Chronic renal failure

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Overview
Chronic renal failure (CRF), also known as chronic kidney failure (CKF) or chronic kidney disease (CKD), or chronic renal insufficiency (CRI) is a slowly progressive loss of renal function over a period of months or years, and defined as an abnormally low glomerular filtration rate, which is usually determined indirectly by the creatinine level in blood serum.

CRF that leads to severe illness and requires some form of renal replacement therapy (such as dialysis) is called end-stage renal disease (ESRD).

Signs and symptoms
Initially it is without specific symptoms and can only be detected as an increase in serum creatinine. As the kidney function decreases:
 * Blood pressure is increased due to fluid overload and production of vasoactive hormones leading to hypertension and congestive heart failure
 * Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy)
 * Potassium accumulates in the blood (known as hyperkalemia with symptoms ranging from malaise to fatal cardiac arrhythmias)
 * Erythropoietin synthesis is decreased (leading to anemia causing fatigue)
 * Fluid volume overload - symptoms may range from mild edema to life-threatening pulmonary edema
 * Hyperphosphatemia - due to reduced phosphate excretion, associated with hypocalcemia (due to vitamin D3 deficiency).
 * Later this progresses to tertiary hyperparathyroidism, with hypercalcaemia, renal osteodystrophy and vascular calcification
 * Metabolic acidosis, due to decreased generation of bicarbonate by the kidney, leads to uncomfortable breathing and further worsening of bone health.

CRF patients suffer from accelerated atherosclerosis and have higher incidence of cardiovascular disease, with a poorer prognosis.

Diagnosis
In many CRF patients, previous renal disease or other underlying diseases are already known. A small number presents with CRF of unknown cause. In these patients, a cause is occasionally identified retrospectively.

It is important to differentiate CRF from acute renal failure (ARF) because ARF can be reversible. Abdominal ultrasound is commonly performed, in which the size of the kidneys are measured. Kidneys in CRF are usually smaller (< 9 cm) than normal kidneys with notable exceptions such as in diabetic nephropathy and polycystic kidney disease. Another diagnostic clue that helps differentiate CRF and ARF is a gradual rise in serum creatinine (over several months or years) as opposed to a sudden increase in the serum creatinine (several days to weeks). If these levels are unavailable (because the patient has been well and has had no blood tests) it is occasionally necessary to treat a patient briefly as having ARF until it has been established that the renal impairment is irreversible.

Numerous uremic toxins (see link) are accumulating in chronic renal failure patients treated with standard dialysis. These toxins show various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other proteins, primarily to albumin. Such toxic protein bound substances are receiving the attention of scientists who are interested in improving the standard chronic dialysis procedures used today.

Complete Differential Diagnosis of Causes of Chronic Renal Failure

 * Analgesic nephritis
 * Chronic Glomerulonephritis
 * Chronic Pyelonephritis
 * Congenital Nephrotic Syndrome
 * Cystinosis
 * Diabetic Nephropathy
 * Fabry's Disease
 * Hereditary Nephritis
 * Interstitial Nephritis
 * Malignant hypertension
 * Nail-Patella Syndrome
 * Nephrosclerosis
 * Oxalosis
 * Polysystic Disease
 * Polycystic kidney disease
 * Renal artery stenosis
 * Renal vein thrombosis
 * Systemic Lupus Erythematosus
 * Vasculitis

The most common causes of CRF are diabetic nephropathy, hypertension, and glomerulonephritis. Together, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy.

Historically, kidney disease has been classified according to the part of the renal anatomy that is involved, as:
 * Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
 * Glomerular, comprising a diverse group and subclassified into
 * Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy
 * Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
 * Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
 * Obstructive such as with bilateral kidney stones and diseases of the prostate

