Glomerulonephritis.  Etiology,  pathogenesis. Classification. Clinical pattern.  Complications. Treatment.

The role of  a doctor-dentist   in prophylaxis.

Pyelonephritis. Etiology, pathogenesis. Classification.

Clinical pattern.  Diagnostics. Treatment.

The role of  a doctor-dentist   in prophylaxis.

In anatomy, urinary system, the kidneys filter wastes (such as urea) from the blood and excrete them, along with water, as urine. The medical field that studies the kidneys and diseases of the kidney is called nephrology (nephro- meaning kidney is from the Ancient Greek word nephros; the adjective renal meaning related to the kidney is from Latin rēnēs, meaning kidneys).

In humans, the kidneys are located in the posterior part of the abdomen. There is one on each side of the spine; the right kidney sits just below the liver, the left below the diaphragm and adjacent to the spleen. Above each kidney is an adrenal gland (also called the suprarenal gland). The asymmetry within the abdominal cavity caused by the liver results in the right kidney being slightly lower than the left one while the left kidney is located slightly more medial.

The kidneys are retroperitoneal, which means they lie behind the peritoneum, the lining of the abdominal cavity. They are approximately at the vertebral level T12 to L3. The upper parts of the kidneys are partially protected by the eleventh and twelfth ribs, and each whole kidney is surrounded by two layers of fat (the perirenal and pararenal fat) which help to cushion it. Congenital absence of one or both kidneys, known as unilateral or bilateral renal agenesis can occur.

Above each human kidney is one of the two adrenal glands.

In a normal human adult, each kidney is about 10 cm long, 5.5 cm in width and about 3 cm thick, weighing 150 grams.^[1] Together, kidneys weigh about 0.5% of a person’s total body weight. The kidneys are “bean-shaped” organs, and have a concave side facing inwards (medially). On this medial aspect of each kidney is an opening, called the hilum, which admits the renal artery, the renal vein, nerves, and the ureter.

The outer portion of the kidney is called the renal cortex, which sits directly beneath the kidney’s loose connective tissue/fibrous capsule. Deep to the cortex lies the renal medulla, which is divided into 10-20 renal pyramids in humans. Each pyramid together with the associated overlying cortex forms a renal lobe. The tip of each pyramid (called a papilla) empties into a calyx, and the calices empty into the renal pelvis. The pelvis transmits urine to the urinary bladder via the ureter.

Nephron The basic functional unit of the kidney is the nephron, of which there are more than a million within the cortex and medulla of each normal adult human kidney. Nephrons regulate water and solute within the cortex and medulla of each normal adult human kidney. Nephrons regulate water and soluble matter (especially electrolytes) in the body by first filtering the blood under pressure, and then reabsorbing some necessary fluid and molecules back into the blood while secreting other, unneeded molecules. Reabsorption and secretion are accomplished with both cotransport and countertransport mechanisms established in the nephrons and associated collecting ducts.

      Glomerulonephritis is a heterogenic  group of progressive kidney disease that involves the glomeruli,  the individual filtering units of the kidney that produce urine. It is immunologicaly mediated diffuse inflammatory disease which involves both kidneys symmetrically affecting mainly the glomerulus and associated with changes in tubules, interstitial tissue and vessels.   When the glomeruli become inflamed, the kidneys can’t filter urine properly. This results in a buildup of excess fluid and toxins in the body. Glomerulonephritis can lead to chronic renal (kidney) failure.

        Etiology and Pathogenesis of Glomerulonephritis. A variety of conditions can cause glomerulonephritis, ranging from infections that affect your kidneys to diseases that affect your whole body, including your kidneys. Sometimes the cause is unknown. Here are some examples of conditions that can lead to inflammation of the kidneys’ glomeruli:

        Infections. Post-streptococcal glomerulonephritis. Glomerulonephritis may develop a week or two after recovery from a strep throat infection or, rarely, a skin infection (impetigo). An overproduction of antibodies stimulated by the infection may eventually settle in the glomeruli, causing inflammation. Symptoms usually include swelling, reduced urine output and blood in the urine. Children are more likely to develop post-streptococcal glomerulonephritis than are adults, and they’re also more likely to recover quickly.

        Bacterial endocarditis. Bacteria can occasionally spread through your bloodstream and lodge in your heart, causing an infection of one or more of your heart valves. Those at greatest risk are people with a heart defect, such as a damaged or artificial heart valve. Bacterial endocarditis is associated with glomerular disease, but the exact connection between the two is unclear.

        Viral infections. Among the viral infections that may trigger glomerulonephritis are the human immunodeficiency virus (HIV), which causes AIDS, and the hepatitis B and hepatitis C viruses.

        Immune diseases.         Lupus. A chronic inflammatory disease, lupus can affect many parts of your body, including your skin, joints, kidneys, blood cells, heart and lungs.

        Goodpasture’s syndrome. A rare immunological lung disorder that may mimic pneumonia, Goodpasture’s syndrome causes bleeding (hemorrhage) into your lungs as well as glomerulonephritis.

        IgA nephropathy. Characterized by recurrent episodes of blood in the urine, this primary glomerular disease results from deposits of immunoglobulin A (IgA) in the glomeruli. IgA nephropathy can progress for years with no noticeable symptoms. The disorder seems to be more common in men than in women.

Vasculitis.          Polyarteritis. This form of vasculitis affects small and medium blood vessels in many parts of your body, such as your heart, kidneys and intestines.

        Wegener’s granulomatosis. This form of vasculitis affects small and medium blood vessels in your lungs, upper airways and kidneys.

Conditions that are likely to cause scarring of the glomeruli

        High blood pressure. Damage to your kidneys and their ability to perform their normal functions can occur as a result of high blood pressure. Glomerulonephritis can also cause high blood pressure because it reduces kidney function.

        Diabetic kidney disease. Diabetic kidney disease (diabetic nephropathy) can affect anyone with diabetes. Diabetic nephropathy usually takes years to develop. Good control of blood sugar levels and blood pressure may prevent or slow kidney damage.

        Focal segmental glomerulosclerosis. Characterized by scattered scarring of some of the glomeruli, this condition may result from another disease or occur for no known reason.

        Chronic glomerulonephritis sometimes develops after a bout of acute glomerulonephritis. In some people there’s no history of kidney disease, so the first indication of chronic glomerulonephritis is chronic kidney failure. Infrequently, chronic glomerulonephritis runs in families. One inherited form, Alport syndrome, may also involve hearing or vision impairment.

Clinical Classification of Gn

Ø ACUTE

Ø Chronic

 

Аcute Glomerulonephritis

         Background: Bright initially described acute glomerulonephritis (GN) in 1927. Acute poststreptococcal glomerulonephritis (PSGN) is the archetype of acute GN. Acute nephritic syndrome is the most serious and potentially devastating form of various renal syndromes. Acute GN is characterized by the abrupt onset of hematuria and proteinuria, often accompanied by azotemia (ie, decreased glomerular filtration rate [GFR]) and renal salt and water retention.

Frequency:

·         In the US: GN comprises 25-30% of all cases of end-stage renal disease (ESRD). About one fourth of affected patients present with acute nephritis syndrome. Most cases that progress do so relatively quickly, and end-stage renal failure may occur within weeks or months of acute nephritic syndrome onset. Asymptomatic episodes of PSGN exceed symptomatic episodes by a ratio of 3-4:1.

·         Internationally: Geographic and seasonal variations in the prevalence of PSGN are more marked for pharyngeally associated GN than for cutaneously associated disease.

Race: Postinfectious GN has no predilection for any racial or ethnic group. A higher incidence (related to poor hygiene) may be observed in some socioeconomic groups.

Sex: Acute GN predominantly affects males (ie, 2:1 male-to-female ratio).

Age: Postinfectious GN can occur at any age but usually develops in children. Outbreaks of PSGN are common in children aged 6-10 years.

CLINICAL

·  Determine onset of disease: Ask the patient about onset and duration of illness.

·  Identify a possible etiologic agent (eg, streptococcal throat infection [pharyngitis], skin infection [pyoderma]): Recent fever, sore throat, joint pains, hepatitis, travel, valve replacement, and/or intravenous drug use may be causative factors. Rheumatic fever rarely coexists with acute PSGN.

·  Identify systemic disease (eg, arthralgia, diabetes).

·  Assess the consequences of the disease process (eg, uremic symptoms): Inquire about loss of appetite, generalized itching, tiredness, listlessness, nausea, easy bruising, nose bleeds, facial swelling, leg edema, and shortness of breath.

·  Identify clinical features: Inquire about edema, decreased volume and frequency of urination, systemic hypertension, uremic symptoms, costovertebral tenderness (ie, enlarged kidneys [rare]), and gross hematuria. Gross hematuria is the most common abnormality observed in patients with acute PSGN and often manifests as smoky-, coffee-, or cola-colored urine.

Symptoms

Common symptoms of glomerulonephritis are:

• Blood in the urine (dark, rust-colored, or brown urine)
• Foamy urine (due to excess protein in the urine)
• Swelling (edema) of the face, eyes, ankles, feet, legs, or abdomen

Symptoms may also include the following:

• Abdominal pain
• Blood in the vomit or stools
• Cough and shortness of breath
• Diarrhea
• Excessive urination
• Fever
• General ill feeling, fatigue, and loss of appetite
• Joint or muscle aches
• Nosebleed

The symptoms of chronic kidney disease may develop over time.

Physical:  Signs of fluid overload.

• Periorbital and/or pedal edema (picture)
• Edema and hypertension due to fluid overload – In 75% of patients
• Crackles (ie, if pulmonary edema)  

 

Periorbital edema

 

 

  Pedal edema

 

Picture  pulmonary edema

• Elevated jugular venous pressure
• Ascites and pleural effusion (possible)
• Rash (ie, vasculitis, Henoch-Schönlein purpura)
• Pallor
• Renal angle (ie, costovertebral) fullness or tenderness, joint swelling, or tenderness

Because symptoms may develop slowly, the disorder may be discovered when you have an abnormal urinalysis during a routine physical or examination for another condition.

Signs of glomerulonephritis can include:

Blood test. A blood test can be used to measure your creatinine level. Creatinine is a substance produced by your muscles that is present in your blood stream. The kidneys remove creatinine from the blood as part of their usual role.

If your kidneys are not working normally, the creatinine level in your blood will rise, and this can be detected during a blood test. The creatinine result is converted into what is known as the estimated glomerular filtration rate (eGFR). The eGFR is the best guide to kidney function.

Specialist blood tests

Several specialist blood tests may be carried out to look for causes of glomerulonephritis. These include:

ü  tests to look for systemic lupus erythematosus, such as an anti-nuclear antibody test

ü  the anti-neutrophil cytoplasmic antibody blood test – used to diagnose vasculitis (a condition that affects the small blood vessels of various organs in the body)

ü  the anti-glomerular basement membrane blood test – used to diagnose Goodpasture’s disease (when antibodies attack the membranes of the glomeruli) 

• Anemia
• High blood pressure
• Signs of reduced kidney function

A kidney biopsy confirms the diagnosis.

Later, signs of chronic kidney disease may be seen, including:

• Nerve inflammation (polyneuropathy)
• Signs of fluid overload, including abnormal heart and lung sounds
• Swelling (edema)

Imaging tests that may be done include:

• Abdominal CT scan
• Kidney ultrasound

Kidney ultrasound

If your kidney problem needs to be investigated further, it is likely that you will need to have a kidney ultrasound. An ultrasound scan uses high-frequency sound waves to allow the specialist to look at images of your kidneys. The specialist will be able to check the size of your kidneys, make sure there are no blockages and look for anything else that might explain why they are not working as they should.

Imaging Studies:

• Abdominal ultrasound

o     Assesses renal size

o    Assesses echogenicity of renal cortex

o    Excludes obstruction

In patient with ACUTE GLOMERULONEPHRITIS –  increased cortical echogenicity with medullary sparing. If you need a kidney biopsy (see below), you will need a kidney ultrasound scan first. 

Ultrasonographic image of the right kidney on the day of admission (A) showing increased renal cortical echogenicity. It has almost the same echo-level as the liver parenchyma (arrows). (B) Three days after treating the patient’s acute gastroenteritis and diarrhea, the ultrasonographic study shows the apparently decreased echogenicity of the renal cortex. The renal size did not significantly change (10.2 cm vs. 10.4 cm) (arrows).

