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The many faces of minimal change nephrotic syndrome: an overview and case study.

Goal

To provide an overview of nephrotic syndrome, its signs and symptoms, and treatment options in the pediatric population.

Objectives

1. Define nephrotic syndrome.

2. Explain the diagnosis process for determining nephrotic syndrome in a pediatric patient.

3. Discuss treatment options for nephrotic syndrome in the pediatric population.

4. Describe steroid-dependent and steroid-resistant complications to treatment in patients being treated for nephrotic syndrome.

5. Identify possible alternatives to steroid treatment in the patient with nephrotic syndrome who is steroid-dependent or steroid-resistant.

Nephrotic syndrome is a disorder that is characterized by high-level protein excretion in the urine (greater than 40 mg/[m.sup.2]/ hour), gravity-dependent edema, hypoalbuminemia, hyperlipidemia, and in some cases, hypertension. It is seen primarily in the pediatric population, with an incidence of approximately 2 to 3 occurrences per 100,000 children (Bogt & Avner, 2007). Causes can be idiopathic, congenital, or secondary.

The most common cause in the pediatric population is idiopathic and is often referred to as primary nephrotic syndrome in the literature. In contrast, it only accounts for approximately one-quarter of the adult cases (Niaudet, 2004). Between 1967 and 1974, the International Study of Kidney Disease in Children (ISKDC) (1978, 1981) conducted a multicenter, prospective study of 521 children with primary nephrotic syndrome. The population consisted of children with primary nephrotic syndrome who were biopsied prior to initiation of treatment. Ninety percent of the patients fell into one of three histopathological categories. Seventy-six percent had minimal change nephrotic syndrome (MCNS) (also called minimal change disease [MCD]), 6.9% had focal and segmental glomerulosclerosis (FSGS), and 7.5% had membranoproliferative glomeruloanephritis (MPGN).

One purpose of the ISKDC (1978, 1981) study was to further evaluate the accuracy of identifying the underlying glomerular disease based on clinical presentation to avoid the need of performing a renal biopsy prior to starting treatment. Researchers found that the child's response to corticosteroids was a more reliable prediction of MCNS versus FSGS. Patients could be classified as steroidsensitive or steroid-resistant. Those classified as steroid-sensitive achieved complete remission within eight weeks of starting steroid therapy. The study also showed that when the child was steroid-sensitive, the diagnosis was most likely MCNS, and a renal biopsy, an invasive and expensive diagnostic tool, could be avoided (ISKDC, 1981). This study established the first guidelines for treating idiopathic nephrotic syndrome and provided a platform for further investigations that, in turn, have increased our knowledge base and improved our approach to the care of children with this disorder.

Over the years, since the findings of the ISKDC study were published, there have been changes in the population that present with nephrotic syndrome. For example, Srivastava, Simon, and Alon (1999) found an increase in the incidence of FSGS in comparison to data provided by the ISKDC study. They reviewed data on pediatric patients with nephrotic syndrome from 1984 to 1995 cared for at their facility. Data from their facility revealed the proportion of MCD and FSGS was 52.7% and 23%, respectively, in contrast to 76.4% and 6.9% for MCD and FSGS, respectively (ISKDC, 1978, 1981). Ethnic differences, with the incidence of FSGS being higher in African Americans than in Caucasians, were noted in both this study as well as in the study by Kim et al. (2005). There was a higher incidence of FSGS versus MCNS, with prevalence of FSGS being higher in African Americans compared to the Caucasians. They also noted a higher incidence of the development of steroid resistance after initial steroid responsiveness than was noted in the ISKDC study. The authors pointed out that the increase in FSGS in their findings in comparison to the ISKDC study may have been due to a higher rate of older children and African-American children in their study group population.

Another change is in the terminology used to describe response to steroids. It has broadened beyond steroid-responsive and steroid-resistant to include frequent relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome To address these changes and develop more current guidelines based on published literature for use in practice and research, the Children's Nephrotic Syndrome Consensus Conference was formed (Gipson et al., 2009). The selected members of this group were all North American pediatric nephrologists. They were provided with a total of 344 articles for review. The guidelines that resulted from this review provide recommendations for evaluation and treatment based on presentation and response to initial steroid therapy. Therapy guidelines are provided for initial therapy, infrequent-relapse, frequently relapsing, steroid-dependent, and steroid-resistant nephrotic syndrome. Frequently relapsing is defined as two or more relapses within six months of the initial therapy, or four lapses or more in any 12-month period. Steroid-dependent is defined as relapsing during taper of steroids or within two weeks of completion of steroid therapy. Steroid-resistant refers to those who are not in remission after four weeks of steroid therapy.

Minimal Change Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome is more common in boys than girls, with a peak incidence between 1 and 4 years of age (Hodson, Alexander, & Graf, 2008). Incidence based on geographical and ethnic background varies. It appears to be less common in African and African-American children.

