BY ANDRZEJ KIELTYKA, PA; PARDEEP THANDI, MD; & ANUMEHA SINGH, MD
A 56-year-old man presented to the emergency department with shortness of breath for one month and pleural effusions on an outpatient chest x-ray. He had been taking adalimumab, methotrexate, and steroids for arthritis and Sjogren's syndrome.
A right pleural effusion in a patient with nephrotic syndrome.
His monoclonal gammopathy of undetermined significance (MGUS) was monitored annually, but no medical intervention beyond surveillance was required. He had excessive thirst but normal urine output. He noted face and hand swelling in the morning that gave way to more significant pedal edema at the end of the day and progressively worsening exertional dyspnea. He noted a low grade fever and loss of appetite. His initial vitals were a blood pressure of 185/96 mm Hg, a heart rate of 106 bpm, a respiratory rate of 20 bpm, a temperature of 100.1°F, and oxygen saturation of 97% on room air.
The patient appeared well, but would not stop sipping water despite obvious myxedema. He also had a history of autoimmune and oncological conditions.
The differential for this case included an infectious process such as viral or bacterial infiltrate. Lung mass or atypical presentation of myeloma with the patient's history of MGUS was also on the differential, but cardiorenal disease, nephrotic disease, and congestive heart failure were higher on the list. Other etiologies were considered, including thyroid disease, syndrome of inappropriate antidiuretic hormone secretion, autoimmune activation of rheumatoid arthritis, and vasculitis.
This patient had abnormalities in almost all labs drawn, but some key findings pointed to cardiorenal syndrome: anemia and thrombocytopenia per H/H of 9/29 with ovalocytes, platelets at 29, and WBC of 12.1 with shift. Inflammation markers were high: CRP 23, ESR 45; cardiac markers troponin I <0.30 and CK of 62 were normal, but pro-BNP, N-terminal was 12,000. The chemistries were largely normal with significant creatinine of 1.1 and BUN 25.
The crucial labs were the serum protein of 5.1, albumin of 2.8, globulin 2.3, and prealbumin 20. The urine analysis was significant for random protein of 289 with protein to creatinine at 2513. The patient was admitted to the medicine service with cardiology and nephrology consulting. Without the inflammatory markers and urinalysis, this may have been congestive heart failure, but the patient's complicated history demanded a more careful look.
Acute or exacerbation of chronic CHF is frequently managed in the ED. The disruption of fluid volume control often results from overlapping renal and cardiac etiologies. Some would argue that CHF is as much a symptom as a diagnosis, and the renal part of the balance should not be ignored. The patient was worked up for cardiorenal syndrome by cardiology, nephrology, rheumatology, and hematology.
Progress and Prognosis
The relationship of the cardiac and renal systems is particularly evident when homeostasis is disrupted. Cardiorenal syndrome was classified in 2008 by the consensus conference of the Acute Dialysis Quality Initiative into two main stems: cardiac and renal. (http://www.adqi.org.) The incidence of each of the five types varies, but type 3 is the most common, noted in up to 70 percent of ICU patients. Renal disease is one of the highest risks of an adverse cardiovascular disease, and the reverse pathway is also noted.
The prognosis and progression of nephrotic syndrome vary greatly depending on whether the syndrome is primary or secondary and the nature of the underlying pathology leading to it. Infants with congenital nephrotic syndrome have a dismal prognosis; most cases require dialysis and then kidney transplant within a few months.
In cases of focal glomerulosclerosis, many patients experience frequent relapses and become dependent on or resistant to steroids. End-stage renal disease develops in 60-70 percent of the cases by 10 years, and about half of the cases require dialysis by five years. (http://bit.ly/2EW5ynx.) The prognosis worsens for patients with proteinuria.
The prognosis for patients with minimal change nephropathy is good, with about 30 percent of children never relapsing and only three percent becoming steroid-resistant. Most respond well to steroid therapy. About 50 percent of children have one or two relapses within five years. Adults with minimal change nephropathy have a relapse rate similar to that of children. (http://bit.ly/2EW5ynx.) The long-term prognosis is excellent, however, with rare renal failure. Idiopathic membranous nephropathy has an excellent prognosis with complications and incidents of renal failure occurring rarely. Poor patient response to steroid therapy may predict a poor outcome. Presence of hematuria and hypertension are also predictors of a poor prognosis.
Infection was a major factor in the mortality rate among patients with nephrotic syndrome in the pre-antibiotic era. Early recognition and aggressive treatment have reduced the mortality and morbidity of the disease, especially in secondary nephrotic syndrome where the prognosis depends on the underlying pathology and adequate management.
One study found that routine treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, plus selective use of corticosteroids or other immunosuppressants, led to a remission rate of 76 percent, with 12 percent of patients requiring hemodialysis. (Nephrol Dial Transplant 2012;27:235.)
The approach to nephrotic syndrome is highly varied, and relies on the guidelines issued in 2012 by the Pathology Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference. (http://bit.ly/2EUBcSu.) These recommend restricting dietary sodium and having adequate caloric intake and protein (1 g/kg/day). Supplemental dietary protein has no proven value. A diet with no added salt will help limit fluid overload, but fluid restriction is not needed. Physical activity is recommended for patients with nephrotic syndrome to reduce the risk of blood clots.
