Acute and chronic glomerulonephritis. Etiology, pathogenesis, clinical features, diagnostics, treatment and prophylaxis. Chronic renal failure. Etiology, pathogenesis, clinical features, diagnostics, treatment, prophylaxis, prognosis.

Many diseases affect kidney function by attacking the glomeruli, the tiny units within the kidney where blood is cleaned.

NORMAL KIDNEY FUNCTION

To understand glomerular disease, it may be helpful to understand how the kidneys normally function. The kidneys are bean-shaped, approximately fist-sized organs that are located in the mid-back, just below the rib cage on each side of the body.

• The kidneys excrete these compounds with water to make urine.
• They also eliminate excess body water while reabsorbing useful chemicals and allowing waste to pass freely into the bladder as urine.
• They allow a person to consume a variety of foods, drugs, vitamins and nutritional supplements, additives, and excess fluids without worry that toxic by-products will build up to harmful levels.
• The kidneys regulate the amount of various substances in the blood and the amount of water in the body.

Blood circulates through the kidneys for filtration.

 

They process about 200 quarts of blood a day to sift out about 2 quarts of waste products and extra water that eventually leave the body as urine.

 

 

The kidneys filter the body’s blood supply with tiny structures, known as nephrons.

Blood enters the kidneys through arteries that branch inside the kidneys into tiny clusters of looping blood vessels. Each cluster is called a glomerulus, which comes from the Greek word meaning filter. The plural form of the word is glomeruli. There are approximately 1 million glomeruli, or filters, in each kidney. The glomerulus is attached to the opening of a small fluid-collecting tube called a tubule. Blood is filtered in the glomerulus, and extra water and wastes pass into the tubule and become urine. Eventually, the urine drains from the kidneys into the bladder through larger tubes called ureters. Each glomerulus-and-tubule unit is called a nephron. Each kidney is composed of about 1 millioephrons. In healthy nephrons, the glomerular membrane that separates the blood vessel from the tubule allows waste products and extra water to pass into the tubule while keeping blood cells and protein in the bloodstream.

Glomerular disease affects the glomerulus, causing it to filter and excrete incorrectly

 

Glomerulonephritis describes the inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood.

Glomerular diseases damage the glomeruli, letting protein and sometimes red blood cells leak into the urine. Sometimes a glomerular disease also interferes with the clearance of waste products by the kidney, so they begin to build up in the blood. Furthermore, loss of blood proteins like albumin in the urine can result in a fall in their level in the bloodstream. Iormal blood, albumin acts like a sponge, drawing extra fluid from the body into the bloodstream, where it remains until the kidneys remove it. But when albumin leaks into the urine, the blood loses its capacity to absorb extra fluid from the body. Fluid can accumulate outside the circulatory system in the face, hands, feet, or ankles and cause swelling.

 

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

Causes

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  bloodstream and lodge in  heart, causing an infection of one or more of  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  body, including  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  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  body, such as  heart, kidneys and intestines.

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

Conditions that are likely to cause scarring of the glomeruli

·                    High blood pressure. Damage to  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.

Classification of Primary Glomerular Disease Based on Clinical Syndrome

Nephrotic Syndrome

Minimal change disease

Membranous glomerular nephropathy

Focal segmental glomerulosclerosis

Membranoproliferative glomerulonephritis

C1q nephropathy

Fibrillary glomerulonephritis

Acute Glomerulonephritis

Membranoproliferative glomerulonephritis

IgA nephropathy

Rapidly Progressive Glomerulonephritis

Antiglomerular basement membrane disease

Immune complex crescentic glomerulonephritis

Pauci-immune crescentic glomerulonephritis

Membranoproliferative glomerulonephritis

IgA nephropathy

Membranous glomerular nephropathy (rare)

Asymptomatic Hematuria and/or Proteinuria

IgA nephropathy

Membranoproliferative glomerulonephritis

*Usually with active sediment; e.g., red blood cell casts, dysmorphic red blood cells), unlike other causes of nephrotic syndrome.

Acute poststreptococcal glomerulonephritis (APSGN) is an inflammation of the kidney tubules (glomeruli) that filter waste products from the blood, following a streptococcal infection such as strep throat. APSGN is also called postinfectious glomerulonephritis.

Description

APSGN develops after certain streptococcal bacteria (group A beta-hemolytic streptococci) have infected the skin or throat. Antigens from the dead streptococci clump together with the antibodies that killed them. These clumps are trapped in the kidney tubules, cause the tubules to become inflamed, and impair that organs’ ability to filter and eliminate body wastes. The onset of APSGN usually occurs one to six weeks (average two weeks) after the streptococcal infection.

APSGN is a relatively uncommon disease affecting about one of every 10,000 people, although four or five times that many may actually be affected by it but show no symptoms. APSGN is most prevalent among boys between the ages of 3 and 7, but it can occur at any age.

 

Symptoms

The signs and symptoms of glomerular disease include

 

–                  proteinuria: large amounts of protein in the urine

    Proteinuria may cause foamy urine.

 

 

–                  hematuria: blood in the urine

Blood may cause the urine to be pink or cola-colored.

–                 

 

 

 

–                  reduced glomerular filtration rate: inefficient filtering of wastes from the blood

–                  hypoproteinemia: low blood protein

–                  edema: swelling in parts of the body

        Edema may be obvious in hands and ankles, especially at the end of the day, or around the eyes when awakening in the morning, for example.

 

·                    Fatigue from anemia or kidney failure

Common Clinical Syndromes of Primary Glomerular Diseases

Symptom	Nephrotic Syndrome	Acute Glomerulonephritis	Rapidly Progressive Glomerulonephritis	Asymptomatic Hematuria and/or Proteinuria
Proteinuria	>3.5 g/1.73 m2/per day*	May be in nephrotic range	May be in nephrotic range	No or non-nephrotic range
Hematuria	Variable and usually monomorphic if present	Micro- or macroscopic with RBC casts and dysmorphic RBCs	Micro- or macroscopic with RBC casts and dysmorphic RBCs	Micro- or macroscopic (may be dysmorphic with RBC casts)
Blood pressure	Normo- or hypertension	Hypertension	Hypertension	Normotension
GFR	Variable decline, depending on diagnosis	Rapid decline (days to weeks)	Progressive decline (weeks to months)	Decline uncommon

GFR, glomerular filtration rate; RBC, red blood cell.

*In children, >40 mg/m²/hr; often accompanied by edema, hypoalbuminemia, hyperlipidemia, with or without lipiduria.

 

Complications

Glomerulonephritis can damage  kidneys so that they lose their filtering ability. This can lead to the accumulation of dangerous levels of fluid, electrolytes and waste in  body (called kidney failure) and deprive  bloodstream of necessary protein.

Complications of glomerulonephritis may include:

·                    Acute kidney failure. Loss of function in the filtering part of the nephron may cause waste products to accumulate rapidly. This condition may mean you’ll need emergency dialysis, an artificial means of removing extra fluids and waste from  blood, typically by an artificial kidney machine (dialyzer).

·                    Chronic kidney failure. In this extremely serious complication, the kidneys gradually lose function. Kidney function at less than 10 percent of normal capacity indicates end-stage kidney disease, which usually requires dialysis or a kidney transplant to sustain life.

·                    High blood pressure. Damage to  kidneys and the resulting buildup of wastes in the bloodstream can raise  blood pressure.

·                    Nephrotic syndrome. This is a group of signs and symptoms that may accompany glomerulonephritis and other conditions that affect the filtering ability of the glomeruli. Nephrotic syndrome is characterized by high protein levels in the urine, resulting in low protein levels in the blood. It’s also associated with high blood cholesterol and swelling (edema) of the eyelids, feet and abdomen.

 

Short Information about different types of Primary Glomerular Diseases

Minimal Change Disease

Pathologic Definition

Minimal change disease (MCD), historically referred to as nil disease, is characterized by an absence of glomerular pathology by light microscopy or immunofluorescence. There may be extraglomerular findings by light microscopy, including intratubular lipid and protein resorption droplets—hence the alternate name, lipoid nephrosis—and focal proximal tubular epithelial flattening. However, although not specific to MCD, the classic finding of MCD is effacement of visceral epithelial cell foot processes seen using electron microscopy.

Prevalence and Risk Factors

MCD is the most common primary glomerular disease in children, accounting for 70% to 90% of cases of nephrotic syndrome for those younger than 10 years, with the incidence peaking between ages 2 and 4 years. The prevalence declines with age, whereby it is responsible for only 10% to 20% of cases of nephrotic syndrome in adults. There appears to be a higher predominance in Asia compared with the United States and Europe, although no strong gender predominance exists.

Pathophysiology and Natural History

The underlying mechanism(s) leading to MCD is unknown. Some studies have implicated upregulation of various cytokine activities, including interleukin-2, during disease activity. It has been postulated that this may induce glomerular permeability factor(s) that interfere with normal function of the charge-selective barrier to filtration of serum proteins. As with all primary glomerular disorders, when approaching a patient with a new diagnosis of MCD, it is important to exclude secondary causes. Most notable on this list is the use of medications that have a strong association with MCD, including nonsteroidal anti-inflammatory drugs and certain antibiotics, including rifampin. Additionally, although rare, lymphoid malignancies such as Hodgkin’s disease and leukemia may manifest along with nephrotic syndrome from MCD.