The onset of high-level proteinuria (greater than 40 mg/[m.sup.2]/hour) is usually preceded by an upper respiratory infection. In some children, the onset can also follow insect bites, bee stings, or poison ivy (Bogt & Avner, 2007). The pathology behind the increased permeability at the level of the podocyte that in turn allows the excretion of large amounts of protein is still not clearly understood. It is suspected

that there is an abnormality in T-cell function due to the positive response to T-cell-suppressing agents. Evidence supports a T-cell-activated permeability factor, but the specific players and changes involved remain unknown (Hodson et al., 2008).

Treatment of Proteinuria

The primary goal of treatment is to control the abundant proteinuria and keep the patient in remission. Initial treatment since the 1950s has been the use of intensive corticosteroid therapy (Hodson et al., 2008). Because of the clear benefits of this approach, no placebo-controlled studies were done. The ISKDC study (1981) set dosing guidelines, and these then became the control group for randomized control studies that followed. This has led to a more effective and standardized treatment regimen for the corticosteroids. At initial presentation, the recommended dosing of prednisone by the ISKDC (1981) was 60 mg/[m.sup.2]/day (maximum of 80 mg/day), given as a single dose or divided into two doses per day for four weeks, followed by 40 mg/[m.sup.2] in divided doses for three consecutive days out of seven for four weeks.

Remission is defined as protein excretion of 4 mg/[m.sup.2]/hour or less or negative-trace of protein on urine dipstick (Hodson et al., 2008). Studies that followed have provided improved dosing regimens that increase time to relapse. A review of two meta-analyses (one of 5 trials and one of 7 trials) that compared duration of steroid therapy for initial onset revealed supporting data that extended therapy of three to seven months compared to two months resulted in fewer relapses within a 12 to 24-month period (Filler, 2003; Hodson, Knight, Willis, & Craig, 2000). There was no significant increase in steroid-related complications with the prolonged dosing regimen. The guidelines set by the Children's Nephrotic Syndrome Consensus Conference recommend an initial dosing regimen of steroids as 60 mg/[m.sup.2] per day for six weeks followed by a six-week course of 40 mg/[m.sup.2] on alternate days (Gipson et al., 2009). No further steroid weaning is required. With relapses, the length of dosing with steroids is shortened. The initial high daily dose is only given until the urine protein excretion normalizes for three consecutive days followed by the lower alternate day dose for four weeks. Further tapering after completion of four weeks is only recommended for the child with frequently relapsing nephrotic syndrome.

For the child who experiences frequent relapses or is steroid-dependent, the chances of unwanted side effects from prolonged use of corticosteroids increases. Adverse effects reported in clinical trials have included growth retardation; hypertension; significant weight gain; cushingoid features; ophthalmic disorders, such as cataracts and increased intraocular pressure; behavioral disorders, such as aggression, sleep disturbances, and hyperactivity; and osteopenia (Hodson et al., 2008). The use of other medications becomes necessary to decrease proteinuria and avoid the complications of prolonged steroid use. These may include alkylating agents, such as chlorambucil and cyclophasphamide; calcinurin inhibitors, such as cyclosporine and tacrolimus; immunosuppresants, such as mycophenolate mefetil; and antiproteinuric therapy with angiotensin-converting enzyme inhibitors (ACE1) and angiotensin receptor blockers (ARBs) (Gipson et al., 2009; Ulinski & Aoun, 2010). The use of levamisole is mentioned, but it is no longer available universally to include the United States. In cases where proteinuria persists despite these treatments, some practitioners have tried a more aggressive approach with use of rituximab (Betjes & Roodnat, 2009; Gilbert, Hulse, & Rigden, 2006; Hofstra, Deegan, & Wetzels, 2007; Smith, 2007). A review of case studies where rituximab has been used is presented later in this article. Its use is still considered experimental, and formal research studies regarding its efficacy are needed.

Renal Biopsy

The question of when to perform a renal biopsy has been an ongoing discussion since the ISKDC (1978, 1981) published its recommendations. Assessment of prognosis and decisions regarding treatment should be based on the prediction of the underlying disorder, and a strong correlation was noted between steroid responsiveness and findings of MCNS on renal biopsy, especially in children with primary nephrotic syndrome presenting at 6 years of age or younger (ISKDC, 1978, 1981). In this group, a renal biopsy is not considered necessary prior to starting treatment with corticosteroids. Such a prediction for non-responders was not as clear, and biopsy was recommended before the initiation of further treatment. Gulati, Sharma, Sharma, Gupta, and Gupta (2002) noted the persistent diversity that still existed regarding the need for renal biopsy in this population and did a prospective study in their center. After review of data, they concluded that all children presenting with nephrotic syndrome younger than 1 year of age should be biopsied due to the high incidence of non-MCD lesions in this group. Recommendations for biopsy in children 1 through 16 years of age included those that present with nephrotic syndrome and have unusual clinical features (such as hypertension or hematuria) and/or laboratory abnormalities (such as abnormal renal functions or low complement C3), and/or steroid non-responders. Gulati et al. (2002) also found that no biopsy was needed before initiating treatment with cyclophosphamide in the steroid responders, requiring more aggressive therapy; data showed the predictive value of cyclophosphamide responsiveness correlated better with steroid responsiveness than with histopathology subtype. The most current guidelines set by the Children's Nephrotic Syndrome Consensus Conference (Gipson et al., 2009) address the need for renal biopsy in children 1 to 18 years of age. Due to the higher incidence of FSGS in children 12 years of age and older, it is recommended that a renal biopsy be done prior to initiating treatment with corticosteroids. Children who present between the ages of 1 to 11 years should be biopsied if found to be steroid-resistant (Gipson et al., 2009).

