Membranoproliferative Glomerulonephritis and Cryoglobulinemic Glomerulonephritis



  • Membranoproliferative glomerulonephritis  is a form of glomerulonephritis (GN)
  • It is also known as membranous nephropathy / Hypocomplementemic /

mesangiocapillary glomerulonephritis 

  • It is considered as a combination of both nephrotic and nephritic syndrome 
  • It is placed under the proliferative group of glomerulonephritis 
  • To define the term in detail  “Membrano” stands for membrane or basement membrane”Proliferative stands for proliferation or cell division Glomeulo stands for Glomeruli, Nephritis stands for inflammation to kidneys 
  • Altogether, It is defined as the inflammatory damage to the glomerular  basement membrane of  kidneys with the(proliferative)changes in the cells of capillary loops
  • Due to the proliferation of cells the thickening of basement membrane happens 


How inflammatory damage will happen?


To put it in simple terms …


  • The damage is caused by abnormal immune response created by antigen -antibody interaction 
  • These antibodies in your body attack some unknown (or) known antigens. These immune complexes get stuck in your kidneys and cause damage.
  • Often Most of the people present to show autoantigens towards their own antibodies in the bloodstream  or antibodies formed outside the kidney targeting basement membrane 
  • So,this results in production of those immune complexes which have more affinity towards the glomerular basement membrane (GBM)
  • Antigen-antibody deposits sediments at the subendothelial layer of GBM 
  • These are called as subendothelial deposits because they are sandwiched between basement membrane ,epithelial cell or podocytes of Glomeruli 
  • Deposits further on thought to activate the complement system cascade of enzyme activation ultimately forms the membrane attack complexes 
  • Overtime ,these immune deposits make the layer thickened 
  • They directly attack & damage the cells called as podocytes,mesangial cells which work on removal of debris 
  • In addition to that it also allows to engage with other inflammatory mediated cells to participate and encourages to devastate the membrane
  • Finally ,provide a route to letting out the desirable contents  out inthe form of   urine .This is known as a ‘ Leak ‘
  • Due to  this damage ,it results in increased permeability and protein being able to filter out through urine causing NEPHROTIC SYNDROME  
  • Sometimes also causes NEPHRITIC SYNDROME 




There are many reasons for possible etiology  to happen 

Immune Complex


Infections includes

  • viral -hepatitis B,C
  • Bacterial-endocarditis ,visceral abscesses ,VA shunt ,leprosy
  • Protozoal -malaria ,mycoplasma,leishmaniasis 

Autoimmune disorders includes 

  • Systemic lupus erythematosus (SLE),sjogren’s syndrome, Rheumatoid arthritis,scleroderma  

Complement mediated 

  • Mutations in complete regulating proteins 


  • Antibodies against complement regarding proteins 


  • Mutations in complement factors 

Non-complement mediated 

  • Radiation nephritis
  • Nephropathy due to marrow transplant 
  • Drug associated 
  • Sickle cell anemia ,polycythemia, leukemia,lymphomas  
  • Transplant glomerulopathy



Unknown cause or malignancies 





Plasma protein in the urine more than 3.5g/day

Happens due to leak of plasma proteins through urine 




blood in  urine 




Due to decreased albumin (a protein which is responsible to  keep up the fluidity in the bloodvessel) it decreases the overall osmotic pressure  which drives out the water from blood to tissues 

This leads to retention of fluid known as edema 




Color appearance is due to protein or blood in urine 

Usually pink or cola coloured 




As tissues which are primarily responsible for filtration is damaged slowly loses their ability to function and form urine 




Losing attention towards daily activities or talking with peers is affected due to unhealthiness 




Inhibition of synthesis of lipids or fats occurs which rises the elimination of lipids through urine 




Increase in blood pressure 




 increased levels of lipid or fats in the blood 




They are histologically 3 types of MPGN 


Type I – Classic form or subendothelial Immune Complex deposition 

Type II-Dense deposit diseases or intramembranous deposition 

Type III-Mixed

Type I


  • Mostly affects adolescent and young adults
  • More than 50%chance + nephrotic syndrome
  • 15-20%+nephritic syndrome
  • Recurrence is present in children after transplantation
  • Mostly occurs secondary to infections or due to autoimmune diseases 


Few key Histological features include 


  • Irregular thickening by interposition of mesangial cells  between endothelium and basement membrane
  • Mesangial ,endocapillary hypercellularity
  • On staining with periodic acid schiff’s(PAS)

It resembles a characteristic tram track appearance/ double contour 

  • Immune complex aggregates form thrombi in the capillary  lumen  and also Inflammatory cells such as neutrophils may present  
  • Flattening of foot process of podocyte cells


Immunofluorescent appearance shows  granular appearance 

Type II


  • More aggressive than type I
  • Due to uncontrolled activation of alternate pathways
  • Presence of high deposits in forms of ribbon
  • Can cause due to infections or familial
  • Present with nephrotic syndrome 
  • They do deposit in other parts of body such as spleen or retina of the eye
  • Recurrence is very high after transplantation with poor prognosis over time 


