Minimal change disease

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Minimal change disease
Minimal Change Disease Pathology Diagram.svg
The three hallmarks of minimal change disease (seen on electron microscopy): diffuse loss of podocyte foot processes, vacuolation, and the appearance of microvilli.
Specialty Nephrology   OOjs UI icon edit-ltr-progressive.svg

Minimal change disease (also known as MCD, minimal change glomerulopathy, and nil disease, among others) is a disease affecting the kidneys which causes nephrotic syndrome. [1] Nephrotic syndrome leads to the loss of significant amounts of protein in the urine, which causes the widespread edema (soft tissue swelling) and impaired kidney function commonly experienced by those affected by the disease. [1] It is most common in children and has a peak incidence at 2 to 6 years of age. [2] MCD is responsible for 10–25% of nephrotic syndrome cases in adults. [3] It is also the most common cause of nephrotic syndrome of unclear cause (idiopathic) in children. [3]

Contents

Signs and symptoms

The clinical signs of minimal change disease are proteinuria (abnormal excretion of proteins, mainly albumin, into the urine), edema (swelling of soft tissues as a consequence of water retention), weight gain, and hypoalbuminemia (low serum albumin). [1] These signs are referred to collectively as nephrotic syndrome. [1]

Periorbital edema that can be seen in minimal change disease Nephrotic eyes.JPG
Periorbital edema that can be seen in minimal change disease

The first clinical sign of minimal change disease is usually edema with an associated increase in weight. [1] The swelling may be mild but patients can present with edema in the lower half of the body, periorbital edema, swelling in the scrotal/labial area and anasarca in more severe cases. [1] In older adults, patients may also present with acute kidney injury (20–25% of affected adults) and high blood pressure. [4] Due to the disease process, patients with minimal change disease are also at risk of blood clots and infections. [4]

Pathology

For years, pathologists found no changes when viewing kidney biopsy specimens under light microscopy, hence the name "minimal change disease." Sometimes, the mesangium may have expanded, but otherwise there is no injury to kidney tissue itself. [1]

Under immunofluorescence, there are no immunoglobulins or complement deposits bound to kidney tissue. [1]

With the advent of electron microscopy, the changes now known as the hallmarks of the disease were discovered. These are diffuse loss of visceral epithelial cells' foot processes (i.e., podocyte effacement), vacuolation, and growth of microvilli on the visceral epithelial cells, allowing for excess protein loss in the urine. [5]

Pathophysiology

Proteinuria

The cause and pathogenesis of the pathology is unclear and it is currently considered idiopathic. However, it does not appear to involve complement or immune complex deposition. Rather, an altered T cell-mediated immunologic response with abnormal secretion of lymphokines by T cells is thought to modify the glomerular basement membrane, specifically the podocytes, increasing permeability. [1] This allows the leakage of albumin and other serum proteins into the urine. Also, the exact cytokine responsible has yet to be elucidated, with IL-12, IL-18 and IL-13 having been most studied in this regard, yet never conclusively implicated. [4] Data from a longitudinal study (Nephrotic Syndrome Study Network – NEPTUNE) published in 2022 suggested that up to 29% of biopsy-confirmed, mixed pediatric and adult minimal change disease cases exhibited serum autoantibodies against nephrin, a structural protein located in the podocyte slit diaphragm. [6]

There has been discussion of B cell involvement in nephrotic syndrome, especially minimal change disease due to the success of immunotherapy that target both B and T cells, increased markers for B cell activation during a relapse of minimal change disease, and alterations in B cell sub-classes during minimal change disease remission. [4] This hypothesis is supported by recent findings of anti-nephrin antibodies isolated in minimal change disease.

Edema

When albumin is excreted in the urine, its serum (blood) concentration decreases. Consequently, the plasma oncotic pressure reduces relative to the interstitial tissue. The subsequent movement of fluid from the vascular compartment to the interstitial compartment manifests as the soft tissue swelling referred to as edema. This fluid collects most commonly in the feet and legs, in response to gravity, particularly in those with poorly functioning valves. In severe cases, fluid can shift into the peritoneal cavity (abdomen) and cause ascites. As a result of the excess fluid, individuals with minimal change disease often gain weight, as they are excreting less water in the urine, and experience fatigue. [1]

Diagnosis

As minimal change disease is a subset of nephrotic syndrome, diagnosis involves looking for a combination of edema, high amounts of protein in urine, low albumin and high serum cholesterol. Initial workup can include a urinalysis, kidney function tests, serum albumin level and a lipid panel. [7] Microscopic amounts of blood are present in the urine of 10-30% adults with MCD. [3]