Etiology of CRI

 * Glomerular Disease
 * Diagnostic Features
 * Red Blood Cell (RBC) casts
 * Proteinuria > 3.5 g/d
 * Systemic disease associated with glomerulopathy
 * Biopsy often needed for definitive diagnosis of nondiabetic glomerular disease
 * Clinical diagnosis diabetic nephropathy
 * Suggested by duration of Diabetes Mellitus (DM)
 * (7-8 years type II, 12-15 years type I),
 * Coexistent retinopathy, progressive
 * Nephrotic range proteinuria
 * Primary Glomerular Disorders
 * Focal glomerulosclerosis
 * Membranous nephropathy
 * Membranoproliferative Glomerulonephritis (MPGN)
 * Secondary Glomerular Disorders
 * Diabetic nephropathy
 * Lupus nephritis
 * Immunoglobulin A (IgA) nephropathy
 * Goodpasture’s syndrome
 * Amyloidosis
 * Interstitial Disease or Vascular Disease
 * Diagnostic Features:
 * Bland urinalysis
 * Protein excretion < 2-3 g/d
 * No glomerulopathy-associated systemic disease
 * Interstitial disorders
 * Polycystic kidney disease (PCKD)
 * Analgesic abuse
 * Autoimmune disorders (sarcoidosis, Sjogren’s)
 * Vesicoureteral reflux
 * Nephrolithiasis
 * Obstructive uropathy
 * Vascular disorders
 * Renal artery stenosis (bilateral)
 * Hypertensive nephrosclerosis (can--chronic insterstitial nephritis)
 * Vasculitis
 * Scleroderma

Measurement of Renal Function

 * Serum creatinine (Cr)
 * Determined by glomerular filtration rate (GFR) and by generation, tubular secretion and extrarenal clearance of Cr
 * May be inaccurate estimate of function, particularly in patients with mild renal insufficiency
 * Drugs may inhibit tubular secretion of Cr and falsely elevated serum Cr (cimetidine, trimethoprim (TMP))
 * Creatinine clearance
 * Estimate: [(140-age) x body wt (kg)] / [Plasma Cr x 72] (multiply result x 0.85 for women)
 * Calculated based on 24-hour urine collection
 * CrCl (mL/min) = [Urine Cr (mg/dL) x Urine volume (mL/d)] / [Plasma Cr x 1440]
 * If GFR < 50, CrCl overestimates GFR
 * Calculate 24-hour blood urea nitrogen (BUN) clearance (underestimates GFR)
 * Average of BUN and Cr clearances = GFR

Determination of Chronicity

 * Prior Cr measurements if available
 * Acute Renal Failure (ARF) associated with:
 * Precipitating factor (nephrotoxin, volume depletion, obstruction)
 * More symptoms at given level of Cr
 * Lesser degree of anemia, hypocalcemia, hyperphosphatemia
 * CRI associated with:
 * Greater likelihood of hematologic and biochemical abnormalities
 * Bilateral small kidneys on ultrasound (though can be normal in chronic disease)

Urinalysis

 * May suggest glomerular vs. nonglomerular cause
 * Urine sodium excretion (FENa):
 * More useful for ARF to distinguish prerenal state from acute tubular necrosis (ATN)
 * May not be low in volume depleted CRI patient due to tubular dysfunction

Ultrasound
 Ultrasound 
 * To rule out obstruction
 * To assess kidney size (small = chronic disease; large = DM, amyloidosis)
 * Can detect PCKD
 * Doppler can evaluate vascular flow – stenosis, thrombosis

MRI and CT
 CT scan 
 * If nephrolithiasis suspected (best test) – can detect radiolucent stones
 * More sensitive than ultrasound for PCKD
 * Best evaluation for cysts/malignancy

Other Imaging Findings

 * Kidney, Ureter, and Bladder (KUB)
 * If nephrolithiasis suspected (screening test)
 * Will detect calcium-containing, struvite, and cystine stones
 * Will miss uric acid stones, small stones, and stones overlying bony structures

Biopsy

 * Indications for Biopsy
 * Isolated glomerular hematuria with proteinuria
 * Nephrotic syndrome
 * Acute nephritic syndrome
 * Unexplained acute or subacute renal failure
 * Contraindications
 * Uncorrectable bleeding disorder
 * Small kidneys indicative of chronic, irreversibile disease (<7-8 cm length)
 * Severe hypertension not controllable with medications
 * Multiple, bilateral cysts or a renal tumor
 * Hydronephrosis
 * Active renal or perirenal infection
 * Solitary native kidney (relative contraindication)

Treatment
The goal of therapy is to slow down or halt the otherwise relentless progression of CRF to ESRD. Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression to ESRD.