Limitations to renal biopsy include the need for an adequate specimen to capture an affected glomeruli. To diagnose FSGS, only a single abnormal glomerulus needs to be recognized. Obtaining a revealing specimen is dependent on the number of affected glomeruli within the kidney at the time of biopsy as well as if they are located at the site from which the biopsy was taken (Howie, 2003; Melk, 2008). Potential complications to consider include macroscopic hematuria, perirenal hematoma, infection, excessive blood loss requiring transfusion, post-procedure pain, and arteriovenous fistula (Melk, 2008). Since renal biopsies in children are commonly done under anesthesia and sedation, the potential complications associated with these interventions need to be considered.

Disease-Associated Complications

Edema

Edema is frequently the first recognized clinical sign of nephrotic syndrome at the time of diagnosis and relapse. Without prompt response with appropriate treatment measures, it can get quite severe, and the child can become symptomatic with ascites, pleural effusion, and/or weeping tissues. This also leaves the patient at increased risk of infection. The pathophysiology that results in the edema may be related to the hypoalbuminemia that develops as a result of the high level proteinuria. Reduction of plasma oncotic pressure occurs, leading to interstitial leakage of fluid and hypovolemia and resulting in activation of the renninangiotensin-aldosterone system with sodium retention. This theory is currently under debate. After review of the literature, Doucet, Guillanme, and Deschenes (2007) noted that clinical and experimental data suggest the edema in nephrotic syndrome develops due to changes in intrinsic properties of the endothelial capillary barriers rather than changes in plasma oncotic pressure. Further, increased sodium retention may be related to a dysregulation that occurs in a regulatory pathway rather than hyperaldosteronemia (Doucet et al., 2007). The specific pathway is still unknown, and further research is needed.

Initiation of treatment at the first signs of edema is preferred. Treatment measures include the restriction of oral salt intake and modest fluid restriction (Gipson et al., 2009). According to the guidelines set by the Children's Nephrotic Syndrome Study Group, a sodium restriction of 1500 to 2000 mg daily is recommended. If the edema continues to increase and the child becomes symptomatic, the child may require hospitalization for treatment with albumin infusions and diuretics. Complications of this more aggressive approach can be quite severe. The albumin infusions have been noted to cause hypertension, pulmonary edema, and congestive heart failure. Excessive use of diuretics can lead to hypovolemia and hyponatremai, as well as renal failure (Bogt & Avner, 2007; Gipson et al., 2009).

Hypertension

Gipson et al. (2009) found that 13% to 51% of children with nephrotic syndrome have hypertension. Hypertension can be related to the disease process as well as the use of corticosteroids. The most recent guidelines set by the Children's Nephrotic Syndrome Study Group recommend that the blood pressure be controlled so that it remains below the 90th percentile for the child's age, gender, and height. Blood pressure usually improves with resolution of proteinuria. Many treatment modalities used to address hypertension are also used for the reduction of urinary protein excretion and edema. These include lowering salt intake and the use of ACE inhibitors and/or ARBs. The ability of the ACE inhibitors and the ARBs to lower proteinuria and slow progression of renal disease has been clearly demonstrated in the literature (Kunz, Friedrich, Wolbers, & Mann, 2008). The increased effectiveness of the combined use of these drugs is still in debate. A small number of studies have shown them to be beneficial (Kunz et al., 2008; Wolf & Ritz, 2005). At present, the recommendation to use these in combination is reserved for patients who are not benefitted by monotherapy. Of note, the population involved in these studies reviewed was primarily middle-aged and not pediatric. Documentation of side effects was also limited. With the use of these drugs, there is the potential for hyperkalemia. Females need to be educated regarding teratogenic effects.

Hyperlipidemia

The presence of hyperlipidemia is a common finding in the child with nephrotic syndrome. It may be related to the hypoalbuminemia and the disruption of lipid metabolism (Querfeld, 1999). With the resolution of proteinuria, there is a rapid normalization in the serum lipid levels. Therefore, long-term complications are of more concern in children with refractory proteinuria. Recommended treatment is the limitation of dietary fat intake to less than 30% of calories, saturated fat to less than 10% of calories, and less than 300 mg/day of dietary cholesterol. The use of drug therapy is limited to those with persistent elevations in serum cholesterol (Gipson et al., 2009).

Infection

Infection is the most common serious complication in children with nephrotic syndrome as a result of the disease process as well as the drug therapies commonly used. Children with nephrotic syndrome have low serum immunoglobulin G (IgG) levels due to urinary loss of IgG, abnormal T lymphocyte function, and disruptions in the complement pathway, which decreases the ability to opsonize encapsulated bacteria, such as Streptococcus pneumonia (Gbadegesin & Smoyer, 2008). The use of corticosteroids and immunosuppressants increases their risk of infection and can minimize the presenting signs and symptoms related to infection. Because of the increased susceptibility and masked presentations, the healthcare provider must maintain a high index of suspicion while caring for this population.

