Nephrotic Syndrome and Diabetic Nephropathy Case File

Nephrotic Syndrome and Diabetic Nephropathy Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 29

A 58-year-old woman presents to your office complaining of persistent swelling of her feet and ankles. She first noted mild ankle swelling approximately 2 to 3 months ago. Now, she cannot put on her shoes. She borrowed a few diuretic pills from a friend and they seemed to help, but she has run out. She also reports that she gained 20 to 25 lb over the last few months, despite regular exercise and trying to adhere to a healthy diet. Her medical history is significant for a 27-year history of type 2 diabetes mellitus, for which she takes a sulfonylurea agent. However, she neither sees a doctor regularly nor monitors her blood glucose at home. She denies dysuria, increased urinary frequency, or urgency. She does report that her urine appears foamy. She denies recent fevers, joint pain, skin rashes, or gastrointestinal symptoms.

Her physical examination is significant for mild periorbital edema and pitting edema of her hands, feet, and legs. Her lungs are clear, heart rhythm is regular without murmurs, and abdominal examination is benign. She has diminished sensation to light touch in her feet and legs to midcalf. Fundoscopic examination shows multiple hard exudates with dot hemorrhages. A urine dipstick performed in the office shows 2+ glucose, 3+ protein, and negative leukocyte esterase, nitrates, and blood.

▶ What is the most likely diagnosis?

▶ What is the strongest risk factor for this condition?

▶ What might have prevented this condition?

▶ What is the best intervention to slow disease progression?

ANSWERS TO CASE 29:

Nephrotic Syndrome and Diabetic Nephropathy

Summary: A 58-year-old woman presents with

• A history of long-standing, uncontrolled type 2 diabetes mellitus
• Diabetic retinopathy and peripheral neuropathy
• Edema and significant proteinuria
• No other findings suggestive of other systemic disease

Most likely diagnosis: Nephrotic syndrome as a consequence of diabetic nephropathy.

Strongest risk factor: Long-standing diabetes without tight glycemic control.

Possible prevention: Regular visits with her primary care provider and better glycemic control with regular hemoglobin A1C measurements.

Best intervention to slow disease progression: Angiotensin inhibition with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).

ANALYSIS

Objectives

1. Recognize the clinical features and complications of nephrotic syndrome. (EPA 1, 10)
2. List the most common causes of nephrotic syndrome. (EPA 2, 3)
3. Understand the natural history of diabetic renal disease and how to diagnose and manage it. (EPA 1, 4)
4. Discuss the principles of treatment of nephrotic syndrome. (EPA 4, 12)

Considerations

Patients develop significant proteinuria as a result of glomerular damage, which can result from many systemic diseases. It is important to screen for diseases such as human immunodeficiency virus (HIV), viral hepatitis, autoimmune diseases, and malignancy by history. Physical examination and laboratory investigation can usually determine the underlying cause of the renal manifestations, but sometimes kidney biopsy is required.

APPROACH TO:

Nephrotic Syndrome

DEFINITIONS

NEPHROTIC SYNDROME: Urine protein excretion greater than 3.5 g over 24 hours, serum hypoalbuminemia (< 3 g/dL), hyperlipidemia, and edema.

CLINICAL APPROACH

Pathophysiology

Normally, the kidneys do not excrete appreciable amounts of protein (< 150 mg/d) because serum proteins are excluded from the urine by the glomerular membrane filter due to both their large size and their net negative charge. Thus, significant proteinuria suggests glomerular disease with disruption of its normal barrier function. Proteinuria in excess of 3 to 3.5 g of protein per day is considered to be in the nephrotic range. The key feature of nephrotic syndrome is the heavy proteinuria, which leads to loss of albumin and other serum proteins. The hypoalbuminemia and decreased intravascular oncotic pressure lead to renal sodium and fluid retention. This results in tissue edema, which usually starts in dependent areas, such as the feet, but may involve the face, the hands, and ultimately the whole body (anasarca). Both increased synthesis and decreased clearance of lipoproteins may lead to hyperlipidemia.

