Proteinuria

Currently, the development of proteinuria is thought to involve dysfunction of the glomerular filtration barrier, tubular dysfunction, or both. 

The glomerular filration barrier seperates the kidney vasculature from the urinary space. One of the barrier's primary purposes is to prevent the passage of plasma proteins notably albumin. The small amount of albumin and non-albumin protein that is filtered is reabsorbed in the proximal convoluted tubule (PCT).

The three components of the glomerular filtration barrier are the podocytes (epithelial cells), the fenestrated endothelial cells, and the glomerular basement membrane (GBM). Proteinuria is prevented by the negative charge and size selectivity of the glomerular filtration barrier. Crosstalk among podocytes, mesangium, and endothelium maintains the normal filtration barrier. As all three are interlinked, damage to any one of them affects the functioning of the others. 

Podocytes are the terminally differentiated visceral epithelial cells of the glomerulus found outside of the glomerular capillares; they face the Bowman space and the tubular infiltrate. Podocytes cover the glomerular capillaries and have extensions called foot processes that interdigitate with neighboring podoctyes, forming slit diaphragms 25-60 nm in size. Changes or effacement of foot processes is seen in many proteinuric states. Mutations in the genes that code for the proteins comprising the structure of the slit diaphragm can result in overt proteinuria.    

Glomerular capillaries are internally lined by endothelial cells that are in contact with the bloodstream. A unique feature of glomerular endothelial cells is their fenestrations—holes in the cell that permit passage of fluid across the glomerular capillary wall. Although these fenestrations are much larger than albumin, the endothelial surface has a covering coat made up of negatively charged glycocalyx, glycosaminoglycans and proteoglycans that retards the positively charged albumin and other plasma proteins. This cellular coat acts as both a size- and charge-based barrier. In addition, endothelium activation and loss of selectivity leads to prolonged exposure of podocytes to proteins. This results in the activation of renin-angiotensin in podocytes[6] and alteration of size selectivity. Damage to podocytes in turns leads to decrease in vascular endothelial growth factor (VEGF) required for endothelial fenestrae formation.[7]

The glomerular fitration barrier is also maintained by the mesangium's mesangial cells.  Mesangial cells lie close to the capillary lumen and play an important role in glomerular hemodynamics and immune complex clearance. The mesangial cells produce a matrix made up of collagen, fibronectin, and proteglycans that supports the glomerular capillaries. This is a common site of deposition of circulating immune complexes. The mesangium is disrupted by cell proliferation, as occurs in diabetic nephropathy or immunoglonin A (IgA) nephropathy.[8]

The GBM is made up of type IV collage, laminin, nidogen/entactin, sulfated proteoglycans, and glycoproteins. The GBM limits fluid movement. Changes in the proteins that make up the GBM, leading to proteinuria, have been described in congenital and acquired nephrotic syndrome. Proteinuria itself can cause endothelial damage: protein-mediated cytotoxicity may result in podocyte loss, leading to the production of chemokines and cytokines that initiate an inflammatory response. The end point is sclerosis and fibrosis of the glomerulus.[9]

High amounts of albumin are filtered in the proximal tubules, and the mechanism is thought to involve two receptors, which can process 250 g of albumin per day. Obviously, any dsyfunction in this protein retrieval pathway wouldl result in nephrotic syndrome.    

The presence of abnormal amounts or types of protein in the urine may reflect any of the following:

• Systemic diseases that result in an inability of the kidneys to normally reabsorb the proteins through the renal tubules
• Overproduction of plasma proteins that are capable of passing through the normal glomerular basement membrane (GBM) and that consequently enter the tubular fluid in amounts that exceed the capacity of the normal proximal tubule to reabsorb them
• A defective glomerular barrier that allows abnormal amounts of proteins of intermediate molecular weight to enter the Bowman space

Glomerular disease

Causes of glomerular disease can be classified as primary (no evidence of extrarenal disease) or secondary (kidney involvement in a systemic disease) and can then subdivided within these two groups on the basis of the presence or absence of nephritic/active urine sediment. In some cases, however, primary and secondary diseases can produce identical renal pathology.

Primary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis) include the following

• Immunoglobulin A (IgA) nephropathy
• Membranoproliferative glomerulonephritis (MPGN)
• Mesangial proliferative glomerulonephritis

Primary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis) include the following:

• Membranous glomerulonephritis ^[10]
• Minimal-change disease
• Primary focal segmental glomerulosclerosis
• Fibrillary glomerulonephritis
• Immunotactoid glomerulonephritis

Secondary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis, including rapidly progressive glomerulonephritis) include the following:

• Anti-GBM disease
• Renal vasculitis - Including disease associated with antineutrophil cytoplasmic antibodies (ANCAs), such as granulomatosis with polyangiitis (formerly known as Wegener granulomatosis)
• Lupus nephritis ^[11]
• Cryoglobulinemia-associated glomerulonephritis
• Bacterial endocarditis
• Henoch-Schönlein purpura
• Postinfectious glomerulonephritis