The most serious and most common infection encountered is bacterial peritonitis (Gbadegesin & Smoyer, 2008; Gipson et al., 2009). Early studies identified Streptococcus pneumonia as the most common pathogen responsible, and a study by Gorensek, Lebel, and Nelson (1988) also found this to be true. However, Gorensek et al. (1988) also noted a rise in the incidence of gram-negative organisms. Predisposing factors, in addition to the impaired immune response, include the presence of ascites and hypoalbuminemia. Signs and symptoms include fever, abdominal tenderness and pain, peritoneal signs, nausea and vomiting, and signs of sepsis. The work-up should include the analysis of peritoneal fluid for gram stain, cell count, and culture. Because of the increased morbidity and mortality associated with this complication, initiation of antibiotic therapy should be considered before the results of the culture are received. Gorenesk et al. (1988) noted a high incidence of negative cultures despite strong clinical presentations and stressed the importance of an adequate amount of peritoneal fluid to increase the yield of reliable results. In an attempt to prevent this type of infection, the use of pneumococcal vaccine is recommended. The initial series of pneumococcal vaccine during infancy is now a part of the recommended immunization schedule for all children.

Children with underlying medical conditions, such as nephrotic syndrome, require increased coverage. The initial course consists of a pneumococcal polysaccharide-protein conjugate vaccine (PCV). This was PCV 7, which only covered seven serotypes (Centers for Disease Control and Prevention, 2010). On February 10, 2010, the U.S. Food and Drug Administration (FDA) approved PCV 13 that covers 13 serotypes and has taken the place of PCV 7. With this came changes to the immunization schedule for both children with and without underlying medical conditions to include the recommendation that all children receive PVC 13 despite completion of the PCV 7 series. In addition to the PCV series, it is also recommended that immunocompromised patients receive the 23-valent pneumococcal polysaccharide vaccine (PPSV23). One dose after 2 years of age is recommended, with revaccination 5 years after the first dose. Immunization schedules are updated as new research findings become available, and it is recommended that the caregiver responsible for patients with nephrotic syndrome review the most current published immunization schedules for children with underlying medical conditions to provide appropriate coverage. It is also important to have an accurate accounting of the child's immunization history to provide the appropriate schedule of vaccine

The need to defer administration of live vaccines to children on corticosteroid therapy and/or immunosuppressant drug therapy leaves them at increased risk for certain viral infections. Varicella infection can be life-threatening to this population. Verification of immunization history and/or immune status is important. If exposure occurs in the immunosuppressed, non-immune child, then varicella immune globulin (VZIG) should be administered within 96 hours to help prevent systemic infection (Gbadegesin & Smoyer, 2008).

Thromboembolism

Thromboembolism is an uncommon but potentially life-threatening complication that can be seen in the patient with nephrotic syndrome. It is more commonly seen in the adult nephrotic patient, with an incidence of approximately 25%. The incidence in the pediatric nephrotic population is approximately 3% (Kerlin, Ayoob, & Smoyer, 2012). Its occurrence also varies based on type of nephrotic syndrome. In the pediatric population, the higher incidence is seen in congenital nephrotic syndrome, secondary nephrotic syndrome, and membranous nephropathy or similar histological process. In children with onset of nephrotic syndrome past the first year of life, there appears to be an increased risk of thromboembolism with increasing age. This puts adolescents at greatest risk. Thromboembolism is most often a complication encountered early in the course of the disease with the presence of nephrotic range proteinuria.

The pathophysiology involved in thrombus formation in nephrotic syndrome is not fully understood. It is most likely a multifactorial process that could include non-renal influences, such as genetic predisposition. There are changes that occur within the coagulation system due to the disease process, as well as side effects of medication management regimens that put these individuals at increased risk. Changes in the kidney that create a state of increased permeability and the leakage of high molecular weight proteins result in the loss of proteins that play a major role in the anticoagulation pathway, such as antithrombin and protein S. In addition, there are proteins in the coagulation pathway that are of higher molecular weights that are not excreted and appear to become markedly elevated, such as fibfinogen, factor V, and factor VIII (Kerlin et al., 2012). There is also increased synthesis by the liver of clotting factors I, II, V, VII, X, and XIII (Gbadegeson & Smoyer, 2008). Thrombocytosis is a common finding in nephrotic syndrome, but the significance that this state plays in abnormal thrombus formation remains debatable. Some evidence suggests there is a state of hyperaggregability, which could be quite significant (Kerlin et al., 2012). There is also the state of intravascular volume depletion as the result of hypoalbuminemia, hyperlipidemia, and in some cases, the use of diuretics.

