Diffuse proliferative nephritis
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Diffuse proliferative glomerulonephritis (DPGN) is a type of glomerulonephritis that is the most serious form of renal lesions in
SLE Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
and is also the most common, occurring in 35% to 60% of patients. In absence of SLE, DPGN pathology looks more like Membranoproliferative glomerulonephritis In DPGN Most of the glomeruli show endothelial and
mesangial The glomerulus (plural glomeruli) is a network of small blood vessels (capillaries) known as a ''tuft'', located at the beginning of a nephron in the kidney. Each of the two kidneys contains about one million nephrons. The tuft is structurally s ...
proliferation Proliferation may refer to: Weapons *Nuclear proliferation, the spread of nuclear weapons, material, and technology *Chemical weapon proliferation, the spread of chemical weapons, material, and technology * Small arms proliferation, the spread of ...
, affecting the entire glomerulus, leading to diffuse hypercellularity of the glomeruli, producing in some cases epithelial crescents that fill Bowman's space. When extensive,
immune complexes An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
create an overall thickening of the capillary wall, resembling rigid "wire loops" on routine
light microscopy Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
. Immune complexes can be visualized by staining with fluorescent
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
directed against immunoglobulins or complement, resulting in a granular fluorescent staining pattern.
Electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
reveals electron-dense subendothelial
immune complexes An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
(between endothelium and basement membrane). In due course, glomerular injury in DPGN gives rise to scarring (
glomerulosclerosis Glomerulosclerosis is the hardening of the glomeruli in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urea from the blood. Proteinuria (larg ...
). Most of SLE patients with DPGN have hematuria with moderate to severe proteinuria,
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, and
renal insufficiency Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
.


Signs and Symptoms

Symptoms can be caused directly from DPGN or from a different disease that is causing DPGN. Many of the symptoms, like
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
and
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, occur due to the decrease in glomerular filtration rate. Patients can experience general systemic symptoms including
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, vomiting, nausea. These would all indicate uremia. Other patients can experience: * Decreased urine output * Hematuria ** Microscopic or gross * Proteinuria ** Which will present as frothy urine * Pedal edema ** Swelling of the feet and ankles


DPGN caused by other diseases

If a patient has DPGN due to IgA nephropathy ( Berger Disease) then they can experience
flank pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...
, gross hematuria, and upper respiratory infections. If a patient has DPGN with underlying
anti-GBM Anti-glomerular basement membrane antibody (anti-GBM Ab) is an antibody which is found in Goodpasture's syndrome but not found in microscopic polyangiitis Microscopic polyangiitis is an ill-defined autoimmune disease characterized by a systemic, pa ...
then they can experience
alveolar Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit. Uses in anatomy and zoology * Pulmonary alveolus, an air sac in the lungs ** Alveolar cell or pneumocyte ** Alveolar duct ** Alveolar macrophage * ...
hemorrhage and respiratory issues. If a patient has DPGN with an underlying
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
then the patient can experience photosensitivity, rash,
joint pains Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...
,
serositis Serositis refers to inflammation of the serous tissues of the body, the tissues lining the lungs (pleura), heart (pericardium), and the inner lining of the abdomen (peritoneum) and organs within. It is commonly found with fat wrapping or creeping ...
, and oral ulcers.


Cause

The cause of diffuse proliferative glomerulonephritis (DPGN) depends on the severity of the disease. DPGN is a secondary disease, in that a disease that a patient already has causes DPGN to occur. The most common associated disease of DPGN is severe
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE). Specifically, Lupus nephritis class IV. The other commonly associated disease is Immunoglobulin A (IgA) nephropathy.
Post-infectious glomerulonephritis Acute proliferative glomerulonephritis is a disorder of the small blood vessels of the kidney. It is a common complication of bacterial infections, typically skin infection by ''Streptococcus'' bacteria types 12, 4 and 1 (impetigo) but also afte ...
can also be caused by bacterial or viral infections. Streptococcal throat or skin infection is most commonly seen as the origin if glomerulonephritis is going to be caused by an infection. Other causes of DPGN are endocarditis, Hepatitis B, and Hepatis C.


Pathophysiology

The
etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
plays a role in the specific mechanism of DPGN. Usually the deposition of immune-complexes (antigen-antibody complex) that activates the
complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
are involved. The
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
that form immune complexes deposits or they bind directly to the nonglomerular antibodies present. Immune-complexes are combinations of DNA, anti-dsDNA ubiquitin, and other proteins in DPGN that are associated with lupus nephritis. C1q, the first component of the complement system, encounters conformational change that leads to C3 convertase breaking C3 into C3a and C3b. C3a, C5a, IL-8 are all
chemotactic factors Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
of the activated complement system. Part of their role is to recruit
polymorphonuclear Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...
cells and leukocytes. Interleukins like IL-6, tumor necrosis factor-alpha, and interferon-gamma, that cause cell injury, are released.
Mesangial The glomerulus (plural glomeruli) is a network of small blood vessels (capillaries) known as a ''tuft'', located at the beginning of a nephron in the kidney. Each of the two kidneys contains about one million nephrons. The tuft is structurally s ...
proliferation is caused by activated platelets. Another mechanism involves antibodies formed against alpha-3 chain of collagen IV. Their deposition occurs in the sub-epithelial spaces. This causes proteinuria by damaging the
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
and creating a loss of negative charge. These are anionic deposits that fail to cross the membrane. Cationic deposits that cross the membrane are then deposited into sub-epithelial spaces. Then the disease advances and crescents are formed. Crescents are a combination of epithelial cells, activated
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, and
fibrin Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
. They lead to rupturing of small blood vessels, ultimately causing
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
and sclerosis.