Clinical Presentation

Patients typically present complaining of the edema and have the laboratory features described previously. Urinalysis usually shows few or no cellular elements (bland sediment) and may show waxy casts or oval fat bodies (which look similar to Maltese crosses under polarized light) if hyperlipidemia is present.

One-third of adult patients with nephrotic syndrome have a systemic disease that involves the kidneys, such as diabetes mellitus or systemic lupus erythematosus (SLE). The rest have a primary renal disease, with one of four pathologic lesions: minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, or membranoproliferative glomerulonephritis. Thus, a new diagnosis of nephrotic syndrome warrants further investigation into an underlying systemic disease. Common tests include serum glucose and glycosylated hemoglobin levels to evaluate for diabetes, antinuclear antibody to screen for SLE, serum and urine protein electrophoresis to look for multiple myeloma or amyloidosis, and viral serologies because HIV and hepatitis B or C can cause nephrosis. Less common causes include various cancers, medications such as nonsteroidal anti-inflammatory drugs, heavy metals such as mercury, and hereditary renal conditions. The most common cause of nephrotic syndrome is diabetes mellitus.

Adults with nephrotic syndrome usually undergo renal biopsy, especially if the underlying diagnosis is unclear or if there is a possibility of a treatable or reversible condition. Patients with advanced diabetes who have heavy proteinuria and evidence of microvascular disease, such as retinopathy, and no active cellular components in their urinary sediment are generally presumed to have diabetic nephropathy. These patients typically do not undergo renal biopsy because the nephrotic proteinuria represents irreversible glomerular damage.

Treatment

Treatment is as follows: (1) treat the underlying disease, (2) if present, manage the edema and hypertension, and (3) limit the progression of the renal disease. For edema, all patients require strict salt restriction, but most patients will also need diuretics. Thiazide and loop diuretics are highly protein bound. Thus, in cases of nephrotic syndrome with very low serum protein levels, there is reduced delivery of these diuretics to the kidney, often creating the need for very large doses to manage the edema. Dietary protein restriction is usually recommended for patients with moderate proteinuria and chronic kidney disease and is thought to protect against the progression of glomerular scarring.

Tight glycemic control with a goal hemoglobin A1C less than 7% has been shown to slow or prevent the progression of renal disease in patients with microalbuminuria. Once macroalbuminuria has developed, however, it is not clear whether improved glycemic control affects the course of renal disease. In addition, as renal function declines, insulin requirements typically fall, and some oral medications, such as sulfonylureas and metformin, can be dangerous in advanced renal insufficiency.

Strict blood pressure control with a goal less than 130/80 mm Hg in all patients with diabetes is essential to slow progression, as recommended by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Angiotensin inhibition, with either an ACE inhibitor or ARB, has been shown to reduce the progression of renal disease independent of blood pressure control by reducing intraglomerular filtration and proteinuria. If additional blood pressure control is needed, nondihydropyridine calcium channel blockers, beta-blockers, or diuretics may be added.

In addition, because cardiovascular disease is the major cause of death of diabetics, aggressive risk factor reduction should be attempted, including smoking cessation and reduction of hypercholesterolemia. Patients with diabetes are regarded as the highest risk category and should be treated with diet and statin agents. Previously, expert guidelines advised a goal of low-density lipoprotein (LDL) cholesterol less than 100 mg/dL. Currently, there is debate about the use of discrete goals versus the initiation of moderate- or high-intensity statin agents for those without cardiovascular disease based on cardiovascular risk (calculator: http://tools.acc

.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/). In general, diabetics aged 40 and above should receive a statin agent because of the strong evidence of cardiovascular primary prevention. If diabetic patients are known to have atherosclerotic coronary disease, they should achieve an LDL goal of less than 70 mg/dL.

Complications

Patients with nephrotic syndrome have consequences of renal protein wasting other than edema. They have decreased levels of antithrombin III and proteins C and S and are often hypercoagulable. This can lead to venous thromboembolism, including renal vein thrombosis characterized by sudden flank pain, hematuria, and increased proteinuria. Patients with evidence of thrombus formation require anticoagulation, often for life. Other complications include hypogammaglobulinemia with increased infection risk (especially pneumococcal infection), iron deficiency anemia caused by hypotransferrinemia, and vitamin D deficiency because of loss of vitamin D–binding protein.

