improves calcium and phosphorus homeostasis, and stimulates bone mineralization.

Dietary phosphate binders promote the binding of phosphate in the gastrointestinal tract to reduce hyperphosphatemia.

Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for the reduction of high phosphorus levels in patients with ESRD.

Lanthanum carbonate dissociates into ions in the upper gastrointestinal tract, binding to dietary phosphate, forming insoluble lanthanum phosphate complexes.

Lanthanum carbonate inhibits phosphorus absorption.

Sevelamer ( Renvela) is used for the reduction of serum phosphorus levels in patients with CKD on hemodialysis.

Sevelamer binds dietary phosphate in the intestine, thus inhibiting its absorption, resulting in fewer hypercalcemic episodes than does calcium acetate therapy.

Sucroferric oxyhydroxide (Velphoro) is an iron-based, calcium-free phosphate binder indicated for control of serum phosphorus levels in patients with chronic kidney disease on hemodialysis.

Paricalcitol (Zemplar), a synthetic vitamin D analogue is used for the prevention and treatment of secondary hyperparathyroidism associated with CKD stage 5.

Daily vitamin D supplementation decreases albuminuria in patients with stage 3-4 chronic kidney disease (CKD) who had low vitamin D levels and high parathyroid hormone (PTH) levels.

Cause of renal impairment in the presence of a small T1a renal mass is not known, as the tumor occupies <5% of the total renal volume.

Anemia is a common complication and usually develops as a consequence of erythropoeitin deficiency.

Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin.

Anemia starts early in the course of the disease and becomes more severe as, the GFR progressively decreases.

In CKD RBC survival is decreased, and bleeding tendency is increased from the uremia-induced platelet dysfunction.

Severity and prevalence of anemia closely associated with kidney dysfunction as the frequency of anemia increases from 27% to 76% with a decline in glomerular filtration rate from more than 60 mL/min1.73m2 to less than 15mL/min1.73m2.

Related anemia associated with excessive cardiovascular mortality, left ventricular hypertrophy, impaired sleep, impaired cognition, impaired exercise capacity and poor quality of life.

Reduced GFR associated with increased venous thromboembolism risk in the general population.

Recommended target hemoglobin of 11.0-12.0 gm per d/L with the use of recombinant human erythropoeitin.

Anemia strongly predictive of complications and death from cardiovascular disease causes in patients with chronic kidney disease.

Anemia associated with impaired quality of life, decreased exercise and increased mortality.

Use of erythropoietin for anemia associated with improved muscle strength, increased exercise capacity, improvement in fatigue, neurocognitive function and depression.

Potential adverse effects of erythropoietin treatment include hypertension, access site thrombosis in dialysis patients with arteriovenous shunts and increased cardiovascular risks.

Darbepoetin alfa and epoetin alfa dose should be managed to avoid hemoglobin levels greater than 12 g/dL.

The CREATE trial found that correction of anemia to a target 13-15 g/dL compared to 10.5-11.5 gm/dL did not affect the likelihood of a first cardiovascular event.

The CHOIR trial found that targeting a hemoglobin of 13.5 g/dL compared to 11.3 g/dL was associated with a significantly increased risk of death, myocardial infarction, congestive heart failure and stroke without any improvement in the quality of life.

Patients with prolonged exposure to aluminum based phosphate binders have lower PTH levels than other patients with similar impaired renal function.

Leads to failure to produce 1,25(OH)2D with reduced serum calcium and impaired absorption of intestinal calcium.

Cardiovascular disease is a major cause of morbidity and mortality.

Kidney disease is the ninth leading cause of death in the United States.

Kidney disease is the ninth leading cause of death in the United States.

New guidelines issued by the Canadian Society of Nephrology recommend delaying dialysis in CKD patients without symptoms until their glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or until the first onset of a clinical indication which includes symptoms of uremia, fluid overload, and refractory hyperkalemia or acidemia.

Close monitoring of the patient should begin when eGFR reaches 15 mL/min/1.73 m2.