Signs and Symptoms

Patients with MCD typically present with findings consistent with the nephrotic syndrome. Although not specific to primary glomerular disorders, the abrupt onset and generalized distribution of edema are typically what lead the patient to medical attention and should indicate that the clinician consider a primary kidney disorder as the causative factor. More common in children, visceral effusions (pleural, peritoneal, and pericardial) may also accompany the peripheral edema. Children are typically normotensive, but elevated blood pressures may be present in adults. Finally, patients may also present with syndromes resulting from the biologic complications of the nephrotic syndrome that are not necessarily specific to MCD. Venous and, much less commonly, arterial, thromboses may occur, caused by several factors that lead to thrombophilia, including loss of normal anticoagulants in the urine (e.g., antithrombin III, plasminogen) and excessive hepatic production of procoagulants (e.g., fibrinogen, factors II, V, VII, VIII, X, and XIII). Additionally, loss of immunoglobulins in the urine may predispose patients to infections of various types.

Diagnosis

Albuminuria detectable by urine dipstick is the most common laboratory finding in patients with MCD. When quantified by a 24-hour urine collection or spot urine protein-to-creatinine concentration ratio, the degree of proteinuria may be severe. Microscopic hematuria is not the norm, but may occur in up to 25% of patients, and macroscopic hematuria is decidedly rare. Active urine sediment changes (e.g., dysmorphic RBCs and RBC casts) should not be present in patients with MCD. However, lipiduria in the forms of free fat, oval fat bodies, and lipid casts may be present on urine microscopy. Hypoalbuminemia correlates with the severity of the degree of proteinuria, and in children can be severely depressed to lower than 1 g/dL. As a result, the hypoalbuminemia and total serum calcium levels are low, but the corrected calcium and ionized calcium levels are usually normal.

Renal function, as evidenced by serum creatinine level, is typically normal, especially in children. However, some patients with MCD also present in acute renal failure, with an elevated serum creatinine level. Risk factors for this include age older than 45 years, the coexistence of hypertension, and heavier degrees of proteinuria. Pathologically, these patients exhibit concomitant acute tubular necrosis on their biopsy specimens. Clinically, successful treatment of the nephrotic syndrome invariably is associated with resolution of the acute renal failure.

An increase in total and low-density lipoprotein (LDL) cholesterol levels is often seen, as is hypertriglyceridemia. If the hyperlipidemia is severe enough, pseudohyponatremia may be present.

Although the circulating red blood cell mass remains normal in the absence of renal failure, given that plasma volume is often decreased in patients with MCD and the nephrotic syndrome, elevations of the hematocrit and hemoconcentration can be observed. Erythrocyte sedimentation rate is often elevated because of hyperfibrinogenemia, but complement levels are normal.

Diagnostic Procedures

Given the predominance of MCD as the leading cause of nephrotic syndrome in children younger than 10 years, many clinicians will treat empirically in this age group, resorting to a kidney biopsy only in cases of treatment failure. In older age groups, however, given that the causes of nephrotic syndrome by primary glomerular disorders are varied, a kidney biopsy for older children and adults is indicated.

Summary

·                    MCD is the most common cause of primary glomerular disease in children.

·                    The typical presentation is the nephrotic syndrome.

·                    Renal failure is uncommon, except in older adults.

Treatment

After the diagnosis of MCD is made, therapy should concentrate on management of the biologic consequences of the nephrotic syndrome (e.g., edema, proteinuria, hypertension if present, and hyperlipidemia), as well as on induction of remission with immunosuppressive agents. Regarding the former, escalating doses of loop diuretics given at least twice daily, with or without concomitant thiazide-type diuretics, may be necessary to maintain euvolemia. Additionally, the use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) reduce proteinuria to some degree; these are the agents of choice if concomitant hypertension is present. Controlling blood pressure to lower than 130/80 mm Hg is advocated for any patient with kidney disorders. Use of antihyperlipidemic agents, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are recommended, although ofteot sufficient to reach the treatment goals in patients with kidney disease if the degree of proteinuria remains severe.

Beyond this symptomatic treatment, induction of remission using immunosuppressive agents is indicated for all patients with MCD if not contraindicated. In select patient populations, up to 90% of children and 80% of adults enter complete remission (i.e., absence of dipstick proteinuria) after 2 and 4 months, respectively, of therapy with prednisone. Typical dosing regimens include daily prednisone (1 mg/kg/day for adults, 60 mg/m²/day for children, maximum 80 mg/day), generally using alternate-day dosing soon after remission or sometimes from onset of therapy, with tapering doses for a total course of 2 to 6 months. Relapses of MCD after steroid withdrawal or during steroid wean (steroid dependence) are common, especially in children. If frequent relapses occur, or in cases of steroid dependence, alternate therapies using cytotoxic agents (usually cyclophosphamide) are indicated as steroid-sparing agents. Steroid-resistant patients may respond to therapy with cyclosporine, but often relapse with withdrawal of that agent.

 

Summary

·                    Nonimmunosuppressive management includes diuretics, ACE inhibitors, ARBs, and statins.

·                    Patients are exquisitely steroid sensitive, with a high remission rate.

·                    Relapses and steroid dependence are common and may require cytotoxics; steroid resistance is rare and may be treated with cyclosporine.

Prognosis

MCD in general carries with it a good renal prognosis and ESRD is extremely rare. However, management of complications of the nephrotic syndrome (e.g., edema, infections, thrombophilia) and complications of the immunotherapy, most notably those related to corticosteroids, may prove challenging to the clinician and affect the morbidity of the patient.

 

Focal Segmental Glomerulosclerosis

Pathologic Definition

Focal segmental glomerulosclerosis (FSGS) defines a characteristic pathologic pattern of glomerular injury and is not necessarily a distinct disease. The hallmark of kidney biopsy is an increased degree of scarring seen on light microscopy of some but not all of the glomeruli present (focal) that involves some but not all portions of the affected glomeruli (segmental). There are five distinct pathologic variants of FSGS. The importance of distinguishing these variants involves their different natural histories and responses to therapy. Apart from this, other nonspecific pathologic manifestations include low-level staining for immunoglobulin M (IgM) or C3 in sclerosed portions of the mesangium and fusion of epithelial foot processes in sclerosed and nonsclerosed portions of affected glomeruli. This pattern of injury can be seen as a manifestation of chronic injury induced by many different kidney disorders, and thus is regarded as secondary FSGS. For example, kidney biopsy specimens of patients with chronic vesicoureteral reflux may show FSGS-like patterns of injury. Conversely, patients with an appropriate clinical presentation (see later) lacking other identifiable kidney disorders who exhibit this pathologic pattern are correctly regarded as having idiopathic or primary FSGS. Such differentiation between primary and secondary FSGS may prove difficult at times, but is crucial when it comes to accurate treatment and prognosis.

Prevalence and Risk Factors

Primary FSGS is one of the two most common causes of idiopathic glomerular disease in adults, accounting for up to 25% to 35% of cases of nephrotic syndrome in all adults. There is a two to four times higher prevalence of the disease in African Americans compared with whites. It is the most common primary glomerular disorder to cause ESRD in the United States, accounting for approximately 2.3% of the ESRD population.

Pathophysiology and Natural History

Similar to MCD, primary FSGS is believed to occur as a result of a T-cell disorder resulting in the production of a circulating permeability factor, the identification of which has proven elusive, but may be a cytokine or lymphokine. This permeability factor is believed to lead to glomerular injury and proteinuria, hyperfiltration, and scarring. A small fraction of primary FSGS cases result from an inherited disorder of structural parts of the glomerular basement membrane or podocyte that results in altered glomerular function; these are not caused by a circulating factor. Secondary FSGS is known to occur in the setting of many different renal disorders, which can be classified based on the following: those leading to reduced nephron mass and/or glomerular hyperfiltration (e.g., aplasia or dysplasia, vesicoureteral reflux, morbid obesity); inflammatory renal disorders causing glomerular epithelial cell injury and subsequent scarring (e.g., lupus, focal proliferative glomerulonephropathy, vasculitis); infectious (e.g., HIV-associated FSGS); and toxins (e.g., heroiephropathy).

Signs and Symptoms

As with MCD, the hallmark of FSGS is the presence of proteinuria, which can vary in severity from only 1 to 2 g/day to more than 10 g/day. Unlike MCD, at presentation, patients with FSGS are more prone to have concomitant microscopic hematuria (up to 50% of the time), hypertension (33% of the time), and a depressed glomerular filtration rate leading to elevated serum creatinine levels (33% of the time). Typically, patients with heavy proteinuria present clinically with signs and symptoms of the nephrotic syndrome (see earlier). As with MCD, serum complement levels are normal.

Diagnosis

The laboratory findings in FSGS are similar to those of MCD, with the exception of a higher likelihood of patients presenting with significant azotemia. Red blood cell (RBC) casts or dysmorphic RBCs are not characteristic of FSGS; their presence should point the clinician to disorders that can manifest with the nephritic syndrome. As with MCD, a kidney biopsy is usually necessary to establish the diagnosis.

 

Summary

·                    FSGS is the most common cause of primary glomerular disease in African American adults.

·                    It typically manifest with the nephrotic syndrome.

·                    Patients are likely to present with an elevated creatinine level.

·                    It is the most common primary glomerular disease leading to ESRD.

Treatment

Similar to MCD, the treatment of FSGS involves conservative measures (e.g., edema control with diuretics, hypertension management, treatment of hyperlipidemia, ACEs and/or ARBs) and those that target the proposed immune basis of the disorder specifically. The former (see earlier, MCD section), is indicated for all patients with FSGS, primary or secondary, regardless of the degree of proteinuria or azotemia. The latter is reserved for those patients with primary FSGS with nephrotic-range proteinuria and the absence of advanced azotemia. The options for immunosuppressive therapy include steroids alone (prednisone, 1 mg/kg daily or 2 mg/kg every other day) or, if comorbid conditions preclude the safe use of high-dose steroids, calcineurin inhibitors such as cyclosporine, 3 to 4 mg/kg/day in divided doses, with or without low-dose steroids. Use of calcineurin inhibitors should be avoided in patients with estimated GFRs lower than 40 mL/min/1.73 m² because of the concern for nephrotoxicity associated with their prolonged use.

