Nephrotic syndrome

ABSTRACT

Nephrotic syndrome represents a constellation of symptoms including hyperalbuminuria, hypoalbuminemia, edema formation, hypercholesterolemia, hypertension, hypercoagulopathy, and increased infection risk. The hallmark of this syndrome is proteinuria greater than 3.5 grams per 24 hours, and the clinical features are sec ondary manifestations of an underlying primary glomerular or systemic disease. The objectives of treatment are threefold: correcting the primary disease, decreasing the symptoms and secondary effects associated with this syndrome, and preventing complications. This article presents a case report of a man diagnosed with nephrotic syndrome secondary to amyloidosis. The clinical aspects of the disease processes, the diagnostic evaluation, the treatment course, and disease management are discussed.

Proteinuria, which frequently presents in primary care, can be a sign of many complex glomerular disease states with diverse clinical presentations. When proteinuria is severe and presents with a constellation of signs and symptoms, it becomes a hallmark of nephrotic syndrome. Nephrotic syndrome is associated with either primary or secondary glomerular disease.1

The Case

J.B., a 36-year-old white man, presented to an internal medicine office as a new patient. His primary complaint was bilateral ankle edema that began several months prior to the visit. The ankle edema had a gradual onset, was present in the morning, and had worsened such that his socks felt tight.

History

J.B. was married and had two children. His 62-year-old father was in good health, except for gout. His 60-year-old mother had Type 2 diabetes mellitus. J.B. had a history of hypertension and reported that it was poorly controlled despite his compliance with previously prescribed therapy. He also had a history of hypercholesterolemia and one prior episode of gout. He was hospitalized in 1995 for pneumonia that was presumably communityacquired. A left knee arthroscopy was performed in 1990, and hand surgery was performed in 1985. J.B. was allergic to intravenous pyelogram dye.

He denied use of cigarettes, illicit drugs, prescribed opiates, or alcohol. He was currently taking 300 mg of allopurinol q.d. He was not taking any antihypertensive drugs. He denied use of over-the-counter drugs, vitamins, or herbs.

A thorough review of systems was conducted. The review was remarkable for increased nocturia (two to three episodes per night), increased thirst and fluid intake at night, and bilateral ankle edema. He denied shortness of breath; dyspnea; paroxysmal nocturnal dyspnea; cough; chest, back, and flank pain; dysuria; abdominal discomfort; recent rash; or any viral syndromes in recent months. He denied headaches, vision or hearing changes, paresthesia, extremity weakness, fatigue, fever, chills, night sweats, and joint or muscle pain.

Physical Examination

The physical examination revealed a well-developed, alert, and oriented man in no acute distress. He had a temperature of 98 deg F [36.6 deg C], a pulse of 72/minute, respirations of 16/minute, and a sitting blood pressure of 180/98 mm Hg. Except for an elevated blood pressure, the only other abnormal physical finding included 4 mm indentation pitting edema bilaterally of the feet and ankles, extending to mid-calf.

Given the patient's hypertension history, renal disease was suspected as a primary cause of the ankle edema. Differential diagnoses for bilateral lower-extremity edema are provided in Table 1. Right-sided heart failure was an unlikely cause because of the lack of subjective and objective evidence for left-sided heart failure. Other causes of rightsided heart failure were not supported in the assessment.

Although bilateral lower-extremity edema may be caused by lymphatic obstruction, compression of the inferior vena cava secondary to abdominal masses, or venous insufficiency, the subjective and objective data available did not support these as likely etiologies in the differential diagnosis. Based on these findings, a urine dipstick test was conducted during the initial visit and provided the following results: 4+ protein and 2+ occult blood with no white blood cells, bilirubin, nitrites, leukocyte esterase, or glucose.