Factors that may affect dialysis initiation include: patient education, and the the severity of existing uremic symptoms, and the rate of renal function decline.

Patients with CKD stages 1-3 (GFR >30 mL/min/1.73 m²) are generally asymptomatic.

Typically, it is not until stages 4-5 (GFR < 30 mL/min/1.73 m²) that endocrine/metabolic derangements or disturbances in water or electrolyte balance become clinically manifest.

Uremic manifestations with CKD stage 5 are believed to be primarily secondary to an accumulation of multiple toxins.

In Stage 5 disease metabolic acidosis may manifest as protein-energy malnutrition, loss of lean body mass, and muscle weaknes

Signs of metabolic acidosis in stage 5 CKD include:

Protein-energy malnutrition

Loss of lean body mass

Muscle weakness

In stage 5 disease alteration in renal handling of salt and water include:

Peripheral edema

Pulmonary edema

Hypertension

Anemia in CKD is associated with:

Fatigue

Reduced exercise capacity

Impaired cognitive function

Impaired immune function

Impaired quality of life

Risk of cardiovascular disease

New onset of heart failure

Increasing severity of heart failure

Increased cardiovascular mortality

Manifestations of uremia in end-stage renal disease (ESRD) include:

Pericarditis

Encephalopathy

Peripheral neuropathy

Restless leg syndrome

Anorexia, nausea, vomiting, diarrhea

Skin manifestations of dry skin, pruritus, ecchymosis

Fatigue

Increased somnolence

Failure to thrive

Malnutrition

Decreased libido

Amenorrhea

Platelet dysfunction with tendency to bleed

Laboratory studies used in the diagnosis of CKD can include the following:

Complete blood count

Basic metabolic panel

Urinalysis

Serum albumin levels

Lipid profile.

Evidence of renal bone disease can be derived from the following tests:

Serum phosphate

25-hydroxyvitamin D

Alkaline phosphatase

Intact parathyroid hormone (PTH) levels

No randomized controlled trials show indicate correcting metabolic acidosis in patients who are not yet in ESRD, provides benefits, but alkali therapy to maintain the serum bicarbonate concentration above 22 mEq/L. is recommended, as patients with CKD who receive bicarbonate supplementation show a slower decline in renal function.

Testng patients with chronic kidney disease (CKD) typically includes:

A complete blood count (CBC), basic metabolic panel, and urinalysis, with calculation of renal function.

Normochromic normocytic anemia is commonly seen in CKD.

The blood urea nitrogen (BUN) and serum creatinine levels will be elevated.

Hyperkalemia or low bicarbonate levels may be present.

Patients may have hypoalbuminemia as a result of urinary protein loss or malnutrition.

A lipid profile.

Serum phosphate, 25-hydroxyvitamin D, alkaline phosphatase, and parathyroid hormone levels are obtained to look for evidence of renal bone disease.

Renal ultrasonography and other imaging studies may be indicated.

Measurement of serum cystatin-C levels has a role in the estimation of kidney function.

Cystatin-C is a small protein that is expressed in all nucleated cells, and is an endogenous marker of renal function.

Cystatin-C is produced at a constant rate, and freely filtered by the glomerulus.

Cystatin-C is not secreted but is instead reabsorbed by tubular epithelial cells and catabolized, so it does not return to the bloodstream.

As part of the evaluation of patients with CKD the following tests may be ordered:

Serum and urine protein electrophoresis, serum and urine free light chains

Antinuclear antibodies (ANA), double-stranded DNA antibody levels to Screen for systemic lupus erythematosus.

Serum complement levels.

Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA) levels.

Anti–glomerular basement membrane (anti-GBM) antibodies.

Hepatitis B and C, human immunodeficiency virus (HIV).

Imaging studies and consideration of bladder function studies to evaluate for possible obstruction and other urologic abnormalities.

Although 24-hour urine collection for total protein and creatinine clearance (CrCl) can be performed, spot urine collection for total protein–to-creatinine (P/C) ratio allows reliable approximation of total 24-hour urinary protein excretion.