Procedures: Generally, a renal biopsy is not necessary for diagnosis of acute PSGN; however, in most cases, it is important because histology guides both prognosis and therapy.   Histologic Findings: Diffuse endocapillary proliferative changes are found

• Chest x-ray
• Intravenous pyelogram (IVP)

Urinalysis and other urine tests include:

• Creatinine clearance
• Examination of the urine under a microscope
• Urine fortotal protein
• Uric acid in the urine
• Urine concentration test
• Urine creatinine
• Urine protein
• Urine RBC
• Urine specific gravity
• Urine osmolality

This disease may also cause abnormal results on the following blood tests:

• Albumin
• Anti-glomerular basement membrane antibody test
• Anti-neutrophil cytoplasmic antibodies (ANCAs)
• Anti-nuclear antibodies
• BUN and creatinine
• Complement levels

Other Problems to be Considered:

• Postinfectious GN must be differentiated from the following conditions:

o   IgA nephritis: The latent period between infection and onset of nephritis is 1- 2 days, or it may be concomitant with upper respiratory tract infection (ie, “synpharyngitic” in contrast to 1-3 wk “postpharyngitic nephritis” in PSGN).

o   MPGN (type I, type II): This is a chronic disease, but it can manifest with an acute nephritic picture with hypocomplementemia; failure of acute nephritis to resolve should prompt consideration of this possibility.

o   Lupus nephritis: Gross hematuria is unusual in lupus nephritis.

o   GN of chronic infection: This can manifest as acute nephritis. Unlike PSGN, in which the infection may have resolved by the time nephritis occurs, patients with nephritis of chronic infection have an active infection at the time nephritis becomes evident. Circulating immune complexes play an important role in the pathogenesis of acute GN in these diseases.

o   Vasculitis: Nephritis of MRSA may have vasculitic lesions of the lower extremities.

Lab Studies: Urinalysis and sediment examination

·        These tests are crucial in the evaluation of patients with acute nephritic syndrome.

·        Look for protein, blood, RBCs and WBCs, dysmorphic red cells, acanthocytes, cellular (ie, RBC, WBC) casts, granular casts, and oval fat bodies. In some instances, marked sterile pyuria is present.

 

Since the early 1980s we know that in the urine we can find two main types of erythrocytes: the so-called glomerular (or dysmorphic) erythrocytes and the so-called non-glomerular (or isomorphic) erythrocytes.

Isomorphic (black arrows), dysmorphic (white arrows) RBC and acanthocytes (arrowheads). b Sickle cells (asterisks) intermingled with isomorphic crenated RBC (phase contrast microscopy, original magnification ×400).

The slide shows a good example of glomerular or dysmorphic erythrocytes. These are cells with irregular shape, size, and cell membrane, which differ remarkably from the image of erythrocytes we have stored in our mind.

While this slide shows a nice example of non glomerular  or isomorphic erythrocytes i.e., erythrocytes with a spherical shape and regular contours, containing (green-bluish cells) or not  (colourless cells) haemoglobin

In this slide you can see how easily the acanthocytes can be identified by phase contrast

.                                                              

Erythrocyte cast

o   Urine electrolytes, urine sodium, and fractional excretion of sodium (FENa) assays are needed to assess salt avidity.

• Blood, urea, and nitrogen (BUN); serum creatinine; and serum electrolytes (especially serum potassium level)

• Complete blood cell count

• Erythrocyte sedimentation rate

• Complement levels (C3, C4, CH50)

o    Low C3 levels are found in almost all patients with acute poststreptococcal nephritis; C4 levels may be slightly low.

o    Type III cryoglobulinemia may be present.

• Twenty-four–hour urine test for total protein and creatinine clearance: This test may not reveal the true picture because of rapidly changing renal function; therefore, it may be better to wait until renal function has stabilized before performing this test.

• Antistreptolysin-O titer (ASOT) or streptozyme titer: Increasing titer levels confirm recent infection. In patients with skin infection, anti-DNase B titers are more sensitive than ASOT for infection with Streptococcus.

• If MRSA is the inciting agent, then hypocomplementemia is usually not present, but plasma immunoglobulins, especially IgA, are markedly elevated.

Medical Care: Treatment of acute PSGN is mainly supportive because there is no specific therapy for renal disease. Treat the underlying infections when acute GN is associated with chronic infections.

• Antimicrobial therapy
• 

• Antibiotics (eg, penicillin) are used to control local symptoms and to prevent spread of infection to close contacts.

• Antimicrobial therapy does not appear to prevent the development of GN, except if given within the first 36 hours.

• Loop diuretic therapy

• Loop diuretics may be required in patients who are edematous and hypertensive in order to remove excess fluid and to correct hypertension.
• Relieves edema and controls volume, thereby helping to control volume-related elevation in BP.
• Vasodilator drugs (eg, nitroprusside, nifedipine, hydralazine, diazoxide) may be used if severe hypertension or encephalopathy is present.

• Glucocorticoids and cytotoxic agents are of no value, except in severe cases of PSGN.

Consultations: Nephrologist

·        Diet: Sodium and fluid restriction – For treatment of signs and symptoms of fluid retention (eg, edema, pulmonary edema)

·        Protein restriction for azotemic patients – If no evidence of malnutrition

Activity: Recommend bed rest until signs of glomerular inflammation and circulatory congestion subside. Prolonged inactivity does not benefit in the patient recovery process. The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the infection.

Antimicrobials (antibiotics) — In streptococcal infections, early antibiotic therapy may prevent antibody response to exoenzymes and render throat cultures negative, but may not prevent the development of PSGN.

Loop diuretics — Decrease plasma volume and edema by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BP.

Vasodilators — Reduce SVR, which in turn may allow forward flow, improving cardiac output.

Calcium channel blockers — In specialized conducting and automatic cells in the heart, calcium is involved in the generation of the action potential. The calcium channel blockers inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity.

  Further Inpatient Care: Patients may require hospitalization for control of edema and hypertension.

Further Outpatient Care: Monitor renal function, BP, edema, serum albumin, and urine protein excretion rate.

In/Out Patient Meds: Patient may require medication to control BP.

Transfer: The expertise available in the ICU may be needed for management of patients with hypertensive encephalopathy or pulmonary edema.

Deterrence/Prevention:

·       Early antibiotic therapy of streptococcal infection (ie, within 36 h of onset) may prevent development of PSGN.

·       Antibiotic treatment of close contacts of the index case may help prevent development of PSGN.

Complications:

·       Renal failure (rare)

·       Pulmonary edema

·       Generalized anasarca and hypoalbuminemia (secondary to severe proteinuria)

·       Hypertension

·       Hypertensive encephalopathy

Prognosis:

·       Prognosis of acute PSGN is generally excellent in children.

·       Within a week or so of onset, most patients with PSGN begin to experience spontaneous resolution of fluid retention and hypertension.

·       C3 levels may normalize within 8 weeks after the first sign of PSGN.

·       Proteinuria may persist for 6 months and microscopic hematuria for up to 1 year after onset of nephritis.

·       Eventually, all urinary abnormalities should disappear, hypertension should subside, and renal function should return to normal.

·       Adults with PSGN, particularly older adults, may have a less favorable prognosis.

·       Few patients with acute nephritis develop rapidly progressive renal failure.

·       Nephritis associated with MRSA and chronic infections usually resolves after treatment of the infection.

·       Immunity to type M protein is type-specific, long-lasting, and protective. Repeated episodes of PSGN are therefore unusual.

·       Approximately 15% of patients at 3 years and 2% of patients at 7-10 years may have persistent mild proteinuria. Long-term prognosis is not necessarily benign. Some patients may develop hypertension, proteinuria, and renal insufficieny as long as 10-40 years after the initial illness.

Patient Education: Counsel patients about the need for the following measures:

o    Salt restriction during the acute phase to control edema and volume-related hypertension

o    BP monitoring at periodic intervals

o    Ongoing long-term monitoring of patients with persistent urinary abnormalities and elevated BP

o    Consideration of protein restriction and angiotensin converting enzyme inhibitors (in patients who show evidence of persistent abnormalities or in those who develop late evidence of progressive disease)

o    Early antibiotic treatment of close contacts

Chronic Glomerulonephritis

 Background: Nearly all forms of acute glomerulonephritis typically progress to chronic glomerulonephritis. The condition is characterized by irreversible and progressive glomerular and tubulointerstitial fibrosis, ultimately leading to a reduction in the glomerular filtration rate (GFR) and retention of uremic toxins. If disease progression is not halted with therapy, the net result is chronic kidney disease (CKD), end-stage renal disease (ESRD), cardiovascular disease, and death. The diagnosis of CKD can be made without knowledge of the specific cause.

The National Kidney Foundation defines CKD as (1) evidence of kidney damage based on abnormal urinalysis results (eg, proteinuria, hematuria) or structural abnormalities observed on ultrasound images or (2) a GFR of less than 60 mL/min for 3 or more months. Based on this definition, the National Kidney Foundation developed guidelines that classify the progression of renal disease into 5 stages, from kidney disease with a preserved GFR to end-stage kidney failure. This classification includes treatment strategies for each progressive level, as follows:

·       Stage 1: This stage is characterized by kidney damage with a normal GFR (>90 mL/min). The action plan is diagnosis and treatment, treatment of comorbid conditions, slowing of the progressing of kidney disease, and reduction of cardiovascular disease risks.

·       Stage 2: This stage is characterized by kidney damage with a mild decrease in the GFR (60-90 mL/min). The action plan is estimation of the progression of kidney disease.

·       Stage 3: This stage is characterized by a moderately decreased GFR (30-59 mL/min). The action plan is evaluation and treatment of complications.

·       Stage 4: This stage is characterized by a severe decrease in the GFR (15-29 mL/min). The action plan is preparation for renal replacement therapy.

·       Stage 5: This stage is characterized by kidney failure. The action plan is kidney replacement if the patient is uremic.

At the later stages of glomerular injury, biopsy results cannot help distinguish the primary disease. Histology and clues to the etiology are often derived from other systemic diseases, if present. Considerable cause-specific variability is observed in the rate at which acute glomerulonephritis progresses to chronic glomerulonephritis.

Pathophysiology: Reduction iephron mass from the initial injury reduces the GFR. This reduction leads to hypertrophy and hyperfiltration of the remaining nephrons and to the initiation of intraglomerular hypertension. These changes occur in order to increase the GFR of the remaining nephrons, thus minimizing the functional consequences of nephron loss. The changes, however, are ultimately detrimental because they lead to glomerulosclerosis and further nephron loss.

In early renal disease, stages 1-3, a substantial decline in the GFR may lead to only slight increases in serum creatinine levels. Azotemia (ie, a rise in BUN and serum creatinine levels) is apparent when the GFR decreases to less than 60-70 mL/min. In addition to a rise in BUN and creatinine levels, the substantial reduction in the GFR results in decreased production of (1) erythropoietin, thus resulting in anemia; (2) decreased production of vitamin D, resulting in hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy; (3) reduction in acid, potassium, salt, and water excretion, resulting in acidosis, hyperkalemia, hypertension, and edema; and (4) platelet dysfunction, leading to increased bleeding tendencies.

Accumulation of toxic waste products (uremic toxins) affects virtually all organ systems. Azotemia occurring with the signs and symptoms listed above is known as uremia. Uremia occurs at a GFR of approximately 10 mL/min. Some of these toxins (eg, BUN, creatinine, phenols, guanidines) have been identified, but none has been found to be responsible for all the symptoms.

Frequency:

• In the US: Chronic glomerulonephritis is the third-leading cause of ESRD and accounts for 10% of patients on dialysis in the United States.

• Internationally: Chronic glomerulonephritis is the leading cause of ESRD and accounts for 40% of patients on dialysis in Japan. Other Asian countries and developing countries have a similar trend.

Mortality/Morbidity: ESRD and death are common outcomes unless renal replacement therapy is instituted.

History: The history should focus on cause-specific symptoms to determine the causes of CKD (if unknown) and on symptoms related to uremia to determine if renal replacement therapy is needed.

• Cause-specific history: Obtain a cause-specific history so that further workup and management of the disease (if systemic) can be planned.

• Uremia-specific history

o   The following symptoms suggest uremia:

§  Weakness and fatigue

§  Loss of energy, appetite, and weight

§  Pruritus

§  Early morning nausea and vomiting

§  Change in taste sensation

§  Reversal in sleep pattern (ie, sleepiness in daytime, wakefulness at night)

§  Peripheral neuropathy

§  Seizures

§  Tremors

o   The presence of edema and hypertension suggests volume retention.

o   Dyspnea or chest pain that varies with position suggests fluid overload and pericarditis, respectively.

o   Leg cramps may suggest hypocalcemia or other electrolyte abnormalities.

o   Weakness, lethargy, and fatigue may be due to anemia.

