it is classified into type 1 ( monoclonal due to paraprotein disorders ) , type 2 ( mixed polyclonal and monoclonal secondary to hepatitis c ) , and type 3 ( polyclonal due to lymphoproliferative disorders ) .
the most common type described in the literature is secondary to hepatitis c , with a prevalence described as high as 50% .
renal disease in mixed cryoglobulinaemia is present in approximately 20% of patients at the time of diagnosis
. clinical presentation encompasses a wide variety of features from generalised bruising , hepatosplenomegaly , and acute renal failure to peripheral neuropathy and hypocomplementaemia [ 3 , 4 ] .
endocapillary proliferation , intraluminal thrombi , and thickening of the glomerular basement membrane are the most specific histological findings for type 2 cryoglobulinaemia .
the current mainstay of management includes plasmapheresis with high - dose prednisolone and cyclophosphamide and treatment of the underlying cause .
rituximab is a monoclonal anti - cd20 antibody used in the treatment of a variety of autoimmune diseases .
we describe a case of type 2 mixed cryoglobulinaemia associated with non - hodgkin 's lymphoma successfully treated with rituximab .
a 61-year - old female presented with severe community - acquired pneumonia complicated by acute renal failure .
the renal failure was attributed to acute tubular necrosis secondary to sepsis and hypotension . at that time
the patient was discharged home after 45 days of hospital stay with normal renal function .
she represented with acute pulmonary oedema and skin rash , requiring readmission to the intensive care unit within 48 h of discharge .
physical examination was consistent with pulmonary hypertension , splenomegaly , hepatomegaly , and bilateral pleural effusion .
her positive investigations were : dysmorphic red cells in urine , proteinuria ( 24-hour urine protein 1 g ) , hypoalbuminaemia ( serum albumin 24
g / l ) , low complement levels , and positive serology for mixed cryoglobulinaemia .
rheumatoid factor was weakly positive and hcv rna was negative , as were all other autoimmune screens .
renal biopsy revealed diffuse mesangiocapillary glomerulonephritis accompanied by hyaline capillary thrombi with focal mild endarteritis affecting the intimal zone of one small artery consistent with cryoglobulinaemic vasculitis ( fig . 1 , fig .
the patient was treated with 5 sessions of plasma exchange and 2 sessions of haemodialysis over 1 week , followed by prednisolone and cyclophosphamide .
there was a good initial response with a decrease in cryoglobulin levels within 3 weeks and symptomatic improvement .
the patient was discharged on prednisolone 50 mg daily , and her renal function was normal on discharge . however , she became symptomatic again on prednisolone after 2 weeks , with reappearance of rash .
the patient 's urea level was disproportionately high ( with steroids and diuretics on board ) compared to her creatinine level .
she required 5 sessions of plasmapheresis and was recommenced on reduced cyclophosphamide with a dose of 50 mg/100 alternate days .
cyclophosphamide was ceased due to recurrent thrombocytopenia , sepsis , and herpes zoster of the chest wall on the left side .
she was commenced on intermittent haemodialysis ( for better control of uraemia and fluid retention ) and plasmapheresis on alternate days for 1 month .
mg / l ) , but negative bence jones protein in urine , normal skeletal survey , and no light chains in the serum .
her bone marrow biopsy showed a low - grade lymphoma with predominant cd20 expression on b cells .
as the patient was not showing any clinical improvement and was requiring regular dialysis / ultrafiltration , second - line treatment was discussed .
she was given 600 mg rituximab / week for 3 weeks in addition to prednisolone and responded within 1 week , with dramatic improvements in symptoms , absence of cryoglobulins , and normal complement levels .
in view of her multiple prior infections ( pneumonia , herpes zoster , and urosepsis ) , it was decided to administer only 3 doses of rituximab .
her renal function gradually improved , and she became dialysis independent after 7 months , with complete renal recovery .
cryoglobulin titres have remained negative and serum complements normal over the current follow - up of 24 months .
non - hodgkin 's lymphoma - associated cryoglobulinaemia presenting with acute renal failure is uncommon . to our knowledge , this is the first case report of a patient with mixed cryoglobulinaemia associated with non - hodgkin 's lymphoma who presented with nephritis and acute renal failure [ 7 , 8 ] .
our patient was responsive to prednisolone , plasmapheresis , and cyclophosphamide but had a recurrence which was resistant to cytotoxics , steroids , and plasma exchange .
rituximab has been shown to be useful in essential and secondary cryoglobulinaemia [ 7 , 9 ] .
it is a human - mouse chimeric monoclonal antibody that reacts with cd20 antigen , a transmembrane protein present in different maturation steps of b lymphocytes ( from early pre - b to mature lymphocyte ) , thus directly and selectively targeting b cells and suppressing the production of rheumatoid factor [ 7 , 10 ] .
rituximab has proved effective and very well tolerated in b - cell non - hodgkin 's lymphomas [ 7 , 11 , 12 ] , but there are conflicting case reports as well [ 13 , 14 ] .
rituximab has the advantage of allowing avoidance of serious immunosuppression and side effects [ 7 , 11 ] and it lacks direct oncogenetic properties that could favour the progression of indolent lymphomas into an aggressive lymphoma .
although a complete and long - term remission of lymphoma is obtained in a minority of cases after rituximab monotherapy , this case is unique for the fact that our patient has not shown signs of clinical or serological recurrence for 24 months after treatment with rituximab .
she has not required maintenance therapy , although concerns about rituximab not being curative and need for ongoing rituximab maintenance therapy have been raised .
the patient showed complete recovery with regard to renal function , although acute renal failure on presentation in mixed cryoglobulinaemia implies poor prognosis .
the usual regimen consists of 375 mg / m with 1 dose per week for 4 weeks .
the fourth dose was not given because of pancytopenia secondary to cytotoxics and sepsis predating the use of rituximab .
our case report highlights the ongoing necessity for further exploration of new therapeutic agents in the treatment of resistant cryoglobulinaemia associated with lymphoma .
no study has yet examined the efficacy of rituximab in mixed cryoglobulinaemia in a prospective controlled manner .
the current literature is restricted to case reports and case series , and further prospective study is needed to fully determine the role of rituximab .
resistant cryoglobulinaemia is a life - threatening condition , and the optimal management is unknown at this moment .
rituximab has emerged as a well - tolerated and effective treatment with no long - term oncogenetic potential , which was confirmed by this case report .
 cryoglobulinaemia is a systemic inflammatory condition characterised by immune complex - mediated small - to - medium - sized vasculitis . 
 it has a wide variety of presentations ranging from bruising , neuropathy , and hepatosplenomegaly to acute renal failure . 
 mixed cryoglobulinaemia is the most common type and is strongly associated with hepatitis c. management approaches include use of cyclophosphamide , prednisolone , and plasmapheresis , with differing views on alternative treatments in resistant cases . 
 rituximab has emerged as an attractive option in resistant cases on account of its potent immunosuppressive effects on b cells . 
 we describe a case of type 2 mixed cryoglobulinaemia in association with non - hodgkin 's lymphoma resistant to standard treatments which responded well to rituximab . 
 this case is remarkable as mixed cryoglobulinaemia associated with non - hodgkin 's lymphoma presenting with nephritis is unusual , and , contrary to the high rate of recurrence in lymphoma - related cryoglobulinaemia , our patient has not shown any recurrence over 24 months . 
 this highlights an alternative treatment modality which can be used in patients not responsive to existing managements for this condition with benefits of minimal side effects and no oncogenetic potential . 
Background
Case Report
Discussion