Secondary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis) include the following:

• Diabetic nephropathy
• Amyloidosis
• Hypertensive nephrosclerosis
• Light-chain disease from multiple myeloma
• Secondary focal glomerulosclerosis

Secondary focal glomerulosclerosis may result from the following:

• The healing phase of other glomerulonephritides
• As a nonspecific result of reduced nephron mass from any cause, including nonglomerular diseases such as reflux nephropathy
• Other causes of glomerular hyperfiltration, such as hypertensive nephrosclerosis and obesity

Unlike primary focal segmental glomerulosclerosis, the secondary type usually is gradual in onset and is not usually associated with hypoalbuminemia or other manifestations of nephrotic syndrome, even in the presence of nephrotic-range proteinuria.

MPGN is usually a pattern of injury seen on light microscopy. The current immunofluorescence-based classification divides MPGN as follows[12] :

• Immunoglobulin- and complement-positive MPGN
• Complement-positive MPGN - Due to dysregulation of complement pathway; includes C3 glomerulonephritis and dense-deposit disease
• Thrombotic microangiopathy (immunoglobulin and complement negative)

Other causes of proteinuria include the following:

• Neoplasms: Carcinoma (eg, bronchus, breast, colon, stomach, kidney), leukemia, lymphomas, melanomas
• Medications/drugs: Heroin, interferon alfa, lithium, nonsteroidal anti-inflammatory drugs, pamidronate, sirolimus
• Viral Infections: Epstein-Barr virus, hepatitis B and C viruses, herpes zoster, human immunodeficiency virus
• Allergic: Antitoxins, insect stings, poison ivy
• Genetic: Hereditary nephritis ( Alport syndrome)
• Other causes: Castleman disease, malignant hypertension, pre-eclampsia, transplant glomerulopathy 

In patients with cancer, treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) has been associated with an increased risk of developing proteinuria. A meta-analysis of randomized controlled trials of five newly approved VEGFR-TKIs (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib)  found an increased risk of episodes of all-grade proteinuria (relative risk [RR] 2.35, 95% confidence index [CI] 1.69-3.27, P < 0.001) and high-grade proteinuria (RR 3.70, 95% CI 2.09-6.54, P < 0.001).[13]

On subgroup analysis, risk of all-grade proteinuria was significantly increased with lenvatinib, axitinib, and vandetanib, while risk of high-grade proteinuria was increased with lenvatinib. In addition, the risk of experiencing high-grade proteinuria was significant for patients with hepatocellular carcinoma and renal cell carcinoma, but not for patients with colorectal cancer and thyroid cancer.[13]

Occurrence in the United States

In the third National Health and Nutrition examination Survey (NHANES III), the prevalence of albuminuria in the US population was found to be 6.1% in males and 9.7 % in females. The prevalence of albuminuria was 28.8% in persons with diabetes, 16.0% in those with hypertension, and 5.1% in those without diabetes, hypertension, cardiovascular disease, or elevated serum creatinine levels. The prevalence of proteinuria starts increasing at 40 years of age. Also, 3.3% of the US adult population was found to have persistent albuminuria with a normal estimated glomerular filtration rate (eGFR).[14]

Race-related demographics

According to the NHANES III survey, the prevalence of microalbuminuria is greater in non-Hispanic blacks and Mexican Americans aged 40 to 79 years compared with age-matched non-Hispanic whites. Similar results were found in the NHANES survey from 2006, where even after adjusting for covariates and medication use, racial and ethnic minorities with and without diabetes had greater odds of albuminuria compared with whites without diabetes. The results were similar when the comparison was made in patients with eGFR < 60 mL/min.[15, 16]

Many causes of proteinuria are particularly common in African Americans and certain other groups. The primary glomerular disorder, focal segmental glomerulosclerosis, has a higher incidence as well as a worse prognosis in African Americans.

In a study by Friedman et al, nondiabetic chronic kidney disease was found to occur in more than 3 million African Americans who had genetic variants in both copies of APOL1, increasing their risk for hypertension-attributable end-stage renal disease and focal segmental glomerulosclerosis. However, African Americans without the risk genotype appear to have a risk similar to that of European Americans for developing nondiabetic chronic kidney disease.[17]

Sex- and age-related demographics

Most primary glomerular diseases associated with proteinuria (eg, membranous glomerulonephritis) and secondary renal diseases (eg, diabetic nephropathy) are more common in males than in females. As a result, persistent proteinuria is at least twice as common in males as in females.

The incidence of hypertension and diabetes increases with age. In consequence, the incidence of persistent proteinuria (and microalbuminuria) also increases with age.

The prognosis for patients with proteinuria depends on the cause, duration, and degree of the proteinuria. Young adults with transient or orthostatic proteinuria have a benign prognosis, while patients with hypertension and microalbuminuria (or higher degrees of albuminuria) have a significantly increased risk of cardiovascular disease.