Physical: Cause-specific physical examination findings are discussed in articles on the specific causes.

ü Uremia-specific findings

ü Hypertension

ü Jugular venous distension (if severe volume overload is present)

o  

 

o   Pulmonary rales (if pulmonary edema is present)

o   Pericardial friction rub in pericarditis

o   Tenderness in the epigastric region or blood in the stool (possible indicators for uremic gastritis or enteropathy)

o   Decreased sensation and asterixis (indicators for advanced uremia)

Causes: All patients with primary glomerulonephritis have a tendency to progress to CKD and ESRD at variable rates; however, complete recovery of renal function is the rule for patients with poststreptococcal glomerulonephritis. Several other glomerulonephritides, such as immunoglobulin A (IgA) nephropathy, often have a relatively benign course and many do not progress to ESRD.

• Rapidly progressive glomerulonephritis or crescentic glomerulonephritis: Approximately 90% of patients progress to ESRD within weeks or months.
• Focal segmental glomerulosclerosis: Approximately 80% of patients progress to ESRD in 10 years. Patients with the collapsing variant, which is termed malignant focal segmental glomerulosclerosis, have a more rapid progression. This form may be idiopathic or related to HIV infection.
• Membranous nephropathy: Approximately 20-30% of patients with membranous nephropathy progress to chronic renal failure (CRF) and ESRD in 10 years.
• Membranoproliferative glomerulonephritis: Approximately 40% of patients with membranoproliferative glomerulonephritis progress to CRF and ESRD in 10 years.
• IgA nephropathy: Approximately 10% of patients with IgA nephropathy progress to CRF and ESRD in 10 years.
• Poststreptococcal glomerulonephritis: Approximately 1-2% of patients with poststreptococcal glomerulonephritis progress to CRF and ESRD. Older children or adults who present with crescentic glomerulonephritis are at greatest risk.
• Lupus nephritis: Overall, approximately 20% of patients with lupus nephritis progress to CRF and ESRD in 10 years; however, patients with certain histologic variants (eg, class IV) may have a more rapid decline. .

Lab Studies:

·       Urinalysis

o   The presence of dysmorphic RBCs, albumin, or RBC casts suggests glomerulonephritis as the cause of renal failure.

o   Waxy or broad casts are observed in all forms of CKD, including chronic glomerulonephritis (picture 15)

o   Low urine-specific gravity indicates loss of tubular concentrating ability, an early finding in persons with CDK.

·       Urinary protein excretion

o   This can be estimated by calculating the protein-to-creatinine ratio on a spot morning urine sample. The ratio of urinary protein concentration (in mg/dL) to urinary creatinine (in mg/dL) reflects 24-hour protein excretion in grams. For instance, if the spot urine protein value is 300 mg/dL and the creatinine value is 150 mg/dL, then the ratio is 300 divided by 150, which equals 2. Thus, in this example, the 24-hour urine protein excretion is 2 g.

o   The estimated creatinine clearance rate is used to assess and monitor the GFR. The 2 formulas available to calculate the value are the Cockroft-Gault formula, which estimates creatinine clearance, and the more recent Modification of Diet in Renal Disease Study (MDRD) formula, which is used to calculate the GFR. The Cockroft-Gault formula is simple to use but overestimates the GFR by 10-15% because creatinine is both filtered and secreted. The MDRD formula is much more complex.

o   The estimated creatinine clearance rate is also used to monitor response to therapy and to initiate an early transition to renal replacement therapy (eg, dialysis access placement, transplantation evaluation). The degree of proteinuria, especially albuminuria, helps predict renal prognosis in patients with chronic glomerulonephritis. Patients with greater than 1 g/d have an increased risk of progression to ESRD.

·       CBC count

o   Anemia is a significant finding in patients with some decline in the GFR.

o   Physicians must be aware that anemia can occur even in patients with serum creatinine levels of less than 2 mg/dL. Even severe anemia can occur at low serum creatinine levels. Anemia is the result of marked impairment of erythropoietin production.

o   Serum chemistry

o   Serum creatinine and urea nitrogen levels are elevated.

o   Impaired excretion of potassium, free water, and acid results in hyperkalemia, hyponatremia, and low serum bicarbonate levels, respectively.

o   Impaired vitamin D-3 production results in hypocalcemia, hyperphosphatemia, and high levels of parathyroid hormone.

o   Low serum albumin levels may be present if uremia interferes with nutrition or if the patient is nephrotic.

Imaging Studies:

·       Renal ultrasonogram: Obtain a renal ultrasonogram to determine renal size, to assess for the presence of both kidneys, and to exclude structural lesions that may be responsible for azotemia. Small kidneys often indicate an irreversible process.

Procedures:

·       Kidney biopsy

o   If the kidney is small, kidney biopsy is usually unnecessary; no specific pattern of disease can be discerned at this point.

o   A kidney biopsy may be considered in the minority of patients who exhibit an acute exacerbation of their chronic disease. This may be particularly pertinent to patients with preserved kidney size and in those with lupus nephritis.

Histologic Findings: In early stages, the glomeruli may still show some evidence of the primary disease. In advanced stages, the glomeruli are hyalinized and obsolescent. The tubules are disrupted and atrophic, and marked interstitial fibrosis and arterial and arteriolar sclerosis occur.

Medical Care: Progression from CKD to ESRD can be slowed by a variety of measures, including aggressive control of diabetes, hypertension, and proteinuria. Dietary protein restriction, phosphate restriction, and hyperlipidemia control may have significant impact on retarding disease progression. Specific therapies for some glomerular diseases (eg, lupus) should be implemented in appropriate settings. Aggressively manage anemia and hypocalcemia before renal replacement therapy. Also, aggressively manage comorbid conditions such as heart disease and diabetes.

·  The target blood pressure for patients with proteinuria greater than 1 g/d is less than 125/75 mm Hg; for patients with proteinuria less than 1 g/d, the target blood pressure is less than 130/80 mm Hg.

o Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used and are usually the first drug of choice for treatment of hypertension in patients with CRF. ACEIs are renoprotective agents that have additional benefits beyond lowering blood pressure. ACEIs effectively reduce proteinuria, in part by reducing the efferent arteriolar vascular tone, thereby decreasing intraglomerular hypertension. Particularly, ACEIs have been shown to be superior to conventional therapy in slowing the decline of the GFR in patients with diabetic and nondiabetic proteinuric nephropathies. Therefore, consider ACEIs for treatment of eveormotensive patients with significant proteinuria.

o The role of angiotensin II receptor blockers in renal protection is increasingly being established, and these medications have been found to retard the progression of CKD in patients with diabetic or nondiabetic nephropathy in a manner similar to that of ACEIs.

o Diuretics are often required because of decreased free-water clearance, and high doses may be required to control edema and hypertension when the GFR falls to less than 25 mL/min.

o Beta-blockers, calcium channel blockers, central alpha-2 agonists (eg, clonidine), alpha-1 antagonists, and direct vasodilators (eg, minoxidil, nitrates) may be used to achieve the target blood pressure.

·  Renal osteodystrophy can be managed early by replacing vitamin D and administering phosphate binders. Seek and treat nonuremic causes of anemia, such as iron deficiency, before instituting therapy with erythropoietin.

·  Discuss options for renal replacement therapy, eg, hemodialysis, peritoneal dialysis, or transplantation. Arrange permanent vascular access when the GFR decreases to less than 20-25 mL/min or if the rate of rise in the serum creatinine level indicates the need for dialysis within 2-6 months. Arteriovenous fistulas are preferred to arteriovenous grafts because of their long-term high-patency rates and should be placed whenever possible. Place peritoneal dialysis catheters 2-3 weeks prior to anticipated dialysis therapy.

·           Treat hyperlipidemia (if present) to reduce overall cardiovascular comorbidity, even though evidence for renal protection is lacking.

·           Expose patients to educational programs for early rehabilitation from dialysis or transplantation.

Surgical Care: Create access for dialysis when the GFR decreases to less than 25 mL/min.

Consultations:

• Nephrologists: Early referral of patients with CRF to a nephrologist is important for the management of complications and the organization of the transition to renal replacement therapy (eg, hemodialysis, peritoneal dialysis, renal transplantation). Some evidence indicates that early referral of a patient with CRF (serum creatinine, 1.5-2 mg/dL) to a nephrologist improves the short-term outcome.

• Surgeons: When dialysis is imminent, seek consultation for creation of an arteriovenous fistula or graft for the insertion of a peritoneal dialysis catheter.

• Transplantation surgeons: Seek consultations for evaluation for kidney transplantation.

Diet:  Protein-restricted diets (0.4-0.6 g/kg/d) are controversial but may be beneficial in slowing the decline in the GFR and in reducing hyperphosphatemia (serum phosphate level >5.5 mg/dL) in patients with serum creatinine levels of greater than 4 mg/dL. Monitor these patients for signs of malnutrition.

·  Educate patients about how diets rich in potassium help control hyperkalemia.

·  Many dietary restrictions are no longer necessary with the initiation of renal replacement therapy.

Activity: Encourage patients to increase their activity level as tolerated. Increased activity may aid in blood pressure control.  The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Angiotensin-converting enzyme inhibitors — For renoprotection. Decrease intraglomerular pressure and, consequently, glomerular protein filtration, by decreasing efferent arteriolar constriction.

Diuretics — Treat edema and hypertension. Increase urine excretion by inhibiting sodium and chloride transporters.

Calcium channel blockers — Treat hypertension, angina, and atrial fibrillation.

Beta-adrenergic blockers — Compete with beta-adrenergic agonists for available beta-receptor sites. Propranolol, nadolol, timolol, penbutolol, carteolol, sotalol, and pindolol inhibit both the beta-1 receptors (located mainly in cardiac muscle) and beta-2 receptors (located mainly in bronchial and vascular musculature), thus inhibiting chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation.

Alpha-adrenergic agonists — Used in combination with other agents for management of hypertension.

Complications: The presence of the following complications generally indicates a need for urgent dialysis:

o    Metabolic acidosis

o    Pulmonary edema

o    Pericarditis

o    Uremic encephalopathy

o    Uremic gastrointestinal bleeding

o    Uremic neuropathy

o    Severe anemia and hypocalcemia

o    Hyperkalemia

Rapidly progressive glomerulonephritis

Background: Rapidly progressive glomerulonephritis (RPGN) is defined as any glomerular disease characterized by extensive crescents (usually >50%) as the principal histologic finding and by a rapid loss of renal function (usually a 50% decline in the glomerular filtration rate [GFR] within 3 mo) as the clinical correlate. Transient azotemia with oliguria is common in patients with acute glomerulonephritis (GN).

Some patients have acute GN and present with rapidly progressive renal failure that develops within weeks to months and displays little tendency for spontaneous or complete recovery. Glomerular crescents can complicate any glomerulopathy, eveoninflammatory glomerulopathy. In patients with noninflammatory glomerulopathies, the crescents tend to be fibrotic rather than cellular. Cellular crescents are a manifestation of a severe inflammatory process.

Pathophysiology: RPGN can develop in any of the following clinical settings:

• Complication of acute or subacute infectious process
• Renal complication of multisystem disease: Secondary forms comprise more than 40% of cases.
• In association with use of certain drugs: A review of published data on an association between hydrocarbon exposure and anti-GBM antibody-mediated disease suggests the possibility of a casual relationship.
• Primary glomerular disease in which the kidney is the sole organ involved and in which extrarenal manifestations are caused by renal function disturbances

Frequency:  Idiopathic crescentic GN accounts for fewer than 10% of all patients presenting with primary glomerulopathy. RPGN type III is more common than RPGN types I or II. More than 50% of patients with crescentic GN present with acute nephritic syndrome and rapidly deteriorating renal function; however, other modes do occur (eg, asymptomatic, 15%; nephrotic, 10%; chronic renal failure, 15%).

• Internationally: Peak incidence of anti-GBM disease occurs in spring and early summer. No seasonal predilection is observed in patients with non–anti-GBM disease.

Mortality/Morbidity: Death or dialysis occurs in 73% of patients who are treated with conventional therapy and in 88% of patients if they are oligoanuric at time of presentation.

Race: No racial predilection exists.

Sex: For RPGN types I and III, a predilection for males exists.

Age: RPGN has a broad age distribution, as follows:

• RPGN type I generally occurs in young adults.

• RPGN types II and III generally occur in older adults (peak incidence occurs in the fourth to sixth decades of life).

History: Clinical and laboratory presentations of all types of acute RPGN are quite similar.

• Some patients present with signs and symptoms of renal disease, eg, anemia, hematuria, fluid retention, oliguria, or even uremia.