The success of therapy is measured by the nephrotic patient’s response in terms of proteinuria reduction: complete remission (CR), lower than 200 mg/day; partial remission (PR), 200 to 3500 mg/day; partial responder (PR), more than 50% reduction in proteinuria from baseline but still >3500 mg/day; and nonresponder (NR), less than 50% reduction in proteinuria and still >3500 mg/day. The success of therapy should not be determined for at least 4 months after initiation of therapy because of the well-described occurrence of fairly late treatment responses that may be missed if therapy is abandoned too soon after initiation. Duration of therapy should continue for 6 to 12 months after the onset of remission, with tapering prednisone doses. Patients who fail to reach a CR or PR with an adequate steroid trial are termed steroid-resistant and deserve a trial of a calcineurin inhibitor, if not contraindicated. Those who reach a CR or PR, but then subsequently develop recurrent nephrotic-range proteinuria during or shortly after steroid weaning, are termed steroid-dependent and may be tried on cytotoxic agents, such as cyclophosphamide, or other novel agents, such as mycophenolate mofetil or sirolimus. On average, approximately 40% to 80% of patients will achieve CR or PR with therapy, although the chance of relapse is high after cessation of cyclosporine (approximately 75%).

 

Summary

·                    Prednisone therapy is used at 1 mg/kg/day for at least 4 months.

·                    Monitor degree of proteinuria to determine therapeutic success.

·                    Calcineurin inhibitors are useful for those intolerant of high-dose steroids but without advanced azotemia.

Prognosis

As noted, primary FSGS is the most common cause of any primary glomerular disease leading to ESRD. Determining a patient’s risk of this and pace of progression of azotemia is dependent on factors determined at clinical presentation (e.g., severity of proteinuria, degree of azotemia, pathologic variant, degree of interstitial disease on biopsy) and during therapy (e.g., CR vs. PR vs. NR). Regarding the former, subnephrotic patients with a normal serum creatinine level at baseline have the slowest rate of progression to kidney failure (i.e., 80% survival-free of ESRD at 10 years) compared with heavily nephrotic patients with more than 10 g/day (i.e., almost all ESRD by 3 years). Regarding the latter, those achieving CR or PR have a superior renal survival compared with nonresponders: less than 15% ESRD at 5 years versus 50% ESRD at 6 months, respectively.

Membranous Glomerular Nephropathy

Pathologic Definition

Membranous glomerular nephropathy (MGN) is a kidney disorder defined by characteristic microscopic and immunofluorescence findings. On light microscopy, there is diffuse thickening of glomerular capillary walls without associated hypercellularity. On immunofluorescence, there is diffuse granular staining of the glomerular capillary loops: typically, for IgG more than IgA or IgM, as well as C3. On electron microscopy, the pathologic hallmark confirming MGN is electron-dense deposits in the subepithelial region of the glomerular basement membrane. These deposits correspond to the immunoglobulins seen on immunofluorescence. Occasionally, these deposits are large enough that they can be seen with special stains on light microscopy directly, or may induce adjacent changes of glomerular basement membrane material, leading to a spike appearance on either side of the deposit.

Prevalence and Risk Factors

Similar to FSGS, MGN is one of the most common primary glomerular diseases to cause nephrotic syndrome, accounting for 33% of cases, with a predominance in men older than 40. And, similar to FSGS, MGN can result as part of a multisystem disease process such as lupus or chronic hepatitis B, or as a paraneoplastic manifestation of extrarenal carcinomas, appropriately called secondary MGN. Although primary MGN can occur in children, it is typically found in adults, with a peak incidence in the fourth or fifth decade of life.

Pathophysiology and Natural History

The cause of immunoglobulin deposition in the subepithelial location of the glomerular basement membranes in MGN, and its subsequent damage and altered structure, function, or both, are not completely known. It is believed that antigen-antibody complexes form in situ in the subepithelial space, possibly as a result of a freely circulating antibody recognizing and binding to a resident antigen within the glomerulus. Whatever the antigen stimulus may be, when the complex is formed, it is believed that complement activation occurs that produces toxic substances (e.g., the C5b-9 membrane attack complex); these directly induce damage to nearby cells and lead to the pathologic changes seen on biopsy and to the clinical manifestation of proteinuria or azotemia, or both. In the absence of other causes, which can accelerate the rate of loss of renal function (e.g., superimposed drug-induced acute interstitial nephritis, bilateral renal vein thrombosis), chronic kidney disease progression in MGN patients is slow in those who remain free of remission, with progression rates to ESRD averaging 30% to 40% at 10 to 15 years. Clinical factors associated with an increased risk of this include age older than 50 years, male gender, proteinuria higher than 8 g/day, an elevated creatinine level at presentation, and higher scores of tubulointerstitial damage seen on biopsy. However, there is a well- documented occurrence of spontaneous remission of proteinuria in those with MGN who initially presented as nephrotic, ranging in up to 50% of cases, if followed untreated long enough: at least 5 years.

Signs and Symptoms

Although patients with MGN may present with asymptomatic proteinuria, most present with signs and symptoms typical of the nephrotic syndrome. Up to 50% of patients may have some degree of hypertension at the onset of the disease. Rarely, patients will present with symptoms attributable to the hypercoagulability that may accompany nephrotic syndrome, most notably lower extremity venous thrombi causing pain or renal vein thrombosis with flank pain. Renal function is usually preserved at presentation unless MGN has gone undiagnosed for many years. Although only 3.5 g of proteinuria/day is sufficient to be regarded as in the nephrotic range, patients with MGN commonly have massive proteinuria, exceeding 10 to 20 g/day. Microscopic hematuria is seen in up to 50% of cases, although as with FSGS, RBC casts or dysmorphic RBCs should not be present. Although known as an immune complex disease, serum complement levels of C3 and C4 are normal.

Diagnosis

Adults presenting with the nephrotic syndrome and a relatively normal serum creatinine level are likely to have MGN in the absence of signs or symptoms suggestive of a systemic disease process. As noted, a kidney biopsy is necessary to delineate the pathology from the other disorders mentioned. However, given that MGN may be the presenting manifestation of a yet undiagnosed systemic disease, combined with the clinical importance of diagnosing such diseases early, all adults diagnosed with MGN on biopsy deserve a dedicated evaluation of secondary causes. This includes a remote hepatitis panel, VDRL, serologic markers of autoimmune disorders (e.g., lupus or mixed connective tissue disease), and age-appropriate cancer screening.

 

Summary

·                    MGN is one of the two most common primary glomerular diseases to cause nephrotic syndrome in adults.

·                    Severe proteinuria of more than 10 g/day and relatively normal serum creatinine level at presentation are not uncommon.

·                    Normal C3 and C4 levels are present, despite immune complex deposition seen pathologically on biopsy specimens.

Treatment

Given the relatively benign course in remission-free patients, together with a moderate chance of spontaneous remission without specific therapy, much controversy exists regarding the appropriate intensity of treatment for MGN. All patients deserve the conservative treatment of blood pressure control to lower than 130/80 mm Hg, ACE or ARB use, or both, and treatment of lipid disorders. Regarding the use of immunosuppressive therapy, however, scrutiny must be given to the risk of such treatment versus a potential benefit over the long term. This risk-to-benefit ratio only favors intense treatment for those patients who have a high likelihood of faster progression of kidney disease, which may be predicted by the presence of additive clinical risk factors present at diagnosis (see earlier). For those patients deemed high risk and ieed of dedicated immunotherapy, treatment options include steroid-only regimens (e.g., prednisone at a dose of 2 mg/kg on alternate days for at least 8 weeks), alkylating agent-based regimens (e.g., 6 months of alternating steroids and cyclophosphamide), and cyclosporine-based regimens (e.g., 6 months of twice-daily cyclosporine, targeting a trough level of 150 μg/L, plus low-dose prednisone). Remission (complete or partial) rates vary among the treatment protocols, from 20% to 40% for steroid alone to almost 67% for alkylating agent or cyclosporine-based regimens, although the latter is complicated by a significantly higher relapse rate.

 

Summary

·                    Immunosuppressive therapy is controversial, given the relatively benign course and moderate chance of spontaneous remission.

·                    Immunosuppressive therapy is reserved only for those at highest risk for faster progression to ESRD.

·                    Steroid-only, alkylating agent–based, or cyclosporine-based regimens are all used, with varying degrees of success.

Prognosis

As noted, the prognosis of MGN is diverse and varied, based on pertinent clinical factors at presentation and the occurrence of remission, whether it is spontaneous or induced by specific immunotherapy. In general, those patients free of remission typically have a slow progressive loss of renal function, leading to ESRD. A pertinent caveat of MGN is the higher degree of hypercoagulability with the nephrotic syndrome compared with other primary glomerular disorders. Although any venous thrombosis event appears to be more likely in patients with MGN compared with other primary glomerular diseases, a significant consideration that may significantly affect renal and patient survival is the development of renal vein thrombosis, which may occur in approximately 15% of cases.

