Chronic renal failure (CRF) is a progressive disease characterized by an increasing inability of the kidney to maintain normal low levels of the products of

• protein metabolism (such as urea)
• normal blood pressure 
• hematocrit
• sodium
• water
• potassium
• acid-base balance

Renal function is clinically monitored by measurement of 

• serum creatinine
• blood urea nitrogen (BUN)
• urinalysis. 

Once serum creatinine in an adult reaches about 3 mg/dL 

•  renal disease are irreversible
•  progress to end-stage renal disease (ESRD)  

In patients with an elevated serum creatinine level (1.5 to 3.0 mg/dL), the term chronic renal insufficiency is useful and implies that progression to CRF and ESRD is not inevitable. 

Azotemia means an elevation of BUN above normal,

Uremia implies the presence of symptoms secondary to renal nitrogen retention

• The uremic syndrome occurs more commonly but not invariably when BUN exceeds 100 mg/dL. 
•  75% of renal function has been lost. 

Renal replacement therapy (RRT). 

• dialysis 
• transplantation

Etiology

• Diabetic glomerulosclerosis
  • CRF develops in about 30% of type I and type II diabetics
  • peak incidence at about 15 years after the development of diabetes mellitus
  • Untreated, the GFR in diabetic glomerulosclerosis progresses downward at a rate of about 10 to 12 mL/minute/year.

  • Predictors of the development of diabetic glomerulosclerosis are 

    • hypertension
    • poor glycemic control
    • microalbuminuria
    • proliferative retinal vascular disease
• Hypertensive nephrosclerosis 
  • Nephrosclerosis is as much as 25 times more likely to cause ESRD in the African-American than the white population.
• Glomerulonephritis
  • Focal glomerulosclerosis and membranoproliferative glomerulonephritis are the most likely chronic glomerulonephritides to progress quickly in adults. 
• SLE, Wegener's granulomatosis 
• Tubulointerstitial disease
• Reflux nephropathy (chronic pyelonephritis)
• Analgesic nephropathy
• Obstructive nephropathy (stones, BPH)
• Polycystic kidney disease
  • Very large cysts
  • onset of the disease at an early age
  • hypertension are associated with progression 

Pathophysiology of chronic renal failure

• Regardless of the primary cause of nephron loss, some usually survive or are less severely damaged 
• These nephrons then adapt and enlarge, and clearance per nephron markedly increases.
•  If the initiating process is diffuse, sudden, and severe, such as in some patients with rapidly progressive glomerulonephritis (crescentic glomerulonephritis), acute or subacute renal failure may ensue with the rapid development of ESRD. 
• In most patients, however, disease progression is more gradual and nephron adaptation is possible. 
• Focal glomerulosclerosis develops in these glomeruli, and they eventually become non-functional. 
• At the same time that focal glomerulosclerosis develops, proteinuria markedly increases and systemic hypertension worsens.
• This process of nephron adaptation has been termed the "final common path." 
• Adapted nephrons enhance the ability of the kidney to postpone uremia, but ultimately the adaptation process leads to the demise of these nephrons.
• Adapted nephrons have not only an enhanced GFR but also enhanced tubular functions in terms of, for example, potassium and proton secretion. 

Pathophysiology and Clinical manifestations of Uremic syndrome 

Patients are often not seen until late in the course of the disease, when much of their kidney function has already been lost  Kidney adapts so well to progressive loss of nephrons and can maintain constancy of the internal environment until about 75% of renal function has been lost. Patients with uremic manifestations, can have a myriad of different complaints referable to almost any organ system.