A first morning urine specimen is preferable to a random specimen, so that so-called orthostatic proteinuria can be excluded. In children, teenagers, and young adults in particular,

A patient with a Protein/Creatine ratio above 200 mg/mg should undergo a full diagnostic evaluation.

A value of greater than 300-350 mg/mg is within the nephrotic range.

Using an albumin-specific dipstick in patients at increased risk of chronic kidney disease is recommended, as it is a more sensitive marker than total protein for CKD from diabetes, hypertension, and glomerular diseases.

A positive dipstick test warrants calculation of the albumin-to-creatinine ratio, with a ratio greater than 30 mg/mg to be followed by a full diagnostic evaluation.

Proteinuria may suggest a glomerular or tubulointerstitial problem.

The urine sediment finding of red blood cells (RBCs) and RBC casts suggests proliferative glomerulonephritis.

Pyuria and/or white blood cell casts suggest interstitial nephritis, particularly if eosinophiluria is present, or urinary tract infection.

A retrograde pyelogram may be indicated if clinical suspicion for obstruction exists despite a negative finding on renal ultrasonography.

Plain abdominal radiography is particularly useful to look for radio-opaque stones or nephrocalcinosis.

A voiding cystourethrogram (VCUG) is the criterion standard for diagnosis of vesicoureteral reflux.

Computed tomography (CT) scanning can better define renal masses and cysts usually noted on ultrasound, and is the most sensitive test for identifying renal stones.

Intravenous (IV) contrast–enhanced CT scans should be avoided in patients with renal impairment to avoid acute renal failure.

Magnetic resonance imaging (MRI) is reliable in the diagnosis of renal vein thrombosis, as are CT scanning and renal venography.

Magnetic resonance angiography (MRA) is becoming more useful for the diagnosis of renal artery stenosis.

MRI contrast is problematic in patients with existing chronic kidney disease because they have a low, but potentially fatal, risk of developing nephrogenic systemic fibrosis.

Percutaneous renal biopsy is performed most often with ultrasonographic guidance.

Percutaneous renal biopsy uses spring-loaded or other semi-automated needle.

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear.

Kidney biopsies are also indicated in the management of diseases such as lupus, in which the prognosis depends on the extent of the involvement

Percutaneous renal biopsy’s most common complication is bleeding, which can be life-threatening.

Early diagnosis and treatment of the underlying cause and institution of secondary preventive measures are imperative in patients with chronic kidney disease.

Imaging studies that can be used in the diagnosis of CKD include: Renal ultrasonography: Useful to screen for hydronephrosis, which may not be observed in early obstruction, or for involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy; small, echogenic kidneys are observed in advanced renal failure

Retrograde pyelography: Useful in cases with high suspicion for obstruction despite negative renal ultrasonograms, as well as for diagnosing renal stones

Computed tomography (CT) scanning: Useful to better define renal masses and cysts usually noted on ultrasonograms; also the most sensitive test for identifying renal stones

Magnetic resonance imaging (MRI): Useful in patients who require a CT scan but who cannot receive intravenous contrast; reliable in the diagnosis of renal vein thrombosis

Renal radionuclide scanning: Useful to screen for renal artery stenosis when performed with captopril administration; also quantitates the renal contribution to the GFR

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after appropriate workup.

Management of patients with CKD:

Treating an underlying condition if possible.

Aggressive blood pressure control.

Treatment of hyperlipidemia.

Aggressive glycemic control for diabetics.

Avoidance of nephrotoxins, including intravenous radiocontrast media, nonsteroidal anti-inflammatory agents, and aminoglycosides.

Use of renin-angiotensin system blockers among patients with diabetic kidney disease and proteinuria.

Use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers in patients with proteinuria.

In patients with advanced CKD and stable hypertension, antihypertensive treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers reduces the likelihood of long-term dialysis and lowers the mortality risk as well.

