Diagnosis and treatment of nephrotic syndrome, renal stones and cancer common and uncommon kidney diseases

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Dr. Jassin M. Jouria is a practicing Emergency Medicine physician, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serve as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.


The kidneys serve as the body’s filtration system. Waste and excess fluids are filtered out of the blood and excreted through the urine. When the kidneys are not working as they should, fluid, electrolytes, and wastes can build up to dangerous levels in the body, even to the point of being fatal. Because kidney disease often does not create noticeable symptoms until the disease is advanced, it is important that medical clinicians are able to recognize the symptoms as soon as they are present and take immediate steps to resolve or mitigate the impact.

Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 3 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.

Pharmacology hours include .5 hours (30 minutes).

Statement of Learning Need

Clinicians need to understand the symptoms of the varied stages of kidney disease and the types of blood or urine laboratory testing that are available to detect abnormalities indicating early stages of kidney disease in order to take immediate steps to resolve or mitigate serious health outcomes.

Course Purpose

To provide health clinicians with knowledge about the varied types of kidney disease, as well as diagnostic methods to achieve early recognition of and to initiate and effectively treat kidney disease.

Target Audience

Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA

Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article.

Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

  1. Nephrotic syndrome is a kidney disorder characterized by

    1. too much protein in the urine.

    2. renal cell carcinoma.

    3. urinary immunoglobulin losses.

    4. inflammation of the glomeruli.

  1. Nephrotic syndrome occurs at any age but is more prevalent in

    1. girls, when studying children under 8.

    2. children ages 1½ and 4.

    3. elderly patients.

    4. adolescent boys.

  1. True or False: Hyperlipidemia is a classic feature of the nephrotic syndrome, rather than a mere complication.

    1. True

    2. False

  1. ______________ is a late feature of hypovolemia.

    1. Oliguria

    2. Tachycardia

    3. Hypotension

    4. Abdominal pain

  1. Infection associated with nephrotic syndrome

    1. occurs in less than 10% of adult patients.

    2. is a major concern and is a significant cause of morbidity.
    3. is most often caused by spontaneous bacterial peritonitis.

    4. are usually caused by viral infections.


There is a wide variety of renal diseases. Commonly seen kidney diseases include nephrotic syndrome, kidney cancer, and kidney stones. Though nephrotic syndrome is a common condition in nephrological practice and should feature in the differential diagnosis of any edematous patient, there can be uncertainty about how best to manage it. Treatment of nephrotic syndrome often includes treating underlying disorders, such as renal carcinoma and stones. The most common type of kidney cancer is renal cell carcinoma, followed by transitional cell cancer. Often physicians recommend monitoring renal cancer closely with regular diagnostic tests rather than recommending immediate surgery. Kidney stones are also common, especially in industrialized countries. The treatment of renal disease involves pain relief as well as dealing with complications of urinary obstruction and infections.

Common Kidney Diseases

Commonly seen kidney diseases discussed here are nephrotic syndrome, kidney cancer and kidney stones.

Nephrotic Syndrome

Nephrotic syndrome (NS) is one of the best-known presentations of adult or pediatric kidney disease. Nephrotic syndrome is a kidney disorder defined by the excretion of too much protein in a patient’s urine, with peripheral edema, hypoalbuminemia and hyperlipidemia. Nephrotic syndrome has multiple causes, significant complications and requires referral to a nephrologist for further investigation and management.83 A wide range of diseases and drugs can cause NS. Secondary glomerular diseases can often have a similar or identical histological lesion to a primary disease but have an identifiable underlying pathological process. Diabetic nephropathy is the most common cause of secondary glomerular disease.

Nephrotic syndrome occurs at any age but is more prevalent in children, mostly between ages 1½ and 4 years. Congenital nephrotic syndromes appear during the first year of life. At younger ages (< 8 yr.), boys are affected more often than girls, but both are affected equally at older ages. Causes differ by age and may be primary or secondary.84 The most common primary causes are minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Secondary causes account for < 10% of childhood cases but > 50% of adult cases, most commonly include diabetic nephropathy and preeclampsia.