Proteinuria has been associated with progression of kidney disease,[18] increased atherosclerosis, and left ventricular abnormalities indirectly contributing to cardiovascular morbidity and mortality. In addition to being a predictor of outcome in patients with renal disease, microalbuminuria also is a predictor of morbidity and mortality in patients who do not have evidence of significant renal disease.

In the Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) study, which included 769 patients who experienced AKI during hospitalization, a higher urine albumin-to-creatinine ratio (ACR) quantified 3 months after hospital discharge was associated with increased risk of kidney disease progression. The hazard ratio was 1.53 for each doubling of ACR (95% confidence index, 1.45-1.62), and urine ACR measurement was a strong discriminator for future kidney disease progression.[19]

In patients with hypertension, the presence of microalbuminuria correlates with the presence of left ventricular hypertrophy. In both hypertensive and normotensive patients, the presence of microalbuminuria predicts an increased risk of cardiovascular morbidity and mortality.

Cardiovascular outcomes and proteinuria

In a study of 2310 patients, Jackson et al concluded that spot urinary albumin-to-creatinine ratios (UACRs) have significant prognostic value in persons with heart failure.[20] These authors determined that, compared with patients with normoalbuminuria, those with an elevated UACR tended to be older, had higher rates of cardiovascular comorbidity and diabetes mellitus, and suffered from worse renal function. Even after adjustment for variables such as renal function and diabetes, an increased UACR was associated with a greater mortality risk.

In the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study, the incidence of myocardial infarction was higher in patients with microalbuminuria than in those with normal urinary albumin levels.[21] In a study by Rein et al, albuminuria was an important predictor of cardiovascular mortality even after adjusting for conventional risk factors.[22] Analysis of 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BENEDICT trial also showed increased cardiovascular problems with any degree of measurable urinary albumin.[23]

Vascular calcification

Results from a study by Chiu et al of 225 proteinuric patients with type 2 diabetes mellitus indicated that vascular calcification, which can be particularly severe in nondialyzed patients with coexisting proteinuria and diabetes, is a prognostic indicator in early-stage type 2 diabetic nephropathy.[24]

In the study, 86% of patients were found to have coronary artery calcification, the degree of which was associated with older age, white ethnicity, and male sex. Fifty-four patients died during the follow-up period, which averaged 39 months.Univariate and multivariate analyses indicated that the degree of coronary artery calcification was, in relation to the calcification's severity, an independent predictor of all-cause mortality in the study's patients, with a 2.5-fold greater mortality risk found in subjects with a calcification score in the highest quartile.[24]

Stroke risk

A study of 3939 subjects enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective observational cohort, found that proteinuria and albuminuria are better predictors of stroke risk in patients with chronic kidney disease than estimated glomerular filtration rate. In patients with albuminuria, treatment with renin-angiotensin blockers did not decrease stroke risk.[25]

COVID-19

Proteinuria is a common finding in patients with COVID-19. Of 646 COVID-19 infected patients in New York City, 42.1% were positive for proteinuria in dipstick results.[26] Cheng et al reported a prevalence of 43.9% in 701 patients upon hospital admission for COVID-19 infection.[27]

In a sample of 333 COVID-19 patients in Wuhan, China, proteinuria was identified in 65.8% (219 patients). When severity of illness was considered, proteinuria was present in only 43.8% of patients with moderate illness compared to 81.2% of severely ill patients and 85.7% of critically ill ones. Patients with acute kidney injury had the highest rate of proteinuria (88.6%). Although the majority of patients with proteinuria experienced remission (68.5%) within 3 weeks, proteinuria was associated with significantly increased mortality.[28]   

In a retrospective single-center study by Huart and colleagues of 153 patients hospitalized with COVID-19 and proteinuria upon admission, 14% of the patients had category 1 proteinuria (<  150 mg/g of urine creatinine), 42% had category 2 (between 150 and 500 mg/g) and 44% had category 3 (> 500 mg/g). Urine α1-microglobulin concentration was higher than 15 mg/g in 89% of patients. Total proteinura and urinary α1-microglobulin were associated with mortality, with the strongest association among a subgroup of patient with normal kidney function and without a urinary catheter.[26]  

Mild to moderate proteinuria may be asymptomatic. The majority of patients will not report any symptoms, and proteinuria will be detected in the course of routine laboratory testing conducted to evaluate systemic disease, such as hypertension or diabetes, or as part of a well-person examination.