Delaying or halting the progression of CKD

Plan for long-term renal replacement therapy.

Anemia: When the hemoglobin level is below 10 g/dL, treat with erythropoiesis-stimulating agents (ESAs).

Hyperphosphatemia is treated with dietary phosphate binders and dietary phosphate restriction.

Hypocalcemia is treated with calcium supplements with or without calcitriol.

Patients with ESRD, the activity of the 1-alpha-hydroxylase enzyme is substantially diminished, and this enzyme is primarily expressed in the kidney and converts 25-hydroxyvitamin D to active 1, 25 dihydroxyvitamin D.

As a consequence of a low 1, 25 dihydroxyvitamin D, parathormone is stimulated to restore its level and incorrect abnormal calcium and phosphate levels.

As a result, avlow 1-alpha–hydroxylase enzyme activity results in severe secondary or tertiary hyperparathyroidism, which is associated with skeletal complications, including fracture, deformity, and growth failure in children.

CKD in children is somewhat more common in boys, because posterior urethral valves, the most common birth defect leading to CKD, occur only in boys.

Many patients with congenital kidney disease do not manifest CKD or ESRD until adulthood.

To interrupt this process, 1, 25 dihydroxyvitamin D is often prescribed to patients with ESRD in the form of vitamin D receptor agonists.

There is a connection between low levels of 25-hydroxyvitamin D (25[OH]D) and all-cause mortality in patients with nondialysis CKD.

Hyperparathyroidism treated with calcitriol or vitamin D analogues.

Volume overload can be treated with loop diuretics or ultrafiltration.

Metabolic acidosis treated with oral alkali supplementation.

Reducing protein may effects adenosine triphosphate (ATP)–dependent ubiquitin proteasomes and increase activity of branched-chain keto acid dehydrogenases.

Metabolic acidosis increases fibrosis and progression of kidney disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion.

Metabolic acidosis is a factor in the development of renal osteodystrophy, because bone acts as a buffer for excess acid, with resultant loss of minerals.

Acidosis may interfere with vitamin D metabolism.

Patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease.

Renal bone disease results in skeletal complications which include abnormality of bone turnover, mineralization, linear growth and extraskeletal complications including vascular or soft-tissue calcification.

Bone disease occur with CKD, as follows:

High-turnover bone disease from high parathyroid hormone (PTH) levels

Low-turnover bone disease (adynamic bone disease)

Defective mineralization (osteomalacia)

Beta-2-microglobulin–associated bone disease

Bone disease in children is similar but occurs during growth.

Children with CKD are at risk for short stature, bone curvature, and poor mineralization.

The treatment of uremia include long-term renal replacement therapy.

Indications for renal replacement therapy include:

Severe metabolic acidosis

Hyperkalemia

Pericarditis

Encephalopathy

Intractable volume overload

Failure to thrive and malnutrition

Peripheral neuropathy

Intractable gastrointestinal symptoms

CKD defined as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months.

In asymptomatic adult patients, a glomerular filtration rate (GFR) of 5-9 mL/min/1.73 m²,[3] irrespective of the cause of the CKD or the presence of absence of other comorbidities

Once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR.

The different stages of CKD form a continuum. The classification of the stages of CKD is as follows:

Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)

Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)

Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)

Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis

In stage 1 and stage 2 CKD, reduced GFR alone does not clinch the diagnosis, because the GFR may in fact be normal or borderline normal.

Other markers of kidney damage, including abnormalities in the composition of blood or urine or structural abnormalities visualized by imaging studies, establish the diagnosis in such cases.

Hypertension is a frequent sign of CKD but should not by itself be considered a marker of it, because elevated blood pressure is also common among people without CKD.

It is advised that GFR and albuminuria levels be used together, rather than separately, to improve prognostic accuracy in the assessment of CKD.

Referral to a kidney specialist is recommended for patients with a very low GFR (< 15 mL/min/1.73 m²) or very high albuminuria (>300 mg/24 h).