As MCD is the most common type of nephrotic syndrome in children, renal biopsy is not usually done in children under the age of 10 unless there are concerning features that are unusual for the disease (high blood pressure, bloody urine, renal dysfunction) and if they fail to respond to corticosteroid therapy. [1] These would suggest that it may not be minimal change disease. In adults, a renal biopsy is required as there is a much wider differential for nephrotic syndrome. [1] As the name suggests, the renal biopsy of a patient with minimal change disease would show minimal or no evidence of disease in light microscopy, which is unique among the causes of nephrotic syndrome. [1]

Treatment

Children

The first line therapy for minimal change disease is prednisone, a corticosteroid, 60 mg/sq.m/day or 2 mg/kg/day. [1] For those children who are unable to tolerate corticosteroid treatment, or are unresponsive (usually after a trial of 8 weeks), another immunosuppressant cyclosporin is an alternative; other immunosuppressants have also been used such as a calcineurin inhibitor, mycophenolate mofetil, and rituximab though studies on their effectiveness is fairly limited. [1] [4] There is no consensus on how long the corticosteroid therapy should be, with treatment length ranging from 4–12 weeks. [1] Along with corticosteroid therapy, acute symptomatic management involves salt and fluid restriction to control the swelling. [1]

Adults

Treatment guidelines for adults are fairly limited, and are largely based on studies done on children. [1] The mainline therapy is also corticosteroid therapy prednisone 1 mg/kg/day with other immunosuppressants as possible alternatives, though there is very little data on these alternatives' efficacy. [1] Other medications such as ACE inhibitors to reduce the amount of protein in the urine or statins to decrease high levels of cholesterol seen with nephrotic syndrome are generally unnecessary. [3] ACE inhibitors may be considered in people with MCD who also have high blood pressure. [3]

Prognosis

Children

Minimal change disease usually responds well to initial treatment with the first-line therapy: corticosteroids, with 95% responding. [1] Younger children, who are more likely to develop minimal change disease, usually respond faster than adults with 50% of children having complete remission with 8 days of corticosteroid therapy and most other patients responding by the 4th week. [1] Few do not respond to corticosteroids and have to rely on an alternative therapy. However, despite positive response to corticosteroids, relapses are common, requiring repeat treatment with corticosteroids. About 25% never relapse, another 25% relapse infrequently (one relapse within 6 months of initial response or 1–3 relapses in 12 months), and 50% relapse frequently (>2 relapses within 6 months of initial response or >4 relapses in 12 months). [1] The relapse rate is the reason behind a discussion on continuing prednisone treatment to even beyond 12 weeks to possibly decrease relapse rate; several studies trying this have failed to show significant improvement. [1] A majority of relapses seem to be triggered by respiratory infections. [1] Long term, children can relapse several years after having no symptoms; though after 2 years, the risk is significantly lower. [4]

In most children with minimal change disease, particularly among those who respond typically, there is minimal to no permanent damage observed in their kidneys. [1] Complications primarily arise from the side effects of therapy. Prolonged use of corticosteroids can lead to immunosuppression (leading to infection), growth complications, weight gain. [7]

Adults

While most adults diagnosed with minimal change disease respond to corticosteroids, 25% fail to respond after 3–4 months of corticosteroid therapy; it is possible that these patients were incorrectly diagnosed, and do not have minimal change disease. [1] Adults with MCD tend to respond more slowly to corticosteroid treatment, taking up to 3 or 4 months, than children do. [3] Data in adults is less complete than for children, but relapses are fairly frequent with 56–76% of patients relapsing and needing further treatment with immunosuppressants such as ciclosporin, tacrolimus, mycophenolate, and rituximab. [3] [4] There is little evidence to support the use of azathioprine for MCD. [3] Complications primarily arise from the side effects of therapy.

Epidemiology

Minimal change disease is most common in very young children but can occur in older children and adults.[ citation needed ]

It is by far the most common cause of nephrotic syndrome in children, accounting for 70–90% of children >1 year of age. [4] After puberty, it is caused by minimal change disease about half the time. [4] Among young children, boys seem to be more likely to develop minimal change disease than girls (about 2:1). [1] Minimal change disease is seen in about 16 in every 100,000 children, being more common in South Asians and Native Americans, but rarer in African Americans. [1]

In adults, it accounts for less than 15% of adults diagnosed with nephrotic syndrome. [4]

Etymology

Minimal change disease has been called by many other names in the medical literature, including minimal change nephropathy, minimal change nephrosis, minimal change nephrotic syndrome, minimal change glomerulopathy, foot process disease (referring to the foot processes of the podocytes), nil disease (referring to the lack of pathologic findings on light microscopy), nil lesions, lipid nephrosis, and lipoid nephrosis.