Because proteinuria occurs frequently in the absence of serious underlying kidney disease, considering the more common and benign causes of proteinuria first is important. Questions to ask include the following:

• Is this transient proteinuria? This may be associated with physical exertion and fever.
• Is this orthostatic proteinuri? This typically is observed in tall, thin adolescents or adults younger than 30 years; it may be associated with severe lordosis; kidney function is normal, and albuminuria usually is less than 1 g/day.
• Is this due to a nonrenal disease (eg, severe cardiac failure, sleep apnea)? Kidney function is normal and proteinuria usually is less than 1 g/day; microalbuminuria frequently is observed in association with hypertension and the early stages of diabetic nephropathy.
• Are symptoms present that suggest nephrotic syndrome or significant glomerular disease?
• Have changes occurred in the urine’s appearance (eg, red/smoky, frothy); did this occur in relation to an upper respiratory tract infection?
• Is edema (eg, ankle, periorbital, labial, scrotal) present?
• Has the patient ever been told that his or her blood pressure is elevated?
• Has the patient ever been told that his or her cholesterol llevel is elevated?
• Does the patient have a history of multisystem disease or of another cause of glomerular disease?
• Does the patient have a past or family history of kidney disease (including pregnancy related)?
• Does the patient have diabetes mellitus, and if so, for how long; are eye diseases or other complications present?
• Does the patient have a family history of diabetes mellitus and if so, does it include kidney disease?
• Is any chronic inflammatory disease (eg, systemic lupus erythematosus [SLE] or rheumatoid arthritis) present?
• Does the patient have any joint discomfort, a skin rash, eye symptoms, or Raynaud syndrome?
• Is the patient taking any medication, including over-the-counter or herbal remedies?
• Does the patient have are any past health problems, such as jaundice, tuberculosis, malaria, syphilis, or endocarditis?
• Are any other systemic symptoms, such as fever, night sweats, weight loss, or bone pain, present
• Does the patient have any risk factors for human immunodeficiency virus (HIV) infection or hepatitis?
• Are symptoms present that suggest complication(s) of nephrotic syndrome?
• Does the patient have any loin pain, abdominal pain, breathlessness, pleuritic chest pain, or rigors?

The physical examination should include the following:

• Assess intravascular volume status - Examine the jugular venous pulse (JVP), erect and supine pulse and blood pressure, and heart sounds
• Assess extravascular volume status - Look for edema (eg, ankle, leg, scrotal, labial, pulmonary, periorbital), which may or may not be pitting, depending on the duration of edema; massive weight gain due to fluid is very common, especially in patients with nephrotic syndrome; patients may also have decreased breath sounds due to pleural effusions
• Examine the patient for signs of systemic disease - Eg, retinopathy, rash, joint swelling or deformity, stigmata of chronic liver disease, organomegaly, lymphadenopathy, and cardiac murmurs
• Examine the patient for complications such as venous thrombosis and peritonitis

Complications of proteinuria include the following:

• Pulmonary edema due to fluid overload
• Acute kidney injury due to intravascular depletion and progressive kidney disease
• Increased risk of bacterial infection, including spontaneous bacterial peritonitis
• Increased risk of arterial and venous thrombosis, including renal vein thrombosis
• Increased risk of cardiovascular disease

Evaluation of proteinuria normally is conducted on an outpatient basis, unless the patient develops a complication of severe nephrotic syndrome. All patients with evidence of glomerular disease or any reduction in kidney function should be referred to a nephrologist.

Integral to the process of evaluating for proteinuria is quantification of the total amount of protein spilling into the urine. The various methods to detect proteinuria include urine dipstick and sulfosalicyclic acid test (SSA); quantification methods include the ratio of albumin or protein to creatinine and the 24-hour urine protein collection. 

The urine dipstick detects albumin primarily. Albuminuria is seen in glomerular proteinuria. False-positive results can occur with recent exposure to iodinated radiocontrast agents, alkaline urine, and gross hematuria. SSA detects all proteins, not just albumin. Proteinuria involving non-albumin proteins as well as albumin is seen more in tubular or overflow proteinuria. Iodinated radiocontrast also will interfere with the accuracy of the SSA test.

The gold standard for quantification of proteinuria is the 24-hour urine collection. The normal amount of protein in the urine is < 150 mg/day.

The 24-hour urine collection is performed by voiding upon waking and then collecting all urine on subsequent voids until the first void of the next day. Obviously, the process can be cumbersome and inaccurate. Results are considered reliable based on comparison with the typical amount of creatinine secreted per kilogram of lean body mass. On average, males secrete 20-25 mg/kg per day and females secrete 15-20 mg/kg. However, after the age of 50 years, lean body muscle mass is lost, so these estimates can be inaccurate in older patients. Another option—possibly more accurate, as it accounts for race and sex—is the following calculation (can be calculated with or without phosphorus):

Estimated creatinne excretion (mg/day) = 1115.89 + (11.97 x weight in kg) - (5.83 × age) - (60.18 × phosphorus in mg/dL) + (52.82 if black) - (368.75 if female) 

The spot albumin or protein–to-creatinine ratio was developed to help make the quantification of proteinuria easier and less laborious. However, the ratio can vary depending on the time of day and the amount of creatinine excreted. Consequently, the patient should collect all samples at about the same time of day. The amount of creatinine excretion to adequately reflect a 24-hour urine collection should be about 1 gram. If it significantly less, that could lead to underestimation of the degree of proteinuria, while overestimation may occur if there is much more than 1 g of creatinine.

