RARE CASE SCENARIO Name: Mrs A, Age: 34years, Sex: female, Occupation: house maker Marital status: married

Presenting complaints: Family history: Generalised swelling of body since fifteen days duration, Fever, myalgia, multiple joint pain, Rash over extremities (L>U) for fifteen days duration Cough with expectoration since five days, SOB since five days. Decreased urine output since three days. Family history: No history any renal disease in family Personal history: Irregular mensural cycles, Mixed diet, bowel movements regular No substance abuse Past history: Hypothyroidism since one year on Thyronorm 50 ug/day. No Diabetes mellitus, Hypertension or Bronchial Asthma or Tuberculosis

Examination: Pulse rate : 100/min, Blood Pressure: 152/100 mmhg, Respiratory rate: 20/min Temperature normal pallor present, anasarca present. Palpable rash present on extremities (L>U). No lymphadenopathy. Wt-50kg, Ht-159cm, BSA-1.5m2, BMI-19.8. Systemic examination: RS: Breath sounds decreased bilaterally (R>L) CVS: Tachycardia, P/A: ascites present, no organomegaly. CNS: HMF normal, no focal deficits.

Blood biochemistry BLOOD UREA NITROGEN 60mg/dl SERUM CREATININE 2.3mg/dl SODIUM/POTASSIUM/CHLORIDE 136/4.2/98meq/ml BILIRUBIN 1.2mg/dl SGOT/SGPT 40/33 ALP 142iu/ml TSP/ALBUMIN 5.2/2.8 mg/dl TOTAL CHOLESTEROL 145mg/dl LDL 95mg/dl TRIGLYCERIDES 156mg/dl CALCIUM/MAGNESIUM/UA/PHOSPHRUS 8.5/1.2/6/3.3 mg/dl FBS/PPBS 92/141mg/dl Iron/%saturation/TIBC/ferritin 102/45/255/158 PT/aPTT 12.2/30.2 CRP 4mg/dl PROCACITONIN 4.5 T3/T4/TSH 1.1/8.2/25.3 LDH 401 24HOUR TV/TP 900ML/0.72grams/day C3 13mg/dl C4 2mg/dl Pleural fluid analysis transudative

pathology Hb% 7.2gm% PCV 25.3 TLC 9200 PC 1.2 PERIPHERAL SMAER Macrocytic and microcytic anaemia, no schistocytes, no parasites ESR 49ml/2hr CUE-pH 7 SG 1.010 PROTEIN 2+ SUGAR Nil EC 2-3 RBCs 8-10 WBCs 3-5

Imaging studies Chest X-ray Bilateral pleural effusion(R>>L) with underlying lung consolidation HRCT Thorax Bilateral moderate to severe pleural effusion(R>>>L) with underlying lung consolidation with scattered lung infiltrates, mediastinum was normal USG abdomen and pelvis Gross ascites, no organomegaly, both kidneys are normal in size with raised echotexture and maintained CMD, Pelvic organs are normal. 2D-ECHO EF-55%, NO RWMA, grade 1 DD+, RSVP- 25mmhg

Microbiological investigations Urine culture No growth Blood culture(1set) Sputum culture TB screening negative Mountau text <5mm after 72 hours Immunology/serology Hbsag ( ELFA) neg Anti HCV Ab (ELISA) HIV(ELISA) NR ANA(IF) 3+ (speckled, 1:100) DsDNA c&p ANCA ASO titre Neg(<200) Rheumatoid factor 161IU/ml POSITIVE(>20IU/ml)

Provisional diagnosis Rapidly progressive renal failure Hypertension Hypothyroidism Mixed anaemia LRTI

Initial management Diuretics Antibiotics Two unit blood transfusion Other supportive measures IVMP 1gm pulses for three days.

Renal biopsy(8365/18)

Special investigations Serum IgG 875mg/dl Serum IgE 480mg/dl Serum IgA 179mg/dl Serum free light assay Kappa-8mg/dl, lamda-15mg/dl. ( ratio <2) Urine BJPs absent Serum electrophoresis Negative for M band Urine electrophoresis Normal pattern DCT/ICT NEGATIVE BONE MARROW EXAMINATION NORMAL

SERUM CRYOGLOBULINS

SKIN BIOPSY(8465/18) C3 IgG

FINAL DIAGNOSIS CRYOGLOBULINEMIC GLOMERLUNEPHRITIS WITH SKIN INVOLVEMENT IDIOPATHIC (ESSENTIAL) MIXED CRYOGLOBULINEMIA HYPERTENSION HYPOTHYROIDISM ANAEMIA OF CHRONIC INFLAMMATION

MANAGEMENT Antihypertensives( tab cilnidipine 10mg OD) Diuretics IVMP 1gm for three days and iv cyclophosphamide 1gms ( NIH protocol). Followed 0.5mg/kg oral prednisolone. Other supportive treatment. KDIGO Recommendations: Among MPGN patients with nephrotic-range proteinuria and/or rapid loss of kidney function and an acute flare of cryoglobulinemia, one of the following therapies should be considered: Plasma exchange (3 liters of plasma thrice weekly for two to three weeks) Rituximab (375 mg/m2 per week for four weeks); OR Cyclophosphamide (2 mg/kg per day for two to four months) Plus Methylprednisolone pulses (0.5 to 1 g/day for three days).

Patient follow-up after month Complaints- SOB on exertion, BP-140/70mmhg Weight-45kg No anasarca, pallor present, resolving rash. Systemic examination is normal. Received 2nd dose cyclophosphamide 1gm on 10/10/2018 Hb% TLC PLATELET BUN SCR 24HR TP TSH CUE-PRO RBCs Pus cells 7gm% 6200 1.5 36 1 0.45gm/day 3.5 1+ nil 1-2

Discussion Cryoglobulins are immunoglobulins in serum that precipitate at temperature below 37⁰C and re-dissolve on rewarming.

SUMMARY AND CONCLUSION Cryoglobulinemia is a rare clinical entity. Renal involvement varies from 8-58% of cases Awareness of its clinical spectrum is important, because diagnosis is facilitated by the demonstration of cryoglobulins in the serum. Treatment is challenging, given the end-organ damage and frequent relapses. Uniform management guidelines are difficult because of heterogeneity.