Amyloidosis, an under-recognized cause, is responsible for 4% of cases.85,86 It has been reported that AL amyloid nephropathy accounted for 10% of cases.84,87-89
When the glomeruli are damaged, albumin, a protein carried the blood, can be excreted in the urine. In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier. Controversy exists regarding the sieving of albumin across the glomerular permeability barrier. On the basis of studies in experimental animals, it has been proposed that ongoing albumin passage into the urine occurs in many grams per day, with equivalent substantial tubular uptake of albumin, the result being that the urine contains 80 mg or less of albumin per day.90
However, studies of humans with tubular transport defects suggest that the glomerular urinary space albumin concentration is 3.5 mg/L.  At this concentration, and a normal daily glomerular filtration rate (GFR) of 150 liters, one would expect at most 525 mg per day of albumin in the final urine. In health, urine albumin is less than 50 mg/day, because most of the filtered albumin is reabsorbed by the tubules. Amounts above 500 mg/day point to glomerular disease.91

Glomerular Diseases

The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which envelops the capillaries with cellular extensions called foot processes. In between the foot processes are the filtration slits. These three structures — the fenestrated endothelium, glomerular basement membrane, and glomerular epithelium — are the glomerular filtration barrier.92

Filtration of plasma water and solutes is extracellular and occurs through the endothelial fenestrae and filtration slits. The importance of the podocytes and the filtration slits is shown by genetic diseases. In congenital nephrotic syndrome of the Finnish type, the gene for nephrin, a protein of the filtration slit, is mutated, leading to nephrotic syndrome in infancy. Similarly, podocin, a protein of the podocytes, may be abnormal in a number of children with steroid-resistant focal glomerulosclerosis. The glomerular structural changes that may cause proteinuria and damage to the endothelial surface, the glomerular basement membrane, or the podocytes. One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may occur or, with greater injury, leakage of all plasma proteins (i.e., proteinuria) may take place.93,94
Proteinuria that more than 85% albumin is selective proteinuria. Albumin has a net negative charge, and it is proposed that loss of glomerular membrane negative charges could be important in causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not involve changes in glomerular net charge but rather a generalized defect in permeability. This construct does not permit clear-cut separation of causes of proteinuria, except in minimal-change nephropathy, in which proteinuria is selective.95

The size-selective and charge-selective filtration barrier of the glomerulus prevents the passage of proteins across it. There are three layers: the fenestrated endothelium, the glomerular basement membrane and podocytes with the slit diaphragm between their foot processes. NS develops from protein leakage caused by injuries to this barrier. These alter its charge and size selectivity through effects on podocytes by immune and non-immune mechanisms, and to the expression of vital adhesion molecules such as nephrin. The underlying process behind sodium retention and edema formation is complex, controversial and not fully resolved.96

Human immunodeficiency virus (HIV)-associated nephropathy is a type of focal segmental glomerulosclerosis that occurs in patients with acquired immunodeficiency syndrome (AIDS). Primary (idiopathic) glomerular diseases account for the majority of cases of NS. Thirty years ago, idiopathic membranous nephropathy was the most common primary cause. The incidence of the other glomerular pathologies, particularly focal segmental glomerulosclerosis (FSGS), has increased. There are marked racial associations with different underlying primary glomerular diseases; membranous nephropathy is the most frequent cause of NS in Caucasians, while FSGS is the cause of 50–57% of cases of NS in black patients.
Systemic Consequences Of Nephrotic Syndrome

Nephrotic syndrome has systemic consequences. In some cases, the first manifestation of NS can be a complication, such as deep venous thrombosis (DVT), breathlessness or infection. There is overproduction of proteins in the liver (as part of the hepatic response to hypoalbuminemia) and loss of low molecular weight proteins in the urine. Significant changes in the protein environment of the body result in many of the complications seen. It is important for clinicians to be aware of their potential and actively prevent their occurrence.97

Nephrotic syndrome results in a hypercoagulable state with an increased risk of thromboembolic events. Embolism affect up to 10% of adults in clinical series of NS. Multiple abnormalities in the coagulation system occur, including increased plasma levels of pro-coagulant factors, reduced plasma levels of anticoagulant factors, abnormal platelet function, altered endothelial function and decreased fibrinolytic activity. Intravascular volume depletion, an increase in hematocrit from diuretics, and immobilization are significant contributory factors. The most common sites of thrombosis in adults are the deep veins of the lower limb. This is often asymptomatic.