• Symptoms of weakness, nausea, and vomiting (indicative of azotemia) usually dominate the clinical picture.

• Other patients present with signs and symptoms of their primary etiology (eg, Goodpasture syndrome, Wegener granulomatosis, systemic lupus erythematosus [SLE]).

• Still others give a history of a flulike or viral prodrome. Vague aches and pains or frank arthritis, sinusitis, otitis, episcleritis, skin rash, neuritis, or encephalopathy are uncommon and are more common with a multisystem disease (suggesting secondary form).

• Oliguria, abdominal or flank pain, and hemoptysis may occur (eg, Goodpasture syndrome).

• Peripheral swelling may be present.

• Fifteen percent of patients may be asymptomatic.

Physical:

·         Blood pressure may be normal or slightly elevated.

·         Peripheral edema may be present in 10% of patients.

·         Pallor is common.

·         Skin rash: A lesion suggesting leukocytoclastic vasculitis may be present.

Causes: Infectious diseases

o  Poststreptococcal glomerulonephritis (PSGN)

o  Infective endocarditis

o  Occult visceral sepsis

o  Hepatitis B infection (with vasculitis and/or cryoglobulinemia)

·        Multisystem diseases

·        SLE

·        Henoch-Schönlein purpura

·        Systemic necrotizing vasculitis (including Wegener granulomatosis)

·        Microscopic polyarteritis

·        Goodpasture syndrome

·        Essential mixed (IgG and immunoglobulin M [IgM]) cryoglobulinemia

·        Malignancy

·        Relapsing polychondritis

·        Rheumatoid vasculitis

• Drugs

• Penicillamine
• Hydralazine (rare case reports)
• Allopurinol (with vasculitis)
• Rifampin (rare case reports)

Lab Studies:

• CBC count may show leucocytosis and anemia.

• Erythrocyte sedimentation rate (ESR) is usually elevated.

• Blood urea nitrogen (BUN) and serum creatinine levels are usually elevated.

• Electrolytes, especially the serum potassium level, are consistent with the degree of renal failure.

• Urinalysis shows modest proteinuria (1-4 g/d), microscopic hematuria, RBCs, and RBC and WBC casts.

• Proteinuria could be quantified by timed (24-h collection) or spot urine protein/creatinine ratio.

• Rarely, urine findings may be minimal.

• An absence of active urine sediment does not exclude a diagnosis of RPGN.

• Complement levels (C3 and C4) are within reference ranges in patients with RPGN types I and III and may be decreased in patients with RPGN type II.

• Circulating anti-GBM antibodies are detected in plasma of patients with RPGN type I, but this finding is neither 100% sensitive nor 100% specific for type I.

• ANCAs: Typically, perinuclear ANCA (p-ANCA) is observed in 80-90% of patients with RPGN type III pauci-immune, but neither p-ANCA nor ANCA is 100% specific for type III.

• Antinuclear antibody findings are usually negative (unless lupus related).

• Serum cryoglobulin levels may be elevated in cryoglobulinemias and may be falsely negative.

Imaging Studies:

• Abdominal ultrasound is used to assess renal size and echogenicity and to exclude obstruction.

• Chest x-ray films are indicated for patients with suspected Goodpasture syndrome and vasculitides and to help manage pulmonary renal syndromes.

• Sinus x-ray films and/or CT scans may show evidence of sinusitis in patients with Wegener granulomatosis.

• Chest CT scans may show reticulonodular infiltrate, even when chest radiographic findings are normal.

Procedures:

• Renal biopsy is usually required to diagnose RPGN types I, II, or III.

The normal renal architecture is lost, and the glomerulus is solid, hypercellular, and surrounded by severe interstitial mononuclear cell infiltrate (see see pic12) is observed in patients with severe types. The glomerular tuft is distorted by proliferation of epithelial cells crescents that occupy most of the Bowman space

Medical Care: Early and aggressive treatment is warranted to preserve renal function. . For specific therapies, see the following related chapters:

Consultations: A nephrologist should be involved early in the disease course.

Diet: Renal diet: Provide a low-protein (0.8 g/kg/d) and low-salt diet. Restrict potassium if the patient has hyperkalemia.

Activity: No specific limitations are necessary other than limiting activity after renal biopsy.

Principles of therapy include supportive and specific therapies. Supportive therapy involves control of infection, control of volume status (providing dialysis if required), and smoking cessation. Specific therapy is directed toward providing immunosuppressive therapy (eg, glucocorticoids, cyclophosphamide), plasma exchange, and anticoagulant agents.

Glucocorticoids — Pulses of intravenous methylprednisolone (5-20 mg/kg) followed by high-dose oral prednisone (2 mg/kg) daily or on alternate days for 2-3 months has shown improved 1-year renal survival rates of 40-70%.

Drug Category: Immunosuppressive agents (cytotoxics) — Addition of cytotoxic agents to corticosteroids has yielded varying success in treating patients with crescentic GN. Although pulse cyclophosphamide is often preferred in lupus nephritis, oral cyclophosphamide appears to have an advantage in Wegener granulomatosis.

Cyclophosphamide 3 mg/kg/d for 12 weeks is a common recommendation, but the duration of therapy should be longer (4-6 mo) in patients with pauci-immune GN. This therapy should be followed by the administration of azathioprine (1.5-2 mg/kg/d) or methotrexate (5-20 mg qwk as a single dose) until the patient is in remission for at least 6-12 months. Recent evidence suggests that mycophenolate mofetil (CellCept) 0.75-1 g bid may also be effective in patients with pauci-immune vasculitis.

Antibiotics — Therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

Further Inpatient Care:

• Intensive plasma exchange: Plasmapheresis (2-4 L of plasma qd or 3 times/wk), combined with glucocorticoids and cytotoxic agents, is beneficial in anti–GBM-mediated disease provided therapy is initiated before renal failure has progressed to require dialysis support.

• Despite aggressive therapy, many patients with oliguria do not respond well.

• In the absence of any response within 3-5 weeks, acceptance of a diagnosis of end-stage renal disease is preferable to death secondary to iatrogenic causes.

• High-dose intravenous immunoglobulin has been reported to be successful in suppressing the activity of pauci-immune ANCA-positive vasculitis. The mechanism is not clear, but pooled normal immunoglobulin contains antibodies that neutralize ANCA and suppress complement activation through a nonspecific effect of the immunoglobulin heavy chains.

• Intravenous immunoglobulin may have a role in the temporary management of severe pauci-immune vasculitis when severe infection is present in patients in whom it is desirable to withhold cytotoxic agents and high-dose corticosteroids until the infection is controlled.

Further Outpatient Care:

• Discontinuation of drug therapy: Once renal function is stable in patients who respond to therapy, the medication should be slowly tapered to a low maintenance dose of prednisone (15-20 mg on alternate days) that should be continued for 6-9 months.

• Monitor BUN, electrolyte, and serum creatinine levels in all patients.

• Drug-responsive relapses may occur as late as 2-4 years after remission.

• RPGN may recur after renal transplantation. At present, after initiating dialysis, a waiting period of 3-6 months is recommended before considering renal transplantation.

• No convincing evidence suggests that a bilateral nephrectomy performed before a renal transplantation reduces the risk of recurrent disease in patients with renal allografts.

• For patients who have achieved remission, evaluation at 2-month intervals is usually sufficient. The following testing is recommended:

o   Urinalysis with special emphasis on the presence of cellular casts: BUN, electrolyte, and serum creatinine levels should be evaluated in all patients.

o   C-reactive protein or ESR (whichever correlates better with disease activity in a given patient)

o   ANCA (in ANCA-positive patients at 6- to 9-mo intervals): An increasing ANCA titer is often evidence of an impending relapse.

o   Anti-GBM titers in anti-GBM patients

In/Out Patient Meds:

• Administer oral cyclophosphamide for 4-6 months, followed by azathioprine or methotrexate until the patient is in remission for 6 months to 1 year.

• Administer prednisone as a low-dose alternative for 6-9 months.

• Administer trimethoprim-sulfamethoxazole 160/800 mg bid (for Wegener granulomatosis) if renal functioormal. Decrease the dose as guided by renal function. A lower dosage as PCP prophylaxis may be considered.

Transfer: Patients may need to be transferred to another center for the following:

• Plasmapheresis (picture)

 

Plasmapheresis

• Dialysis (picture )

Hemodyalisis

• Ventilatory support (picture)

Patient with Ventilatory Support

Complications:

ü Renal failure

ü Pulmonary edema

ü Pulmonary hemorrhage

ü Respiratory failure

Prognosis:

Ø In general, prognosis is poor and aggressive therapy is warranted.

Ø Fifty percent of patients require maintenance dialysis within 6 months of disease onset.

Ø Spontaneous remission is uncommon, except among patients with infection as the basis for formation of antigen-antibody complexes, in whom removal of the antigen can take place.

Ø Poor prognostic factors are as follows:

Ø Large crescents in more than 80% of glomeruli (especially if fibrocellular or acellular)

Ø Initial serum creatinine level of more than 500 mmol/L or GFR of less than 5 mL/min at presentation

Ø Oliguria

Ø Presence of anti-GBM antibody

Ø Age older than 60 years

Ø Coexistence of HLA-DR2 and HLA-B7

Patient Education:

Ø Patients receiving immunosuppressive therapy should be educated about early signs of infection and advised to see their physician or health care worker at the early signs of infection in order to monitor WBC count.

Ø Patients on a high dose of prednisone should be monitored for the development of diabetes and peptic ulcer disease and receive therapy to prevent steroid-induced osteoporosis.

Glomerulonephritis, Diffuse Proliferative

Background: Diffuse proliferative glomerulonephritis (DPGN) is a distinct histologic form of glomerulonephritis. The condition is a renal manifestation of various systemic inflammatory diseases, including autoimmune disorders (eg, systemic lupus erythematosus [SLE]), vasculitis syndromes (eg, Wegener granulomatosis), and infectious processes. More than 50% of the glomeruli (diffuse) demonstrate increased mesangial, epithelial, endothelial (proliferative), and inflammatory cells (ie, glomerulonephritis). In contrast, when fewer than 50% of the glomeruli are involved, the condition is termed focal proliferative, an entity with a potential to progress to DPGN. The diagnosis is often suspected in a patient presenting with systemic inflammatory disease who manifests hematuria, proteinuria, and active urinary sediment or azotemia (ie, rise in serum blood urea nitrogen, creatinine); histologic findings from kidney biopsy tissue are used to confirm the diagnosis.

Sporadic forms of renal diseases manifesting as focal, segmental, necrotizing, and crescentic glomerulonephritis or DPGN with undetermined incidence include microscopic polyangiitis; Churg-Strauss syndrome; essential mixed cryoglobulinemia, which also may manifest as membranoproliferative glomerulonephritis; Henoch-Schönlein purpura; and connective tissue diseases.

In severe forms, epithelial proliferation obliterates the Bowman space (ie, crescents). The resulting acute renal failure may manifest as an acute anuria or a steady decline in renal function. Spontaneous remission is rare, and treatment results are anecdotal.

Pathophysiology: Most cases of DPGN result from the deposition of immune complexes in the mesangium, glomerular basement membrane (GBM), or subendothelial or subepithelial locations. Antibodies may form immune complexes with circulating DNA before deposition (ie, immune complex deposition) or may bind directly to nonglomerular antigens already planted in the mesangium or GBM (ie, in situ immune complex formation). In anti-GBM disease, the antibodies act against the GBM. The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis is unknown, although microvasculitis is the predominant feature without immune complex formation.

Activation of the complement system through the classic pathway by immune complexes or direct cell-mediated injury in ANCA-associated glomerulonephritis results in the recruitment of inflammatory cellular infiltrates (eg, lymphocytes, macrophages, neutrophils), proliferation of the mesangial and endothelial cells, and necrosis. Cellular crescents and fibrin thrombi may be present in more severe cases. The net result is obliteration of the capillary loops and sclerosis, predisposing the patient to hypertension and renal failure.

The cellular and immunologic attack of the glomerulus renders the GBM permeable to protein, red blood cells, and white blood cells. Therefore, urinalysis during active inflammation characteristically shows an active urinary sediment, ie, red blood cells or casts, white blood cells or casts, and variable degrees of proteinuria (ie, nephritic pattern).