The thromboembolism can occur in a vein or artery. Venous presentation is more common. There should be a high suspicion for renal vein thrombosis in those patients that present with macrohematuria, flank pain, and/or renal failure. Treatment of this disorder is the same as in the patient without nephrotic syndrome. Prophylactic use of anticoagulation therapy has been proposed for individuals at highest risk, but more research is needed to identify specific risk criteria and evaluate efficacy as well as safety before such an intervention becomes a formal recommendation (Kerlin et al., 2012). Gbadegesin and Smoyer (2008) state that children with nephrotic syndrome with a history of thromboembolism should be treated with prophylactic anticoagulation therapy during any future relapses to help prevent recurrence of this complication.

Prognosis

Patients who respond well to prednisone and achieve prolonged remission will most likely outgrow the disorder with maintenance of good renal function. The prognosis for patients that become steroid-dependent or are steroid-resistant is less clear. Research has shown that reducing proteinuria is renoprotective (Ruggenenti, Perna, & Remuzzi, 2003). The goal of every treatment regimen is to achieve long-lasting remission of proteinuria and preserve kidney function. Maintenance of renal function is of primary importance, but the need to preserve quality of life cannot be underestimated. Kyrieleis et al. (2009) studied patients with a history of frequently relapsing nephrotic syndrome who had been followed in their program and were still experiencing relapses after 16 years of age into adulthood to gain a better understanding of long-term outcomes. The study group was rather small, with only 15 participating, and all patients had good renal function with normal creatinine clearance. Complications noted were primarily due to prolonged use of corticosteroids and other treatment strategies. Complications included osteoporosis, hypertension, and decreased visual acuity secondary to cataracts and myopia, as well as decreased sperm count and motility in males treated with cyclophosphamide. Kyrieleis and colleagues (2009) concluded that less toxic and more effective therapies need to be developed for this population. Toxic effects may not be apparent for several years, and longitudinal study of new and current therapies is needed.

Brief Review of the Literature On Immunoglobulin M (IgM) Nephropathy and the Use Of Rituximab

Significance of IgM In the case study presented below, the renal biopsy revealed minimal change disease with immunoglobulin M (IgM) staining. The question arises as to the significance of the IgM and a return to the debate of whether some histopathological findings are individual disorders or just spectrums of the same disorder, as well as whether the presence of IgM-positive immunofluorescence on renal biopsy (IgM+IF) is a clinically significant finding in predicting a more difficult course of the disorder. In a study that evaluated 64 children ages 2 to 14 years with history of renal biopsies that showed IgM+IF between 1985 to 1997, Zeis et al. (2001) concluded that IgM nephropathy is a distinct clinicopathological entity. The children were followed over a 1to 12-year period; 20 children had nephrotic level proteinuria (greater than or equal to 40 mg/hour per [m.sup.2]), and 44 children had non-nephrotic range proteinuria and/or microscopic hematuria (3 to 5 red blood cells per high power field). Due to the high prevalence of IgM+IF in the nonnephrotic population, the researchers saw it as distinct nephropathy. Thirteen of the children with IgM+IF had a second biopsy that showed FSGS. Nine of these children showed histology consistent with minimal change nephrotic syndrome (MCNS) on first biopsy, while 4 showed diffuse mesangial hypercellularity (DMH). The study also revealed an increased incidence of transition from MCNS to DMH to FSGS among the patients with IgM+IF.

A retrospective chart analysis study by Swartz, Eldin, Hicks, and Feig (2009) was performed on 170 children who had had a renal biopsy due to steroid-dependent or steroid-resistant nephrotic syndrome. Fifty-five of the biopsies showed minimal change disease (MCD), the hisological finding suggestive of minimal change nephrotic syndrome; 43 showed mesangial hypercellulatriy (MH); and 72 revealed focal and segmental glomerulosclerosis (FSGS). Findings of IgM+IF were noted in 44% of the MCD cases, 47% of the MH cases, and 19% of the FSGS cases. They found that children with MCD and IgM+IF had a poor response to steroids and a relatively poor response to adjuvant therapy. Prognosis was similar to that of children with FSGS, with 17% progressing to chronic kidney disease.

Myllymaki, Saha, Mustonen, Helin, and Pasternack (2003) conducted a longitudinal study of adult and pediatric patients with renal biopsy findings consistent with IgM nephropathy. Their focus was to identify factors that may predict the natural course of IGM nephropathy and incidence of FSGS. They were also looking at any characteristics that may favor the progression to FSGS. One hundred and ten biopsies obtained between October 1977 and July 1998 and evaluated at Tampere University Hospital, Tampere, Finland, met their criteria for IgM nephropathy. Indications for biopsy included nephrotic syndrome (proteinuria with 3.5g/24 hours or greater with decreased serum albumin less than 3g/dL and edema), asymptomatic proteinuria (protein excretion of greater than 0.15 g/24 hours), hematuria, or proteinuria and hematuria. Thirty-six patients were children between 1 to 15 years of age. Of these pediatric patients, 32 had nephrotic syndrome and 4 had asymptomatic proteinuria. The indication for biopsy for the other 4 pediatric patients was asymptomatic proteinuria. Seventy-four adults ranged in age from 17 to 75 years. Indication for biopsy for 18 of these patients was nephrotic syndrome with a protein excretion level of 3.5 g/24 hours or greater; for 33 patients, it was asymptomatic proteinuria defined as a protein excretion of 0.15 g/24 hours; for 18 patients, hematuria was defined as three or more erythrocytes/high-power field of urinary sediment; and 5 patients had both proteinuria and hematuria. Corticosteroids were used to treat 17 of the adults and 33 of the children diagnosed with nephrotic syndrome. Overall, more than one-half of the population in the study was steroid-dependent, and about one-third was steroid-resistant. It was concluded that response to steroids is considerably worse in IgM nephropathy than in MCD. As for progression to FSGS, only 10% of the patients in the study had a repeat renal biopsy performed, and less than half showed a histopathological picture of FSGS. All patients fell into either the nephrotic syndrome or asymptomatic proteinuria group. The authors concluded that based on their findings, two different diseases within the diagnosis of IGM nephropathy may exist.

