MATERIALS AND METHODS
STUDY DESIGN: Prospective observational cohort study.
PATIENT RECRUITMENT: All patients presenting at Outpatient Department and Inpatient Department in the Department of Nephrology, PGIMER, Chandigarh or seen in other departments as nephrology consultation, between July 2014 and September 2015 were screened for IgG4 related kidney disease in case of following conditions:
1. Unexplained acute kidney injury or acute kidney disease.
2. Unexplained urinary abnormalities.
3. Renal involvement with conditions known to be associated with IgG4 related disease. These include:
i. Autoimmune pancreatitis
ii. Retroperitoneal fibrosis or mediastinal fibrosis
iii. Mikulicz disease
iv. Large vessel vasculitis
v. Reidel’s thyroiditis
vi. Sclerosing cholangitis and cholecystitis
vii. Inflammatory pseudotumor of lung, alveolar interstitial disease.
4. Renal imaging suggestive of IgG4 related kidney disease (as per Japanese criteria 2011).
5. Histology suggestive of IgG4 related kidney disease.
INCLUSION CRITERIA:
Patients fulfilling the Japanese Society of Nephrology criteria31 for IgG4-related kidney disease were included in the study.
1. Clinical features
Clinical or laboratory evidence of kidney damage, including abnormal renal function or abnormal urinalysis with elevated serum IgG or IgE level or hypocomplementemia
2. Imaging Abnormal radiographic findings: multiple low-density lesions on contrast-enhanced computed tomography scan, diffuse kidney enlargement, hypovascular solitary kidney mass, hypertrophic lesion of the renal pelvic wall
3. Serology Elevated serum IgG4 or total IgG level
4. Histology
(a) Dense lymphoplasmacytic infiltrate with>10 IgG4+ Plasma cells/hpf and/or IgG4/IgG+ plasma cell ratio of>40%
(b) Characteristic storiform fibrosis
5. Other organ involvement Characteristic histologic findings of IgG4-RD in other organs
Definite： Clinical + Serology + Histology (a + b)
Imaging + Serology + Histology (a + b)
Imaging + Serology + Histology (a) + Other organ involvement
Imaging + Serology + Other organ involvement
Probable：Clinical + Histology (a + b)
Imaging + Histology (a + b)
Imaging + Other organ involvement
Serology + Histology (a) + Other organ involvement
Possible：Clinical + Serology
Clinical + Histology (a)
Imaging + Histology (a)
EXCLUSION CRITERIA:
• Any definite etiology of renal impairment
• History of steroid intake within last 3 months
• Patient not giving consent.
Methodology:
After informed consent, patients with suspicion of IgG4 related kidney disease were screened in terms of following parameters:
1. Clinical: Standardized precoded history and standardized thorough physical examination (Annexure 1: Pro forma)
2. Imaging: NCCT/CECT KUB depending upon renal function (wherever required)
3. Serology: Serum IgG4 levels and serum total IgG levels (by ELISA) and IgG4:total IgG ratio
4. Histology: Renal biopsy for light microscopy and immunoflorescence when clinically indicated.
Patients satisfying the inclusion criteria (Japanese Society of Nephrology criteria for IgG4-related kidney disease) were taken up in the study.
Following clinical, laboratory and histological factors were analysed:
1. Clinical:
– Age
– Sex
– Presence of Hypertension/ Diabetes Mellitus (yes/no)
– Known case of extra-renal IgG4 RD (yes/no)
– Number and type of organs involved
– Duration of symptoms
– Presence of constitutional symptoms (fever/anorexia/malaise) [yes/no]
– RRT requirement at presentation (yes/no)
2. Laboratory:
– Complete haemogram including haemoglobin (Hb), total leukocyte count and platelet count.
Anaemia was defined as Hb < 12 gm/dl in females and < 13 gm/dl in males.
Thrombocytopenia was defined as platelet count < 1 lac/mm3 and platelet count > 4.5 lac/mm3 was considered thrombocytosis.
TLC between 4,000 and 11,000/mm3 was taken as normal.
– Liver Function Test including bilirubin, Aspartate transaminase (AST), Alinine transaminase (ALT), Alkaline phosphatise (ALP)
– Serum creatinine and estimated Glomerular Filtration Rate (eGFR) (by modification of diet in renal disease (MDRD) method] at presentation.