Acute kidney injury is a rare complication of NS. It can happen as a consequence of excessive diuresis, interstitial nephritis related to diuretic or nonsteroidal anti-inflammatory drug (NSAID) use, sepsis and renal vein thrombosis. It can happen spontaneously, usually at presentation and occurs more often in older patients. Patients can require dialysis and can take weeks to months to recover.86
A thorough and careful history is important in elucidating the cause of NS. Patients can notice breathlessness, leg and facial swelling and, more rarely, frothy urine (protein acting like a detergent in the urine). Particular note should be made of any features suggestive of systemic disease, for example systemic lupus erythematosus (SLE), drug history (especially any recent or new medications, be they prescribed or over the counter) as well as any acute or chronic infections.
It is important to remember the links with malignancy particularly of the lungs and large bowel. A history of chronic inflammation may point towards a diagnosis of secondary amyloid. A family history is also important, as there are a number of congenital causes of NS.91,99

Metabolic consequences of nephrotic syndrome include:92

Acute kidney injury may indicate an underlying glomerulonephritis but is more often precipitated by hypovolemia or sepsis. Edema of the kidneys that causes a pressure-­mediated reduction in the GFR has also been proposed. Additional consequences that may develop include:95

  • Hypertension related to fluid retention and reduced kidney function
  • Edema of the gut (may cause defective absorption, leading to malnutrition)

  • Ascites and pleural effusions

Pulmonary embolism is also a potential consequence. Arterial thrombosis, affecting mesenteric, axillary, femoral, ophthalmic, renal, pulmonary and coronary arteries has also been (much more rarely) reported.92,98

Renal Vein Thrombosis

Renal vein thrombosis (RVT) is a well-recognized, though uncommon, complication of NS and is said to be more common when NS is caused by membranous nephropathy (inflammation and thickening of the glomeruli) or amyloidosis. Renal vein thrombosis and its treatment are discussed more fully below.


Infection is a major concern in nephrotic syndrome. Infection can occur in up to 20% of adult patients with NS and is a significant cause of morbidity and, occasionally, mortality. Patients have an increased susceptibility to infection from low serum IgG concentrations, reduced complement activity and depression of T cell function. A variety of infectious complications, particularly bacterial, can occur.84

Cellulitis is common, especially in severely edematous limbs, due to skin splits or punctures. Spontaneous bacterial peritonitis is a serious but rare infection in adults. It can present insidiously with mild abdominal colicky pain or as fulminant sepsis. Streptococcus pneumoniae and gram-negative organisms are the most frequent causative bacteria. Viral infections have been linked to relapses in minimal change NS. Infections are a risk in patients receiving immunosuppressive treatment for NS.84
Proposed explanations for the increased infection risk include:100

  • Urinary immunoglobulin losses

  • Edema fluid acting as a culture medium
  • Protein deficiency

  • Decreased bactericidal activity of the leukocytes

  • Immunosuppressive therapy

  • Decreased perfusion of the spleen caused by hypovolemia

  • Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria

Hyperlipidemia and Atherosclerosis

Hyperlipidemia is a classic feature of nephrotic syndrome, rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of lipoproteins.  In addition, reduced plasma levels of lipoprotein lipase results in diminution of lipid catabolism. Some of the elevated serum lipoproteins are filtered at the glomeruli, leading to lipiduria and the classic findings of oval fat bodies and fatty casts in the urine sediment. Atherosclerotic vascular disease appears to occur in greater frequency in persons with nephrotic syndrome than in healthy persons of the same age.88,101


Hypocalcemia is common in nephrotic syndrome, but rather than being a true hypocalcemia, it is usually caused by a low serum albumin level. Nonetheless, low bone density and abnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin D–binding proteins, with consequent hypovitaminosis D and, as a result, reduced intestinal calcium absorption. Tessitore, et al., reported that when the GFR was normal, persons with nephrotic syndrome had no consistent calcium or bony abnormalities.  Yet in that same study, when the GFR was reduced, bone mineralization defects were found by biopsy. A later study found osteomalacia on bone biopsy in over half of adults who had longstanding nephrotic syndrome but whose GFR was preserved.