 

Immunoglobulin a Nephropathy

Pathologic Definition

The hallmark of IgA nephropathy (IGAN) is the presence of IgA deposits, predominantly in the mesangium, on biopsy specimens. Other immunoglobulins may also be present to a lesser degree, such as IgG or IgM. On light microscopy, pathologic findings may vary, from completely lacking to a severe diffuse proliferative glomerulonephritis, depending on the severity of clinical presentation. Typically, mesangioproliferative and focal proliferative findings are evident. The most severe cases will show diffuse proliferation as well as more than 50% of glomeruli with cellular crescents. Electron microscopic findings include electron-dense deposits in an expanded sclerotic mesangium.

Prevalence and Risk Factors

IGAN is believed to be the most common primary glomerular disease worldwide, but its incidence is likely underestimated by a bias against doing a biopsy in patients with a relatively benign presentation and clinical course. This is seen by the discrepancy in prevalence rates in Asia (>40% of biopsy specimens), where patients are more likely to receive a kidney biopsy with any urine sediment alterations as opposed to North America, where biopsies are typically reserved for patients with heavier degrees of proteinuria accompanying hematuria.²⁰ Although seen at all ages, it is predominant in the second and third decades of life, with a male predominance.

Pathophysiology and Natural History

Although not exactly known, it is believed that IGAN represents abnormal polyclonal IgA production as part of mucosal host defense, specifically a post-translational glycosylation defect of that protein. This abnormal glycosylation impairs the normal clearance from the bloodstream of the circulating IgA molecules, as well as predisposing their deposition within the kidneys. Given the inability of IgA molecules to fix complement once it is deposited, the mechanism of renal injury is poorly understood. In the absence of a severe presentation of IGAN, with heavy proteinuria and azotemia, most patients have a favorable renal course. Most will have one or a few intermittent episodes of IGAN that spontaneously resolve, without long-term effects on renal function. Indeed, only 1% to 2% of patients will develop ESRD as a result of IGAN. However, with extended follow-up of higher risk patients, especially those with persistent microscopic hematuria and heavier proteinuria, up to 20% to 30% will develop ESRD two decades after diagnosis.

Signs and Symptoms

Patients with IGAN present on a wide spectrum, from asymptomatic microscopic hematuria to rapidly progressive renal failure, with heavy degrees of proteinuria. Knowing how IgA production is related to a mucosal host defense mechanism, it has been found that many patients present with abnormal urine findings soon after a current or recently resolved upper respiratory tract infection.

The most common presentation (40%-50% of cases) of IGAN is a single or sparsely recurrent episodes of gross hematuria at the time of or soon after a respiratory infection; this occurs more in children than in adults. Patients may also complain of dysuria and be mistakenly diagnosed with a urinary tract infection or with fevers and myalgias, and deemed to have a nonspecific viral syndrome. Such patients typically present with normal renal function and dysmorphic RBC, or RBC casts may be present.

The next most common presentation of IGAN (40% of cases), and the most predominant in adults, is asymptomatic microscopic hematuria with dysmorphia or RBC casts, with or without concomitant proteinuria or intermittent gross hematuria. Renal function is typically normal at baseline, although it may worsen slowly over time.

The final 20% of patients with IGAN present with hematuria and the nephrotic syndrome or, rarely, with the nephritic syndrome and rapidly progressive renal failure because of a crescentic glomerulonephritis.

Diagnosis

Given the appropriate clinical scenario—new hematuria in the setting of an upper respiratory tract infection with no significant proteinuria and normal renal function—many clinicians would opt for expectant management and reserve kidney biopsy for those with persistent abnormal urine findings, significant proteinuria (>500 mg/day), or an abnormal serum creatinine level. Serum IgA levels may be modestly elevated, although this usually is not helpful in the diagnosis. As expected, serum complement levels are normal.

 

Summary

·                    IGAN is the most common primary glomerular disorder worldwide.

·                    It involves the temporal relation of hematuria to an upper respiratory tract infection.

·                    Intermittent macroscopic hematuria, without proteinuria, and persistent microscopic hematuria, with or without proteinuria, are the most common presentations.

Treatment

Treatment of IGAN nephropathy is dictated by the clinical presentation of the patient and, if obtained, the pathologic changes seen. Those patients with isolated or recurrent gross hematuria following a respiratory tract infection, without alteration in renal function or significant proteinuria, may be observed without specific treatment. Similarly, patients with isolated microscopic hematuria, or with minimal proteinuria and favorable pathologic changes on biopsy, may be observed without specific treatment. In patients with significant proteinuria or azotemia, treatment with ACEs or ARBs is warranted, with blood pressure targeted at lower than 130/80 mm Hg. One study used ACEs plus ARBs, with favorable results on long-term renal function compared with either agent alone. Controversy exists about whether treatment with fish oil in such patients is beneficial but, because of apparently little toxicity with their use, this is reasonable to try in patients at risk for progressive disease. Immunosuppressive therapy should be reserved for patients with the most severe clinical presentation or biopsy findings, or both. Patients with nephrotic syndrome may be tried on steroid-only regimens, such as prednisone, 2 mg/kg every other day for 3 months, tapered off over 3 months. For the most severe cases of rapidly progressive crescentic glomerulonephritis, a combined regimen of oral or intravenous cyclophosphamide along with steroids should be used for 3 months, followed by a prolonged steroid taper.

 

Summary

·                    Treatment is dictated by clinical presentation and biopsy findings.

·                    Moderate-risk patients should receive ACE inhibitors or ARBs, or both, statins, and possibly fish oil therapy.

·                    Severe cases are treated with steroids, with or without cyclophosphamide.

Prognosis

Generally, the long-term renal prognosis of IGAN is favorable. The most common clinical and most benign course is isolated events of macroscopic hematuria without proteinuria and normal renal function. These patients do well over time, without significant renal events. Patients with persistent urine abnormalities, especially those with higher degrees of proteinuria, are at risk for progression of renal disease over time, although the pace may be significantly slowed by the treatment regimens discussed. The worst prognosis is limited to those with crescentic glomerulonephritis, as would be expected.

 

Membranoproliferative Glomerulonephritis

Pathologic Definition

Biopsy specimens from patients with membranoproliferative glomerulonephritis (MPGN) are characterized by global capillary wall thickening and glomerular hypercellularity. The increased cellular content occurs because of proliferation of resident glomerular cells, as well as infiltrating mononuclear cells and neutrophils. Often seen, but not necessarily specific to MPGN, is double contouring or splitting of the glomerular capillary basement membranes. A subset of patients with MPGN may exhibit cellular crescents within Bowman’s space. Immunofluorescence studies demonstrate diffuse granular or bandlike intense staining of capillary loops and mesangium with C3, and to a lesser extent IgG and IgM. MPGN pathognomonic changes on electron microscopy are subendothelial and mesangial electron-dense deposits; the former are found in an expanded subendothelial region of the glomerular basement membrane formed by projections of mesangial cytoplasm. Some subepithelial deposits may also been seen, but they are not as prominent as in cases of MGN. A subset of MPGN cases (type II MPGN) have a different hallmark electron microscopic finding than the discrete subendothelial deposits (type I MPGN). In the former, a bandlike, almost continuous, ribbon of the electron-dense material is found in the subendothelial space.

Prevalence and Risk Factors

MPGN is a rare primary glomerular disorder and appears to be decreasing in frequency. A possible reason for this is correction of what used to be known as primary MPGN, but actually was a renal manifestation of hepatitis C virus infection and mixed essential cryoglobulinemia. Such cases are now correctly defined as secondary MPGN. Primary MPGN is a disease mostly found in children, with more than 75% of cases diagnosed between ages 8 and 16 years.²³ It accounts for approximately 10% of biopsy specimens of primary glomerular disorders.

Pathophysiology and Natural History

Similar to MGN, MPGN is classified as an immune complex disease and the presumptive pathophysiologic mechanism is the inappropriate production of antibodies recognizing a nephritogenic antigen. Unlike MGN, in which it is believed that antigen is inherent in the glomerular structure itself, MPGN is believed to occur as a result of deposition of circulating antigen-antibody complexes. These traverse the large pores found between glomerular endothelial cells and deposit between them and the glomerular basement membrane. Complement activation results from the deposition of these antigen-antibody complexes and results in a cascade of proinflammatory signals that stimulate local cell proliferation and recruitment of circulating immune cells, which augments the inflammatory reaction. This ongoing inflammation is believed to be the major reason for the ensuing renal damage.

Signs and Symptoms

Patients with MPGN may present with different clinical syndromes. Approximately 50% exhibit signs and symptoms typical of the nephrotic syndrome, whereas 25% of patients only present with asymptomatic hematuria and proteinuria. The remaining 25% present more severely, with the acute nephritic syndrome. Although 50% of all patients may have some degree of azotemia at presentation, those exhibiting a nephritic as opposed to a nephrotic picture tend to have more depressed renal function at baseline, which declines rapidly.

Diagnosis

As with all glomerular diseases, one must be cognizant of systemic processes in which MPGN may be a common renal manifestation. These include autoimmune diseases such as lupus, viral infections such as hepatitis C or B, and chronic bacterial infections such as endocarditis or chronic abscesses. Rarely, MPGN may represent a paraneoplastic manifestation of solid or liquid malignancies. Correct identification of a systemic disease leading to MPGN is critical because treatment of the underlying disorder, and not the renal lesion itself, is appropriate. Beyond the typical findings of the nephrotic or nephritic syndrome, few other symptoms may aid the clinician in distinguishing primary MPGN from other primary glomerular disorders. However, the urine sediment becomes a valuable tool in this setting. Unlike the other primary glomerular diseases that cause nephrotic syndrome, patients with MPGN exhibit an active sediment, defined by hematuria with associated dysmorphic RBCs (e.g., acanthocytes) as well as RBC casts. Additionally, because the inflammatory reaction induced by the deposition of the immune complexes is in the subendothelial space and directly in contact with circulating complement, which they can fix and activate, hypocomplementemia is characteristic of all types of MPGN. C3 and C4 levels are more equally depressed in type I MPGN because of activation of the classic complement pathway as opposed to type II MPGN, in which C3 levels are lower than C4 because of preferential activation of the alternative complement pathway.