A spot protein or albumin–to-creatinine ratio of > 3-3.5 mg protein/mg creatnine or a 24-hour urine collection showing > 3-3.5 g of protein is nephrotic-range proteinuria.

Screening for proteinuria can be done using a urine dipstick or early-morning spot protein or albumin–to-creatinine ratio. If significant proteinuria is found or the clinical situation is suspicious for significant proteinuria, a 24-hour urine collection should be done. The spot albumin or protein–to-creatinine ratio can be used for followup. If the ratio shows a significant increase, the 24-hour urine collection should be repeated.[5, 29, 30]  

Laboratory studies

To determine whether patients have transient proteinuria, perform the following:

• Urinalysis and microscopic examination on at least three separate occasions
• Albumin-to-creatinine or protein-to-creatinine ratio in a random urine sample ^{[31, 32]}
• Urinalysis on an early-morning sample, before the patient is involved in physical activity

To determine whether patients have orthostatic proteinuria, perform the following:

• Urine microscopy
• Split urine collection - Daytime (7 am to 11 pm) and overnight (11 pm to 7 am)

To determine whether proteinuria may be glomerular in origin, perform the following:

• Urine microscopy – To search for dysmorphic red blood cells and casts
• Urine collection (24 h) for quantification of albumin (or protein) excretion and creatinine clearance – Especially if the patient is muscular or cachectic; spot protein/creatinine ratio can be used for subsequent assessments
• Serum creatinine, albumin, cholesterol (see HDL cholesterol and LDL cholesterol), and blood glucose determinations
• Autoantibody determinations - If indicated, including antistreptolysin O titers, antinuclear antibodies (ANAs), anti-DNA antibodies, complement levels (C3 and C4), anti-phospholipase A1 receptor autoantibody, and cryoglobulins
• Hepatitis B, hepatitis C, and HIV serologies - If indicated
• Urine and plasma protein electrophoresis for light chains - If indicated
• Anti–glomerular basement membrane (anti-GBM) antibodies and antineutrophil cytoplasmic antibodies (ANCA) – If there is a suspicion of pulmonary renal syndrome.
• Hemoglobin A1C

Techniques for calculating proteinuria, to determine prognosis in patients with glomerular proteinuria, include the following[33] :

• Time-averaged  (obtained from average values over the duration of follow-up
• Time-varying (calculated from any instantaneous value at any given time point)
• Time-varying cumulative (obtained from the time-weighted average of all values prior to that same time point)

Results of a study by Kee et al suggest that in patients with glomerular disease, time-varying proteinuria can delineate the association between proteinuria levels and risk of renal progression better than a time-averaged model, as time-varying proteinuria reflects the dynamic change of proteinuria over time.[34]

Imaging studies

Imaging studies in proteinuria can include the following:

• Renal ultrasonography – If glomerular disease is being considered, it is important to review the size and echogenicity of the kidneys
• Chest radiography or computed tomography – If indicated

Kidney biopsy should be considered in adult patients with persistent proteinuria (usually, above 1 g per day), because the diagnostic and prognostic information yielded is likely to guide the choice of specific therapy.

In children, most cases of nephrotic syndrome are due to steroid-sensitive minimal-change disease. The clinician may reasonably assume this to be the diagnosis and give a trial of therapy, reserving biopsy for unresponsive cases.

In adult patients who have isolated proteinuria of less than 1 g/day and no other indicators of kidney disease, the renal prognosis is good and the need for specific treatment is unlikely. Most nephrologists would treat these patients with nonspecific measures (see Treatment) and would proceed to biopsy only if the degree of proteinuria increases or if the patient undergoes progressive decline in kidney function.

Medical management of proteinuria has the following two components:

• Nonspecific treatment - Treatment that is applicable irrespective of the underlying cause, assuming the patient has no contraindications to the therapy
• Specific treatment - Treatment that depends on the underlying renal or nonrenal cause and, in particular, whether or not the injury is immune mediated

Referral to a nephrologist is indicated for any patient who develops proteinuria, especially those with any adverse prognostic markers (eg, rise in albumin excretion of > 1 g/day), or any worsening in kidney function.

As an example of specific treatment, sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin, empagliflozin) have gained wide use in the management of type 2 diabetes mellitus and have effects beyond glucose lowering that include reducing the risk of development or worsening of albuminuria.[35] A meta-analysis concluded that although SGLT2 inhibitors did not have a statistically significant effect on estimate glomerular filtration rate (eGFR) in patients with type 2 diabetes, compared with monotherapy, the combination of SGLT2 inhibitors with other hypoglycemic agents can reduce albuminuria levels (SMD - 0.13, 95% CI - 0.19, - 0.06, p <  0.0001).[36]

Infection concerns

Patients with nephrotic syndrome are at increased risk of infection. The risk is greatest for bacterial infection (including spontaneous bacterial peritonitis) due to renal losses of immunoglobulin and complement components. No data, however, support the routine use of prophylactic antibiotics or immunoglobulin infusions.