•  All CRF patients with the exception of those with medullary cystic kidney disease  have fixed proteinuria (>200 mg/24 hours). 
• The syndrome may also come to attention because of an elevated BUN or serum creatinine concentration in laboratory testing done for a variety of reasons. 
• Progressive metabolic acidosis 
  • The major cause of the failure to excrete enough acid is diminished renal ammonia production and excretion. 
  • Although the metabolic acidosis of CRF is commonly referred to as an anion gap acidosis, this gap does not develop until the serum creatinine concentration approaches 5 to 6 mg/dL. 
  • Before this stage, serum chloride initially rises as the serum bicarbonate level falls.
  • High serum parathormone levels and extracellular fluid volume lead to proximal tubular acidosis but do not seem to fully account for the early hyperchloremic metabolic acidosis of CRF.
  • Patients who have hyperkalemic distal (type 4) renal tubular acidosis (e.g., in hyporeninemic hypoaldosteronism, common in diabetics) because of tubulointerstitial disease have a much more severe non-anion gap metabolic acidosis relative to the stage of progression of CRF.
• Hypertension 
  • Hypertension develops in 95% of patients with CRF before ESRD does
  •  is due to retention of NaCl, inappropriately high renin levels for the status of expended extracellular fluid volume, sympathetic stimulation via afferent renal reflexes, and impaired renal endothelial function with deficient nitric oxide and enhanced endothelin production. 
  • If untreated, this type of hypertension is much more likely to enter the malignant phase than is essential hypertension.
• Acute cardiovascular events, especially stroke and myocardial infarction, account for about half of the deaths occurring in dialysis patients and also deaths after the first year post-transplantation.
• Heart failure is common and is due to sodium and water retention, acid-base changes, hypocalcemia and hyperparathyroidism, hypertension, anemia, coronary artery disease, and diastolic dysfunction secondary to increased myocardial fibrosis with oxalate and urate deposition and myocardial calcification. Uremia itself may also impair myocyte function.
• In the gastrointestinal tract, anorexia and morning vomiting are common. 
  • In severe uremia, gastrointestinal bleeding may occur secondary to platelet dysfunction and diffuse mucosal erosions throughout the gut.
  • Bloody diarrhea can occur secondary to uremic colitis. 
• Uremic serositis is a syndrome of pericarditis, pleural effusion, and sometimes ascites in any combination.
  • Pericarditis is fibrinous, hemorrhagic, and usually associated with a mild fever and may cause pericardial tamponade. 
• Pruritus is a common and troublesome complication of uremia that is only partially explained by hyperparathyroidism and a high Ca × P product with increased microscopic calcification of subcutaneous tissues. 
• Renal osteodystrophy  is characterized by secondary hyperparathyroidism, which is due to hyperphosphatemia, hypocalcemia, marked
  parathyroid hypertrophy, and bony resistance to the action of parathormone; by inadequate formation of 1,25-dihydroxyvitamin D in the kidney resulting in osteomalacia in adults and rickets in children; and for as yet obscure reasons, by areas of osteosclerosis. 
• High parathormone levels and high cytosol calcium concentrations probably contribute to uremic encephalopathy, myocyte dysfunction, and an impaired bone marrow response to erythropoietin. 
• Severe syndromes termed calciphylaxis include metastatic calcification in soft tissues and small blood vessels and ischemic necrosis of skin and muscle. In such circumstances, partial parathyroidectomy--removal of 3½ glands--may be required, but secondary hyperparathyroidism is best prevented. 
• Other joint diseases include secondary gout and pseudogout, which may be associated with chondrocalcinosis.
• Patients in late CRF often appear hypothyroid and thyroid function tests may be abnormal, despite normal free levothyroxine; free triiodothyronine levels are low and binding of levothyroxine to thyroxine-binding globulin is diminished. 
• Most women are amenorrheic--although occasionally menorrhagia can occur--and infertile, at least in the later stages of CRF. Impotence and oligospermia are common in men.
• Diabetic patients commonly require less exogenous insulin as CRF progresses because of diminished degradation by renal insulinase.
• As uremia progresses, subtle mental and cognitive dysfunction develops and, if untreated, progresses to coma. 
• Neuromuscular abnormalities with asterixis and muscle twitching are common, as are muscle cramps. 
• The restless legs syndrome is a manifestation of sensory peripheral neuropathy. 
• Motor neuropathy is a late phenomenon in uremia.
• Progressively more severe normochromic, normocytic anemia develops as the GFR and renal erythropoietin secretion decrease. 
  • In most patients, the hematocrit reaches about 20 to 25% by the time that ESRD develops.
•  Uremic coagulopathy is secondary to a defect in platelet function, as well as abnormal Factor VIII function. 
• It is characterized by a prolonged bleeding time but usually normal prothrombin and partial thromboplastin times, platelet count, and clotting time. 
• The platelet dysfunction responds to dialysis and to infusion of desmopressin. Epistaxis, menorrhagia, bruising, and purpura, as well as gut bleeding, may all occur.
• Uremic patients should be regarded as immunocompromised, and infection is an important cause of death in CRF and dialysis patients. 