 

Summary

·                    MPGN is more prevalent in children and young adults.

·                    The clinical presentation may be nephrotic syndrome, nephritic syndrome, or asymptomatic hematuria and proteinuria.

·                    An active urine sediment and hypocomplementemia in the absence of systemic diseases are useful clinical clues.

Treatment

Patients with MPGN follow the rule of thirds. That is, approximately one third will have a spontaneous remission, one third will have persistent manifestations that intermittently wax and wane, and one third will have a progressive decline to ESRD. Factors that may predict the latter include heavier degrees of proteinuria or the nephrotic syndrome, or both, hypertension, advanced azotemia at baseline, and a nephritic presentation, especially with crescents on biopsy. After excluding important secondary causes of MPGN, most notably hepatitis C infection, immunosuppressive therapy should be tried for these patients, in addition to conservative management. Most data on treatment have come from pediatric studies, but a potential adult regimen includes prednisone, 2 mg/kg every other day for 3 to 12 months, depending on the rate of response. If a significant response is seen, with a decline in proteinuria, stabilization of serum creatinine level, and improvement in activity of the urine sediment, the steroids may be tapered to 20 mg every other day and maintained for another few years. Other therapies, in addition to steroids, such as antiplatelet agents (e.g., aspirin, dipyridamole), with or without cytotoxic agents, have not convincingly proven to be of benefit.

 

Summary

·                    Restrict immunosuppressive patients to those at highest risk for progression-heavier proteinuria, nephritic syndrome, elevated creatinine level at baseline, and crescents on biopsy.

·                    It is crucial to exclude secondary causes, most notably hepatitis C, before initiating immunosuppressive therapy.

·                    Prednisone, 2 mg/kg every other day for many months, tapered to 20 mg every other day for several years, may be given.

Prognosis

Given the rule of thirds, the renal prognosis of patients with MPGN depends exactly on presentation. Those with asymptomatic hematuria and non-nephrotic proteinuria have a relatively benign course, whereas those with more severe presentations who fail to remit spontaneously or with therapy will progress to ESRD faster. On average, progression to ESRD 10 years after diagnosis will occur in is 35% to 60% of patients with MPGN.

 

Special Cases of Crescentic Glomerulonephritis

Pathologic Definition

As discussed for MPGN and IGAN, there are some severe forms of primary glomerular diseases that manifest clinically, with rapid deterioration of renal function associated with diffuse cellular crescents on biopsy. However, there are other forms of primary crescentic glomerular diseases pathologically distinct from those discussed that also lead to rapidly progressive glomerulonephritis (RPGN). Anti–glomerular basement membrane (anti-GBM) disease refers to cases of RPGN characterized by linear staining, as opposed to granular patterns (as in MPGN or IGAN) of IgG along the glomerular basement membranes, almost always in the presence of cellular crescents and fibrinoid necrosis, but usually in the absence of significant hypercellularity. Although most cases of anti-GBM disease occur as part of a systemic process involving other systems—most notably the lungs in the form of Goodpasture’s syndrome, with pulmonary hemorrhage—idiopathic anti-GBM disease can occur as a renal-limited disorder.

Pauci-immune antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis is characterized by a necrotizing, hypercellular, crescentic, glomerular lesion similar to that in anti-GBM disease that lacks any significant immunoglobulin staining in a granular or linear pattern. Again, although usually occurring with multisystem small-vessel ANCA-associated vasculitis syndromes (e.g., Wegener’s granulomatosis, Churg-Strauss syndrome), patients can present with a renal-limited pauci-immune glomerulonephritis. Rarely, there are some forms of crescentic glomerulonephritis with granular immunoglobulin staining similar to but not completely classifiable as other lesions, such as IGAN or MPGN, and are thus known as idiopathic immune complex glomerulonephritis.

Prevalence and Risk Factors

Anti-GBM disease is rare, accounting for less than 20% of all cases of crescentic glomerulonephritis, and has a bimodal distribution, the first in the second to third decade of life and the second in the sixth and seventh decades. Pauci-immune ANCA-associated crescentic glomerulonephritis, renal-limited or as part of a systemic vasculitis syndrome, is the most common cause of RPGN in older adults, with a predominance in whites observed.

Pathophysiology and Natural History

Although many antigens have been described to which the IgG of anti-GBM disease binds, 90% of the time they are directed toward a mutated α₃ chain of type IV collagen, which is a predominant component of the GBM. It is believed that once bound, these IgG molecules stimulate a T lymphocyte-dependent inflammatory reaction that leads to the pathologic and clinical findings observed, including crescent formation and rapid deterioration of renal function. In cases of pauci-immune glomerulonephritis, because of the absence of immunoglobulin deposition, it is believed that the ANCAs directly stimulate a neutrophilic inflammatory process and subsequent damage. If left untreated, both syndromes will lead to complete loss of renal function over a short period of time, in weeks to months).

Signs and Symptoms

Patients with crescentic glomerulonephritis syndromes in the absence of systemic processes present with the nephritic syndrome with varying degrees of proteinuria, hematuria with dysmorphic RBCs and RBC casts, hypertension, and some degree of azotemia at the time of diagnosis. Patients may also exhibit concomitant or subsequent extrarenal signs and symptoms if the anti-GBM disease is present as part of Goodpasture’s syndrome (e.g., hemoptysis or frank pulmonary hemorrhage, respiratory failure), or if the pauci-immune glomerulonephritis is part of systemic small-vessel vasculitis syndromes (e.g., recurrent sinusitis, hemoptysis, abdominal pain, arthralgias, mononeuropathies).

Diagnosis

Although pathologic determination is necessary to classify the exact glomerular syndrome, patients exhibiting the nephritic syndrome should also undergo a serologic workup, including determination of complement levels, which are normal in anti-GBM or pauci-immune cases but are usually depressed in cases of idiopathic immune complex glomerulonephritis. Additionally, the presence of circulating anti-glomerular basement antibodies or ANCAs (e.g., c-ANCA against proteinase-3 antibodies or p-ANCA against myeloperoxidase) should be investigated. However, because significant time may elapse before the results of these assays are available, combined with the rapid deterioration of renal function if appropriate therapy is delayed, the clinician should not delay pursuing a renal biopsy if clinical suspicion is high.

Summary

·                    These rare disorders can manifest with the nephritic syndrome as a renal-limited process or as part of a multisystem disease.

·                    Although serologic markers are specific, the delay in obtaining the results of such assays should not postpone a kidney biopsy for a definitive diagnosis if clinical suspicion is high.

·                    Immunofluorescence staining is necessary to differentiate between specific causes, which affect the correct treatment modality to be used.

Treatment

Once the specific type of crescentic glomerulonephritis is determined by kidney biopsy, appropriate treatment should be instituted immediately to preserve renal function and optimize patient survival. Anti-GBM disease treatment includes daily or alternate-day plasmapheresis for 2 to 3 weeks and immunosuppressive therapy with steroids and a cytotoxic agent, such as cyclophosphamide. The goal of the former is to remove the pathologic circulating anti-GBM antibody and the latter is to decrease its production. A typical daily regimen is 1 mg/kg of prednisone plus 2 mg/kg of oral cyclophosphamide. The duration of cyclophosphamide therapy is usually 3 months, with a slow taper of the prednisone over a 6- to 9-month period after cessation of the cytotoxic agent.

In general, all patients with anti-GBM should be treated, but some caveats do exist. In patients requiring dialysis, the chance of renal recovery is sufficiently low that the potential toxicity outweighs the chance of success and should be avoided. A possible exception to this involves patients with crescentic glomerulonephritis who have circulating anti-GBM antibodies and ANCAs. In such cases, cytotoxic therapy may lead to a late renal recovery, despite early dialysis requirements, and so its use should at least be contemplated. Similarly, those patients who present with pulmonary hemorrhage should undergo treatment regardless of their renal status because patient, and not just renal, survival takes precedence in this situation.

Optimal treatment for pauci-immune ANCA-associated crescentic glomerulonephritis is different than that for anti-GBM disease. In this case, plasmapheresis has not shown to add any advantage to a combination of cytotoxic and steroid therapies unless the patient also has hemoptysis or anti-GBM antibody present. Initial steroid dosing should be more aggressive in the form of pulse intravenous high doses, such as methylprednisolone, 1000 mg daily for 3 consecutive days, followed by oral prednisone at a dosage of 1 mg/kg daily. Cytotoxic therapy should accompany this steroid therapy, typically either 2 mg/kg of oral cyclophosphamide daily, or monthly intravenous pulse cyclophosphamide. Typical duration of therapy is 6 to 12 months, depending on how quickly the patient has entered remission. Patients who need dialysis should still be treated unless contraindicated, because the chance for renal recovery is higher than with anti-GBM disease, although adjusting down the dose of cyclophosphamide is necessary.

 

Summary

·                    Early institution of plasmapheresis and cytotoxic therapy is essential in anti-GBM disease, because there is a small chance of renal recovery when progression to dialysis dependence has occurred.

·                    Steroid dosing should be more aggressive in patients with pauci-immune crescentic glomerulonephritis and cytotoxic therapy should be used, even for patients requiring dialysis, unless otherwise contraindicated.