Laboratory Values

The primary features of nephrotic syndrome were exhibited in the pabent's laboratory data. Microscopic urinalysis showed 3+ protein and 2+ occult blood and was otherwise negative. His serum creatinine was 1.9 0.7 to 1.4) mg/dl with a blood urea nitrogen (BUN) of 34 (7 to 25) mg/dl, and a BUN:creatinine ratio of 18 (10:1-20:1). Based on these findings, a 24-hour urinalysis for creatinine clearance and total protein was obtained. The results were consistent with nephrotic syndrome, revealing 18 grams of urinary protein over 24 hours (norm of 25 to 150 mg/24 hours). Increased triglycerides, decreased hemoglobin, hematocrit, serum albumin, and total protein were also observed.

Although the laboratory data confirmed a nephrotic syndrome diagnosis, the primary etiology of the renal disease remained unclear. There are several possible causes of nephrotic syndrome, each of which has a different course of action for instituting appropriate treatment. Some of the primary diseases that cause nephrotic syndrome may be ruled out with further laboratory findings. Consequently, a hepatitis profile, serum lead level, antinuclear antibodies, rapid plasma reagin, HIV antibody, and serum protein electrophoresis were obtained and were normal except for the serum protein electrophoresis. The decreased albumin and gamma globulins in conjunction with increased levels of alpha^sub 2^-globulins were also consistent with nephrotic syndrome.

Referral

At the follow-up visit, J.B. was referred to a nephrologist for further evaluation and probable renal biopsy He was placed on lisinopril to control the hypertension, decrease the protein loss in the urine, and resume renal function. J.B. was told what to expect during the nephrology evaluation, including the possibility of a kidney biopsy. He was educated on the relationship between renal disease and edema symptoms, as the edema was causing discomfort. He was given information on a lowcholesterol diet and on reducing dietary protein and sodium intake.

Following the nephrology evaluation the next week, J.B. was scheduled for a renal biopsy. The biopsy report was consistent with amyloidosis.

Treatment

After learning of his diagnosis and the absence of effective treatment, J.B.'s nephrologist recommended that he contact the Amyloid Treatment and Research Program to learn more about participating in a clinical trial. Within weeks, J.B. was accepted into a trial and received two cycles of oral melphalan (an antineo plastic drug) and prednisone over a 3-month period. Following the 3-month period, his peripheral blood stem cells were stimulated with granulocyte-colony-stimulating factor, harvested, and stored for future transplant. Two high doses of intravenous melphalan were given over 2 days, and he underwent an autologous stem-cell transplant. He was discharged 15 days after the transplant.

On returning home, J.B.'s followup care was provided by a nurse practitioner and internist. The amyloid program was given regular reports on his progress. J.B.'s hypertension, hypercholesterolemia, platelet count, and serum creatinine and liver enzymes were monitored.

At his first follow-up visit, J.B. was concerned about the time period necessary before an evaluation of his disease could be provided. The evaluation and prognosis could be given after repeat biopsies after 3 months and 1 year. The only adverse symptoms J.B. exhibited were occasional insomnia and morning nausea.

His blood pressure remained approximately 138/88 mm Hg on 5 mg of lisinopril q.d., and this was further increased to 10 mg; his ankle edema was marginally improved to 2 mm indentation with the addition of 20 mg of furosemide every morning as needed; and his insomnia and morning nausea were relieved with 1 mg lorazepam before bedtime as needed. He had hepatomegaly at 4 cm below the costal margin, with the liver border slightly tender to palpation after the transplant; there was no accompanying splenomegaly. His simvastatin was temporarily discontinued because of hepatotoxicity concerns. His platelets, blood pressure, hepatomegaly, ankle edema, and other laboratory indices remained relatively unchanged throughout the first 3 months following the transplant.