Differential diagnosis

It is sometimes difficult to differentiate between acute and chronic renal failure when a patient with azotemia and an elevated serum creatinine concentration is recognized for the first time. 

A diagnosis of CRF is supported by a 

• history of nephrotic or nephritic syndrome
• long-standing nocturia
• renal osteodystrophy
• renal anemia 
• bilaterally small kidneys 
• increased echogenicity on renal ultrasonography

Acute-on-chronic renal failure is a common circumstance, and reversible factors should always be sought when a diagnosis of CRF is made or when a patient with CRF shows unexpectedly rapid deterioration in renal function. 

Potentially reversible factors in chronic renal failure

• Pre-renal Failure
  • ECF volume depletion
• Cardiac failure
  • NSAIDs, ACE inhibitors
• Post-renal Failure
  • Obstructive uropathy
• Intrinsic Renal Failure
  • Severe hypertension
  • Acute pyelonephritis
  • Drug nephrotoxicity (ATN, AIN, vasculitis)
  • Acute interstitial nephritis
  • Radiocontrast agents (ATN)
  • Hypercalcemia
  • Vascular
• Renovascular
• Renal vein thrombosis 

Specific diagnosis

History

• A history of nephrotic syndrome suggests primarily previous glomerular disease as a cause of the CRF. 
• Recurrent gross hematuria may accompany IgA nephropathy or mily history for hypertension and diabetes mellitus should be obtained, including information on any family members in whom ESRD developed. 
• It now appears that some families have a genetic predisposition not only for essential hypertension and diabetes mellitus but also
  for the development of renal disease secondary to these systemic diseases. 
• A history of recurrent renal stones or obstructive uropathy, including prostatism, or excessive mixed analgesic intake may suggest primarily tubulointerstitial disease. 
• The family history is also very helpful in the diagnosis of autosomal dominant polycystic kidney disease--although in about 30% a spontaneous mutation occurs--familial glomerulonephritis (Alport's syndrome), IgA nephropathy, and medullary cystic kidney disease.

Physical

• On physical examination, signs of hypertensive (left ventricular hypertrophy and hypertensive retinopathy) or diabetic disease (peripheral neuropathy, diabetic retinopathy) are important.
•  Knobby, bilaterally enlarged kidneys support a diagnosis of polycystic kidney disease, and a palpable bladder or large prostate suggests obstructive uropathy and is an indication for measurement of residual urinary volume after voiding.
• Gouty tophi and a history of gout may be relevant. 
• Signs and symptoms of polyarteritis nodosa, systemic lupus erythematosus, Wegener's granulomatosis, scleroderma, and essential mixed cryoglobulinemia should be sought because these systemic diseases often involve the kidney. 
• The findings of rheumatoid arthritis are important because this disease is now the most common cause of systemic amyloidosis, which often involves the kidneys. 
• Hepatosplenomegaly and macroglossia also suggest renal amyloidosis.

Laboratory

Laboratory studies should include measurement of serum electrolytes, calcium, phosphorus, alkaline phosphatase, and albumin. 