Prognosis

The renal and patient prognoses of untreated crescentic glomerulonephritis are dismal and bely the aggressiveness of treatment. In general, with early intervention, patient response to therapy is good, with renal and patient survival approaching 70% and 90%, respectively. Relapses can occur and, when present, adversely affect overall outcome. As expected, success of treatment and prognosis is highly dependent on the degree of renal dysfunction at the time of diagnosis.

 

·                     

Investigations

The investigations consist of an assessment of the severity of glomerular injury, together with a search for the cause:

·                    Urine dipstick and microscopy: haematuria and/or proteinuria will be found and, in some forms, red-cell casts.

·                    Urine protein quantification: measured in a 24-hour urine sample or by protein:creatinine ratio.

·                    GFR: is provided by most biochemistry laboratories as the estimated glomerular filtration rate (eGFR) but can be calculated by 24-hour creatinine clearance or from the serum creatinine by the Cockcroft and Gault formula:

·                    FBC, ESR, CRP.

·                    Biochemistry: renal function, electrolytes, liver function; serum albumin low in nephrotic syndrome; high potassium, low bicarbonate and high phosphate in renal failure.

·                    Glucose: to exclude diabetes.

·                    Serum immunoglobulins, serum and urine protein electrophoresis: to exclude myeloma.

·                    Serum complement: low in SLE and cryoglobulinaemia and some forms of primary glomerulonephritis.

·                    Autoantibodies: ANA, anti–double stranded DNA, ANCA, antiglomerular basement membrane antibodies.

·                    HBsAg; anti–HCV; antistreptolysin O titre (ASOT).

·                    Radiology: renal ultrasound, CXR.

·                    Renal biopsy: except in the mildest cases, or in nephrotic syndrome in children.

·                   

 

 

The “classic” form is characterized by massive mesangial proliferation, mesangial matrix expansion and diffuse thickening of the glomerular basement membrane.

 

Indications for Renal biopsy:

·                    Proteinuria and haematuria:

o         Isolated microscopic haematuria or proteinuria of less than 1 g/24 hours are not usually indications for renal biopsy because it is unlikely that any specific treatment would be required.

o         Microscopic haematuria with dysmorphic red cells or casts, a possible hereditary condition, associated proteinuria, hypertension or reduced glomerular filtration rate (GFR) would be considered an indication for biopsy.

o         Low levels of proteinuria associated with haematuria, hypertension or reduced GFR would also be considered as an indication for biopsy.

o         Higher levels of proteinuria (more than 1 g/24 hours) or the combination of proteinuria and haematuria (especially with casts) are indications for biopsy, because of the potential of effective treatment for glomerulonephritis and interstitial nephritis.

o         Nephrotic syndrome: in patients less than 1 year or above 10 years of age. Children between the ages of 1 and 10 years usually have minimal change nephropathy, which responds to steroid treatment and so the risks of biopsy are thought to outweigh the likely benefits of treatment. However, these children may need biopsy if there is a poor response to initial treatment.

·                     Acute renal failure:

o         To exclude ischaemic acute tubular necrosis: with abnormal urinary sediment, proteinuria, positive antineutrophil cytoplasmic antibody (ANCA)/antinuclear antibody (ANA)/antiglomerular basement membrane (anti-GBM) antibody results, severe hypertension, no obvious cause or prolonged history.

o         Presumed ischaemic acute tubular necrosis: biopsy is indicated if recovery is delayed.

·                    Chronic kidney disease: equal-sized kidneys which are not small and shrunken, with proteinuria or dysmorphic haematuria.

·                    Known renal diagnosis: equal-sized kidneys which are not small and shrunken, with sudden unexplained reduction of GFR or unexplained increased proteinuria.

Histological patterns

The commonly used pathological classification depends on light microscopy, but immunofluorescence and electron microscopy provide additional information and may give clues as to the aetiology.

Minimal change disease

·                    Light microscopy is virtually normal, but electron microscopy shows widespread fusion of the epithelial cell foot processes on the outside of the glomerular basement membrane. Immunofluorescence is usually negative.

·                    Most often presents in children aged between two and four years. Accounts for 90% of cases of nephrotic syndrome in children, and about 20% of cases in adults.

·                    Clinical features: nephrotic syndrome with selective proteinuria; normal renal function, normal blood pressure, normal complement levels; increased risk of infections, especially urinary tract infections and pneumococcal peritonitis (therefore give prophylactic penicillin if oedematous).

·                    Associated with atopy in children, especially those who are HLA-DR7 positive.

·                    May also be related to underlying Hodgkin’s disease in adults.

·                    Usually responds to a course of high-dose prednisolone, but relapse is frequent.

·                    Relapsing disease may go into remission following treatment with prednisolone and cyclophosphamide or ciclosporin.

·                    One third of patients have one episode, one third develop occasional relapses and one third have frequent relapses which stop before adulthood.

·                    Minimal change disease does not progress to end-stage chronic renal failure.

Focal segmental glomerulosclerosis

·                    Some of the glomeruli show segmental scarring, together with foot process fusion as in minimal change disease.

·                    A common cause of nephrotic syndrome in older children and younger adults; it may be associated with haematuria, hypertension and impaired renal function.

·                    About 50% of patients may respond to a course of high-dose prednisolone, although treatment for up to four months is often required in adults. If this is unsuccessful, some patients may respond to the addition of cyclophosphamide, and ciclosporin can be used to reduce proteinuria.

·                    Progresses to end-stage renal failure over several years in up to 50% of patients, but progression may be halted by treatment with corticosteroids.

·                    A variant known as ‘collapsing glomerulopathy‘ is associated with HIV infection.

Membranous nephropathy

·                    Widespread thickening of the glomerular basement membrane occurs.

·                    Immunofluorescence reveals granular deposits of immunoglobulin and complement.

·                    Although most cases are idiopathic, it may also be secondary to SLE, hepatitis B, malignancy, or the use of gold or penicillamine.

·                    It is more common in men.

·                    It is the most common cause of nephrotic syndrome in adults. It may present with proteinuria or nephritic syndrome, hypertension. Haematuria is rare.

·                    The idiopathic form may respond to a treatment regimen involving alternate months of corticosteroids with chlorambucil or cyclophosphamide, or to ciclosporin.

·                    It progresses to end-stage renal failure in 30-50% of patients. The remainder with idiopathic membranous nephropathy have a complete or partial spontaneous remission of nephrotic syndrome with stable renal function.

Mesangiocapillary glomerulonephritis (MCGN)

·                    This is also known as membranoproliferative glomerulonephritis.

·                    There is proliferation of mesangial cells, an increase in mesangial matrix and thickening of the glomerular basement membrane.

·                    It can be subdivided according to the appearance on electron microscopy.

·                    It is uncommon. It may present with nephrotic syndrome or nephritic syndrome in children and young adults.

·                    It is associated with low levels of C3.

·                    Secondary forms of the disease are associated with hepatitis C with or without cryoglobulins, other chronic infections and SLE.

·                    Nephrotic patients are often treated with corticosteroids but there is no treatment of proven benefit.

·                    Approximately 50% of patients will develop end-stage renal failure within ten years.

Mesangial proliferative nephritis

·                    Mesangial cell proliferation combined with matrix expansion occurs. It is most often seen in the context of IgA deposition, when it is known as IgA nephropathy. Other immunoglobulins and complement components may also be present.

·                    IgA nephropathy (Berger’s disease) often presents with macroscopic haematuria, which may be precipitated within a few days by an upper respiratory tract infection. It is also detected as asymptomatic haematuria and/or proteinuria, and can present with nephrotic syndrome.

·                    It is more common in males.

·                    There is association with HLA B35 and D4, coeliac disease, alcoholic liver disease and HIV.

·                    Some studies suggest that a course of high-dose prednisolone can reduce proteinuria and delay renal impairment. In patients with deteriorating renal function, immunosuppressive drugs are also often used.

·                    Although progression is slow, 20-30% of patients (unusual in children but more common in adults) may eventually develop end-stage renal failure.

·                    The renal lesion of Henoch-Schönlein purpura is similar to that of IgA nephropathy, and this may be a variant of the same disease. 20% develop impaired renal failure and 5% develop end-stage renal failure.

Diffuse proliferative glomerulonephritis

·                    Widespread hypercellularity occurs, caused by both infiltrating inflammatory cells and proliferation of endothelial and mesangial cells. There is generally deposition of immunoglobulins and complement around the capillary loops.

·                    It generally presents with an acute nephritic syndrome two or more weeks after an infection.

·                    It is classically caused by streptococcal infection.

·                    It is rare in developed countries, but post-streptococcal glomerulonephritis remains common in the developing world.

·                    Many other bacterial and viral causes have now been described and is also associated with SLE.

·                    Almost all children will recover without treatment (other than antibiotics for the infection), but a small proportion of adults may develop renal impairment.

Focal segmental proliferative glomerulonephritis

·                    This usually occurs secondary to systemic disease, eg SLE, Alport’s syndrome.

·                    There is often associated segmental necrosis of the capillary loops, which is followed by crescent formation.

·                    The term crescentic glomerulonephritis is used when there is an accumulation of cells outside the capillary loops, but within Bowman’s capsule.

Crescentic glomerulonephritis

·                    This may occur as part of the evolution of certain forms of primary glomerulonephritis (eg IgA nephropathy or mesangiocapillary glomerulonephritis), but is more often seen in conditions such as Goodpasture’s syndrome and systemic vasculitis.

·                    Idiopathic crescentic glomerulonephritis is now regarded as a form of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis limited to the kidney.

·                    It presents with the clinical syndrome of rapidly progressive glomerulonephritis.

·                    Without treatment, the disease progresses to end-stage renal failure within a few months Prednisolone and cyclophosphamide are generally effective in patients before severe renal damage occurs.