During the progression of diabetic nephropathy, the glomerular filtration rate (GFR) initially increases and then declines over time. The earliest stages of diabetic nephropathy can be detected as microalbuminuria. This is defined as urine albumin excretion between 30 and 300 mg/d. It is possible to measure this in a random urine sample rather than a timed collection because a ratio of albumin (in milligrams) to creatinine (in grams) of 30 to 300 usually correlates with the total excretion described. When albuminuria exceeds 300 mg/d, it is detectable on ordinary urine dipsticks (macroalbuminuria), and the patient is said to have overt nephropathy.

After the development of microalbuminuria, most patients will remain asymptomatic. However, the glomerulopathy will continue to progress over the subsequent 5 to 10 years until overt nephropathy develops. At this point, many patients have some edema, and nearly all patients have developed hypertension. The presence of hypertension will markedly accelerate the decline of renal function. If left untreated, patients progress to end-stage renal disease (ESRD), usually requiring dialysis or transplant within a 5- to 15-year period.

The development of nephropathy and proteinuria is significant because they are associated with a much higher risk for cardiovascular disease, which is the leading cause of death in patients with diabetes. By the time patients with diabetes develop ESRD and require dialysis, the average life expectancy is shorter than 2 years.

CASE CORRELATION

• See also Case 28 (Acute Glomerulonephritis) and Case 30 (Acute Kidney Injury).

COMPREHENSION QUESTIONS

29.1 A 49-year-old woman with type 2 diabetes presents to your office for new-onset swelling in her legs and face. She has no other medical problems. However, she says that she was told the diabetes had started to affect her eyes at her last ophthalmologic appointment. She takes glyburide daily for her diabetes. Physical examination shows a blood pressure of 140/82 mm Hg. The rest of the examination is normal except for hard exudates and dot hemorrhages on fundoscopic examination and diminished sensation up to the midshin bilaterally. Urine analysis shows 2+ protein and 2+ glucose (otherwise negative). Which of the following is the best treatment for this patient?

A. Have the patient return in 6 weeks and check a repeat urine analysis at that time.

B. Start metoprolol.

C. Change the glyburide to glipizide and have the patient return for

follow-up in 6 weeks.

D. Start lisinopril.

E. Refer the patient to a cardiologist.

29.2 A 19-year-old man was seen at the university student health clinic a week ago complaining of pharyngitis and now returns because he has noted discoloration of his urine. He is noted to have elevated blood pressure (178/110 mm Hg), and urinalysis reveals red blood cell (RBC) casts, dysmorphic RBCs, and 1+ proteinuria. Which of the following is the most likely diagnosis?

A. Systemic lupus erythematosus

B. Amyloidosis

C. Postinfectious glomerulonephritis

D. HIV nephropathy

E. Diabetic nephropathy

29.3 Which of the following is the best screening test for early diabetic nephropathy?

A. Urine microalbuminuria

B. Dipstick urinalysis

C. Renal biopsy

D. Fasting blood glucose

E. Twenty-four hour urine collection for creatinine clearance

29.4 A 58-year-old Caucasian man with type 2 diabetes that is controlled with metformin is being seen in the office for follow-up. He has no known cardiac disease and denies chest pain. He has never smoked and is currently not taking aspirin. On examination, his blood pressure is 110/70 mm Hg. The remainder of the physical examination is unremarkable. Laboratory findings include a hemoglobin A1C level of 6%, baseline creatinine of 1.4 mg/dL, and a fasting lipid profile of triglycerides 205 mg/dL, total cholesterol 220 mg/dL, high-density lipoprotein 35 mg/dL, and LDL 148 mg/dL. What is the most appropriate treatment?