Treating the underlying pathology depends on whether the systemic pathology gives rise to a nephrotic syndrome such as lupus, diabetes, and infection. ACE inhibitors and angiotensin-receptor blockers are frequently started in patients with nephrotic syndrome because of their anti-proteinuria action, but studies have failed to demonstrate any evidence showing benefit.
A Cochrane review showed that combining an alkylating agent with a corticosteroid has short- and long-term benefits for membranous nephropathy. (Cochrane Database Syst Rev 2014 Oct 16;:CD004293.) Immunosuppressive therapy is not needed for most adults with idiopathic nephrotic syndrome. Other immunosuppressive treatments should be considered if the patient is steroid-resistant.
Immunosuppressive therapy for nephrotic syndrome secondary to systemic lupus erythematosus is highly effective and supported by multiple studies. It may lead to partial or complete remission in patients with minimal change disease or primary focal segmental glomerulosclerosis. Secondary amyloidosis with nephrotic syndrome should improve with anti-inflammatory treatment of the primary disease.
Treating fluid retention and edema with diuretics is indicated for symptomatic management. These patients are usually resistant to diuretics and may require a higher dose. Sometimes preloading with 20% human albumin helps. Assisted mechanical ventilation might be required in patients presenting with CHF.
Despite the known risk of venous thrombosis in patients with nephrotic syndrome, no randomized controlled trials guide whether prophylactic anticoagulation should be used or for how long. Prophylaxis can be considered in severe disease and for known pre-existing risk factors for thrombosis.
Infection has been reported in up to 20 percent of adults with nephrotic syndrome. A Cochrane review found no strong evidence to recommend a specific intervention to prevent infection in adults. (Cochrane Database Syst Rev2012 Apr 18;: CD003964.) No clear review or study has shown any benefit from routine use of anti-lipid agents.
Treatment and Outcome
The KDIGO guidelines recommend using primarily alkylating agents (cyclophosphamide) in combination with corticosteroids for six months if the criteria for immunosuppressive therapy are met. Alternatively, calcineurin inhibitors and corticosteroids are recommended for six months.
Corticosteroids are recommended to induce remissions in minimal change disease (MCD). The guidelines also suggest alkylating agents (oral cyclophosphamide 2-2.5 mg/kg/day for eight weeks) in cases of frequent relapses and steroid resistance. Corticosteroids are also recommended for focal segmental glomerulosclerosis. Calcineurin inhibitors can be considered if corticosteroid therapy is contraindicated.
Cardiology, hematology/oncology, infectious disease, nephrology, pulmonary, and rheumatology were consulted. A TEE showed cardiomyopathy. Our patient was admitted for seven days and discharged with primary diagnoses of nephrotic syndrome, MGUS, cardiomyopathy, and essential hypertension. He was discharged on carvedilol, alendronate, furosemide, and spironolactone with nephrology follow-up. (The patient was allergic to lisinopril.)
Final recommendations from rheumatology were pending a bone marrow biopsy. He was not a candidate for anti-TNF agents or methotrexate. Prednisone was recommended, but the patient was against it, and it was held off until biopsy to prevent any influence on the read.
Nephrology said the patient's condition was likely multifactorial. The etiology of his symptoms remained unclear, but preliminary workup was notable for reduced cardiac output (EF 35%), bilateral pulmonary nodules of unclear chronicity of unclear etiology (infectious, inflammatory, or malignant; origin unclear), and nephrotic range proteinuria (2.5 g) with associated hematuria. An underlying glomerulonephritis was a consideration given his history of autoimmune disease. Venous congestion and poor forward flow were other considerations given his low cardiac output.
ID was consulted for an initial fever of 100.9°F in the hospital. Ceftriaxone was initiated and then discontinued during his hospital stay because cultures and sources were negative. The patient was discharged in stable condition after seven days.
Unfortunately, the patient returned a week later complaining of worsening pedal edema and increasing shortness of breath. The patient was diagnosed with symptomatic anemia and AKI. He was readmitted, and his second course was complicated by nosocomial pneumonia.
The patient was switched to torsemide, and cardiology started him on aspirin and a statin. Vancomycin was initiated for MRSA pneumonia, and high-dose methylprednisolone was initiated by rheumatology. The patient received two units of packed red blood cells for symptomatic anemia, and was started on iron and folate supplements. His symptoms gradually improved after an 18-day admission. He was discharged on torsemide, prednisone, a statin, and vancomycin along with his previous medications.
Mr. Kieltyka is an emergency medicine physician assistant and a graduate of Drexel University's physician assistant program in Philadelphia. Dr. Thandi is an emergency physician and simulation fellow at Hartford (CT) Hospital. Dr. Singh is an assistant professor of emergency medicine at the University of Connecticut and an emergency physician at Hartford Hospital. She and her emergency physician-husband, Daksh Rampal, MD, also own Priority Urgent Care in Ellington, CT.