·                    Plasma exchange is recommended in patients with advanced renal disease.

·                    Goodpasture’s syndrome:

o        Due to autoantibodies directed against the alpha 3 chain of type IV collagen, which is a major structural component of the glomerular basement membrane.

o        50% of patients also have pulmonary haemorrhage.

o        The syndrome presents with rapidly progressive glomerulonephritis, usually leading to renal failure within six months if untreated.

o        Treatment with prednisolone, cyclophosphamide and plasma exchange is generally effective as long as it is started before renal disease is advanced.

o        It is very rare for patients to relapse, and the long-term outcome is good following successful treatment.

 

Inpatient Management

 

General management begins with a decision to admit the child with acute glomerulonephritis to the hospital or merely have him or her undergo frequent outpatient examinations. Hospitalization is indicated if the child has significant hypertension or a combination of oliguria, generalized edema, and elevation of serum creatinine or potassium.

Severe hypertension

Severe hypertension, or that associated with signs of cerebral dysfunction, demands immediate attention. Debate exists regarding the agent that is most effective in patients with severe hypertension.

Three drugs are commonly cited as having a high benefit-to-risk ratio: labetalol (0.5-2 mg/kg/h intravenously [IV]), diazoxide, and nitroprusside (0.5-2 mcg/kg/min IV; in patients with severe hypertension that is refractory to the previous agents). In combination with any of these agents, the simultaneous IV administration of furosemide at doses of 2 mg/kg may be merited. Diazoxide use for blood pressure (BP) control is limited because, once administered, no further control of pressure is possible, unlike labetalol or nitroprusside.

Severe hypertension without encephalopathy can be treated in the manner described above or, more commonly, by administration of vasodilator drugs, such as hydralazine or nifedipine.

The doses of these drugs can be administered either by injection or by mouth and can be repeated every 10-20 minutes until a suitable response is obtained. For most children, the need for more than 2-3 doses is unusual.

Mild-to-moderate hypertension

Mild-to-moderate hypertension does not warrant emergency management and is treated most effectively with bedrest, fluid restriction, and less-frequent doses of the medications mentioned above.

The use of loop diuretics, such as furosemide (1-3 mg/kg/d oral [PO], administered 1-2 times daily), may hasten resolution of the hypertension.

For patients resistant to treatment, either hydralazine or nifedipine is indicated.

Angiotensin-converting enzyme (ACE) inhibitors are effective, although these agents have the potential to produce hyperkalemia and usually are not first-line drugs in acute glomerulonephritis.

Edema and circulatory congestion are usually not sufficiently marked to produce more than minimal discomfort. Restriction of fluids to those amounts needed to replace insensible losses is the best treatment for edema and circulatory congestion.

Loop diuretics (furosemide) administered PO have been reported to reduce the length of hospitalization in children who are edematous. If congestion is marked, administer furosemide parenterally (2 mg/kg).

Phlebotomy, rotating tourniquets, dialysis, or digitalization is rarely necessary.

Anuria or oliguria

Anuria or severe and persistent oliguria may occur in 3-6% of children with acute glomerulonephritis and may necessitate hospitalization. Fortunately, both of these conditions are usually transient.

Because they may be ototoxic, avoid large doses of furosemide in children with symptoms of anuria or severe and persistent oliguria. In addition, osmotic diuretics, such as mannitol, are contraindicated, as they might increase vascular volume.

Other medical management strategies

A course of penicillin can be administered to avoid contamination of contacts with a nephritogenic strain of streptococci; however, in most instances, these contacts do not develop overt acute glomerulonephritis. Such therapy may not influence the course of the disease in the index patient, but it may alter the response that confers type-specific immunity. To date, only one report suggests that patients with APSGN who receive antibiotic treatment have a milder clinical course.  Throat cultures of immediate family members might detect patients who are asymptomatic but infected.

The diagnosis of streptococcal pharyngitis on clinical grounds alone is uncertain, and only 10-20% of the patients who present with sore throat in general clinical practice have a positive culture for group A streptococci.

Several clinical scoring systems have been developed to increase the accuracy of diagnosis for the prescription of antibiotics. These have a range of 1-4 and incorporate age as a risk factor. The following is the McIsaac score, showing each criterion and its corresponding score:

·                     Temperature higher than 38^º C and no cough – 1 point

·                     Tender anterior cervical adenopathy – 1 point

·                     Tonsillar swelling or exudates – 1 point

·                     Age between 3 and 14 years – 1 point

Age 15-44 years is assigned no points, and age older than or equal to 44 years garners -1 point. Based on the scoring systems, it is recommended that antibiotic treatment is administered based on clinical grounds alone when the score is 4, antibiotic treatment is not recommended (and culture is unnecessary) when the score is 0 or 1, and culture should be obtained and treatment given only when the result is positive if the score is 2 or 3. Rapid test for streptococcal antigen detection may be used as a confirmatory test for children with tonsillar exuduate.

 However, the sensitivity is too low to support use without culture confirmation of negative results.

In resource-limited settings, the author is of the view that all patients with acute APSGN be treated as though they have active streptococcal infection. This recommendation is based on the finding of positive cultures for Streptococcus in patients with APSGN in whom upper respiratory tract or skin infections are not clinically evident.

Steroid therapy is indicated only in patients with severe crescentic glomerulonephritis or in those with rapidly progressive glomerulonephritis. Selected patients with Henoch-Schönlein purpura (HSP) nephritis and membranoproliferative glomerulonephritis (MPGN) also may benefit from such agents. An experienced nephrologist should make decisions regarding the indication for such treatment.

The need for medicines in acute poststreptococcal glomerulonephritis (ASPGN) is usually limited in scope and in length. Administer antibiotics (penicillin or erythromycin) for 10 days to ensure eradication of the streptococcus if the disease is believed to be acute poststreptococcal glomerulonephritis and if risk of contamination is present. Some clinicians use this treatment only when evidence suggests an active infection.

Antihypertensives are usually not necessary after the child leaves the hospital, although mild hypertension may persist for as many as 6 weeks. The medications that can be used span the entire range of antihypertensives, such as vasodilators (eg, hydralazine), calcium channel-blocking agents (eg, long-acting nifedipine, amlodipine), or angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril).

Carefully monitor blood pressure (BP) for at least 1 week after the drug is discontinued to ensure that rebound hypertension does not occur.

Diuretic agents (eg, furosemide) are rarely necessary after the first 2 days; hypertension persisting beyond the first week may suggest a diagnosis other than acute glomerulonephritis.

Prevention of APSGN

A vaccine targeted against group A streptococci will prevent both invasive disease and nonsuppurative complications. The current thrust of group A streptococcal vaccine research has been to target the M protein. A 26-valent vaccine as been developed that targets the variable region of the M proteins of the most common rheumatogenic cocci. Unfortunately, no M protein from nephritogenic streptococci were included in the vaccine. In addition, the most common M protein types in the developing world differ from those of more developed countries, thus rendering the vaccine less efficacious. The most effective public health measure in the developing world is to improve hygiene and provide better housing conditions to avoid overcrowding. This offers the best hope for elimination of epidemic pyoderma and thus preventing APSGN.

Approach Considerations

By the time the child with acute poststreptococcal glomerulonephritis (APSGN) presents with symptoms, the glomerular injury has already occurred, and the healing process has begun. Thus, influencing the ultimate course of the disease by any specific therapy directed at the cause of the nephritis is not possible. Conversely, morbidity and early mortality are influenced considerably by appropriate medical therapy. Even then, treatment is usually supportive and directed toward the potential complications.

Only a small percentage of patients with acute glomerulonephritis require initial hospitalization, and most of those are ready for discharge in 2-4 days. As soon as the blood pressure (BP) is under relatively good control and diuresis has begun, most children can be discharged and monitored as outpatients.

If indicated at any time during the course of the disease, an experienced nephrologist should perform renal biopsy percutaneously.

Transfer of responsibility for the patient with acute glomerulonephritis is rarely indicated, except in those instances in which a consultation with a nephrologist is not easily obtainable in the local area or by telephone, facsimile, or e-mail.

Diet and activity

A low-sodium, low-protein diet should be prescribed during the acute phase, when edema and hypertension are in evidence; however, prolonged dietary restrictions are not warranted. Limitation of fluid and salt intake is recommended in the child who has either oliguria or edema. Curtailment of fluid to amounts consistent with insensible losses helps to minimize vascular overload and hypertension.

Limited activity is probably indicated during the early phase of the disease, particularly if hypertension is present. Bedrest may lessen the degree and duration of gross hematuria if present; however, longer periods of bedrest do not appear to influence the course or long-term prognosis; therefore, they are generally not recommended.

Acute kidney failure

Acute kidney failure is the sudden loss of  kidneys’ ability to eliminate excess salts, fluids, and waste materials from the blood. When kidneys lose their filtering ability, body fluids can rise to dangerous levels. The condition will also cause electrolytes and waste material to accumulate in  body.

Acute kidney failure, also called acute kidney injury, is common in patients who are already in the hospital. It may develop rapidly over a few hours. Or it may develop more slowly over a few days. People who are critically ill and need intensive care are at the highest risk of developing acute kidney failure.

Acute kidney failure can be fatal and requires intensive treatment. However, it may be reversible. If you are in good health otherwise, recovery is possible.