Follow-Up

J.B. returned to the amyloid program 3 months after the transplant for a follow-up visit. His serum creatinine was 1.9, and his first 24-hour urine continued to show excessive amounts of total protein at 13.5 grams/ 24 hours. Amyloid deposits remained extensive in the marrow space on bone marrow biopsy 3-months posttransplant, although there was a normal number of plasma cells with no abnormal staining and normal light chain proteins. J.B. was considered to be in complete remission of his plasma cell dyscrasia. He continued to exhibit nephrotic syndrome, as prior amyloid deposits affected his kidney function. His alkaline phosphatase returned to normal levels, the hepatomegaly improved, and he was restarted on simvastatin. His immune function continued to be compromised between 3 and 12 months posttransplant; he experienced several episodes of bronchitis and one episode of herpes zoster.

He returned to the amyloid program on his 1-year transplant anniversary date for repeat evaluation. At that time, his 24-hour urinary protein was 5.2 grams/24 hours and serum creatinine was 2.6 mg/dl, which has remained stable.

J.B. is coping with his disease process and his questionable prognosis and has resumed working full-time, exercising, and sleeping normally. His nephrotic syndrome symptoms, hypertension, and further amyloid complications are monitored by physical examination and laboratory diagnostics. He remains on his current pharmacologic therapy. His progress is communicated to the Amyloid Treatment and Research Program, and specialists are consulted when necessary. Given the uncertain effectiveness of the treatment, J.B. will be monitored for signs and symptoms of clinical depression.

Laboratory Assessments for Proteinuria

The urine dipstick test is the most convenient and economical method for detecting protein in the urine. Although urine dipstick tests are relatively sensitive and able to detect 20 mg to 30 mg of protein/dl, falsepositives may occur if the urine is alkaline (pH greater than 7.5). Falsenegative results may be obtained if globulins other than albumin are present or if the urine is concentrated.2 When proteinuria is accompanied by symptoms suggestive of glomerular disease, or when it is excessive, persistent, or recurrent, microscopic analysis should be performed.

In addition to a serum creatinine, a 24-hour urine specimen should be collected to measure creatinine clearance and 24-hour protein excretion because proteinuria can affect renal filtration and function reflected by the creatinine clearance. The amount of proteinuria over 24 hours aids in differentiating the primary disease process.

Urinary protein excretion greater than 200 mg and less than 3.5 grams in a 24-hour urine sample is classified as nonnephrotic. Values greater than or equal to 3.5 grams are classified as being within nephrotic range. Values falling within the nephrotic range are indicative of glomerular disease.

Nephrotic Syndrome Clinical Manifestations

The hallmark of nephrotic syndrome is severe proteinuria: proteinuria that is greater than or equal to 3.5 grams per 24 hours. Other clinical features of nephrotic syndrome include edema, hypoproteinemia (particularly hypoalbuminemia), hypercholesterolemia, hyperlipidemia, and lipiduria.1 Defects in the glomerular capillary wall that lead to nephrotic syndrome can occur from a variety of disease processes, including immunologic disorders, toxic injuries, vascular disorders, biochemical defects, and metabolic abnormalities. The physiologic changes that manifest as nephrotic syndrome may be either primary or secondary to other diseases. A list of the range of disorders that may cause nephrotic syndrome is presented in Table 2.

The cause of edema with nephrotic syndrome is most frequently primary renal sodium retention. When plasma albumin concentration falls below 2.0 grams/dl, a decreased plasma oncotic pressure and subsequent translocation of water out of the intravascular space into the interstitial tissues may be causing the edema.3 More recent studies suggest that the edema formation is the result of several mechanisms that promote primary renal sodium retention.4,5 The exception occurs when serum albumin levels fall below 2.0 grams/dl. At this point, changes in oncotic pressure are primarily responsible.6

The underlying pathogenesis of elevated triglyceride levels often present in nephrotic patients with concomitantly reduced renal function is not well defined but is believed to be a consequence of increased hepatic lipoprotein synthesis.7 Reduced oncotic pressure associated with urinary loss of protein stimulates hepatic production of lipoproteins.8-10 In the majority of patients, low-density lipoproteins and cholesterol are increased, whereas lowdensity lipoproteins and triglycerides tend to rise in patients with severe disease. The severity of hypercholesterolemia tends to be inversely related to the degree of hypoalbuminemia and oncotic pressure.11