– Urine routine and microscopy for proteinuria and hematuria.
– 24 hour urine protein estimation:
Nephrotic range proteinuria was defined as 24 hour urine protein > 3.5 gm.
– Serum IgG4 levels (Normal: 7 – 60 mg/dl)
– Total Serum IgG:
Total IgG levels were done in patients finally diagnosed as IgG4 RKD.
Total IgG level >1640 mg/dl was considered elevated.
– IgG4:IgG ratio
– ANA
– ANCA
3. Histopathology:
– TIN (yes/no)
– Degree of lymphoplasmacytic infiltration
– Ratio of IgG4+:IgG+ plasma cells
– Presence of associated glomerulonephritis
– Immune complex deposition in TBM
– Degree of fibrosis
– Eosinophilic infiltration
4. Radiology (CT abdomen)
– Multiple low-density lesions
– diffuse bilateral renal swelling (in case of NCCT)
– diffuse thickening of the renal pelvis wall with smooth intra-luminal surface
– hypovascular solitary nodule of the renal parenchyma
Treatment protocol:
Prednisolone at a dose of 0.6 mg/kg/day for 2 to 4 weeks.
Prednisolone was tapered over a period of 3 to 6 months to 5.0 mg per day and then was planned to be continued at a dose between 2.5 and 5.0 mg per day for up to 3 years.545454 43
Treatment response:
Response was assessed after 3 months of treatment and was categorised as follows:
• Treatment response: Reduction in 24 hour urine protein >50% and stabilization of S.Creatinine (±25%).
• Remission: 24 hour urine protein < 500 mg and normalization of S.Creatinine.
• Refractory disease: Patients who do not fulfil the criteria for response or remission.
Follow up:
Patients were followed up for a period of at least three months after inclusion. Patients were followed at week 1, 2, 4, and then, monthly.
At each follow up, following parameters were seen:
– Serum creatinine and eGFR
– Urine routine and microscopy
– 24 hour urine protein
Serum IgG and IgG4 levels were done at the end of three months and when clinical and laboratory parameters suggested relapse.
Statistical analysis:
Data was summarised as mean ± SD or median (range) in case of continuous variables and as proportions, n (%) in case of categorical variables.
RESULTS
A total of 40 patients were screened for IgG4 RKD on the basis of clinical or imaging features or if they had IgG4 related disease confined to other organs. Clinical, radiological and laboratory features of these 40 patients are shown in Table no … .
22 patients had elevated IgG4 levels. Of these 17 had IgG4 RD (8 renal and 9 only extra renal). There were five patients who had suspicion of IgG4 RD on the basis of their clinical presentation and were also found to have elevated serum IgG4 levels. However, on further evaluation, none of them were found to have any other evidence of IgG4 RD and alternative diagnosis was established in each case (table no. )
Table : Clinical profile of patients screened for IgG4 RKD
Age/Sex Presenting complaint Reason for screening S.Cr S.Alb 24 hr UP IgG4 Imaging Biopsy finding Final diagnosis
25/M Pain abdomen Pancreatitis with renal dysfunction 3.6 3.4 (-) 430 B/L mild HDUN Primary hyperparathyroidism
62/M Dysuria Earlier diagnosed as MGN, now unexplained AKI 7.8 3.3 2500 59 Bulky kidneys MGN MGN with AKI/ATN
31/M Fever, occasional cough, anorexia, weight loss Bulky kidneys, AKD 2.7 3.8 (-) 430 Bulky kidneys TIN Definite IgG4 RKD
30/M Pain abdomen, vomiting, oliguria Pancreatitis with AKI
3.8 2.5 (-) 420 Normal kidneys – Alcoholic Pancreatitis
16/M T1DM;
Swelling Rt lower limb RPF 0.8 3.1 3000 25 Right HDUN – Idiopathic RPF
50/F Screening IgG4 Pancreatitis 0.7 3.9 (-) 420 Normal kidneys –
56/F Screening IgG4 Pancreatitis 0.5 4.2 (-) 136 Normal kidneys
45/M Screening IgG4 Pancreatitis 0.7 4.5 (-) 200 Normal kidneys
67/M Pedal edema, dyspnea on exertion Aortic aneurysm with unexplained CKD 2.3 4.1 600 251 Right shrunken kidney – Possible IgG4 RKD
66/M Evaluation of RPRF with microscopic hematuria; past h/o ?IE PSC+AIH with RPRF 2.1 3.6 240 57 Normal kidneys ICGN (crescentric)