A. Niacin

B. Low-protein diet

C. Gemfibrozil

D. Simvastatin

ANSWERS

29.1 D. The most significant finding in this patient is the presence of proteinuria, which is a foreboding sign of diabetic nephropathy. Starting an ACE inhibitor to decrease proteinuria is the best choice for initial treatment for this patient. Changing from one sulfonylurea to another (answer C) is of no benefit because all of the agents are essentially equally efficacious. There is no indication for referral to a cardiologist (answer E) based on the information provided in the vignette. Returning for another urinalysis in 6 weeks (answer A) is not prudent since there is already evidence of significant proteinuria. Metoprolol (answer B) will not help with the proteinuria and can also mask the symptoms of hypoglycemia.

29.2 C. This patient has hypertension and urinary sediment consistent with a nephritic rather than nephrotic syndrome (RBC casts, mild degree of proteinuria). Given his recent episode of pharyngitis, the most likely cause would be postinfectious, probably due to streptococcal infection. SLE (answer A) can produce a variety of renal diseases with both nephritic and nephrotic manifestations. However, SLE would be unlikely in a male patient, especially without other clinical manifestations of lupus, such as arthritis. Amyloidosis (answer B), diabetes (answer E), and HIV (answer D) all cause renal disease, but they more commonly cause nephrotic syndrome.

29.3 A. Although a 24-hour urine collection for creatinine (answer E) may be useful in assessing declining GFR, it is not the best screening test for the diagnosis of early diabetic nephropathy. In the outpatient setting, a dipstick urinalysis (answer B) is readily available but will detect only patients with overt nephropathy (proteinuria > 300 mg/d). Thus, a random urinary albumin/creatinine ratio of 30/300 is the best test to screen for early diabetic nephropathy. A fasting blood glucose (answer D) may aid in the diagnosis of diabetes but not nephropathy. Finally, although most patients with nephrotic syndrome require a renal biopsy (answer C) for diagnosis, a patient with worsening renal function who has had long-standing diabetes is assumed to have renal disease secondary to diabetic nephropathy. Most of these patients do not undergo a renal biopsy.

29.4 D. This patient should be started on a statin agent. Patients with diabetes are considered at high risk for the development of coronary artery disease, and a statin agent should be initiated unless contraindicated. Previously, strong consideration was given for strict LDL goals such as LDL of less than 100 mg/dL for primary prevention of cardiac disease; however, the ACC currently recommends the use of a 10-year atherosclerotic cardiovascular disease (ASCVD) risk calculator and moderate-dose versus high-intensity dose statin therapy based on risk. This patient’s 10-year ASCVD risk result is 15%, and the recommendation would be that a statin agent of moderate intensity be initiated. Additionally, statin agents have been shown to be effective in primary prevention of cardiovascular disease in type 2 diabetics aged 40 to 75. Answer A (niacin) has been shown to lower LDL cholesterol, but it has not been shown to reduce mortality. Answer C (gemfibrozil) is used primarily to treat a mixed dyslipidemia such as hypertriglyceridemia and high LDL; however, this agent is not as efficacious in reducing cardiovascular mortality as statin agents. Answer B (low-protein diet) is not indicated in this situation since the patient has no proteinuria and a normal serum creatinine level.

CLINICAL PEARLS

▶ Nephrotic syndrome is characterized by proteinuria greater than 3.5 g over 24 hours, hypoalbuminemia, and edema. Often, hypercoagulability and hyperlipidemia are present.

▶ Nephrotic syndrome can be a result of a primary renal disease but is often a manifestation of a systemic disease such as diabetes, viral hepatitis, HIV infection, autoimmune disease, or malignancy.

▶ Patients with diabetes mellitus should be screened for microalbuminuria (albumin excretion 30-300 mg/d); if present, treatment should be initiated with an ACE inhibitor or ARB even if the patient is normotensive.

▶ Patients with diabetic nephropathy are at a very high risk for cardiovascular disease. Aggressive risk factor reduction, such as use of statins with a goal LDL less than 100 mg/dL, is very important.

REFERENCES

Bargman JM, Skorecki K. Chronic kidney disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018. 

Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164-176. 

Lewis JB, Neilson EG. Glomerular diseases. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018. 

Sidall EC, Radhakrishnan J. The pathophysiology of edema formation in the nephrotic syndrome. Kidney Int. 2012;82:635-642.

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