• Careful urine analysis
• urinary microscopy
  • Marked proteinuria with an abundance of red blood cell, white blood cell, and granular casts suggests a proliferative type of glomerulonephritis, 
  • whereas membranous glomerulopathy and focal glomerulosclerosis are associated with less active findings on urinary microscopy. 
  • Predominant pyuria occurs in analgesic abuse nephropathy, polycystic kidney disease, and renal tuberculosis, even without superimposed bacterial urinary tract infection.
• measurement of 24-hour urine protein excretion. 
  • Urinary protein excretion of over 3 g/24 hours suggests primary glomerular disease.
• Renal ultrasound is a useful noninvasive test that can demonstrate 
  • cortical scarring (consistent with reflux nephropathy or segmental infarction)
  • renal stones
  • hydronephrosis
  • ureteric obstruction
  • polycystic kidney disease
  • Medical kidney disease may be associated with symmetrically diminished size and increased echogenicity; these findings are otherwise non-specific. 
  • Asymmetry of renal size raises a question of renovascular renal failure or previous obstruction from a stricture or stone.
•  A more severe degree of anemia than would be anticipated for the degree of renal failure suggests myeloma kidney; serum and urine immunoelectrophoresis should be performed to detect monoclonal antibodies. If a monoclonal antibody is found, bone marrow
  examination is usually necessary to confirm the diagnosis.
• Special studies
  • Serum complement and antinuclear antibodies should then be measured because of the association of hypocomplementemia with membranoproliferative glomerulonephritis and lupus nephritis. 
  • Serologic screens for hepatitis B and C are important because of their respective associations with membranous and membranoproliferative glomerulonephritis.
  • Human immunodeficiency virus-associated glomerulopathy is an important cause of focal glomerulosclerosis. 
  • Antineutrophil cytoplasmic antibodies are often positive in Wegener's granulomatosis.
• If the diagnosis remains obscure and kidney size is normal or only slightly reduced, renal biopsy should be considered for diagnosis after control of blood pressure and, if necessary, dialysis.

Monitoring

Patients with systemic disease (diabetes mellitus, hypertension, Wegener's granulomatosis, and systemic lupus erythematosus) potentially involving the kidney must be regularly checked 

• Proteinuria 
• Abnormal urinary findings on microscopy. 
• Diabetics should also be routinely monitored for microalbuminuria before the development of fixed proteinuria.
• All patients with hypertension should be screened by urinalysis. 

Prevention

• Diabetic glomerulosclerosis
  • The drug of choice for diabetic patients with hypertension and/or microalbuminuria or fixed proteinuria is an angiotensin-converting enzyme (ACE) inhibitor. 
  • Even after fixed albuminuria has developed, ACE inhibitors can markedly delay progression of the decline in the glomerular filtration rate (GFR) to about 2 mL/minute/year.
• Hypertensive nephrosclerosis 
  •  Evidence is increasing that microalbuminuria (>30 mg/24 hours) is a harbinger of hypertensive nephrosclerosis and that progression to fixed albuminuria may be diminished by some, but probably not all, antihypertensive drugs. 
  • Microalbuminuria is certainly well documented as a cardiovascular risk factor, and that alone justifies intensifying antihypertensive treatment in such patients.
  •  It has not yet been established whether normalization of blood pressure can delay or stop progression once the serum creatinine concentration is elevated and/or fixed albuminuria has developed. 
  • Nor it is yet known which is the best antihypertensive to use in such clinical circumstances
• Glomerulonephritis
  • Focal glomerulosclerosis  No therapy has yet been proved to consistently prevent progression in these glomerular diseases in randomized controlled studies.
• Chronic hemodialysis is equivalent, for example, to only about 10 to 15% of normal renal function. 
• The major cause of death in patients receiving RRT is cardiovascular. 
  • Patients with progressive renal disease must be regarded as "vasculopaths" and cardiovascular risk factors sought and treated vigorously.