Patients with nephrotic syndrome are at increased risk of infection. Both humoral and cell-mediated immunity are affected. Renal losses of immunoglobulin and complement, as well as a decrease in the number of circulating T lymphocytes, place nephrotic patients at a very high risk for bacterial infection, including spontaneous bacterial peritonitis.[37, 38]

The Advisory Committee on Immunization Practices (ACIP) recommends immunization with 13-valent pneumococcal conjugate vaccine (PCV13), followed by a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) at least 8 weeks later, in patients with nephrotic syndrome. A second dose of PPSV23 is given at least 5 years after the first.[39]

Follow-up

Patients may require regular follow-up care by a family physician, general internal medicine specialist, or nephrologist, depending on the cause and setting of proteinuria. Monitoring of the following is required:

• Proteinuria
• Presence or absence of other indicators of kidney disease
• Complications of nephrotic syndrome
• Treatment effectiveness
• Adverse effects

ACE inhibitors and ARBs

The degree of proteinuria depends on the integrity (charge and size selectivity) of the glomerular capillary wall (GCW) and the intraglomerular pressure. Intraglomerular pressure is controlled by the afferent arteriole, which transmits systemic blood pressure to the glomerulus, and the efferent arteriole.

Normalization of systemic blood pressure in a patient with hypertension[40] should result in a reduction in intraglomerular pressure and a fall in albuminuria.

Some vasodilatory antihypertensives (eg, hydralazine, nifedipine) dilate the afferent arteriole, which may attenuate the reduction in intraglomerular pressure despite the fall in arterial blood pressure. As a consequence, these agents may not reduce proteinuria to the same degree, particularly if systemic blood pressure is not adequately reduced at the same time that the afferent arteriole is dilated.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure by inhibiting angiotensin II ̶ mediated efferent arteriolar vasoconstriction.[40, 41] These classes of drugs have a proteinuria-reducing effect independent of their antihypertensive effect.[42]

Other hemodynamic and nonhemodynamic effects of ACE inhibitors that may partly explain the renoprotective properties of these drugs include the following[43] :

• Reduced breakdown of bradykinin (an efferent arteriolar vasodilator)
• Restoration of size and charge selectivity to the GCW
• Reduced production of cytokines that promote glomerulosclerosis and fibrosis, such as transforming growth factor (TGF)–beta.

Normotensive patients with proteinuria also should be given ACE inhibitors, because low doses usually are well tolerated and do not usually cause symptomatic hypotension.

Patients who develop adverse effects from ACE inhibitors, such as cough, should be given an ARB. The development of angioedema, which is due to the increase in bradykinin levels that accompany the use of ACE inhibitors, also warrants cessation of treatment. and substitution of an ARB. Patients who experience mild hyperkalemia should receive dietary counseling. Those with significant hyperkalemia should have the medication immediately discontinued and should be treated with a potassium-binding resin.

When treatment with an ACE inhibitor or ARB does not adequately control proteinuria in a patient with chronic kidney disease (eg, diabetic nephropathy), a further reduction in proteinuria can be achieved by adding a mineralocorticoid receptor antagonist (MRA) such as eplerenone or spironolactone. However, MRA therapy is associated with a three- to eightfold increased risk for hyperkalemia. In a phase 2 trial of finerenone, a nonsteroidal MRA, this new agent reduced proteinuria while producing lower rates of hyperkalemia than have been seen with other MRAs.[44]

Immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive kidney insufficiency or with vasculitic lesions on kidney biopsy.[45]

Diuretics

Patients with moderate to severe proteinuria are usually fluid overloaded and require diuretic therapy along with dietary salt restriction. In spite of good kidney function, these patients may not respond to normal doses of diuretics and may require increased doses for the drug to be delivered to renal tubule.

If fluid overload becomes refractory to therapy with a single diuretic agent, a combination of diuretics acting at different sites of the nephron can be tried. If the edema is due to marked hypoalbuminemia, aggressive diuresis may put the patient at risk of acute kidney injury due to intravascular volume depletion.

The routine use of albumin infusion combined with diuretics is not advocated in patients with nephrotic syndrome. Treatment with a loop diuretic or a combination of diuretics such as a thiazide and loop diuretic produces diuresis in most patients. The addition of albumin may improve natriuresis in patients with refractory salt and water retention, but the potential benefits must be weighed against the cost and risks of albumin infusion, which include the possibility of exacerbating fluid overload.

Anticoagulants

Patients with proteinuria tend to be hypercoagulable due to urinary losses of coagulation inhibitors, such as antithrombin III and protein S and C. The risk of thrombosis appears to be highest in patients with membranous glomerulonephritis. Numerous case reports have described renal vein thrombosis (which usually presents as acute onset of gross hematuria and back pain) in patients with membranous glomerulonephritis.