Causes of Acute Kidney Failure

Acute kidney failure can occur for many reasons. Among the reasons are:

·                    acute tubular necrosis (ATN)

·                    autoimmune kidney diseases such as acute nephritic syndrome and interstitial nephritis

·                    urinary tract obstruction

Low blood pressure can reduce blood flow and cause damage to  kidneys. These health problems can decrease blood flow to  kidneys:

·                    burns

·                    dehydration

·                    hemorrhage

·                    injury

·                    septic shock

·                    serious illness

·                    surgery

Certain disorders can cause clotting within  kidney’s blood vessels:

·                    hemolytic uremic syndrome

·                    idiopathic thrombocytopenic thrombotic purpura (ITTP)

·                    malignant hypertension

·                    transfusion reaction

·                    scleroderma

Some infections can directly injure  kidneys, such as:

·                    septicemia

·                    acute pyelonephritis

Pregnancy can cause complications that harm the kidneys:

·                    placenta previa (in pregnancy)

·                    placenta abruption (in pregnancy)

·              

 

 

Kidney failure may be acute or chronic. Acute diseases develop quickly and can be very serious. Although an acute disease may have long-lasting consequences, it usually lasts for only a short time and then goes away once the underlying cause has been treated. Chronic diseases, however, do not go away and tend to get worse over time. When the kidneys stop working, doctors use a treatment called dialysis to remove waste products and extra water from patients with chronic kidney failure.

Acute Kidney Diseases

Acute kidney disease may result from an injury or from poisoning. Any injury that results in loss of blood may reduce kidney function temporarily, but once the blood supply is replenished, the kidneys usually return to normal. Other kinds of acute kidney disease in children are

·                     Hemolytic uremic syndrome. This rare disease affects mostly children under 10 years of age and can result in kidney failure. Eating foods contaminated by bacteria leads to an infection in the digestive system, which in the first stages causes vomiting and diarrhea. When these symptoms subside, the child is still listless and pale. Poisons produced by the bacteria can damage the kidneys, causing acute kidney failure. Children with hemolytic uremic syndrome may need blood transfusion or dialysis for a short time. Most children, however, return to normal after a few weeks. Only a small percentage of children (mostly those who have severe acute kidney disease) will develop chronic kidney disease.

·                     Nephrotic syndrome. A child with this syndrome will urinate less often, so the water left in the body causes swelling around the eyes, legs, and belly. The small amount of urine the body makes contains high levels of protein. Healthy kidneys keep protein in the blood, but damaged kidneys let it leak from the blood into the urine. Nephrotic syndrome can usually be treated with prednisone to stop protein leakage, and sometimes a diuretic is used to help the child urinate and reduce the swelling. Usually, the child can take smaller and smaller doses of prednisone and eventually return to normal with no lasting kidney damage. This temporary condition is called minimal change disease. Relapses are common but usually respond to prednisone treatment.

Symptoms of Acute Kidney Failure

·                    bloody stools

·                    breath odor

·                    slow, sluggish movements

·                    swelling – generalized (fluid retention)

·                    fatigue

·                    pain between ribs and hips

·                    hand tremor

·                    bruising easily

·                    changes in mental status or mood, especially if you are elderly

·                    decreased appetite

·                    decreased sensation, especially in  hands or feet

·                    prolonged bleeding

·                    seizures

·                    nausea

·                    vomiting

·                    hiccups that won’t resolve

·                    elevated blood pressure

·                    metallic taste

Diagnosing Acute Kidney Failure

If you have acute kidney failure you may have generalized swelling. The swelling is caused by fluid retention.

Using a stethoscope,  physician may hear crackling in the lungs. These sounds can signal fluid retention.

Results of laboratory tests may also show sudden changes. Some of these tests include:

·                    blood urea nitrogen (BUN)

·                    serum potassium

·                    urinalysis

·                    creatinine clearance

·                    serum creatinine

An ultrasound is the preferred method for diagnosing acute kidney failure. However, abdominal X-ray, abdominal CT scan, and abdominal MRI can determine if there is a blockage in  urinary tract.

Certain blood tests may also reveal underlying causes of acute kidney failure..

Treating Acute Kidney Failure

Treatment will depend on the cause of  acute kidney failure. The goal is to restore normal kidney function. Preventing fluids and wastes from building up in  body while  kidneys recover is important.

 doctor will restrict  diet and the amount of liquids you eat and drink. The goal is to reduce the buildup of toxins that are normally eliminated by the kidneys. A diet high in carbohydrates and low in protein, salt, and potassium is usually recommended.

Antibiotics may be prescribed to treat or prevent any infections that occur at the same time. Diuretics may be used to help  kidneys eliminate fluid. Calcium and insulin can be given to help avoid dangerous increases in  blood potassium levels.

Dialysis might be needed, but is not always necessary. Dialysis involves diverting blood out of  body into a machine that filters out waste. The clean blood is then returned to  body. If potassium levels are dangerously high, dialysis can save  life. Dialysis is used if there are changes in  mental status, or if you stop urinating. You may also need dialysis if you develop pericarditis, inflammation of the heart. Dialysis can help eliminate nitrogen waste products from  body.

What is Expected in the Long Term

Acute kidney failure can be a life-threatening illness. Intensive treatment may be required. But if you are in good health otherwise, chances of recovery are good.

Chronic renal failure or end-stage renal disease can develop. Death is more common if kidney failure is caused by severe infection, trauma, or surgery. Lung disease, recent stroke, advanced age, blood loss, and progressive kidney failure also increase  risk of death.

Some of the complications of acute kidney failure may be:

·                    chronic kidney failure

·                    heart damage

·                    nervous system damage

·                    end stage renal failure

·                    high blood pressure

Preventing Acute Kidney Failure

Preventing and treating illnesses that can lead to acute kidney failure is the best method for avoiding the disease.

 

Chronic kidney failure results when a disease slowly destroys the kidneys. Destruction occurs over many years, usually with no symptoms until the late stage of kidney failure. Progression may be so gradual that symptoms may not occur until kidney function is less than one-tenth of normal.

Unfortunately, the conditions that lead to chronic kidney failure in children cannot be easily fixed. Often, the condition will develop so slowly that it goes unnoticed until the kidneys have been permanently damaged. Treatment may slow down the progression of some diseases, but in many cases the child will eventually need dialysis or transplantation.

• Birth defects. Some babies are born without kidneys or with abnormally formed kidneys. The kidney abnormality is sometimes part of a syndrome that affects many parts of the body.
• Blocked urine flow and reflux. If blockage develops between the kidneys and the opening where urine leaves the body, the urine can back up and damage the kidney.
• Hereditary diseases. In polycystic kidney disease (PKD), children inherit defective genes that cause the kidneys to develop many cysts, sacs of fluid that replace healthy tissue and keep the kidneys from doing their job. In Alport syndrome, the defective gene that causes kidney disease may also cause hearing or vision loss.
• Glomerular diseases. Some diseases attack the individual filtering units in the kidney. When damaged, these filters-which are called glomeruli-leak blood and protein into the urine. If the damage to the glomeruli is severe, kidney failure may develop.
• Systemic diseases. Diabetes and lupus can affect many parts of the body, including the kidneys in some people. In lupus, the immune system becomes overactive and attacks the body’s own tissues. Diabetes leads to high levels of blood glucose that damage the glomeruli. Diabetes is the leading cause of kidney failure in adults. In children, however, diabetes is low on the list of causes because it usually takes many years of high blood glucose for the kidney disease of diabetes to develop. However, an increasing number of children have type 2 diabetes, which is usually associated with adults. As a result, we may see more children with chronic kidney failure caused by diabetes in the future.

From birth to age 4 years, birth defects and hereditary diseases are by far the leading causes of kidney failure. Between ages 5 and 14 years, hereditary diseases continue to be the most common causes, followed closely by glomerular diseases. In the 15- to 19-year-old age group, glomerular diseases are the leading cause, and hereditary diseases become rarer.

Treatments for kidney failure

A child whose kidneys fail completely must receive treatment to replace the work the kidneys do. The two types of treatment are dialysis and transplantation.

Dialysis

Dialysis is a way to remove the waste products and extra water from the blood of patients with kidney failure. The two main types of dialysis are peritoneal dialysis and hemodialysis.

• Peritoneal dialysis. This method uses the lining of the child’s abdominal cavity, the peritoneum, as a filter. A catheter placed in the child’s belly is used to pour a solution containing dextrose (a sugar) into the abdominal cavity. While the solution is there, it pulls wastes and extra fluid from the blood. Later, the solution is drained from the belly, along with the wastes and extra fluid. The cavity is then refilled, and the cleaning process continues. Peritoneal dialysis can be performed in the home, usually while the child sleeps, without a health professional present. You and your child will receive extensive training before you start home treatments.
• Hemodialysis. This method uses a machine that carries the child’s blood through a tube to a dialyzer, a canister that contains thousands of fibers that filter out the wastes and extra fluid. The cleaned blood is then returned to the child through a different tube. Hemodialysis is usually performed in a clinic under the supervision of a nurse and kidney specialist. It is generally required three times a week for about 3 to 4 hours each time.

 

Transplantation

Transplantation provides the closest thing to a cure for kidney failure. In this procedure, a surgeon places a healthy kidney in the child’s body. The kidney may come either from a living donor or from someone who has just died.

• Living donor. Most people can donate a kidney without hurting their health. Many children receive a kidney from one of their parents, but the donor does not have to be a family member.
• Deceased donor. If no living donors are available, a child may be placed on a waiting list to receive a kidney from someone who has just died. The United Network for Organ Sharing (UNOS) maintains a computerized system for matching kidneys with appropriate recipients.

People who have transplants must take drugs to keep the body’s immune system from rejecting the new organ. These immunosuppressive drugs can help maintain good function in the transplanted kidney for many years. However, they may have some undesirable side effects such as making a child vulnerable to infections.