Few key Histological features include 

  • Less cellular proliferation compared with type I
  • Ribbon like thickening is present at basement membrane of Glomeruli,tubules and bowman’s capsule  hence the name dense deposit disease
  • Results shows positive when stained with PAS & silver stain shows pale thickening 


 Immunofluorescent appearance shows discontinuous , granular appearance with thick ribbon like membrane walls


Type III


  • Shows both sub endothelial or epithelial deposits 
  • Clinically similar to type I
  • There are 2 other variant subtypes 
  • Idiopathic 




Traditionally basic tests are initially done to rule out the cause of disease 


1.Blood Analysis


  • It is usually done to check the levels of lipids/fats ,proteins or any residues in the blood 
  • To Check for the cell profile because of the inflammatory reactions or infections it alters 
  • Blood cultures will also help to evaluate 


2.viral serology 


  • Used for the examination and evaluation of certain viral load infections such as hepatitis B,C by Polymerase chain reaction (PCR)


3.urine and stool test 


  • Will helps to find out the protein and blood levels in urine
  • Urine analysis to check complement levels  
  • If in cases of known or unknown history  of parasitic  diseases




  •  for any valvular vegetations


5.bone marrow evaluation 


  • any dyscrasias or lymphoproliferative causes 


6 serum electrophoresis 


7.Glomerular filtration rates 


  • These rates ensure how well the kidney is performing to remove debris or other contents 




  • To evaluate any benign or malignancies or associated tumors 


9.gene testing 


  • In case of positive family history of MPGN or abnormal renal conditions 




  1.  Before proceeding to get treated  the specialist should know the possible etiology and treat underlying disease or secondary cause accordingly.If not the cause doesn’t get cured and everything goes in vain 

     2)   The treatment is given to manage your symptoms and prevents it from progression


     3) Palliative treatment is given based on symptoms 

a .Corticosteroids used to prevent the further damage caused by immune complexes 

  1. Antihypertensive drugs such as angiotensin converting enzyme inhibitors or ARE inhibitors angiotensin renin blockers or ARB ‘ s to control blood pressure 
  2. Diet with less protein and sodium intake 

d .Immunosuppressive drugs for maintenance or induction phase of disease 

e.physical and mental exercises can be done .strenuous exercises are needed to avoid and mindful asanas like yoga , meditation can improve health and ability to concentrate 

     4)   If the cause is primary or idiopathic 

  •  Advices supportive care &


      5)  cause is  idiopathic with proteinuria less than 3.5 grams per day with no nephrotic syndrome and normal eGFR then 

  • Advise supportive therapy 
  • Medications 

      6) idiopathic with nephrotic syndrome and near or normal serum protein 

  • Advise use of steroids with limited course

If untreated , membranoproliferative glomerulonephritis end up in chronic renal failure ,uncontrolled diabetes and hypertension may even lead to coma and death 




  • It also depends on the underlying secondary disease .
  • Successful treatment of secondary diseases can bring up with good prognosis 
  • As type I progresses slowly it has better time to get treated than type II
  •  The overall prognosis is poor with high recurrence rates 






  • The term description is as follows ” cryo ” means low temperatures globulin means a immunoglobulin which is protein in nature “anemic” means the cryoglobulins in blood whereas Glomerulo means glomeruli  , nephritis means inflammation to nephrons
  • It is described as a disease which occurs due to presence of cryoglobulins  present in the blood  precipitates out at cold temperatures and cause organ damage
  • These cryoglobulins get dissolved when rewarmed  and get precipitated in colder temperature 
  • Most of the types are asymptomatic but few are symptomatic 
  • may be associated with membranoproliferative glomerulonephritis or represent the similar to MPGN intraluminal deposits (immune microthrombi) which are suggestive findings of cryoglobulinemia


Type I is seen in lymphoproliferative diseases whereas type II is associated with chronic Inflammatory diseases ,rarely in proliferative diseases  


  •  Females are more prone than males 
  • Age between 45-55 years 
  • Can occur in presence of infections mainly Hepatitis C,B 
  • Autoimmune diseases 
  • monoclonal gammopathies  
  • Blood cell abnormalities such as multiple myeloma or lymphoproliferative diseases
  • Idiopathic or even familial ,certain vaccinations( sometimes )




Immunoglobulins are divided into two types as monoclonal (bond only to single antigen)

or polyclonal type (have multiple sites for different antigens)

There are classified as 3 types based on type of immunoglobulin composition 


Type I 


  • Simple and classic form of cryoglobulinemia 
  • It is a lesion composed only of monoclonal immunoglobulin 
  • Cryoglobulin are usually Ig G/M but ig A and monoclonal with cryoglobulins free light chains may occur 
  • Resulting mainly from underlying hematologic malignancy or lymphoproliferative disease 
  • If Absence of malignancy is known then diagnosis  for Monoclonal gammopathy Renal Significance or MGRS  is established 
  • Usually asymptomatic 
  • Nephropathy usually occurs in about 25-30 % of people with type I cryoglobulinemia
  • Renal diseases can be manifested in approximately 20-60% of patients 
  • MPGN is Manifested  as proteinuria or hematuria sometimes as nephrotic syndrome 