Anti-GBM disease is an autoimmune disease in which autoantibodies are directed against type IV collagen in the GBM. Binding of these autoantibodies to the GBM induces rapidly progressive glomerulonephritis (RPGN) and crescentic glomerulonephritis. The clinical complex of anti-GBM nephritis and lung hemorrhage is Goodpasture syndrome. The typical morphologic pattern using light microscopy is DPGN, with focal necrotizing lesions and crescents in more than 50% of glomeruli (ie, crescentic glomerulonephritis). Acute nephrotic syndrome is rare, and a bimodal peak in incidence exists. Although any age group may be affected, the first peak in incidence occurs in the third to the sixth decades of life and the second occurs in the sixth to the seventh decades of life.

In patients with Wegener granulomatosis, renal biopsy findings typically reveal focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation.

In microscopic polyarteritis nodosa (PAN), the usual histopathologic lesion is a pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. In Churg-Strauss syndrome, a minority of patients may develop focal segmental necrotizing glomerulonephritis; in mixed cryoglobulinemias, the characteristic morphologic lesions are diffuse mesangial proliferative or membranoproliferative glomerulonephritis. For Henoch-Schönlein purpura, light microscopic appearances can vary from mild mesangial proliferation and expansion to diffuse proliferation with glomerular crescents.

In rheumatoid arthritis (RA), lesions of mesangial proliferative glomerulonephritis and basement membrane thickening caused by subepithelial immune deposits may be observed. Occasional cases of focal mesangial proliferative glomerulonephritis with mesangial deposition of immunoglobulin G (IgG) and complement have been described in polymyositis and dermatomyositis.

In addition to poststreptococcal glomerulonephritis, the nephritic syndrome and RPGN can complicate acute immune-complex glomerulonephritis due to other viral, bacterial, fungal, and parasitic infections. Some of these warrant specific mention. Diffuse proliferative immune complex glomerulonephritis is a well-described complication of acute and subacute bacterial endocarditis and usually is associated with hypocomplementemia. The glomerular lesion typically resolves following eradication of the cardiac infection. Shunt nephritis is a syndrome characterized by immune complex glomerulonephritis secondary to infection of ventriculoatrial shunts inserted for treatment of childhood hydrocephalus.

The most common offending organism is coagulase-negative Staphylococcus. Renal impairment usually is mild and is associated with hypocomplementemia. Nephrotic syndrome complicates 30% of cases. Acute proliferative glomerulonephritis can also complicate chronic suppurative infections and visceral abscesses. Patients typically present with a fever of unknown origin and an active urine sediment. Although renal biopsy is used to detect immune deposits containing IgG and C3, serum complement levels usually are within the reference range.

Frequency:

• In the US: The incidence of SLE in urban areas varies from 15-50 cases per 100,000 population per year. Renal involvement is evident clinically in 40-85% of patients with SLE. DPGN is the lesion observed in 35-40% of biopsies in lupus nephritis, and as many as 30% of these patients progress to terminal renal failure.

• Internationally: The incidence of DPGN in renal biopsies varies from approximately 10-27% in Europe and 30% in the Middle East to 41% in Japan. Worldwide, the most common glomerulopathy is due to immunoglobulin A (IgA) nephropathy, accounting in most series for 10-40% of all glomerulonephritis. Up to 80% of patients with Henoch-Schönlein purpura (ie, anaphylactoid purpura), which is a distinct systemic vasculitis syndrome that is characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, and gastrointestinal signs and symptoms, have DPGN.

Mortality/Morbidity: Advances in immunosuppressive therapy and renal replacement therapy have markedly reduced the mortality and morbidity rates of DPGN in the last 2 decades. A significant portion of morbidity and mortality rates in DPGN is due to complications of immunosuppressive therapy, including drug toxicity and infection.

Race: Lupus nephritis has a 3-4 times greater incidence in black patients than in white patients. IgA nephropathy is more common in people of Asian origin than it is in whites of African American origin. Wegener granulomatosis is extremely rare in blacks compared to whites

Sex: Men tend to have more aggressive disease than women. However, for SLE, the female-to-male incidence ratio is 9:1 for women of childbearing age. By comparison, the female-to-male ratio is only 2:1 for disease developing during childhood or in people aged 65 or older. Males who develop SLE have the same incidence of renal disease as do females.

• Suspect DPGN in patients with SLE, infectious disease processes, a recent streptococcal throat infection, or in patients with sinopulmonary disease who have recent onset of the following:

o    Hypertension

o    Microscopic or gross hematuria

o    Nonnephrotic or nephrotic range proteinuria or an increase in proteinuria from baseline

o    Serum creatinine of more than 0.4 mg/dL from the reference range or the baseline

o    Oligoanuria and symptoms of uremia in severe cases of RPGN with crescent formation

• Also suspect DPGN in a patient with other systemic diseases who has recent onset of the same findings listed above.

• Nonspecific symptoms, including nausea, vomiting, fatigue, or weight loss may indicate uremia or symptoms of the primary disease process.

• A history of rash; photosensitivity; oral ulcers; arthralgias; arthritis; serositis; or a renal, neurologic, hematologic, or immunologic disorder suggests SLE as the primary disease.

• A history of cough, dyspnea, hemoptysis, and renal disease suggests Goodpasture syndrome, but other pulmonary-renal syndromes must be ruled out, including SLE pneumonitis, Wegener granulomatosis, cryoglobulinemia, renal vein thrombosis with pulmonary embolism, legionella infection, and congestive heart failure.

• Patients with Wegener granulomatosis present with sinopulmonary disease (ie, paranasal sinus pain and drainage with purulent or bloody nasal discharge and occasional nasal mucosal ulceration/perforation, leading to saddle nose deformity), serous otitis media (ie, blockage of the eustachian tube), cough, dyspnea, and hemoptysis.

• Patients with IgA nephropathy (ie, Berger disease) may present with the classic findings of flank pain and gross hematuria following upper respiratory infections. Others may simply have indolent microhematuria found incidentally. Much less commonly, patients present with acute glomerulonephritis, renal failure, and nephrotic syndrome.

Physical:

• If azotemia is present, exclude prerenal and postrenal causes
• Nonspecific findings that suggest DPGN
• Hypertension
• Fever, present in both infectious and noninfectious glomerulonephritis
• Findings pertaining to SLE include the often acute onset of conjunctivitis, episcleritis, photosensitivity, oral ulcers, malar rash (eg, erythema of the nose and malar eminences in a butterfly distribution), discoid lupus, pleural or pericardial friction rub, psychosis, seizures, nonerosive arthritis, or arthralgia
• Findings relating to pauci-immune disease (eg, anti-GBM disease, Wegener granulomatosis) and Goodpasture syndrome
• Sinusitis, otitis, saddle nose deformity, hemoptysis
• Lung consolidation, which suggests pulmonary hemorrhage
• Findings relating to IgA nephropathy (usually postinfectious) and other infectious glomerulonephritis
• Pharyngitis, gastroenteritis
• Impetigo, which is the most common cause of poststreptococcal glomerulonephritis worldwide

Causes:

• Immunoglobulin A (IgA) nephropathy and SLE are the most common causes. Other etiologies are less frequent but are more likely to lead to RPGN.
• Systemic diseases

• Lupus nephritis class IV, IgA nephropathy
• Goodpasture syndrome, Wegener granulomatosis, microscopic polyangiitis, Henoch-Schönlein purpura
• Cryoglobulinemia, vasculitis

• Infectious causes

·         Poststreptococcal glomerulonephritis, which occurs 2-4 weeks after streptococcal sore throat or skin infection

·         Infective endocarditis, hepatitis B, hepatitis C

Lab Studies:

• Urinalysis

·        No specific urinary finding can be used to accurately predict the presence of DPGN.

·        However, the finding of red blood cells and red blood cell casts strongly suggests glomerulonephritis. Proteinuria, white blood cells, and white blood cell casts may be present or absent. Renal biopsy should be obtained for histologic diagnosis and, in lupus, for classification.

·        In patients with lupus who already have a histologic classification, an increase in urinary sediment abnormality should raise the suspicion of histologic transformation. A repeat biopsy may be indicated if reclassification will guide management.

·        A 24-hour urine collection is used for determination of protein and creatinine excretion. Creatinine in a 24-hour urine collection is used to determine completeness of the collection as well as to calculate creatinine clearance. On average, in adults younger than 50 years, creatinine excretion less than 15-20 mg/kg (lean body mass) for women or less than 20-25 mg/kg (lean body mass) for men suggests undercollection of the urine specimen. Values greater than these suggest overcollection. Both overcollection and undercollection lead to inaccurate estimation of creatinine clearance and, therefore, of glomerular filtration rate (GFR). A 24-hour urinary protein excretion in excess of 3.5 g is in the nephrotic range. A finding below 3.5 g indicates nonnephrotic proteinuria. A specific pattern for DPGN is not identified, but nephrotic range proteinuria is more common.

·         CBC count findings

o    Anemia

o    Leukopenia, lymphopenia, and thrombocytopenia are often observed in SLE.

·         Serum chemistry

o    Serum creatinine and urea nitrogen often are elevated.

o    Serum albumin may be low if the patient is nephrotic.

·         Serologic tests

• Positive antinuclear antibodies (ANAs) indicate lupus nephritis. Ninety-five percent of patients with SLE have positive ANA; however, it is not specific.
• Positive tests for anti–double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies are more specific for lupus (rising titers may indicate active or chronic disease).
• Depressed complement levels of C3, C4, and CH50 may suggest SLE, infectious glomerulonephritis, poststreptococcal glomerulonephritis, or cryoglobulinemia.
• ANCAs are positive (>1:40) in almost all cases of Wegener granulomatosis. Eighty to 95% are cytoplasmic ANCA (C-ANCA) while 5-20% are perinuclear ANCA (P-ANCA). In one study, a positive result for C-ANCA was used to identify Wegener granulomatosis, with a sensitivity and specificity of 65% and 88%, respectively, while a positive result for P-ANCA was used to identify Wegener granulomatosis with a sensitivity and specificity of 75% and 98%, respectively.
• Tests results that are positive for anti-GBM antibodies indicate consideration of anti-GMB disease (ie, idiopathic) and Goodpasture syndrome. Circulating anti-GBM antibodies are present in over 90% of patients, although the antibody titer does not correlate well with the manifestations or course of either the pulmonary or renal disease.
• A high titer of antistreptolysin O (ASO) shows recent streptococcal infection, indicating the possibility of poststreptococcal glomerulonephritis. Healthy children of school age (eg, 6-12 y) commonly have titers of 200-300 Todd units per mL. After streptococcal pharyngitis, the antibody response peaks at about 4-5 weeks. Antibody titers decline rapidly in the next several months and reach a slower decline after 6 months. Because 20% of patients with documented infection do not show a rise in the titer of antistreptolysin, other antistreptococcal antibodies such as anti-deoxyribonuclease (DNAse) B, anti-DNAse, and antihyaluronidase should be tested if ASO findings are negative.
• Throat culture findings for group A beta-hemolytic streptococci usually are negative at the time of glomerulonephritis, while ASO titers peak.
• Serum IgA levels are elevated in as many as half of patients with IgA nephropathy.

Imaging Studies:

• Renal sonogram: This test is used to determine renal size, confirm the presence of 2 kidneys, and rule out structural lesions that may be responsible for azotemia.

Procedures:

• Kidney biopsy

• Renal biopsy is the criterion standard for diagnosis of anti-GBM nephritis. Obtain a renal biopsy for histologic diagnosis and, in lupus, for classification.
• In patients with lupus who already have a histologic classification, an increase in urinary sediment abnormality should raise the suspicion of histologic transformation. A repeat biopsy may be indicated if reclassification will influence management.

Medical Care: Because of the high risk of ESRD, clinicians recommend early aggressive therapy. Studies suggest the use of high-dose corticosteroids and cyclophosphamide in DPGN. For pregnant patients, specialists recommend only high-dose corticosteroids. The therapies below are disease specific.

Consultations:

• Involve a nephrologist in the initial management and as part of the multidisciplinary team.

• Involve a surgeon when progression to dialysis is inevitable for the creation of an arteriovenous fistula or a graft for dialysis or for insertion of a peritoneal dialysis catheter in the abdomen and for evaluation for kidney transplantation.

• Consult an otolaryngologist (ENT) and a pulmonologist for diagnosis and management of sinopulmonary disease in cases of Wegener granulomatosis and Goodpasture syndrome, respectively.

Diet: Salt restriction (ie, <2 g/d) is recommended in all patients with hypertension and nephrosis.

• Protein restriction (ie, 40-60 g/d or 0.6-0.8 mg/kg/d) may slow progressive renal disease, but evidence in support of this view is still being debated.

• In those with diuretic-resistant edema, fluid restriction may be required.