Patients with stages 1-3 CKD are frequently asymptomatic.

Clinical manifestations resulting from low kidney function typically appear in stages 4-5.

Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative, as tese may slow, or possibly halt, progression of the disease.

The medical care of patients with CKD should focus on the following:

Slowing or halting the progression of CKD

Treating the pathologic manifestations of CKD

Timely planning for long-term renal replacement therapy, including dialysis and transplantation

New guidelines issued by the Canadian Society of Nephrology recommend delaying dialysis in CKD patients without symptoms until their glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or until the first onset of a clinical indication which includes symptoms of uremia, fluid overload, and refractory hyperkalemia or acidemia.

Close monitoring of the patient should begin when eGFR reaches 15 mL/min/1.73 m2.

Factors that may affect dialysis initiation include: patient education, and the the severity of existing uremic symptoms, and the rate of renal function decline.

Patients with CKD stages 1-3 (GFR >30 mL/min/1.73 m²) are generally asymptomatic.

Typically, it is not until stages 4-5 (GFR < 30 mL/min/1.73 m²) that endocrine/metabolic derangements or disturbances in water or electrolyte balance become clinically manifest.

Signs of metabolic acidosis in stage 5 CKD include:

Protein-energy malnutrition

Loss of lean body mass

Muscle weakness

In stage 5 disease alteration in renal handling of salt and water include:

Peripheral edema

Pulmonary edema

Hypertension

Anemia in CKD is associated with:

Fatigue

Reduced exercise capacity

Impaired cognitive function

Impaired immune function

Impaired quality of life

Risk of cardiovascular disease

New onset of heart failure

Increasing severity of heart failure

Increased cardiovascular mortality

Manifestations of uremia in end-stage renal disease (ESRD) include:

Pericarditis

Encephalopathy

Peripheral neuropathy

Restless leg syndrome

Anorexia, nausea, vomiting, diarrhea

Skin manifestations of dry skin, pruritus, ecchymosis

Fatigue

Increased somnolence

Failure to thrive

Malnutrition

Decreased libido

Amenorrhea

Platelet dysfunction with tendency to bleed

Laboratory studies used in the diagnosis of CKD can include the following:

Complete blood count

Basic metabolic panel

Urinalysis

Serum albumin levels

Lipid profile.

Evidence of renal bone disease can be derived from the following tests:

Serum phosphate

25-hydroxyvitamin D

Alkaline phosphatase

Intact parathyroid hormone (PTH) levels

Initial evaluation of a patient with CKD initial should include: Serum and urine protein electrophoresis to rule out plasma cell dysplasia, monoclonal gammopathies, serum complement levels, screening for collagen-vascular diseases with lupus panel screens, cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA) levels, Anti–glomerular basement membrane (anti-GBM) antibodies, Hepatitis B and C, human immunodeficiency virus (HIV), and VDRL) serology.

Imaging studies that can be used in the diagnosis of CKD include: Renal ultrasonography: Useful to screen for hydronephrosis, which may not be observed in early obstruction, or for involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy; small, echogenic kidneys are observed in advanced renal failure

Retrograde pyelography: Useful in cases with high suspicion for obstruction despite negative renal ultrasonograms, as well as for diagnosing renal stones

Computed tomography (CT) scanning: Useful to better define renal masses and cysts usually noted on ultrasonograms; also the most sensitive test for identifying renal stones

Magnetic resonance imaging (MRI): Useful in patients who require a CT scan but who cannot receive intravenous contrast; reliable in the diagnosis of renal vein thrombosis

Renal radionuclide scanning: Useful to screen for renal artery stenosis when performed with captopril administration; also quantitates the renal contribution to the GFR

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after appropriate workup.

Management of patients with CKD:

Delaying or halting the progression of CKD

Treatment of the underlying condition, if possible.

Plan for long-term renal replacement therapy.

Anemia: When the hemoglobin level is below 10 g/dL, treat with erythropoiesis-stimulating agents (ESAs).