In an attempt to gain a better understanding of incidence and history of IGM nephropathy in the population served at their center, Singhai et al. (2011) conducted a retrospective study of patients with renal biopsies diagnosed as IgM nephropathy. Patients were selected from all adolescents (aged 13 years and older) and adults with nephrotic syndrome from Western India cared for at that facility from January 2004 to September 2009. There were 117 patients who met criteria of having IgM on renal biopsy. Steroid dependency was the most common presentation followed by steroid resistance. The incidence of IgM was found to be 4.3%, which they noted was similar to previous studies in other populations. They attempted to evaluate the pathogenic role as well as the role of IgM deposits in therapeutic management, but no consensus was reached. A very high level of circulating IgM immune complexes was noted. The authors described IgM nephropathy as an ill-understood glomerulonephritis.

The Southwest Pediatric Nephrology Study Group (1985) collected data from multiple centers in the United States on children under 18 years of age with a biopsy that revealed FSGS in an attempt to gain a better understanding of the characteristics of this disorder. In contrast to the studies above, these authors noted no relationship between the presence of IGM and/or DMH in predicting a poorer prognosis or progression to renal failure. They did note, however, that the presence of DMH was less in patients with long-term disease, suggesting this is an early response in the course of the disease.

More recent studies suggest that controlling proteinuria can be a problem in the patient population with nephrotic syndrome and IgM+IF on renal biopsy. One finding fairly consistent in the research is the increased incidence of IgM in the steroid-dependent and steroid-resistant nephrotic syndrome patient population, as well as high incidence of progression to FSGS. The question still exists as to whether IgM nephropathy represents a separate disease or is just an entity in the progression from MCD to FSGS. Existence of IgM+IF in patients with non-nephrotic-level proteinuria supports the view that it represents a separate nephropathy, but more studies that look at similar populations are needed. After review of the literature, Swartz et al. (2009) noted that the significance of the presence of IgM remains controversial. Finding an answer to this question will not be easy.

Some problems in researching histopathological changes within the kidney were demonstrated in a study by Siegel et al. (1981). These authors wanted to determine the histopathologic types of lesions present in children with frequently relapsing steroid-dependent nephrotic syndrome at the time when more aggressive treatment with cyclophosphamide was initiated. They found that since the ISKDC guidelines had been published, very few biopsies were done in patients that responded to initial prednisone therapy. Their presenting histopathologic picture is unknown and is only assumed to be consistent with MCD. There may have been other pathological changes present that were not identified. In this study, renal biopsies occurred approximately six years after initial diagnosis, and only 47% of the children had minimal change histology, 24% had mesangial proliferative changes, and 29% had FSGS. If MCD was truly present at the time of initial treatment, then the theory of a progressive process warrants attention. Limitations with the biopsy itself make the study of this theory even more difficult. As pointed out earlier in the discussion on biopsy, to diagnose FSGS, only one affected glomeruli needs to be present. It is not guaranteed that the biopsy site chosen will provide a specimen that contains a true representation of the existing histophathology.

Role of Rituximab

The pathogenesis of steroid-dependent and steroid-resistant minimal change nephrotic syndrome is still not clearly understood. Clinical observations have implicated B-cell involvement and led to the fairly recent, experimental use of rituximab (Rituxan[R]) for the treatment of persistent, high-level proteinuria (Gilbert et al., 2006). The success of this approach has been noted in the literature, mostly through the presentation of case studies. Clinical research findings regarding the use of rituximab are still quite limited.

Gilbert et al. (2006) presented the case report of a female patient who was diagnosed with nephrotic syndrome at 18 months of age. She initially responded well to steroid therapy but experienced multiple relapses. At 3 years of age, a renal biopsy was done, and findings were consistent with MCNS. Between the ages of 2 to 15 years, she relapsed 37 times. During this period of time, she had been treated with various steroids and various immunosuppressants without success. Treatment with rituximab was received at 15 years of age. Response was favorable, and she went into remission. Nine months later, she relapsed, and steroid therapy was initiated. This approach was once again unsuccessful, and a second treatment of rituximab was given. She responded well. Eight weeks after treatment, she remained in remission.