28/M Pain abdomen Pancreatitis with AKI 4 3.2 (-) 96 Normal kidneys AIN Alcoholic pancreatitis with AIN ?drug induced
58/M Generalized swelling Bulky prostate 10.5 4 500 145 b/l mild HDN – Carcinoma prostate
20/M Fever, anorexia, weight loss Bulky pancreas 1 2.4 (-) 295 Normal kidneys – Tuberculosis
21/M Fever, shortness of breath Unexplained AKD 7.5 3.2 600 55 Normal kidneys IgAN IgAN
49/M Screening IgG4 pancreatitis 0.7 3.8 (-) 420 Normal kidneys –
50/M Screening IgG4 pancreatitis 0.6 4 (-) 160 Normal kidneys –
19/M Screening IgG4 pancreatitis 0.5 4.2 (-) 162 Normal kidneys –
46/F Fever, weight loss RPF 0.7 3.0 (-) 48 Normal kidneys – IgG4 related RPF
32/M Decreased urine output, uremic symptoms Unexplained AKD; renal histology s/o IgG4 disease 10 4.2 200 54 Normal kidneys Chronic TIN Idiopathic chronic TIN
74/M Screening IgG4 pancreatits 1.2 4.6 260 361 B/L renal cysts – Possible IgG4 RKD
59/F Recurrent pancreatitis Idiopathic pancretitis 0.8 3.4 120 50 Normal kidneys – Idiopathic recurrent pancreatitis
33/F Fever Bulky kidneys, background of AIH 0.9 3.1 (-) 25 Bulky kidneys with few cysts – Septicemia
52/F Pain abdomen RPF 3.7 3.6 200 45 B/L HDUN – Idiopathic RPF
76/M Decreased urine output Renal histology s/o IgG4 disease 6 3 2200 38 Normal kidneys Chronic TIN Idiopathic chronic TIN
18/M Fever Parotitis, thyroiditis 1.4 2.6 6 30 Normal kidneys ?MPGN ICGN
20/M Fever, anorexia, h/o desi medications Bulky kidneys with hypodense lesions 4 3.5 (-) 24 B/L Hypodense lesions Repeat renal imaging normal Acute viral hepatitis B
45/M Generalized swelling and frothuria Renal histology s/o IgG4 disease 2.5 3 1100 20 Normal kidneys MGN MGN
25/F Fever Imaging s/o IgG4RKD 1.9 3.1 1500 44 Hypodense lesions in left kidneys ICGN CGN
31/F Fever, nausea, anorexia Imaging s/o IgG4 8 2.9 1000 40 B/L renal masses Granulomatous inflammation; AFB –ve ? TB
67/M Anorexia, weight loss IgG4 RPF 2.3 3.7 (-) 253 B/L mild HDN – Possible IgG4 RKD
44/M Screening IgG4 pancreatitis + ?pulmonary fibrosis 0.6 4.0 (-) 160 Normal kidneys –
52/M Screening IgG4 oesophagitis 0.8 3.6 (-) 200 Normal kidneys –
60/M Asymptomatic, deranged RFT on routine evaluation Imaging s/o IgG4RKD 6.2 3.2 (-) 430 Hypodense lesions in LK IgG4 TIN Definite IgG4 RKD
22/M Generalized swelling Histology s/o IgG4 disease 2.5 3.2 8000 23 Normal kidneys MGN, chronic TIN MGN, chronic Idiopathic TIN
70/M Anorexia, weight loss Histology s/o IgG4 disease 0.8 3.0 (-) 52 Mass right kidney RCC with features of IgG4 TIN in tumour periphery RCC
39/F Fever, left flank pain, incontinence Retroperitoneal soft tissue 2.5 3.5 220 196 B/L HDUN – IgG4 related RPF, possible IgG4 RKD
60/M Fever Imaging s/o IgG4 RKD 0.8 3.6 0 85 Patchy lesion Left kidney IgG4 TIN + IC crescentric GN Probable IgG4 RKD
15/M Generalized swelling Idiopathic pancreatitis 2.5 2.5 4000 36 Normal kidneys C3 crescentric GN C3 GN
47/M Fever, generalized swelling, dyspnea, urine output Histology s/o IgG4 disease 6.5 2 2500 147 Normal kidneys IgG4 TIN + IC crescentric GN Definite IgG4 RKD
22/F Screening IgG4 Pancreatitis 0.3 3 (-) 267 Normal kidneys –
Abbreviations: HDUN: hydroureteronephrosis, B/L: bilateral, MGN: membranous glomerulonephritis, AKI: acute kidney injury, ATN: acute tubular necrosis, AKD: acute kidney disease, IgG4 RD: IgG4 related disease, IgG4 RKD: IgG4 related kidney disease, RPF: retro peritoneal fibrosis, TIN: tubulointerstitial nephritis, T1DM: type1 diabetes mellitus, RPRF: rapidly progressive renal failure, PSC: primary sclerosing cholangitis, AIH: auto-immune hepatitis, IE: infective endocarditis, ICGN: immune complex glomerulonephritis, IgAN: IgA Nephropathy, MPGN: membranoproliferative glomerulonephritis, CGN: chronic glomerulonephritis, TB: tuberculosis, AFB: acid fast bacilli, s/o: suggestive of, RCC: renal cell carcinoma.