Hyperphosphatemia is treated with dietary phosphate binders and dietary phosphate restriction.

Hypocalcemia is treated with calcium supplements with or without calcitriol.

Hyperparathyroidism treated with calcitriol or vitamin D analogues.

Volume overload can be treated with loop diuretics or ultrafiltration.

Metabolic acidosis treated with oral alkali supplementation.

The treatment of uremia include long-term renal replacement therapy.

Indications for renal replacement therapy include:

Severe metabolic acidosis

Hyperkalemia

Pericarditis

Encephalopathy

Intractable volume overload

Failure to thrive and malnutrition

Peripheral neuropathy

Intractable gastrointestinal symptoms

CKD defined as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months.

Once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR.

The different stages of CKD form a continuum. The classification of the stages of CKD is as follows:

Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)

Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)

Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)

Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis

In stage 1 and stage 2 CKD, reduced GFR alone does not clinch the diagnosis, because the GFR may in fact be normal or borderline normal.

Other markers of kidney damage, including abnormalities in the composition of blood or urine or structural abnormalities visualized by imaging studies, establish the diagnosis in such cases.

Hypertension is a frequent sign of CKD but should not by itself be considered a marker of it, because elevated blood pressure is also common among people without CKD.

It is advised that GFR and albuminuria levels be used together, rather than separately, to improve prognostic accuracy in the assessment of CKD.

Referral to a kidney specialist is recommended for patients with a very low GFR (< 15 mL/min/1.73 m²) or very high albuminuria (>300 mg/24 h).

Patients with stages 1-3 CKD are frequently asymptomatic.

Clinical manifestations resulting from low kidney function typically appear in stages 4-5.

Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative, as tese may slow, or possibly halt, progression of the disease.

The medical care of patients with CKD should focus on the following:

Slowing or halting the progression of CKD

Treating the pathologic manifestations of CKD

Timely planning for long-term renal replacement therapy, including dialysis and transplantation

Patients with chronic kidney disease and AF have a 3-fold higher risk for stroke.

Estimated 40% of patients with stable coronary artery disease and diabetes have chronic kidney disease.

High dose atorvastatin therapy 80 mg/day in patients with CRD, diabetes and hyperlipidemia results in significant reduction in major cardiovascular events compared to patients with 10 mg daily of atorvastatin.

Cardiovascular disease the leading cause of death in stage 5 end stage renal disease.

Stage 3-4 end stage renal disease also associated with increased incidence of cardiovascular disease, particularly in those patients with diabetes.

Many patients die of cardiovascular disease before the need of dialysis or renal transplant.

Physical activity confers metabolic benefits that may moderate long-term risks of glomerulosclerosis and progressive renal dysfunction.

Prevalence of coronary disease among hemodialysis patients in the U.S. is approximately 40%.

Patients have cardiovascular mortality rates at least 10 times greater than the general population.

Increased cardiovascular risk among patients with CRD related to LVH, smoking, physical inactivity, diabetes, hypertension, and nonuse of alcohol.

Heavy alcohol consumption is associated with faster progression of chronic kidney disease.

Pruritus common in chronic renal disease with an incompletely understood pathogenesis.

Puritus hypotheses include metastatic metabolic disturbances, dysregulated immune responses, and imbalances in the endogenous opioid system, and peripherally distributed kappa opioid receptors.

Dyslipoproteinemia develops early during asymptomatic stages and becomes more pronounced with advanced renal failure.

Associated with high levels of triglycerides and low levels of high-density lipoproteins (HDL).

Modest lipid lowering treatment in patients with diabetes or chronic kidney disease does not translate into consistent improvements in cardiovascular outcomes.

Even if mild is a strong predictor of congestive heart failure.

Patients with chronic renal insufficiency have an increased risk of bone fractures.

With persistent PTH elevation a high bone turnover process, known as osteitis fibrosa, develops.

Osteitis fibrosa, is one of several bone lesions known as renal osteodystrophy develops in patients with severe CKD, and is common in patients with ESRD.

Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation.

Low-turnover osteomalacia is less common than high bone turnover disease.

Classical bone lesions seen with secondary hyperparathyroidism is osteitis fibrosa cystica.

Most patients with chronic renal disease do not progress to ESRD.

A delay in progression and arrest of chronic renal disease can be achieved in many patients.

Patients with serum creatinine between 1.4 and 2.3 mg/dL have a 1.4 times greater risk of cardiovascular death, myocardial infarction, stroke compared to individuals with a serum creatinine below 1.4 mg/dL.

Cardiovascular risk factors more prevalent in persons with chronic kidney disease include: elevated CRP, fibrinogen, interleukin 6, factor VIII and lipoprotein(a).

ACE inhibitors can be used in advanced kidney disease, in generous doses, and provides benefits even in patients with increasing creatinine levels.

ACE inhibitors and angiotenisn receptor blockaers (ARBs) are used as monotherapoies to decrease proteinuria and delay renal disease progression.

Reduction in proteinuria slows progression of chronic renal diseae and correlates closely with a decline in GFR over time.

Both ACE inhibitors and ARBs retard the decline in GFR associated with proteinuria which suggests that the renin-angiotensin system plays a significant role in the pathogenesis of chronic renal disease.

Only 25% of patients with proteinuria have reduced GFR, and a similar proportion of those with lower GFR have proteinuria (Garg AX).

Proteinuria is an independent risk factor for progressive renal damage, and it’s reduction with antihypertensive medications, particularly ACE inhibitors or ARBs, reduces the rate of decline in the GFR both in diabetics or nondiabetics.

ARBs administered to hypertensive patients with type II diabetes, proteinuria, and chronic kidney disease resulted in significant reduction in the risk of progression of chronic kidney disease from 15-37%, cardiovascular events and death (Lweis EJ, Brenner BM).

Hypertensive nephrosclerosis has no distinct markers of kidney damage, but albuminuria can occur after the onset of decreased GFR.

Risk of mortality and kidney failure are associated with GFR and concentration of albuminuria.

When ACE inhibitors and ARBs are used together risk of adverse effects including hyperkalemia,, hypotension and worsening renal failure outweigh beefits of dual blockade and their simultaneous use should be discouraged.

Predisposes to hyperkalemia by impaired glomerular filtration rate, a frequently high dietary potassium intake relative to residual renal function, extracellular shift of potassium caused by the metabolic acidosis of renal insufficiency, and treatment with renin-angiotensin-aldosterone system blockers that inhibit renal potassium excretion.

Patients with CKD maintain potassium excretion at near-normal levels as long as aldosterone secretion and distal flow are maintained.

In CKD a defense against potassium retention in patients with CKD is potassium excretion in the gastrointestinal tract, which also is under control of aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium.

Hyperkalemia can be observed sooner with ingestion of a potassium-rich diet or have low serum aldosterone levels.

Low aldosterone levels are seen in diabetes mellitus and the use of ACE inhibitors or NSAIDs.

Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as occurs in the setting of acidemia or from lack of insulin.

Hypokalemia is uncommon in CKD but can develop in patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics.

Metabolic acidosis often is a mixture of normal anion gap and increased anion gap.

In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium.

In stage 5 CKD, accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in anion gap.

Metabolic acidosis is observed generally with stage 5 CKD, but the anion gap generally not higher than 20 mEq/L.

In patients with CRD close follow-up every one to three months of renal function is required assessment.

In the Modification of Diet in Renal Disease hello protein intake does not change the progression of chronic kidney disease and individuals with nondiabetic window disease.

Sodium intake has no effect on the rate of decline of GFR or progression of proteinuria in patients with advanced diabetic chronic kidney disease.

Clinical trials and observational studies indicate that control of systemic hypertension slows the rate of progression to chronic kidney disease, with ir without diabetes.