No randomized controlled trials support the use of prophylactic anticoagulation in patients with nephrotic syndrome. However, guidelines published by Kidney Disease–Improving Global Outcomes (KDIGO) in 2012 recommend treatment with warfarin in patients with nephrotic syndrome who have a low serum albumin level (< 2.5 g/dL), especially if the patient has other risk factors for thrombosis.[46]

Calcium Channel Blockers

Non-dihydropyridine calcium channel blockers (NDCCBs), diltiazem and verapamil, have been shown to decrease proteinuria greater than dihydropyridine calcium channel blockers (DCCBs). The difference between the two is thought to stem from the fact that DCCBs affect only the afferent arteriole and not the efferent, whereas NDCCBs affect both. The effect of action on the afferent arteriole only is impaired autoregulation and increased intraglomerular pressure, leading to kidney damage.

L type calcium channels are found only in the proximal tuble and are the primary channel affected by DCCBs. However, N and T type calcium channes are found in both the afferent and efferent arteriole; the newer NDCCBs such as efonidipine and benedipine work on these channels. The newer NDCCBs, used in combination with ARBs, have been shown to reduce proteinuria.[47, 48]

Endothelin Antagonists

Renal inflammation and fibrosis has been associated with endothelin activation. Endothelin A (ETA) receptor activation leads to vasoconstriction in vascular smooth muscle. ETA blockade leads to dilation of the glomerular capillaries, decreasing the permeability of  albumin. Endothelin B (ETB) decreases arterial pressure by inhibiting salt and water reabsorption in the kidneys. A trial of an experimental ETA-selective antagonist, avosentan, in patients with diabetic nephropathy showed a decrease in albuminuria, but with adverse effects including fluid retention and heart failure exacerbation. Atrasentan, another experimental ETA antagonist with a better adverse effect profile than avosentan, has also been shown to reduce proteinuria.[49, 50]  

Vitamin D and proteinuria

In animal studies, vitamin D and vitamin D analogues decrease inflammatory mediators and may act as immunosuppressive agents. Vitamin D may play a role in down-regulating prorenin gene expression and thereby enhancing renin-angiotensin-aldosterone system (RAAS) blockade.

A randomized controlled trial showed a reduction in proteinuria of around 20% in diabetic patients with paricalcitol.[51] A similar conclusion was reached in a systematic review by Borst et al, which found that treatment with active vitamin D reduced proteinuria even in the setting of RAAS blockade in most patients.[52]

Lipid abnormalities are quite common in patients with nephrotic syndrome. No evidence-based recommendations are available for the treatment of hyperlipidemia associated with nephrotic syndrome. Since proteinuria and hyperlipidemia may increase the risk for atherosclerotic disease, it should be treated in the same way as in the general population. 

Dietary measures are usually not very effective and most of these patients do require medication. The treatment of choice is statin therapy. Some studies have reported statins to be renoprotective and decrease levels of proteinuria.[53, 54] Dyslipidemia usually improves once the proteinuria resolves or immunosuppression is started.

Sodium restriction

The glomerular capillary pressure can increase in the presence of high sodium intake. Vegter et al found that for nondiabetic patients with chronic kidney disease, high dietary salt (>14 g daily) appeared to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for end-stage renal disease, independent of blood pressure control.[55]  Patients with nephrotic syndrome and fluid overload should have a salt-restricted diet. A "no-added-salt" diet usually is sufficient, although some patients may need restrictions of as low as 40 mmol/day.

Protein restriction

The issue of dietary protein restriction is controversial. Evidence indicates that protein restriction may slow the rate of deterioration in the glomerular filtration rate in patients with glomerular diseases, including diabetic nephropathy. The presumed mechanism is a reduction in intraglomerular pressure.

However, concern exists that protein-restricted diets may increase the risk of protein malnutrition. Other methods of reducing intraglomerular pressure, such as the use of ACE inhibitors, may be safer than protein restriction. Most nephrologists recommend no restrictions or only mild restriction in protein intake (0.8-1 g/kg daily).[56, 57]

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure by inhibiting angiotensin II ̶ mediated efferent arteriolar vasoconstriction.[41] These drugs also have a proteinuria-reducing effect that is independent of their antihypertensive effect.

In addition, ACE inhibitors have renoprotective properties, which may be partially due to the other hemodynamic and nonhemodynamic effects of these drugs. ACE inhibitors reduce the breakdown of bradykinin (an efferent arteriolar vasodilator); restore the size and charge selectivity to the glomerular cell wall; and reduce the production of cytokines, such as transforming growth factor–beta (TGF-beta), that promote glomerulosclerosis and fibrosis.

Class Summary

ACE inhibitors reduce intraglomerular pressure and may restore size and charge integrity to the GCW. They also reduce level of profibrotic cytokines. ACE inhibitors reduce proteinuria and also reduce rate of deterioration of renal function in patients with diabetic and nondiabetic renal disease associated with proteinuria.