Hypercoagulability is another metabolic complication of nephrotic syndrome. As a result, spontaneous peripheral arterial or venous thrombosis, renal vein thrombosis, and pulmonary embolism may develop. Although this is rare, the associated morbidity is significant.12 The incidence of thromboembolic events has been variable, ranging from 6% to 44%.(13,14) In patients with nephrotic syndrome caused by membranous glomerulopathy, membranoproliferative glomerulonephritis, and amyloidosis, renal vein thrombosis is common, occurring in up to 40% of cases.3

Other metabolic abnormalities associated with nephrotic syndrome include hypocalcemia, protein malnutrition, iron-resistant microcytic hypochromic anemia (secondary to the loss of transferrin), depressed thyroxine levels, and increased infection susceptibility. Mortality rates from infection as high as 40% have been reported in children.3 The physiologic changes in nephrotic syndrome associated with an increased risk of infection include lower plasma levels of IgG, a reduced antibody response to antigens, a reduction in phagocytosis capability, and a reduced total number of T cells.3,15 Because of the urinary loss of protein, the pharmacokinetics of agents normally bound to plasma proteins may be altered.13

Nephrotic Syndrome Treatment Strategies

Nephrotic syndrome treatment is threefold: treating the underlying disease, treating the symptoms, and implementing interventions to reduce the risk of secondary complications (see Table 3). The essential step to treatment is first confirming the cause of nephrotic syndrome histologically. Treatment decisions are then based on the specific form of glomerular disease. For symptomatic treatment, most nephrotic syndrome patients (for example, those with serum albumin greater than or equal to 2 grams/dl), plasma volume is maintained and the edema is safely treated with diuretics.3 In patients with reduced plasma volume (for example, those with serum albumin less than 2 grams/dl), treatment with diuretics may precipitate acute renal failure and contribute to the development of arterial or venous thromboses.16 If reversal of nephrotic syndrome is possible, the hypercholesterolemia as a secondary complication generally resolves, and treatment is aimed at the primary disease. However, there is evidence that hyperlipidemia accelerates loss of renal function.17 Therefore, in addition to the concerns of hastened atherosclerosis, patients with unremitting nephrotic syndrome should be considered for hypercholesterolemia treatment. Although fibric acid drugs have been associated with serious adverse effects in nephrotic syndrome patients,18 HMG CoA reductase inhibitors have not shown the same deleterious effects and are the most widely used drugs in the treatment of hypercholesterolemia secondary to nephrotic syndrome. 19 Educating patients on the advantages of a low-cholesterol diet may also be beneficial.

Because of the variable absorption of warfarin in nephrotic patients and the frequent monitoring required for subcutaneous heparin therapy, preventing thromboembolic events with pharmacologic therapy is difficult. A preliminary study of low molecularweight heparin in severe nephrosis is promising, but additional studies are needed.20 Angiotensinconverting enzyme (ACE) inhibitors and high-dose nonsteriodal anti-inflammatory drugs (NSAIDs) may be required to reduce the glomerular capillary pressure and decrease urinary protein losses. ACE inhibitors and nondihydropyridine calcium channel blockers may be used in combination to decrease protein loss and preserve renal function. ACE inhibitors and calcium channel blockers may also be required to treat hypertension. Instituting the majority of these treatments requires consultation with a nephrologist, although monitoring may be performed by primary care providers collaborating with specialists.

Amyloidosis

Amyloidosis represents a heterogeneous group of disorders characterized by protein metabolism dysfunction and the extracellular deposition of insoluble, fibrous amyloid proteins frequently in the organs and tissues. Depending on the amyloid type, fibrils may be deposited locally or systemically. Amyloidosis has an estimated incidence of 8 in every 1 million people, and represents approximately 2.8% of the disorders determined by renal biopsy.21 Given its insidious onset, the diagnosis is usually not made until the disease is advanced.