Similar cases were reported by Smith (2007) and Hofstra et al. (2007). Smith (2007) presented the case study of a male patient who was diagnosed with nephrotic syndrome at 3 years of age. Renal biopsy was done due to frequent relapses during treatment with steroids, and findings were consistent with MCNS. Treatment with various immunosuppressants was unsuccessful, and he received rituximab therapy after 11 years of multiple relapses. He went into remission shortly after completion of the therapy and was still in remission 9 months after on tacrolimus and prednisolone. Hofstra et al. (2007) reported the successful use of rituximab in a 20-year-old female who was originally diagnosed with idiopathic nephrotic syndrome at 2 years of age. A renal biopsy done at 4 years of age showed MCNS. Various treatment regimens were used over the years, and she went into remission for short periods of time. At 18 years of age, her high-level proteinuria persisted while on prednisone, mycophenolate mofetil, and tacrolimus. She was treated with rituximab, and within 2 weeks, showed a significant decrease in proteinuria. She was in partial remission 4 months after treatment.
Figure 1 Case Study

The following case study demonstrates how dynamic minimal change
nephrotic syndrome (MCNS) can be. It also shows some of the
challenges the practitioner faces when trying to effectively manage
a somewhat unpredictable disorder such as this.

TC, an 11-month-old male, presented to the emergency department
with a 6-day history of increasing edema in his face, abdomen,
legs, and scrotum. Urinalysis showed a high level of proteinuria
(greater than 40 mg/[m.sup.2]/hour). Serum lab studies revealed
good kidney function with normal BUN of 18 mg/dL and creatinine of
0.4 mg/dL. His serum albumin was low at 1.8 g/dL, and cholesterol
was elevated at 389 mg/dL. Electrolytes remained normal. TC was
diagnosed with nephrotic syndrome, and he was admitted to the
hospital for medical management and family education. Medical
management included daily oral steroid therapy with prednisolone to
treat proteinuria, as well as enalapril to control mild
hypertension and proteinuria. He also received albumin and
furosemide IV for treatment of severe edema.

Initial response to the oral steroids was encouraging, and his
level of proteinuria improved. Treatment with the daily dose of
oral prednisolone and enalapril was continued after discharge. He
was in remission within 4 weeks from presentation. After completing
6 weeks of daily steroid dosing, the steroids were weaned to every
other day. Three weeks later, he was diagnosed with acute otitis
media. Urinalysis showed 1+ protein. Steroids were held at the same
weaning dose. TC's proteinuria continued to increase, and he
developed facial, extremity, scrotal, and abdominal edema. He was
placed back on corticosteroid therapy at 60 mg/[m.sup.2]/day.
Response was poor, and he was eventually admitted to the hospital
with increased abdominal distension and pain with a diagnosis of
peritonitis and pleural effusion. Urinalysis showed 4+ proteinuria
and large blood upon admission. Serum creatinine was slightly
elevated at 0.8 mg/dL with a low serum albumin of 1.5 g/dL. Since
he was no longer responding to the steroid therapy, oral tacrolimus
was added to his medication regimen, and a kidney biopsy was done
to clarify the diagnosis. The kidney biopsy findings were
consistent with MCNS and included mesangial hypercellularity with
mesangial IgM deposition. No change in treatment plan was
indicated.

After 5 to 6 months, TC was finally weaned off the prednisolone.
The tacrolimus and enalapril were continued. He remained in
remission for 6 months. When he did relapse, it took 6 to 7 months
to get him off the corticosteroid therapy. He remained in remission
and off the steroids for approximately 9 months. During this time,
the tacrolimus dose was decreased. He did quite well and showed no
signs of relapse even during febrile illnesses. When he eventually
did relapse, he was started back on the high-dose steroids.
Response was not prompt, and adjustments in his tacrolimus dose
were required to reduce his level of protein excretion. Over time,
he showed signs of becoming steroid dependent, with relapses
occurring before he was completely weaned off the prednisolone.
Eventually, he became steroid-resistant. Other medications were
added to his medication regiment, including losartan and
mycophenolate mofetil. The level of edema he was experiencing
became more difficult to manage. Recurrent admissions to the
hospital were required. His serum albumin remained quite low, and
he developed a significant pleural effusion. Despite aggressive
medical treatment, his high-level proteinuria persisted, and his
serum albumin remained at or below 0.8 g/dL. He had intermittent
mild increases in his serum creatinine, but overall, it remained
within normal limits for his age. The family was introduced to the
possible benefits as well as side effects of a course of IV
rituximab. They agreed to the treatment.

TC received a dose of rituximab once per week for 4 weeks. He was
seen n the clinic two months after his last dose, and urinalysis
showed a significant decrease in his protein excretion. The small
dose of steroid that he was on was discontinued, and he continued
on his medication regimen of tacrolimus, mycophenolate mofetil,
enalapril and losartan. Four months after the rituximab, he was in
remission, and his serum albumin was up to 1.5 g/dL.

The next challenge was decreasing the oral immunosuppressive
therapy he was on. Discussion of the need to decrease his
medication was met with some resistance by the parents. TC's
clinical course had been quite stressful for the family,
emotionally and financially. They understood that the rituximab
treatments had increased his state of immunosuppression and agreed
to a conservative weaning approach. Before changes to his
medication regimen could be implemented, TC developed persistent
watery stools along with periodic episodes of non-bilious,
non-bloody emesis. The stool was described as greasy-looking and
foul-smelling.