Related Research Articles

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein;less than 150mg/day,an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Nephrotic syndrome</span> Collection of symptoms due to kidney damage

Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.

<span class="mw-page-title-main">Henoch–Schönlein purpura</span> Medical condition

Henoch–Schönlein purpura (HSP), also known as IgA vasculitis, is a disease of the skin, mucous membranes, and sometimes other organs that most commonly affects children. In the skin, the disease causes palpable purpura, often with joint pain and abdominal pain. With kidney involvement, there may be a loss of small amounts of blood and protein in the urine, but this usually goes unnoticed; in a small proportion of cases, the kidney involvement proceeds to chronic kidney disease. HSP is often preceded by an infection, such as a throat infection.

<span class="mw-page-title-main">Podocyte</span> Type of kidney cell

Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule filters the blood, retaining large molecules such as proteins while smaller molecules such as water, salts, and sugars are filtered as the first step in the formation of urine. Although various viscera have epithelial layers, the name visceral epithelial cells usually refers specifically to podocytes, which are specialized epithelial cells that reside in the visceral layer of the capsule. One type of specialized epithelial cell is podocalyxin.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Membranous glomerulonephritis</span> Medical condition

Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people.

<span class="mw-page-title-main">Nephritic syndrome</span> Medical condition

Nephritic syndrome is a syndrome comprising signs of nephritis, which is kidney disease involving inflammation. It often occurs in the glomerulus, where it is called glomerulonephritis. Glomerulonephritis is characterized by inflammation and thinning of the glomerular basement membrane and the occurrence of small pores in the podocytes of the glomerulus. These pores become large enough to permit both proteins and red blood cells to pass into the urine. By contrast, nephrotic syndrome is characterized by proteinuria and a constellation of other symptoms that specifically do not include hematuria. Nephritic syndrome, like nephrotic syndrome, may involve low level of albumin in the blood due to the protein albumin moving from the blood to the urine.

<span class="mw-page-title-main">Focal segmental glomerulosclerosis</span> Kidney disease

Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. This process damages the filtration function of the kidney, resulting in protein loss in the urine. FSGS is a leading cause of excess protein loss—nephrotic syndrome—in children and adults. Signs and symptoms include proteinuria, water retention, and edema. Kidney failure is a common long-term complication of disease. FSGS can be classified as primary versus secondary depending on whether a particular toxic or pathologic stressor can be identified as the cause. Diagnosis is established by renal biopsy, and treatment consists of glucocorticoids and other immune-modulatory drugs. Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure. FSGS is estimated to occur in 2–3 persons per million, with males and African peoples at higher risk.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood. There are several causes that all result in edema once serum protein levels fall below a certain threshold.

<span class="mw-page-title-main">Hypoalbuminemia</span> Medical condition

Hypoalbuminemia is a medical sign in which the level of albumin in the blood is low. This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or kidneys, increased use in the body, or abnormal distribution between body compartments. Patients often present with hypoalbuminemia as a result of another disease process such as malnutrition as a result of severe anorexia nervosa, sepsis, cirrhosis in the liver, nephrotic syndrome in the kidneys, or protein-losing enteropathy in the gastrointestinal tract. One of the roles of albumin is being the major driver of oncotic pressure in the bloodstream and the body. Thus, hypoalbuminemia leads to abnormal distributions of fluids within the body and its compartments. As a result, associated symptoms include edema in the lower legs, ascites in the abdomen, and effusions around internal organs. Laboratory tests aimed at assessing liver function diagnose hypoalbuminemia. Once identified, it is a poor prognostic indicator for patients with a variety of different diseases. Yet, it is only treated in very specific indications in patients with cirrhosis and nephrotic syndrome. Treatment instead focuses on the underlying cause of the hypoalbuminemia. Albumin is an acute negative phase respondent and not a reliable indicator of nutrition status.

HIV-associated nephropathy (HIVAN) refers to kidney disease developing in association with infection by human immunodeficiency virus, the virus that causes AIDS. The most common, or "classical", type of HIV-associated nephropathy is a collapsing focal segmental glomerulosclerosis (FSGS), though other forms of kidney disease may also occur. Regardless of the underlying histology, kidney disease in HIV-positive patients is associated with an increased risk of death.