Activity: No restriction in activity is required, and patients should be encouraged to maintain physical activity as tolerated

Corticosteroids and cytotoxic therapy can induce remission. Corticosteroids are potent anti-inflammatory agents and immunosuppressants. These drugs suppress both cellular and humoral response to tissue injury, thereby reducing inflammation. Oral prednisone generally is required for maintenance therapy. Cytotoxic drugs induce alkylation of DNA.

Corticosteroids — Have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body’s immune response to diverse stimuli.

Cytotoxins — Inhibit cell growth and proliferation.

Further Inpatient Care:

• Patients should be monitored closely for steroid-induced diabetes, electrolyte abnormalities, abnormal gas exchange, and opportunistic infections.

Further Outpatient Care:

• Renal function should be monitored closely.

• Hypertension should be treated aggressively.

• Patients should be monitored closely for steroid-induced diabetes and opportunistic infections.

Deterrence/Prevention:

• No clear risk factors are associated with development of DPGN; thus, no known preventive methods can be advocated.

Complications:

• End-stage renal disease

• Complications of steroid or cytotoxic therapy are discussed. The commonly encountered complications include diabetes, opportunistic infections, and infertility.

• Complications of the specific diseases are discussed in other articles.

Prognosis:

• Evidence of glomerulosclerosis, fibrous crescents, tubular atrophy, and, particularly, interstitial fibrosis using light microscopy indicates advanced disease and a poor prognosis.

• Being a male is a higher risk factor for a bad prognosis. Other risk factors associated with a bad prognosis include heavy proteinuria, hypertension, interstitial fibrosis, oliguria, and azotemia at presentation.

• Renal survival is best with IgA and worse with anti-GBM disease. In some series, the rate of progression to ESRD in class IV lupus was 50% during a 2-year follow-up.

• Overall, about 50% of patients with DPGN require dialysis within 6-12 months after presentation.

Pyelonephritis

Pyelonephritis (PN) – is non-specific infectious inflammatory process with primary localization in kidney’s pelvis and calyces, further involvement of interstitial tissue leading to nephrosclerosis

Classification (due to WCD – 10)

 Acute pyelonephritis noncomplicated and complicated

Chronic pyelonephritis noncomplicated and complicated; phase of activation and remission; degrees of activity I, II, III.

 

Pyelonephritis, Acute

Background: Acute pyelonephritis is a potentially organ- and/or life-threatening infection that characteristically causes some scarring of the kidney with each infection and may lead to significant damage to the kidney (any given episode), kidney failure, abscess formation (eg, nephric, perinephric), sepsis, or sepsis syndrome/shock/multiorgan system failure. More than 250,000 cases occur in the United States each year (1995 estimate), and approximately 200,000 patients require hospitalization (1997 data). Wide variation exists in the clinical presentation, severity, options, and disposition of acute pyelonephritis.

Diagnosing and managing acute pyelonephritis is not always straightforward. In the age range of 5-65 years, it typically presents in the context of a symptomatic (eg, dysuria, frequency, urgency, gross hematuria, suprapubic pain) urinary tract infection (UTI) with classic upper urinary tract symptoms (eg, flank pain, back pain) with or without systemic symptoms (eg, fever, chills, abdominal pain, nausea, vomiting) and signs (eg, fever, costovertebral angle tenderness) with or without leukocytosis. However, it can present with nonspecific symptoms.

A number of studies using immunochemical markers have shown that many women, who initially present with lower tract symptoms, actually have pyelonephritis. This group of young women is often identified when short-course therapy for uncomplicated cystitis fails. In the extremes of age, the presentation may be so atypical that pyelonephritis is not in the differential diagnosis. In the infant, the presentation may be feeding difficulty or fever. In the elderly, the presentation may be mental status change or fever. Acute pyelonephritis is complex, and there is no consistent set of signs and symptoms that are both sensitive and specific for the diagnosis; therefore, clinicians must maintain a high index of suspicion.

Pathophysiology: Acute pyelonephritis results from bacterial invasion of the renal parenchyma. In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic (ABU) and do not lead to infection. Infection is influenced by bacterial factors and host factors.

Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs. A subset of E coli, the uropathogenic E coli (UPEC), also termed extraintestinal pathogenic E coli (ExPEC), accounts for most clinical isolates from UTIs. UPEC derives commonly from the phylogenetic groups B2 and D, which express distinctive O, K, and H antigens. UPEC genes encode several postulated virulence factors (VFs), including adhesins, protectins, siderophores, and toxins, as well as having the metabolic advantage of synthesizing essential substances.

Adhesins have specific regions that attach to cell receptor epitopes in a lock-and-key fashion. Mannose-sensitive adhesins (usually type 1 fimbriae) are present on essentially all E coli. They contribute to colonization (eg, bladder, gut, mouth, vagina) and possibly pathogenesis of infection; however, they also attach to polymorphonuclear leukocytes (PMN), leading to bacterial clearance. Mannose-resistant adhesins permit the bacteria to attach to epithelial cells, thereby resisting the cleansing action of urine flow and bladder emptying. They also allow the bacteria to remain in close proximity to the epithelial cell, enhancing the activity of other VFs.

The P fimbriae family of adhesins are epidemiologically associated with prostatitis, pyelonephritis (70-90% of strains), and sepsis. This same family of adhesins in associated with less than 20% of ABU strains. The AFA/Dr family is associated with diarrhea, UTI, and particularly pyelonephritis in pregnancy. The S/F1C family is associated with neonatal meningitis and UTI. Siderophores are involved iron uptake, an essential element for bacteria, and possibly adhesion.Protectins include lipopolysaccharide (LPS) coatings (resist phagocytosis), Tra T and Iss (both resist action of complement), and Omp T (cleave host defense proteins, such as immunoglobulins).  Toxins, including alpha hemolysin, cytotoxic necrotizing factor-1, cytolethal distending toxin, and secreted autotransporter toxin, affect various host cell functions; LPS shed from a membrane or released by bacterial lysis leads to cytokine release. No single VF is sufficient or necessary to promote pathogenesis. It seems that a multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role.

Bacterial strains producing ABU may provide, in some instances (controversial), a measure of protection against symptomatic infections from UPEC and other organisms; but, it may also cause increased morbidity and mortality. Once bacteriuria is established, these strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction. The frequency of ABU in preschool girls is less than 2%; in pregnant women, 2-9.5%; in women aged 65-80 years, 18-43%; in men aged 65-80 years, 1.5-15.3%; in women older than 80 years, 18-43%; and in men older than 80 years, 5.4-21%. There is considerable morbidity associated with ABU in pregnancy, renal transplantation, and genitourinary surgery (see Table 1).

As noted above, UPEC account for most infections in uncomplicated pyelonephritis and a significant portion to most infections in complicated pyelonephritis. Other microorganisms commonly isolated are Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis, enterococci, Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter species. This is the same spectrum of organisms cultured with UTIs. In 10-15% of symptomatic UTI cases, bacteria are not cultured using routine methods, although they typically respond to antibiotic therapy. In some UTI cases, using selective media, Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum have been cultured. These UTI data cannot be extended to acute pyelonephritis, but they do illustrate the difficulties in isolating the causative organism.

Evidence suggests that the pathogenesis of pyelonephritis takes a 2-step path. First, UPEC attaches to the epithelium and triggers an inflammatory response involving at least 2 receptors, glycosphingolipid (GSL) and TOLL-like receptor 4 (TLR4). In the mouse model, GSL is the primary receptor and TLR4 is recruited and is an important receptor for the release of chemokines. When TLR4 is genetically absent, an asymptomatic carrier state develops in the infected mice. Second, as a result of the inflammatory response, chemokines, such as interleukin-8 (IL-8), chemotactic for PMNs, are released and attach to the neutrophil-activating chemokine receptor 1 (CXCR1), allowing PMNs to cross the epithelial barrier into the urine. In children prone to pyelonephritis, for example, CXCR1 expression has been shown to be significantly lower than in control subjects.

Several other host factors mitigate against symptomatic UTI. Phagocytosis of bacteria in urine is maximized at pH 6.5-7.5 and osmolality of 485 mosM; values deviating from these values lead to significantly reduced or absent phagocytosis. Other important factors are the flushing action of urine flow in the ureter and bladder, the inhibiting of attachment of type 1 fimbriae E coli to uroepithelial cells by tubular cell–secreted Tamm-Horsfall protein, and the inhibiting of attachment by some surface mucopolysaccharides on the uroepithelial cells.

When a UTI or pyelonephritis becomes complicated (complicated UTI), host defenses are compromised, thereby increasing the likelihood of infection. The definition of a complicated UTI is an infection of the urinary tract involving urinary tract structural abnormalities, urinary tract functional abnormalities, metabolic abnormalities predisposing to UTIs, unusual pathogens, recent antibiotic use, recent urinary tract instrumentation, or a combination of these such that the efficacy of antibiotics is reduced. These abnormalities include but are not limited to obstruction (congenital or acquired), stents, vesicoureteral reflux, incomplete bladder emptying, use of spermicide, diabetes mellitus, atrophic vaginal mucosa, prostatitis, immunodeficiency (congenital or acquired), unusual organisms (eg, Mycoplasma, Pseudomonas), urea-splitting organisms (eg, Proteus, sometimes E coli, Klebsiella, Pseudomonas, Staphylococcus), medullary scars, and pregnancy.

Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Intrinsic obstruction occurs with bladder outlet obstruction, cystocele, fungus ball, papillary necrosis, stricture, and urinary stone. The probability of stone passage decreases while the probability of obstruction increases with increasing size of the stone. Nonetheless, stones as small as 2 mm have resulted in obstruction, while 8 mm stones have occasionally passed spontaneously. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass.

Incomplete bladder emptying may be medication related (eg, anticholinergics). Spermicide nonoxynol-9 inhibits the growth of lactobacilli, which produce hydrogen peroxide. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners. Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Atrophic vaginal mucosa in postmenopausal women predisposes to the colonization of urinary tract pathogens and UTIs due to the higher pH (5.5 vs 3.8) and the absence of lactobacilli. Bacterial prostatitis (acute or chronic) produces bacteriuria, while nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not.

Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme S urea-splitting organisms produce urease, which hydrolyzes urea (urea-splitting), yielding ammonia, bicarbonate, and carbonate, leading to a more alkaline urine, allowing crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both.

Complications of obstruction with superimposed infection include hydronephrosis, pyonephrosis, urosepsis, and xanthogranulomatous pyelonephritis (XGP). Additionally, the organisms can sequester in the struvite stones protected from the host’s immune system. Proteus species are the most common urea-splitting organisms; however, E coli, Klebsiella, Pseudomonas, and Staphylococcus can produce urease; therefore, they sometimes are also involved in staghorn calculus formation.

Pregnancy (hormonal and mechanical changes) predisposes a woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, is manifested as dilatation of the renal pelvis and ureters (left > right) with the ureters containing up to 200 mL urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis. Complicated UTI can result from one or more diverse factors.

Occult upper urinary tract infections (pyelonephritis) occur in 15-50% (or more) of all UTIs, based on several studies on localization of organisms within the urinary tract. If the host is healthy, particularly young, premenopausal women, without any of the complicating factors listed above, then the occult pyelonephritis can be considered an uncomplicated infection. However, if the host is male, elderly, or a child, or if the host has had symptoms for more than 7 days, then the infection should be considered complicated until proven otherwise.

Acute pyelonephritis usually occurs secondary to bacteria ascending from the lower urinary tract. Hematogenous spread to the kidney can occur. Sources for gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Hematogenous spread to the kidney by gram-negative organisms appears less likely based on the observation that experimental pyelonephritis is difficult to reproduce by intravenous introduction of gram-negative bacilli, unless an underlying problem, such as an obstruction, exists. Little or no evidence supports lymphatic spread of uropathogens to the kidney.

Frequency:

·         In the US: There are at least 250,000 cases of diagnosed pyelonephritis in the United States annually (1995 estimate) with 192,000 admissions (1997 National Inpatient Sample database). Lower UTIs predispose to pyelonephritis.

Acute pyelonephritis develops in 20-30% of pregnant women with untreated ABU (2-9.5%), most often during the late second and early third trimesters.

Mortality/Morbidity: Pyelonephritis causes considerable morbidity, but these data can only be extrapolated from the morbidity data for acute lower UTIs. Specifically, acute cystitis in women produces approximately 6.1 days with symptoms, 2.4 days of restricted activity, 1.2 days that the patient is unable to work or attend class, and 0.4 days bed-ridden.

In women, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and immunosuppression. Morbidity (prolonged hospital stay) is increased with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter.