Serum laboratory studies were done and ruled out Epstein Barr Virus
(EBV) and Parvovirus. His signs and symptoms were suspicious for
Giardia infection, so he was started on a treatment of
metronidazole (Flagyl[R]). Clinical status improved with cessation
of emesis and decrease in watery stools. His appetite returned, and
he gained some of his weight back. Unfortunately, the improved
state of health did not last, and his symptoms returned with even
greater weight loss. TC was admitted to the hospital for a GI work
up. Test results and cultures were unremarkable. His urinalysis
remained negative for protein, and the decision was made to
discontinue the mycophenolate mofetil. Within 2 weeks, the vomiting
had stopped, the watery stools had decreased significantly in
amount and frequency, and he started to gain weight. One month
later, he remained in remission and had gained 4 kg in body weight.
He continues on a medication regimen of tacrolimus, enalapril, and
losartan.


Betjes and Roodnat (2009) presented a case report of a 26-year-old male with IgM nephropathy who was treated with rituximab and went into complete remission. This patient was diagnosed with nephrotic syndrome at 3 years of age. Due to multiple relapses, he was biopsied at 14 years of age, and a diagnosis of IgM nephropathy was made. Treatment of high-level proteinuria with cyclophosphamide and cyclosporine was unsuccessful, and he was in Stage V chronic kidney disease by 22 years of age. After two years of peritoneal dialysis, he received a living related donor kidney transplant. Within one month of transplant, he was showing hematuria and progressive proteinuria. A repeat renal biopsy revealed the recurrence of IgM nephropathy. Steroid pulse therapy was unsuccessful, and he was eventually treated with rimximab. Response was good, and he was still in remission a year after treatment.

In a multicenter study, Gulati et al. (2010) evaluated the response of patients with steroid-resistant and steroid-dependent nephrotic syndrome to treatment with rimximab. Charts were reviewed on 57 patients from three different tertiary care centers. Two centers were located in the Unites States and one in India. All patients had a history of receiving some form of immunosuppressant therapy that was ineffective at achieving/maintaining remission. They were followed for at least 12 months after receiving rituximab. The steroid-resistant group contained 3 adults and 30 children; 15 of these patients remained in remission for 12 to 48 months after infusion, and 18 had no response to treatment. In the group that achieved remission, 64.7% had minimal change disease on renal biopsy, and 31.2% had FSGS. There were 24 patients in the steroid-dependent group. All were children. At 12 months after treatment, 20 patients achieved sustained remission. After 12 to 38 months, 17 remained in remission, and a significant decline in the number of relapses per year in those without sustained remission was noted.

The use of rituximab for improving proteinuria in steroid-dependent and steroid-resistant MCNS looks promising. Some patients in these case studies suffered complications of long-term steroid use. Initiating rituximab is still one of the many unanswered questions. It does have some documented life-threatening complications, including progressive miltifocal leukoencephalopathy and acute lung injury (Gulati et al., 2010), which need to be taken into consideration before proceeding with treatment. Unfortunately, the long-term consequences of rituximab therapy in this population are not known. Controlled studies regarding its dosing, efficacy, and safety are needed.

Summary

The nephrology nurse is an essential member of the team in the management of the patient with nephrotic syndrome. It is important to have an understanding of the complexity of this diagnosis to provide the patient and family with the appropriate support. Ongoing education of the family is essential for the successful management of these children due to the key role they play in identification of symptoms and adherence to treatment plans. The family needs to understand that the treatment plan is not always well defined, and multiple changes to the plan may be made over time. The nephrology nurse is in an excellent position to detect improvements or complications early with the disease process and/or treatment regimen. Prompt changes in the plan of care can lead to enhanced patient outcomes.

There have been advances in the treatment of steroid-dependent and steroid-resistant nephrotic syndrome, yet many questions remain. Approaches to treating persistent high-level proteinuria beyond steroids still vary. Long-term consequences of drugs used to treat this population are not well understood. The case study (see Figure 1) questions the implications of a diagnosis of MCNS when histopathological findings include IgM. Does this mean that the family should expect a more complicated course with the remission of proteinuria becoming more difficult to achieve over time? What is the right time to introduce a more aggressive treatment, such as rituximab? Further research is needed to bring light to these difficult issues.

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Martha A. Richardson, RN, CPNP, is a Certified Pediatric Nurse Practitioner, Nephrology Clinic, Children's Medical Center Dallas, Dallas, TX, and a member of ANNA's Dallas Chapter. She may be contacted directly via email at marcpnp@sbcglobal.net

Author Note: The use of Rituximab to achieve reduction or elimination of proteinuria in nephrotic syndrome is off-label use and still considered experimental.

Statement of Disclosure: The author reported no actual or potential conflict of interest in relation to this continuing nursing education activity.
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Title Annotation:CNE: Continuing Nursing Education
Author:Richardson, Martha A.
Publication:Nephrology Nursing Journal
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Sep 1, 2012
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