Basic Summary

The glomeruli are the filters in the kidneys. When working normally they will move the waste, excess electrolytes, and unnecessary fluid from the bloodstream to the urine. When a person develops DPGN, over 50% of the glomeruli (diffuse) become inflamed. There is also an increase in
mesangial The glomerulus (plural glomeruli) is a network of small blood vessels (capillaries) known as a ''tuft'', located at the beginning of a nephron in the kidney. Each of the two kidneys contains about one million nephrons. The tuft is structurally s ...
, epithelial, and endothelial (proliferative) cells. Inflammatory cells are also rapidly developed. This causes damage to the kidneys and does not allow for proper filtration.


Diagnosis

The presentation of all types glomerulonephritis are the same. If a patient is suspected to have DPGN, a blood and urine test will be done first. A urine test will be done to determine if there is protein or blood in the urine. A blood test will be to measure the levels of creatine in the blood. An ultrasound will be done to see if there is inflammation of the kidneys and to look for blockages. A kidney biopsy is the most important diagnostic tool. With a biopsy, the sample will be looked at histologically. With this information, a proper diagnosis can be completed. There are many forms of glomerulonephritis, but under a microscope, DPGN will show increased cell count of
polymorphonuclear Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...
cells, cellular crescents, and fibrinoid necrosis. A patient with DPGN will have more than 50% of their glomeruli involved. If a patient has DPGN, that means they have an active form of glomerulonephritis.


Treatment

Treatment of DPGN depends on the severity of the disease. An optimal treatment for DPGN is
immunosuppressive therapy Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
. Two common immunosuppressive drugs used to treat DPGN are
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
(CYC) and mycophenolate mofetil (MMF) if the DPGN is caused by SLE. CYC and MMF both preserve the renal function in patients with SLE and DPGN. CYC and MMF have been known to improve proteinuria. There can be adverse side effects; including CYC can cause
infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
in both women and men. MMF has been seen to have less
drug toxicity An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...
. There are a variety of dosing options (oral or intravenous medications) available. If the DPGN is caused by IgA nephropathy then
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s,
angiotensin-converting enzyme inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volum ...
(ACEIs), angiotensin receptor blockers (ARBs), or both ACEIs and ARBs should be used. Corticosteroids are used to suppress the immune system and to reduce inflammation. ACEIs will decrease hypertension by preventing the body from creating
angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
, which narrows the blood vessels. ARBs block angiotensin II from acting. The patient's diet should also be changed. The patient should restrict salt intake to improve the hypertension and nephrosis. Protein restriction may reduce the progression of the disease. Fluid restriction may also be necessary if the patient is experiencing edema.


Prognosis

Prognosis is determined by the stage of the disease. Aggressive therapy is recommended to avoid progressing to end-stage renal disease (ESRD), which is a strong possibility. About 10% of DPGN patients will go into ESRD. If the biopsy shows the presence of crescents, tubule-interstitial injury with inflammation
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
and fibrosis, the outcome is worse. Other factors that will influence the survival rate are the severity of proteinuria,
blood urea nitrogen Blood urea nitrogen (BUN) is a medical test that measures the amount of urea nitrogen found in blood. The liver produces urea in the urea cycle as a waste product of the digestion of protein. Normal human adult blood should contain 6 to 20 mg/dL ...
levels, serum creatine levels, and eGFR. Other bad prognosis features are the presence of hypertension, accelerated hematuria, and hypoalbuminemia. Males are at a higher risk factor than females. Overall, about 50% of patients with DPGN require daily dialysis within 6–12 months after disease presentation. The percentage of glomeruli that show crescents usually correlates to the severity of the renal failure. The survival rate after 5 years is about 30%.


Epidemiology

DPGN prevalence varies among races. Whites are the less likely to have DPGN (12-33%); while African Americans (40-69%), Hispanics (36-61%), and Asians (47-53%) are more likely to develop it. Men are more likely to develop a more aggressive disease than women. However, women are nine times more likely to develop DPGN. DPGN occurs in all age groups, but is more prevalent in women of childbearing years. Eighty-five percent of patients develop DPGN before 55 years.


End Stage Renal Disease

* About 38% of people with ESRD will be diagnosed with DPGN. * In the United States, about 4.5 per million cases of ESRD are caused by DPGN.


Research Directions

In 2014 a study was completed to diagnose glomerulonephritis based on etiology. Using
immunofluorescence Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specif ...
and
light microscopy Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
, the investigators were determining the classification for the disease based on if the disease was immune complex mediated, pauci- immune, or complement mediated. They then looked at the
complement factors The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
and
immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
deposits to identify the underlying cause. The aims of this study were classifying pathophysiology and to obtain a better understanding of glomerulonephritis. Much of the research within the last 10 years has been to identify the best treatment for DPGN. Other studies about DPGN from the past 10 years has included studies for other diseases that are linked to DPGN. There are no current clinical trials for DPGN happening.


Future Studies

Activating complement pathways plays a large role in mediating inflammation. The
classical pathway Classical may refer to: European antiquity *Classical antiquity, a period of history from roughly the 7th or 8th century B.C.E. to the 5th century C.E. centered on the Mediterranean Sea *Classical architecture, architecture derived from Greek and ...
, lectin pathway, and
alternative pathway The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections. The alternative pathway is one of three complement pathways that opsonize and ...
of complement are all involved in glomerulonephritis, depending on the etiology. Inactive and active complement proteins that split fragments are found in the glomeruli. There are currently drugs available that will target the complement pathway. It has been proposed that if fluorescently tagged antibodies were used to target different split products of the complement proteins, then identification of specific pathways involved and the accumulated complement proteins in the glomeruli should be achievable. This would lead to identifying which pathways and proteins drive each type of glomerulonephritis.


References


External links

{{Glomerular disease Kidney diseases