Congenital nephrotic syndrome is a rare kidney disease which manifests in infants during the first 3 months of life, and is characterized by high levels of protein in the urine (proteinuria), low levels of protein in the blood, and swelling. This disease is primarily caused by genetic mutations which result in damage to components of the glomerular filtration barrier and allow for leakage of plasma proteins into the urinary space.

<span class="mw-page-title-main">Rapidly progressive glomerulonephritis</span> Medical condition

Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of kidney function, with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute kidney failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents.

AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein (SAA), an acute-phase protein which is normally soluble and whose plasma concentration is highest during inflammation.

Glomerulonephrosis is a non-inflammatory disease of the kidney (nephrosis) presenting primarily in the glomerulus as Nephrotic Syndrome. The nephron is the functional unit of the kidney and it contains the glomerulus, which acts as a filter for blood to retain proteins and blood lipids. Damage to these filtration units results in important blood contents being released as waste in urine. This disease can be characterized by symptoms such as fatigue, swelling, and foamy urine, and can lead to chronic kidney disease and ultimately end-stage renal disease, as well as cardiovascular diseases. Glomerulonephrosis can present as either primary glomerulonephrosis or secondary glomerulonephrosis.

<span class="mw-page-title-main">Idiopathic multicentric Castleman disease</span> Medical condition

Idiopathic multicentric Castleman disease (iMCD) is a subtype of Castleman disease (also known as giant lymph node hyperplasia, lymphoid hamartoma, or angiofollicular lymph node hyperplasia), a group of lymphoproliferative disorders characterized by lymph node enlargement, characteristic features on microscopic analysis of enlarged lymph node tissue, and a range of symptoms and clinical findings.

Monoclonal Immunoglobulin Deposition Disorder, or MIDD, is a disease characterised by the deposition of monoclonal immunoglobulins on the basement membrane of the kidney. Monoclonal immunoglobulins are produced by monoclonal plasma cells, which are found in a variety of plasma cell dyscrasias. The deposition of monoclonal immunoglobulins on the basement membrane of the kidney causes renal impairment. As well as the kidney, MIDD may also affect the liver, heart, peripheral nerves, lung and skin.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Johnson, Richard J.; Feehally, John; Floege, Jürgen (2018-06-26). Comprehensive clinical nephrology (Sixth ed.). Edinburgh. ISBN   9780323547192. OCLC   1047958109.{{cite book}}: CS1 maint: location missing publisher (link)
  2. ↑ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2014). Robbins and Cotran pathologic basis of disease. Kumar, Vinay, 1944–, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A. (Ninth ed.). Philadelphia, PA. ISBN   9781455726134. OCLC   879416939.{{cite book}}: CS1 maint: location missing publisher (link)
  3. 1 2 3 4 5 6 7 8 Hogan J, Radhakrishnan J (April 2013). "The treatment of minimal change disease in adults". Journal of the American Society of Nephrology. 24 (5): 702–11. doi: 10.1681/ASN.2012070734 . PMID   23431071.
  4. 1 2 3 4 5 6 7 8 9 10 Vivarelli, Marina; Massella, Laura; Ruggiero, Barbara; Emma, Francesco (February 7, 2017). "Minimal Change Disease". Clinical Journal of the American Society of Nephrology. 12 (2): 332–345. doi:10.2215/CJN.05000516. ISSN   1555-905X. PMC   5293332 . PMID   27940460.
  5. ↑ Fogo, Agnes B.; Lusco, Mark A.; Najafian, Behzad; Alpers, Charles E. (Aug 2015). "AJKD Atlas of Renal Pathology: Minimal Change Disease". American Journal of Kidney Diseases. 66 (2): 376–377. doi:10.1053/j.ajkd.2015.04.006. ISSN   1523-6838. PMID   26210726.
  6. ↑ Watts, Andrew (January 2022). "Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology". Journal of the American Society of Nephrology. 33 (1): 238–252. doi:10.1681/ASN.2021060794. PMC   8763186 . PMID   34732507.
  7. 1 2 Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan JD, Wigfall D, Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum LA (August 2009). "Management of childhood onset nephrotic syndrome". Pediatrics. 124 (2): 747–57. doi:10.1542/peds.2008-1559. PMID   19651590. S2CID   8226984.
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