Lisinopril (Zestril, Prinivil)

Lisinopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. The target blood pressure is less than 125/75 mm Hg in patients with proteinuria of greater than 1 g/day.

Patients who develop a cough, angioedema, bronchospasm, or other hypersensitivity reactions after starting ACE inhibitors should receive an angiotensin receptor blocker.

Ramipril (Altace)

Ramipril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Captopril

Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.

Class Summary

Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function and delaying the onset of end-stage renal disease.

Candesartan (Atacand)

Candesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, candesartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. This drug can be used in patients who are unable to tolerate ACE inhibitors.

Eprosartan (Teveten)

Eprosartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, eprosartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. This drug can be used in patients who are unable to tolerate ACE inhibitors.

Irbesartan (Avapro)

Irbesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II at the tissue receptor site. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Losartan (Cozaar)

Losartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, Losartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. It can be used in patients who are unable to tolerate ACE inhibitors.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictive effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptors in vascular smooth muscle. Its action is independent of the pathways for angiotensin II synthesis.

Valsartan (Diovan)

Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from AT1 receptors and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Valsartan may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. Valsartan can be used in patients who are unable to tolerate ACE inhibitors.

Class Summary

Patients with fluid overload should be treated with diuretics. Use a combination of diuretics acting at different sites of the nephron (eg, loop diuretic ± thiazide ± spironolactone). They increase urine excretion by inhibiting sodium and chloride transporters.

Furosemide (Lasix)

Furosemide is the diuretic of choice. It increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Bumetanide (Bumex)

Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase the urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs after administration, renal vascular resistance decreases, and renal blood flow is enhanced. In terms of effect, 1 mg of bumetanide is equivalent to approximately 40 mg of furosemide.

Ethacrynic acid (Edecrin)

Ethacrynic acid increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. This agent is used only in refractory cases. Continuous IV infusion is preferable in many cases. It is indicated for temporary treatment of edema associated with heart failure when greater diuretic potential is needed.

Class Summary

Patients with fluid overload should be treated with diuretics. Use a combination of diuretics acting at different sites of the nephron (eg, loop diuretic ± thiazide ± spironolactone). Diuretics are used to treat edema and hypertension. They increase urine excretion by inhibiting sodium and chloride transporters.

Metolazone (Zaroxolyn)

Metolazone treats edema in congestive heart failure. It increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. It may be more effective in cases of impaired renal function.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Class Summary

Patients with fluid overload should be treated with diuretics. Use a combination of diuretics acting at different sites of the nephron (eg, loop diuretic ± thiazide ± spironolactone). Aldosterone antagonists are used to lower the blood pressure and normalize serum potassium.

Spironolactone (Aldactone)

Spironolactone is the agent most commonly used to treat hyperaldosteronism because it directly antagonizes aldosterone effects at the distal tubule.

Class Summary

These agents may help to reduce proteinuria.

Diltiazem (Cardizem, Dilacor, Tiazac, Dilacor, Cartia XT)

During depolarization, diltiazem inhibits the influx of extracellular calcium across myocardial and vascular smooth muscle cell membranes. (Serum calcium levels remain unchanged.) The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

Diltiazem decreases conduction velocity in the atrioventricular node. In addition, it increases the refractory period by blocking calcium influx. This, in turn, stops the reentrant phenomenon.

The drug decreases myocardial oxygen demand by reducing peripheral vascular resistance, reducing the heart rate by slowing conduction through the sinoatrial and atrioventricular nodes and reducing left ventricular inotropy.

Diltiazem slows atrioventricular nodal conduction time and prolongs the atrioventricular nodal refractory period, which may convert supraventricular tachycardia or slow the rate in atrial fibrillation. It also has vasodilator activity but may be less potent than other agents. Total peripheral resistance, systemic blood pressure, and afterload are decreased.

Amlodipine (Norvasc)

Amlodipine blocks slow calcium channels, causing relaxation of vascular smooth muscles.

Nifedipine (Procardia)

Nifedipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Sublingual administration is generally safe, theoretical concerns notwithstanding.

Felodipine

Felodipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Calcium channel blockers potentiate ACE inhibitor effects. Renal protection is not proven, but these agents reduce morbidity and mortality rates in congestive heart failure. Calcium channel blockers are indicated in patients with diastolic dysfunction. They are effective as monotherapy in black patients and elderly patients.

Isradipine (DynaCirc)

Isradipine is a dihydropyridine calcium-channel blocker. It inhibits calcium from entering select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization. This causes relaxation of coronary vascular smooth muscle, which results in coronary vasodilation. Vasodilation reduces systemic resistance and blood pressure, with a small increase in resting heart rate. Isradipine also has negative inotropic effects.

Verapamil (Calan, Isoptin, Verelan)

During depolarization, verapamil inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. It can diminish premature ventricular contractions (PVCs) associated with perfusion therapy and decrease risk of ventricular fibrillation and ventricular tachycardia.