In men, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and recent use of antibiotics (within 1 mo). Morbidity (prolonged hospital stay) is increased in those older than 65 years and also with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter.

Acute pyelonephritis (single episode; first UTI ever in one half of cases) in an adult woman leads to renal scarring in 46%, as demonstrated by Tc99m-labeled dimercaptosuccinic acid scanning 10 years later. Subsequent UTIs do not appear to affect the risk of future scarring.

Acute pyelonephritis during pregnancy leads to acute renal dysfunction (creatinine, 1.2) in 2% of cases (20-25% in the past), acute renal failure in 0.03% of cases, acute respiratory distress syndrome (bilateral chest x-ray infiltrates and hypoxemia without pulmonary hypertension) in 1-8% of cases, low birth weight (<2500 g) in 7% of cases, preterm delivery (<37 wk gestation) in 5% of cases (6-50% in the past), recurrence prior to delivery in 18-20% of cases, and sepsis (positive blood cultures) in 17% of cases. Renal scarring has been demonstrated to be 4 times more likely after pyelonephritis in pregnant women than ionpregnant women.

Acute renal transplant pyelonephritis occurring in the first 3 months after transplant has a significant association with graft loss (>40%) by 96 months as compared to all renal transplant cases with or without the occurrence of pyelonephritis at any time after the transplant up to 96 months (25-30%).

Race: No racial predilection of pyelonephritis has been demonstrated.

Sex: Pyelonephritis is significantly more common in females than in males. This separatioarrows considerably with increasing age, especially in patients aged 65 years and older. Quantitative information regarding bacteriuria and UTI reflects this observation about pyelonephritis. Revalence rate of bacteriuria in young nonpregnant women is 1-3%. The prevalence rate in adult men is less than or equal to 0.1%. After age 65 years, the prevalence rates for women and men are 20% and 10%, respectively. Approximately 10-30% of women develop a symptomatic UTI at some point in their lives

History:

·         Patients may present with minimal or severe symptoms. Symptoms usually develop over hours or over the course of a day. Infrequently, symptoms develop over days and may even be present for a few weeks before a patient presents for evaluation.

·         Symptoms of lower UTI may or may not be present to varying degrees.

o      Internal dysuria usually refers to the urinary tract. External dysuria most commonly refers to the vagina.

o      Symptoms may include urinary frequency, hesitancy, lower abdominal pain, and urgency.

o      Gross hematuria (hemorrhagic cystitis) is present in 30-40% of female cases, most often young adults. It may occur in males but is unusual and a more serious cause must be considered.

o      The description of suprapubic symptoms varies and may include discomfort, heaviness, pain, or pressure.

·          Symptoms of acute pyelonephritis may be present to varying degrees.

o    Severity of pain may be mild, moderate, or severe. Flank pain may be unilateral or sometimes bilateral. Discomfort or pain may be present in the back (lower or middle) and/or the suprapubic area. Upper abdominal pain is unusual, and radiation of pain to the groin is suggestive of a ureteral stone.

o  

·        Fever is not always present. When present, it is not unusual for the temperature to exceed

·        The patient may demonstrate rigor, and chills may be present in the absence of demonstrated fever.

·        Malaise and weakness may also be present.

·        Gastrointestinal symptoms vary. Anorexia is common. Nausea and vomiting vary in frequency and intensity from absent to severe. Diarrhea occurs infrequently.

Physical: Vital signs

Ø   There may or may not be a fever. The temperature may be greater than 103،مF (39.4،مC), or it may be subnormal in patients with associated sepsis.

Ø   Tachycardia may or may not be present, depending on associated fever, dehydration, and sepsis.

Ø   Blood pressure is usually within the reference range, unless the patient has underlying hypertension; in cases of underlying hypertension, the pressure may be elevated above the patient’s baseline. A systolic blood pressure less than 90 mm Hg suggests shock secondary to sepsis or perinephric abscess.

• Appearance

o    The patient’s appearance is variable. Most commonly, the patient is uncomfortable or appears ill.

o    Patients usually do not have a toxic appearance unless an underlying problem, such as sepsis, perinephric abscess, or significant dehydration, is present.

·         Abdominal examination. Suprapubic tenderness usually ranges from mild to moderate without rebound. Abdominal tenderness other than in the suprapubic area suggests another diagnosis. Usually, abdominal rebound, rigidity, or guarding is not found.

o    Bowel sounds are ofteormoactive.

o    Flank or costovertebral angle (CVA) tenderness is most commonly unilateral over the involved kidney, although bilateral discomfort may be present. Discomfort varies from absent to severe. This is usually not subtle and may be elicited with mild or moderately firm palpation.

• Pelvic examination

o    A pelvic examination should be performed. Tenderness of the cervix, uterus, and adnexa should be absent. Any positive finding suggests an additional or alternative diagnosis.

o    If any doubt remains as to the diagnosis, if any signs or symptoms of urethritis or vaginitis are present, or if a history of dyspareunia is present, a gynecologic cause of the symptoms should be pursued.

Causes: When considering the cause of acute pyelonephritis, there are 3 considerations. First, what are the uropathogens that are typically cultured and at what.

Second, UTIs that are complicated indicate a high risk for upper urinary tract infection or occult pyelonephritis in the absence of signs and symptoms typical of acute pyelonephritis. A complicated UTI is defined as a UTI in the presence of at least one of several factors that will reduce the efficacy of antimicrobial therapy, leading to failure of therapy (eg, progression to overt pyelonephritis, sepsis, renal failure, abscess formation, worsening clinical condition, resistant organism), relapse, or persistence of infection.  Any patient with a complicated UTI should be referred, if possible, to a nephrologist, a urologist, an infectious disease specialist, or another physician trained to managed complicated UTIs. The patient will require ongoing management, including repeat cultures, metabolic studies, and appropriate imaging studies.

Lab Studies:

·         In the outpatient setting, pyelonephritis is usually suggested based on the history and physical examination and is supported by urinalysis results, which should include microscopic analysis. Other lab studies are used to evaluate for complicating conditions and to assist in determining if the patient should be admitted.

·         Most easily diagnosed cases occur in women, both pregnant and nonpregnant. Men, patients at the extremes of age, patients harboring subclinical pyelonephritis, and patients who are hospitalized may present with an insidious onset. This section presents information relative to the perspective of pyelonephritis versus UTIs, in general.

o   Urinalysis

§     Gross hematuria occurs infrequently with pyelonephritis and is more common with lower UTI (hemorrhagic cystitis). When present, the differential should include calculi, cancer, glomerulonephritis, tuberculosis, trauma, and vasculitis.

§    Pyuria is defined as more than 5-10 WBCs per high-power field (hpf) on a specimen spun at 2000 rpm for 5 minutes. Almost all patients with pyelonephritis have significant pyuria (>20 WBCs/hpf), although the numbers may be smaller, particularly in those with subacute pyelonephritis.

§  The dipstick leukocyte esterase test (LET) helps screen for pyuria. LET results have a sensitivity of 75-96% and a specificity of 94-98% for detecting more than 10 WBC/hpf.

§  The nitrite production test (NPT) for bacteriuria has 92-100% sensitivity and 35-85% specificity and may be falsely negative in the presence of diuretic use, low dietary nitrate, or organisms that do not produce nitrate reductase (eg, Enterococcus, Pseudomonas, Staphylococcus). Combined, the LET-NPT has a sensitivity of 79.2% and a specificity of 81%, which is too low for it to be used as the only screening study for bacteriuria.

§  Microscopic examination may reveal hematuria, but other causes should be considered, particularly calculi. This is especially true if the patient does not respond to therapy. White cell casts are suggestive of pyelonephritis; however, centrifuge speeds (>2000 rpm) used for urinalysis sediment preparation often fracture them and lead to their absence in the sediment.

§  Proteinuria is expected (up to 2 g/d). When it exceeds 3 g/d, glomerulonephritis should be considered.

§  The presence of a single bacterium in an unspun urine specimen by oil-immersion microscopic examination is equivalent to at least 105 organisms. Bacteria are identified much more easily on a stained versus an unstained specimen/ dfcteral cast are specific for PN (.

o    Urine culture

§   Urine culture is indicated in any patient with pyelonephritis, whether treated in an inpatient or an outpatient setting, because of the possibility of antibiotic resistance.

§   Specimens can be collected by clean catch, catheter, or suprapubic puncture (rarely performed or indicated).

• Blood cultures

§  Blood cultures are indicated in any patient who is being admitted or who has already been admitted.

§  Approximately 12-20% are positive for infection. Bacteremia has not been associated with a poor outcome unless sepsis or another significant comorbidity is present.

Imaging Studies:

• Imaging studies are rarely indicated for the diagnosis of acute pyelonephritis in the adult who presents with typical signs and symptoms. Imaging may be warranted if the presentation is atypical or confusing. It is also warranted if the patient deteriorates or does not respond to therapy, as illustrated by the following scenarios, in which the important considerations are nephrolithiasis, obstructive uropathy, and perinephric abscess:

Ø The patient has a fever or positive blood culture results that persist for longer than 48 hours.

Ø The patient’s condition suddenly worsens.

Ø Toxicity persists for longer than 72 hours.

Ø The patient has a complicated UTI

• The following studies have been used in the diagnosis of acute pyelonephritis:

• As mentioned above, CECT is the imaging study of choice in adults. It is more sensitive than ultrasound and intravenous pyelogram (25% sensitivity), and it can more readily identify alterations in renal parenchymal perfusion, alterations in contrast excretion, perinephric fluid, and nonrenal disease.

o   Noncontrast helical/spiral CT findings may be normal in acute pyelonephritis with mild parenchymal involvement, but the findings are usually positive when the involvement is moderated or severe. It is the standard study for demonstrating gas-forming infections, hemorrhage, inflammatory masses, and obstruction. It also has 97% accuracy in identifying renal stones.

o   US can sometimes detect acute pyelonephritis, but a negative study does not exclude the possibility. Power Doppler US is superior to color Doppler US in the detection of pyelonephritis but remains inferior to CECT. It is useful in screening for urinary obstruction in children admitted for febrile illnesses. It can help differentiate solid and cystic structures, detect hydronephrosis and stones, and measure blood flow.

o    99mTc-DMSA scintigraphy is almost as sensitive clinically as CECT in detecting focal renal abnormalities during acute pyelonephritis in adults. 99mTc-DMSA scintigraphy is not used much in adults because the focal abnormalities are not specific; rather, they are consistent with abscess, cyst, infarct, pyelonephritis, or tumor. Additionally, it is much less available in the acute setting than CECT. In children, it is the preferred study to lessen radiation exposure from CT scans. It is excellent for helping detect inflammation, scarring, and the distribution of renal function between kidneys. DMSA is a radiotracer that localizes to the renal cortex.

o Experience with MRI in evaluating acute pyelonephritis is limited but growing. It is a suitable alternative in the patient with iodinated-dye allergy. It can evaluate the genitourinary system prenatally, renal infection/masses/vasculature, and urinary obstruction, using gadolinium-enhanced MRI, a nonnephrotoxic dye study.

·       CT urography and MR urography are evolving modalities that allow evaluation of the renal parenchyma and urothelium, according to one comprehensive study. Currently used in the evaluation of hematuria, these modalities will become more applicable to the study of other urological problems.

·       Imaging may be required to make the diagnosis in infants and children in whom pyelonephritis presents insidiously.

·       Imaging studies in conjunction with urological procedures, including cystoscopy and excretory urography, may be used during a follow-up examination to evaluate for urinary tract abnormalities that can predispose the patient to infection.

·       Patients with complicated UTIs should be considered for follow-up imaging to assess the urinary tract.

Procedures:

• Urine specimens obtained for examination and culture should approximate the urine contained in the bladder as closely as possible. The 3 procedures for collecting such a urine specimen are clean catch, urethral catheterization, and suprapubic needle aspiration.

Medical Care:

• Supportive care

• Rest
• Antipyretics as needed
• Oral or parenteral pain medications as needed
• Oral or parenteral antiemetics as needed
• Urinary tract analgesics to relieve dysuria (up to 3 d)
• Intravenous or oral fluids to maintain hydration status

• Reasons for hospital admission

• Cannot tolerate oral intake
• Unstable social situation (eg, possibility of poor compliance or poor follow-up)
• Unstable vital signs
• Severe signs and symptoms
• Pregnancy
• Comorbid disorders that increase the complexity of management or the complication rate (eg, diabetes mellitus, chronic lung disease, congenital or acquired immunodeficiency syndrome)

• Antibiotic selection

o   Antibiotic selection is typically empirical, because the results of blood or urine cultures are rarely available by the time a decision must be made.

o   Initial selection should be guided by local antibiotic resistance patterns. Urine cultures should be checked in 48 hours to determine antibiotic efficacy.

o   When using an oral-only regimen, the initial dose should be administered at the time of the evaluation.

o   The etiology of community-acquired infections is usually E coli or other Enterobacteriaceae. Infections usually involve women aged 18-50 years and, infrequently, men of the same age. Accepted outpatient regimens include the following:

Surgical Care: Surgical intervention may be emergent if it occurs during active infection, or it may be elective if it occurs after recovery from infection. Emergent surgery is performed to preserve kidney function or to save the life of the patient. Elective surgical intervention reduces or prevents future morbidity.