Multiple amyloid forms with different clinical features and biochemical compositions exist, although all the forms assume a common secondary structure: fibrillar morphologies that render them resistant to proteolysis. The biochemical structure of the fibril-forming protein amyloids determines the classification. Systemic amyloidosis is neoplastic, inflammatory, genetic, or iatrogenic in origin, whereas localized or organ-limited amyloidosis occurs in isolated organs and is associated with diabetes and aging.22 Predominantly, the two types of amyloid that affect the kidney and cause nephrotic syndrome are light chain amyloid (AL) and amyloid A protein amyloid (AA).1 J.B. was afflicted with AL amyloid.

AL amyloid is the most common form and is also known as primary idiopathic amyloidosis. It is associated with multiple myeloma, as the formation of fibrils in AL also arise from monoclonal antibody light chains. Only 20% of patients with AL amyloid have multiple myeloma, as the light chains' composition dif fers. Once deposited, the beta-pleated sheet fibrils formed by the monoclonal light chain proteins are resistant to degradation and removal. The fibrils accumulate, and this results in progressive impairment of organ function.23

Although individuals with AL amyloid have survived for 21 years or more,24 the mean survival is approximately 12 months.22 Approximately 20% of patients with AL amyloid survive for 5 years following diagnosis.21 The course of amyloidosis is difficult to discern because the actual onset of the disease is unknown in the majority of cases. However, certain AL amyloid clinical features are fairly useful in assessing prognosis. Researchers found that patients with amyloid neuropathy as the sole manifestation of their disease had the best outcomes (S-year survival of 32%),21 while other research found that the presence of heart failure or orthostatic hypotension was associated with a median survival of less than 1 year.23

Patients with an increase in their serum creatinine level have median survival rates of approximately 15 months.21 The amount of total protein in the 24-hour urine has not been found to impact survival.25

AL Amyloidosis Treatment

Current therapy for AL amyloidosis is directed at inhibiting the production and deposition of amyloid fibrils and promoting lysis or mobilization of existing amyloid deposits. Presently, completely effective AL amyloidosis treatment does not exist; however, clinical trials are underway to determine the superior course of therapy for treating this amyloid form.

A recent trial of 100 AL amyloid patients found that those given a combination of melphalan, prednisone, and colchicine had improved survival rates (12.2 months) over those treated with colchicine alone (6.7 months).26 Survival rates for those with cardiac involvement were worse than for those with renal involvement only; those with renal involvement had the longest survival rates.26

Autologous stem-cell transplantation is being tested in AL amyloid because of its effectiveness in multiple myeloma treatment and the similar origins of these two diseases. This appears to be the most promising therapy to date, as there are initial reports of improved amyloid-affected organ function and a 68% survival rate at a median of 24 months in 25 patients.27 Both of these clinical trials were conducted at the Amyloid Treatment and Research Program at Boston University School of Medicine. Other current clinical trials for AL amyloid include the evaluation of DOXIL, vincristine, and decadron at the Cleveland Clinic.

AL Amyloidosis in Practice

Clinical trials are ongoing to identify more effective AL amyloid treatments. The research may require primary care providers to work collaboratively with clinical trial researchers. Prompt recognition and referral for a definitive diagnosis and treatment, physical and psychological monitoring, and education are all necessary in ensuring optimal patient outcomes.

ACKNOWLEDGMENT

The authors thank Kathy Finn, ARNP MSN, of the Boston University School of Medicine Amyloid Program for her contributions to this article.

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Cheryl Cummings Stegbauer, CFNP, PhD, editor of this column, is an Associate Professor at the University of Tennessee, Memphis.

ABOUT THE AUTHORS

Shawn Kneipp, ARNP, PhD, is assistant professor, University of Florida College of Nursing in Gainesville and practices at Eastside Community Practice.

Stuart B. Himmelstein, MD, is in private practice at Quality Medical Association, Delray Beach, Fla.

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