Replacement of erythropoietin and vitamin D3, two hormones processed by the kidney, is usually necessary, as is calcium. Phosphate binders are used to control the serum phosphate levels, which are usually elevated in chronic renal failure.

After ESRD occurs, renal replacement therapy is required, in the form of either dialysis or a transplant.


 * Treatment of Reversible Exacerbants
 * Volume Depletion
 * May be subtle
 * Autoregulation impaired with DM, hypertension, CRI--decreases GFR with mild volume depletion
 * Careful trial of volume repletion may--return of baseline renal function
 * (Increase dietary Na, reduce diuretic dosing)
 * Nephrotoxins
 * NSAIDs
 * Most toxic in setting of volume depletion, CHF, diuretic use
 * Reduce prostaglandin (PG) synthesis--unopposed vasoconstriction with decreased GFR
 * Can also cause ATN (acute tubular necrosis)
 * Aminoglycosides
 * Nonoliguric ARF typically occurs at 7-10 days
 * Increased risk with older patients, prolonged therapy and greater total dose
 * IV contrast
 * ARF usually occurs within 24-48 hours of dye administration
 * Peak Cr after 5-7 days with return to baseline at 10-14 days
 * Risk ARF increased with DM and higher volume of dye
 * Note: certain meds increase serum Cr (via inhibiting Cr secretion or interfering with assay) without changing GFR, e.g. cimetidine, trimethoprim (TMP), cefoxitin, flucytosine; BUN will not rise because GFR is preserved
 * Urinary Tract Obstruction
 * Most commonly due to prostatic hypertrophy in men
 * Other causes:
 * Nephrolithiasis
 * Tumor
 * Neurogenic bladder
 * Results in reduced GFR and impaired tubular function
 * Consider ultrasound, urologic evaluation
 * Reduce Progression
 * Protective therapy most effective if initiated early, before Cr > 1.5-2.0 mg/dL
 * Treat Hypertension
 * Systemic hypertension--elevated intraglomerular pressure +/or glom hypertrophy
 * Blood Pressue (BP) control shown in multiple trials to slow progression of renal disease
 * Goal BP < 130/80-85; < 125/75 in patients with proteinuria > 1-2 g/d
 * ACE inhibitors (ACEI) and Angiotensin II receptor blockers (ARB) preferred 1st line agents due to renoprotective effects
 * Additional agents as needed, including diuretics if volume overload
 * Restrict Dietary Protein
 * Controversial – may decrease intraglomerular pressure
 * Conflicting studies – some show benefit, others do not
 * No significant adverse effects shown in large trial
 * Recommendations
 * No restriction (> 0.8 g/kg/d) if GFR 25-55 mL/min
 * Limit protein to 0.8 g/kg/d if progression or uremic symptoms
 * Limit to 0.6 g/kg/d if severe CRI (GFR 13-25 mL/min)
 * Close follow-up by dietician given risk of malnutrition in CRI population
 * Control blood sugar:
 * Tight control (A1c < 7.0, FBS 70-120) reduces progression in DM I
 * Unclear if as beneficial in DM II, but potentially helpful
 * Treat complications
 * Volume Overload
 * Impaired excretion of Na/H2O due to decreased GFR +/- AII/aldo activation
 * Restrict dietary Na to 1-2 g/d if hypertension or edema
 * Diuretics
 * Thiazides ineffective if GFR < 25 mL/min (~ Cr > 2-3)
 * Switch to loop diuretic as Cr rises; may need bid dosing
 * Addition of thiazide to loop diuretic can--additional diuresis
 * Watch for excessive volume depletion
 * Hyperkalemia
 * K usually maintained until GFR < 15-20 mL/min
 * Increased risk of hyperkalemia with oliguria, high K diet, (ACEI therapy)
 * Increased risk with many meds: ACEI, NSAIDs, K-sparing diuretics, digoxin, TMP
 * Increased risk in diabetics with type IV RTA
 * Management
 * Low K diet (< 60 mEq/d) once GFR < 15 mL/min
 * Avoidance of salt substitutes (may contain K salts)
 * +/- loop diuretic
 * Low dose Kayexelate (5 g with meals) if needed
 * Ca/PO4 Abnormalities
 * Reduced renal synthesis 1,25-(OH)2D--low serum Ca-- 2° hyperparathyroidism