ACE inhibitors or angiotensin-receptor blockers (ARBs) are the first line of antihypertensive treatments for patients with renal disease, with or without diabetes.

Blood pressure should be lowered to less than 130/80 mm Hg or in all patients with chronic kidney disease.

If too rapid decline in blood pressure is achieved deterioration in the GFR may occur and close renal function monitoring is required.

Salt intake may decrease effects of antihypertensive medications and antiproteinuric effects of ACE inhibitors and decreased dietary salt is suggested in the management of hypertensive patients with chronic renal disease.

Dihydropyridine calcium-channel blockers can be used in hypertensive management of patients with chronic renal disease receiving ARBs or ACE inhibitors.

Clinical practice guidelines on the management of mineral and bone abnormalities due to chronic kidney disease recommend specific target levels for serum phosphorus, calcium, and parathyroid hormone: analysis of 8380 citations in the literature found that the risk of death increased 18% for every 1 mg per deciliter increase in serum phosphorus, no significant association between all cause mortality and serum level of parathyroid hormone or serum level of calcium was found (Palmer SC et al).

In the above analysis there was no strong and consistent association between death and serum levels of parathyroid hormone and calcium in individuals with chronic kidney disease.

Based on the above study evidence is lacking for seum mineral target levels as risk factors for poor health outcomes in individuals with chronic kidney disease despite nearly universal adoption of such targets in clinical practice: Data does not support that patients with chronic kidney disease have treatment targets of serum parathyroid hormone level or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in tetany and seizures.

Patients with chronic kidney disease frequently develop deficiency of 1, 25-dihydroxyvitamin D3 ( calcitriol) because of a lack of its precursor 25-hydroxyvitamin D3, and impaired activity of the kidney enzyme 1aplha hydroxylase, which converts this precursor to the active hormone (Quarles LD et).

Altered vitamin D metabolism can lead to secondary hyperparathyroidism, which is the primary indication for calcitriol therapy.

Markedly decreased fetal survival is associated with advanced CKD and ESRD.

Many patients with CKD have low circulating levels of 25(OH)D.

Patients with advanced CKD and the lowest levels of 1,25(OH)(2)D (< 15 pg/mL) is associated with death and initiation of long-term dialysis therapy compared with levels >22 pg/mL.

A study in 12,763 non–dialysis-dependent patients with CKD found that 25(OH)D levels below 15 ng/mL were associated independently with all-cause mortality.

Chronic kidney disease adversely effects on vitamin D metabolism, with a reduction in the renal reserve of the enzyme 1-alpha-hydroxylase.

Vitamin D deficiency is common in chronic kidney disease, with 70-80% of patients with stage 3-5 disease having such a deficiency.

Adjusted risk of mortality is 33% higher in patients whose 25(OH)D levels are below 15 ng/mL.

Morbidity and mortality among children with CKD and ESRD are much lower than among adults with these conditions.

Morbidity and mortality among children with CKD and ESRD is dramatically higher than for healthy children.

Morbidity and mortality risk is highest among dialysis patients, making transplantation is the preferred treatme

Observational studies in chronic kidney disease indicate association with vitamin D deficiency and increased risk of cardiovascular events and between therapy with calcitriol and related analogues and reduced cardiovascular events.

In a multinational double-blind randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, preserved left ventricular ejection fraction 48 weeks of therapy with paicalcitriol did not alter left ventricular mass index or improved measures of diastolic dysfunction (The PRIMO Randomized Controlled Trial).

There is an association of low testosterone levels and renal disease.

Renal disease typically reduces prolactin clearance, which inhibits production of luteinizing hormone, which reduces testosterone production.

Uremia inhibits luteinizing hormone receptors in Leydig cells.

Erectile dysfunction is commonly in renal failure, with up to 87% of patients experiencing this difficulty.

Hypogonadism among men with renal failure is associated with increased mortality rates.

The four interventions that reduce the progression of chronic kidney disease are blood pressure control, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers for albuminuria and hypertension, diabetes control, and correction of metabolic acidosis.

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