Type II


  • Mixed type with mixture of  monoclonal immunoglobulin M with Rheumatoid factor and  bound to polyclonal heavy chains 
  • Activating directed directly against a polyclonal igG
  • Occurs due to chronic infection such as HCV mostly ,HBV or HIV 
  • Can also occurs by autoimmune diseases , particularly sjogren’s syndrome 
  • In HCV patients this is considered as first manifestation of renal disease 
  • Usually symptomatic or sometimes asymptomatic



Type III


  • It is a mixed type of cryoglobulinemia Composed only of polyclonal immunoglobulin G/M
  • Overlap between underlying cause of type II and III Cryoglobulin
  • Mostly seen in HCV infected patients as well as by inflammatory or autoimmune disease



  1. Deposition in the arteries ,arterioles or small capillaries by immune complexes formed by antigen and antibody clinical manifestations occurs 
  2. Commonly associated with HCV infection
  3. If symptomatic effects 
    • Skin
    • Kidney
    • Intravascular injury
    • Nerves 
  4. Clinical manifestations include  



  1. Skin


  • Red ,non blanching macules and papules is visible
  • Visible in 90%of cases 




  • Blueness at the end of digits of extremities due to limited supply of oxygen 


               c.Raynaud’s disease 


  • In Response to cold temperatures the arteries gets constricted and don’t supply blood adequately to affected organ 


  1. Livedo Reticularis 


  • This is also happens due to temperature the skin surface looks mottled over the surfaces commonly over lower extremities 






                  Membranoproliferative glomerulonephritis  manifested as proteinuria and hematuria 


  1. Thrombosis


           Present mostly in type I which lead to renal injury 




  1. Intra Articular injury 


        Arthritis may not present ,but may cause symptomatic arthralgia or weakness mostly in type II & III


[iv]   Nerves 


          Manifested occasionally

They are multiple non contiguous  and nerves being inflamed                


    Few others include 


  • Renal insufficiency 
  • Fatigue 
  • Peripheral neuropathy
  • Necrosis at end of the digits 
  • Pulmonary infiltrates 
  • Mesenteric ischemia 


Clinical presentation 


  • Varies from type to type from microscopic hematuria with low grade proteinuria full blown nephrotic or nephritic syndrome or associated with both 
  • There is an common estimated  risk of hypertension which is  high and severe 
  • Long-term prognosis is determined by the presence of renal disease and lead to substantial increase in mortality 




  • Can be evaluated based on C3 /C4 levels Associated with rheumatoid factor
  • 30-40% of cryoglobulins are not detected as in type II & type III 
  • IF decreased levels of C4 and presence of high titres of Rheumatoid factors can be indicative of type II or III Cryoglobulinemic glomerulonephritis 
  • To detect cryoglobulins ,it is warmed at temperatures to 37° C without anticoagulant
  • If in presence of anticoagulants may cause false positive results 
  • Renal disease is present 
  • Renal biopsy shows more than 80% of lesion as Membranoproliferative glomerulonephritis 
  • Light microscopy shows increase number of macrophages more when compared with MPGN with intraluminal thrombi 
  • Positive with PAS stain with hyaline like deposit
  • Composition of intraluminal thrombi consists of precipitated cryoglobulins 
  • On Immunofluorescence shows diffuse deposition of IgM in capillary loops 

In Electron microscope reveals a characteristic appearance made by subendothelial deposits has fingerprint pattern 





Treatment should be done for the secondary underlying infection mostly HCV if not the spread of disease continuous and contributes unhealthiness of the patient 


  • If patient has HCV infection associated with glomerular disease is in stable condition and proteinuria is of non nephrotic origin then it is treated with Direct acting antiviral (DAA)drug therapy 
  • If the treatment is working then the possible symptom of proteinuria is decreased and HCV clearance is noticed 
  • If patient has rapidly  progressive kidney disease then the treatment includes DAA + immunosuppressants +with or without plasma exchange 
  • Highly active HCV is present then Rituximab or plasmapheresis  is prescribed as 1st line therapy of immunosuppressive agents 
  • Sometimes suppression of b cell synthesis is helpful which further decrease the release of immunoglobulins which are responsible for disease
  • Avoiding NSAIDS can relieve symptoms 




Purely depends upon the underlying disease of patient is present with concomitant renal disease then the overall prognosis is known to be worse 

If not(infections) then the prognosis is manageable and reversible 




  •           Congestive heart failure
  •           Acute kidney injury 
  •           Pericarditis
  •           Respiratory distress
  •           Necrosis 
  •           Gangrene 
  •            Coma or death 



  • These type of diseases are described as histological damage  rather than a clinical entity
  • Even Though they are rare they do need attention if not can lead to irreversible organ damage 
  • Patient education is required to inform regarding the complications or the symptoms
  • Long-term survival is not better but still early detection and prevention can helps to achieve overall goal of treatment to be long-term and successful 
  • Expert visits and approaches can be beneficial 

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