 * (Occurs when GFR < 40 mL/min)
 * Reduced GFR--phosphate retention
 * Elevated parathyroid hormone (PTH)--mobilization of Ca from bone; increased excretion PO4
 * Allows maintenance of normal Ca/PO4 while GFR > 30 mL/min
 * Causes renal osteodystrophy
 * Once GFR < 25-30 mL/min, hyperphosphatemia occurs
 * Therapy goals = normalize Ca/PO4 and maintain parathyroid hormone (PTH)< 200 (2-3x uln)
 * Ca/PO4 management should be initiated when Cr ~ 2
 * CaxPO4 product should be < 60 to prevent met calcification
 * Low PO4 diet: < 800 mg/d (challenging)
 * Ca-based oral PO4 binders: Ca acetate or CaCO3 with meals
 * Avoid Al-based PO4 binders except for acute therapy of hi CaxPO4 products
 * (Al toxicity = osteomalacia, anemia, encephalopathy)
 * Avoid Ca citrate (increases gastrointestinal absorption of aluminum)
 * RenaGel = new non-Ca/Al-containing PO4 binder (cationic polymer)
 * (For patients who cannot tolerate CaCO3 or need additional agent)
 * Calcitriol 0.125-0.25 mg/d improves Ca & PTH levels, decreases bone disease
 * (Monitor Ca--reduce dose if hyercalcemic)
 * Metabolic Acidosis
 * Occurs when GFR < 25 mL/min due to inability to excrete H+ ions
 * Underlying cause = impaired renal NH3 prodxn and HCO3 reabsorption
 * Risk = bone buffering of acidosis--worsened osteodystrophy via Ca/PO4 loss
 * Increased skeletal muscle breakdown--loss of lean body mass
 * Therapy goal = HCO3 > 22 mEq/L via alkali therapy (NaHCO3 0.5-1 mEq/kg/d)
 * Anemia
 * Normocytic, normochromic, hypoproliferative anemia due to reduced erythropoietin production
 * May be exacerbated by reduced rbc survival, coexistent Fe/folate deficiency, etc.
 * Generally occurs when Cr > 2-3 mg/dL
 * If untreated, hematocrit (Hct) usually stabilizes at ~ 25
 * Therapy recommendations = erythropoietin if symptomatic anemia or Hgb < 10 g/dL (in pre-dialysis patients)
 * Goal Hct 33-36
 * Must replete Fe stores first (oral FeSO4)
 * Initial dose ~ 150 U/kg sc weekly to increase Hct
 * Maintenance dose ~ 75 U/kg weekly once Hct goal reached
 * Improves symtoms and may reduce left ventricle (LV) mass (via improvemt of hyperdynamic state)
 * Side effects = increased blood pressure (BP); may need to augment antihypertensive regimen
 * Plan for Renal Replacement Therapy (RRT)
 * Indications for Dialysis
 * Malnutrition
 * CrCl M 10-15 mL/min
 * Symptoms of uremia related complications (pericarditis, encephalopathy)
 * Hyperkalemia, acidosis not responsive to medical therapy
 * Volume overload / CHF
 * RRT modalities
 * Hemodialysis
 * Peritoneal dialysis
 * Renal transplant
 * Access for hemodialysis should be established when GFR < 25 mL/min (estimated ESRD within 1 year)
 * Diabetics tend to require dialysis sooner than non-diabetics because more symptomatic at given GFR
 * Indications for referral to nephrologist
 * Unclear etiology of new or chronic renal insufficiency
 * For diagnostic evaluation, e.g. biopsy
 * GFR < 50 mL/min: i.e. before vascular access/RRT required

Prognosis
The prognosis of patients with chronic kidney disease is guarded as epidemiological data has shown that all cause mortality (the overall death rate) increases as kidney function decreases. The leading cause of death in patients with chronic kidney disease is cardiovascular disease, regardless of whether there is progression to ESRD.

While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely affected. Renal transplantation increases the survival of patients with ESRD significantly when compared to other therapeutic options; however, it is associated with an increased short-term mortality (due to complications of the surgery). Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional thrice weekly hemodialysis and peritoneal dialysis.

Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D., Rebecca Cunningham, M.D.