Low bone mass may be found in relation to cumulative steroid dose. However, intermittent corticosteroid treatment of childhood steroid-sensitive nephrotic syndrome was not associated with bone mineral deficits in one study.  It is possible that long duration of either the nephrotic syndrome or treatments for it are the important risk factors for bone disease in these patients.83,84,97

Venous thrombosis and pulmonary embolism are well-known complications of nephrotic syndrome. Hypercoagulability in these cases appears to derive from urinary loss of anticoagulant proteins, such as antithrombin III and plasminogen, along with the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X. A study of almost 300 patients with nephrotic syndrome confirmed that the annual incidence of venous thromboembolism (VTE) was almost 10 times higher in these persons than in the normal population (1% vs 0.1 to 0.2%).  Moreover, that risk appeared especially elevated during the first 6 months of nephrotic syndrome, being at almost 10%. This high incidence may justify the routine use of preventive anticoagulation treatment during the first 6 months of a persistent nephrotic syndrome.89,102

A recent study also showed an increased risk of arterial thrombotic events in subjects with nephrotic syndrome, including coronary and cerebrovascular ones. Unlike the risk of VTE, which was related to proteinuria, this arterial risk was related to usual risk factors for arterial disease, such as hypertension, diabetes, smoking, and reduced GFR.100


Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL. Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet, delayed capillary filling, oliguria, and tachycardia. Hypotension is a late feature.84,101


Patients usually present with increasing peripheral edema. Up to four liters of fluid can remain clinically undetectable. Edema is often first noticed periorbitally and it can become very severe with lower leg and genital edema as well as ascites, pleural and pericardial effusions. It is important to mention to the non-specialist that neither raised blood pressure (BP) nor elevated jugular venous pressure/pulmonary edema are cardinal features of NS. If these are present, it is more likely that one is dealing with (acute) nephritic syndrome (i.e., secondary to acute glomerulonephritis, which is inflammation of the glomeruli) or there is significant cardiac or renal failure. Nephrotic syndrome is distinct from nephritic syndrome as the former is characterized by proteins excreted into the urine. The BP in NS can be low, normal or raised; this depends on many factors, including previous history of raised BP, underlying cause of NS, renal function, extracellular fluid volume status and cardiac function. Features of the underlying disorder may be evident, such as the butterfly facial rash of systemic lupus erythematosus (SLE) or the neuropathy and retinopathy associated with diabetes mellitus. Hyperlipidemia is one of the classic accompaniments to the condition and eruptive xanthomas can appear. The nails can show white bands due to persistent hypoalbuminemia.90,91,100

Treatment is directed at the causative disorder and includes angiotensin inhibition, sodium restriction, use of statins, use of diuretics for excessive fluid overload, and, rarely, nephrectomy.

Treatment Of Disorders Causing Nephrotic Syndrome

Treatment of underlying disorders may include prompt treatment of infections (i.e., staphylococcal endocarditis, malaria, syphilis, schistosomiasis), allergic desensitization (i.e., for poison oak or ivy and insect antigen exposures), and stopping drugs (i.e., gold, penicillamine, NSAIDs). These measures may cure nephrotic syndrome in specific instances.92,99,100,102,103


All patients should receive pneumococcal vaccination if not otherwise contraindicated.

Angiotensin Inhibition

Angiotensin inhibition (using ACE inhibitors or angiotensin II receptor blockers) is indicated to reduce systemic and intraglomerular pressure and proteinuria. These drugs may cause or exacerbate hyperkalemia in patients with moderate to severe renal insufficiency. Protein restriction is no longer recommended because of lack of demonstrated effect on progression.

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