Diet: A regular diet is permitted as tolerated. Special dietary considerations, such as those associated with diabetes mellitus, should be honored. Hydration status is very important.

·  If oral intake is not tolerated, intravenous hydration is warranted. Intravenous fluids should include 1 L of 5% dextrose in saline to reverse any existing ketosis, regardless of whether ketones are detected in the urine. Additional intravenous hydration is accomplished with saline.

·  If admission is not indicated and the patient will be monitored in an outpatient setting, hydration status should be normalized with intravenous fluids; the physician should not assume that the patient can or will accomplish this with oral hydration alone.

·  When hydrating intravenously, exercise caution regarding conditions that might be adversely affected by improper amounts of fluid, saline, or glucose.

Activity: Rest is essential for recovery. Activity should be minimized. Patients who are treated in an outpatient setting should not return to work for 2 weeks in order to allow time for the infection to be eliminated. This time also allows the patient to recuperate physical strength. This recommendation can be tempered in special circumstances as warranted by the clinician.

Several classes of drugs may be required for the management of pyelonephritis. These pharmaceuticals include antibiotics, analgesics, antipyretics, and antiemetics. Only antibiotics and urinary tract analgesics are specifically addressed. Symptomatic management using analgesics, antipyretics, and antiemetics is accomplished by oral or parenteral means according to the clinical condition of the patient. Not all antibiotics reported to be effective in the management of acute pyelonephritis are listed in the pharmacological information below because of space limitations. Other effective antibiotics include parenteral penicillins (eg, piperacillin, piperacillin-tazobactam, ticarcillin-clavulanate), third-generation cephalosporins (eg, cefotaxime), oral fluoroquinolones (eg, enoxacin, lomefloxacin, ofloxacin), parenteral fluoroquinolones (eg, lomefloxacin), aminoglycosides (eg, amikacin), monobactams (eg, aztreonam), and carbapenems (eg, imipenem).

Antibiotics — Therapy should cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood or urine culture sensitivity results whenever feasible.

Urinary analgesics — Indicated when patient has dysuria to such an extent that it disrupts activities of daily living.

 

Deterrence/Prevention:

Ø  Prevention of pyelonephritis involves identifying clinical situations that could lead to pyelonephritis and developing a strategy to decrease that likelihood. These strategies may include a change in contraceptive behavior, administration of prophylactic antibiotics, or early identification and treatment of UTIs. Several such strategies are elaborated below. Failure of these strategies to eliminate infection, recurrence of infection, or relapse (reinfection <14 d after completing an appropriate regimen) indicates the need to refer the patient for systematic evaluation for predispositional anatomic, functional, or structural abnormalities.

Ø  Children with recurrent UTIs or urinary tract structural abnormalities require prompt evaluation of urinary tract symptoms and appropriate treatment.

Ø  Premenopausal or postmenopausal women with recurrent, uncomplicated UTIs

Complications:

·           Complications occur more often in patients with diabetes mellitus, chronic renal disease, sickle cell disease, renal transplant (particularly the first 3 mo), AIDS, and other immunocompromised states. Sometimes, determining if the entities listed below are occurring as a complication of pyelonephritis or presenting in the absence of pyelonephritis with signs and symptoms suggestive of pyelonephritis is difficult. The important point is to have a high index of suspicion because they are associated with markedly increased morbidity and mortality.

o              Acute renal failure

o              Chronic renal damage leading to hypertension and renal failure

Prognosis:

• In healthy, nonpregnant women with uncomplicated disease, the prognosis is excellent for full recovery and minimal damage to the kidney.

• In healthy men without any known complicating conditions, the prognosis is good for full recovery; however, urologic evaluation is recommended to rule out an underlying complicating condition.

• In children, the prognosis is good. Importantly, children should undergo a urological evaluation after the first episode to rule out structural abnormalities.

• If the patient has a known complicating condition, urological evaluation is indicated to determine the status of the complicating condition and the status of the kidney.

Pyelonephritis, Chronic

Background: Chronic pyelonephritis is renal injury induced by recurrent or persistent renal infection. It occurs almost exclusively in patients with major anatomic anomalies, including urinary tract obstruction, struvite calculi, renal dysplasia, or, most commonly, vesicoureteral reflux (VUR) in young children. Sometimes, this diagnosis is established based on radiologic evidence obtained during an evaluation for recurrent urinary tract infection (UTI) in young children. VUR is a congenital defect that results in incompetence of the ureterovesical valve due to a short intramural segment. The condition is present in 30-40% of young children with symptomatic UTIs and in almost all children with renal scars. VUR may also be acquired by patients with a flaccid bladder due to spinal cord injury. VUR is classified into 5 grades (I-V), according to the increasing degree of reflux.

Pathophysiology: Chronic pyelonephritis is associated with progressive renal scarring, which can lead to end-stage renal disease (ESRD), eg, reflux nephropathy. Intrarenal reflux of infected urine is suggested to induce renal injury, which heals with scar formation. In some cases, scars may form in utero in patients with renal dysplasia with perfusion defects. Infection without reflux is less likely to produce injury. Dysplasia may also be acquired from obstruction. Scars of high-pressure reflux can occur in persons of any age. In some cases, normal growth may lead to spontaneous cessation of reflux by age 6 years. Factors that may affect the pathogenesis of chronic pyelonephritis are (1) the sex of the patient and his or her sexual activity; (2) pregnancy, which may lead to progression of renal injury with loss of renal function; (3) genetic factors; (4) bacterial virulence factors; and (5) neurogenic bladder dysfunction. In cases with obstruction, the kidney may become filled with abscess cavities

Frequency:

·  In the US: VUR may be present in 30-45% of children with UTIs. The prevalence rate of VUR in siblings of patients with chronic pyelonephritis is approximately 35%. VUR and chronic pyelonephritis are less common in black children than in white children.

Mortality/Morbidity: Conditions associated with mortality and morbidity related to chronic pyelonephritis include (1) progressive renal scarring, (2) proteinuria, (3) hypertension, (4) ESRD, (5) focal glomerulosclerosis, and (6) xanthogranulomatous pyelonephritis (XPN). XPN occurs in 8.2% of patients and in 25% of patients with pyonephrosis.

Race: Chronic pyelonephritis is less common in black children than in white children.

Sex: Chronic pyelonephritis is more common in females than in males.

Age: Chronic pyelonephritis occurs in children and adults

History:

·       Many cases of VUR are suggested based on prenatal sonography findings.

·       Patients with chronic pyelonephritis may report the following:

Ø Fever

Ø Lethargy

Ø Nausea and vomiting

Ø Flank pain or dysuria

Ø Some children may present with failure to thrive.

Physical: The following may be noted:

Ø Hypertension

Ø Failure to thrive in young children

Ø Flank tenderness

Causes:

Chronic pyelonephritis is renal injury induced by recurrent or persistent renal infection. Lab Studies:  Urinalysis

Ø Urinalysis results may reveal pyuria.

Ø Obtain a urine culture, which often isolates gram-negative bacteria such as Escherichia coli or Proteus species.

Ø A negative result from urine culture does not exclude a diagnosis of chronic pyelonephritis.

Ø Proteinuria may be present and is a negative prognostic factor for this disease.

Ø Serum creatinine and blood urine nitrogen levels are elevated (azotemia).

Imaging Studies:

·  Findings from an intravenous urogram help establish the diagnosis of pyelonephritis because they reveal caliceal dilatation and blunting with cortical scars. Ureteral dilatation and reduced renal size also may be evident.

· 

·       Voiding cystourethrogram (VCUG) findings may document the reflux of urine to the renal pelvis and ureteral dilatation in children with gross reflux.

·     Radioisotopic scanning with technetium dimercaptosuccinic acid is more sensitive than intravenous pyelography for helping detect renal scars. This is the preferred test for many pediatric nephrologists and radiologists because it is sensitive and easy to perform.

·   Cystoscopy images show evidence of reflux at the ureteral orifices.

 

·         Renal sonography images may show calculi.

Pyelonephritis. Transverse gray-scale (A) and color flow Doppler (B) sonography of the right kidney demonstrate two wedge-shaped areas of decreased echogenicity (arrows) in the renal cortex with absence of color flow, consistent with multifocal pyelonephritis

·         CT scan is the procedure of choice to help diagnose XPN.

·         Renal ultrasonography images may show calculi, but ultrasound is not a sensitive screening procedure for reflux nephropathy

Procedures:

·         Cystoscopy findings show evidence of previous reflux at the ureteral orifices, even if VCUG images show no reflux because of the spontaneous cessation of reflux due to puberty.

Histologic Findings: Renal biopsy specimens show focal glomerulosclerosis in advanced reflux nephropathy, while XPN must be distinguished from renal malakoplakia based on the presence of inclusions called Michaelis-Gutmann bodies.

Medical Care:

·         Stages I and II VUR

Ø This is reflux of urine to the ureter or renal pelvis without ureteral dilatation.

Ø Medical therapy with antibiotics such as amoxicillin, trimethoprim/sulfamethoxazole (Bactrim), trimethoprim alone, or nitrofurantoin is usually sufficient.

Ø Continue antibiotic therapy until puberty or until reflux resolves.

Ø The rule in these cases is spontaneous resolution; surgery is not indicated.

·         Stages III and IV VUR (severe reflux)

Ø  Data from the Birmingham Reflux Study (international reflux study in children) show that medical and surgical therapies for reflux are equally effective.

Ø  Surgery for severe reflux involves reimplantation of the ureters.

Ø  The indications for surgery include (1) medical noncompliance with formation of new scars and (2) reflux persisting after puberty in women (should be surgically treated to prevent possible complications, eg, pyelonephritis, abortions in pregnancy).

Surgical Care:

·         The following are indications for surgical therapy:

Ø Failure to comply with medical regimen

Ø Breakthrough infections occurring in patients who are compliant

Ø Women of childbearing age who prefer surgical therapy

·         Surgery entails the reimplantation of the ureters with the creation of an adequate submucosal tunnel and detrusor support.

Diet:  Progressive renal injury can be reduced by restricting dietary protein intake. The penicillins (amoxicillin) and first-generation cephalosporins are the drugs of choice because of good activity against gram-negative rods and good oral bioavailability. In infants, the choice of antibiotics is either amoxicillin or a first-generation cephalosporin. In patients aged 3-6 months, therapy can be changed to sulfamethoxazole or nitrofurantoin. Older children and adults may be treated with trimethoprim-sulfamethoxazole (Bactrim). Once one antibiotic is chosen, frequent changes in the antibiotic regimen are discouraged to help prevent the development of resistance. Antibiotics — Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

 

Complications:

ü Proteinuria

ü Focal glomerulosclerosis

ü Progressive renal scarring leading to ESRD

ü XPN (may occur in approximately 8.2% of cases)

ü Pyonephrosis (may occur in cases of obstruction)

ü Progressive renal scarring (reflux nephropathy)

Ø  The characteristic renal scars of VUR are often present at the time of initial diagnosis of chronic pyelonephritis.

Ø  New renal scars may develop in 3-5% of patients after the initial evaluation.

Ø  The progression of renal scars is inversely related to the promptness with which specific antibiotic therapy is instituted.

Ø  The presence of new scars often suggests the occurrence of breakthrough infections.

Ø  Hypertension

Prognosis:

·        Although most children with chronic pyelonephritis due to VUR may experience spontaneous resolution of reflux, approximately 2% can still progress to renal failure and 5-6% can have long-term complications, including hypertension.

·        The Birmingham Reflux Study clearly shows that medical and surgical management are equally effective in preventing subsequent renal damage.

·        Almost all children should receive a trial of medical management.

Special Concerns:

·        XPN may be confused with renal cancer.

·        Analgesic abuse nephropathy may resemble chronic pyelonephritis.

·        Renal tuberculosis and renal malakoplakia also may resemble chronic pyelonephritis. However, in malakoplakia, the characteristic Michaelis-Gutmann bodies may be seen