Table: Spectrum of diagnoses (other than IgG4-RD) associated with high serum IgG4
levels
No. of patients
Pancreatitis
Alcohol related 2
Hypercalcemia related (primary hyperparathyroidism) 1
Ca prostate 1
Disseminated TB 1
Of the 40 patients screened, 8 were diagnosed as IgG4 RKD. Of these 3 (37.5 %) patients had definite, 1 (12.5 %) had probable and 4 (50 %) had possible IgG4 RKD (Fig. no. ).
Fig : IgG4 related kidney disease
Three patients were diagnosed as having definite IgG4 related disease. One patient was diagnosed as definite IgG4 RKD on the basis of the clinical, serological and histology criteria while the other two fulfilled the imaging criteria as well.
The patient diagnosed as probable IgG4 RKD had only mild elevation of serum IgG4 levels (not high enough to satisfy the criteria for definite IgG4 RKD) but fulfilled the imaging and histopathology criteria.
Four patients were diagnosed as possible IgG4 RKD on the basis of clinical and serological criteria. Three of these patients had evidence of extra-renal IgG4 RD (one had IgG4 related pancreatitis and two had IgG4 related RPF). Histological diagnosis could not be established in these three patients as one had multiple renal cysts, one patient with RPF had parenchymal thinning secondary to back pressure changes due to ureteral trapping in the RPF tissue; while the another one with RPF had minimal hydronephrosis but he was unwilling for kidney biopsy. Fourth patient in the possible group had aortic aneurysm, asymmetric kidneys, and inactive urinary sediment with deranged renal function. Kidney biopsy was deferred in view of asymmetric kidneys, normal urinary examination and stable serum creatinine.
A summary of the clinicopathological features of these 8 patients is shown in Table
Table Clinicopathological features of patients with IGg4 RKD
Patients ›› 1 2 3 4 5 6 7 8
Age/Sex 60/M 74/M 67/M 39/F 67/M 31/M 60/M 47/M
Proteinuria (-) (-) 600 220 (-) (-) (-) 2500
S.Albumin 3.6 4.6 4.1 3.5 3.7 3.8 3.2 2
S.Cr 0.8 1.2 2.3 2.5 2.6 2.7 6.2 6.5
IgG 2079 NA NA NA 1354 2404 3407
1753
IgG4 85 361 251 196 253 430 430 147
Extra-renal lesion (-) AIP (-) RPF RPF (-) (-) (-)
Renal imaging Patchy lesions Cysts Normal HDN HDN Bulky kidneys Pa Normal
Biopsy findings TIN + ICGN NA NA NA NA TIN TIN TIN + ICGN
Criteria fulfilled I + H C + S C + S C + S C + S S + H + I S + H+ I C + S + H
Diagnosis Probable Possible Possible Possible Possible Definite Definite Definite
M: male, F: female, NA: not available, RPF: retroperitoneal biopsy, AIP: autoimmune pancreatitis, HDN: hydronephrosis, I: imaging, S: serology, C: clinical, H: histology
Baseline characteristics of these patients are summarised in table and discussed in detail subsequently.