Diabetes: To Biopsy or not to Biopsy - Part 2

In my experience the appetite to biopsy patients with clinical renal disease varies widely between clinician, institution and country. This is most apparent when it comes to the diabetic patient with renal disease. In my opinion there is a fear among nephrologists of biopsying patients with potential diabetic nephropathy (DN). Of course there are clinical features that increase the likelihood that a diabetic with renal disease has DN. Retinopathy in a type 1 diabetic, longstanding DM and progressive proteinuria over years preceding an elevated creatinine. However, the role of microalbuminuria and proteinuria in predicting CKD progression and the traditional course of rising albuminuria in DM1 has been challenged. In DM type 2 the picture is less clear and these patients frequently have many comorbidities. Gearoid posted on this subject about a year ago now. In CJASN (October) Sharma et al from Columbia University reviewed the characteristics and renal diagnoses in 620 diabetics who had a renal biopsy. Over 90% had type 2 diabetes. In Columbia in 2011 approximately ¼ of all biopsies were on patients with diabetes. The results of this retrospecive review were that 37% of patients had DN alone, 36% had non-diabetic renal disease (NDRD) alone, and 27% had DN plus NDRD.

In NDRD alone: FSGS (22%), hypertensive nephrosclerosis (18%), acute tubular necrosis (ATN) (17%), IgA nephropathy (11%), membranous GN (8%), and pauci-immune GN (7%) comprised 80% of diagnoses.

In DN plus NDRD: ATN (43%), hypertensive nephrosclerosis (19%), FSGS (13%), and IgA nephropathy (7%).

In multivariate analysis longer duration of DM was associated with a greater likelihood of DN and less likelihood of NDRD.

The table illustrates the features of patients at the time of biopsy. Older age, having DM2 vs DM1, short duration of DM and less proteinuria are more likely in those with NDRD alone vs DN alone in this cohort. 

I think this study highlights the importance of considering biopsy in diabetics (especially type 2). I would be interested to hear about the experience of others with respect to biopsy in diabetics.

Posted by Andrew Malone

Characteristics	DN Alone	DN Plus NDRD	NDRD Alone
Participants (n)	227	164	220
Age (yr)	59 (49–65)	63 (55–72)	63 (54–70)
Male sex	129 (56.8)	100 (61.0)	142 (64.6)
Race
Unknown	108 (47.6)	57 (34.8)	104 (47.3)
White	62 (27.3)	63 (38.4)	70 (31.8)
African American	39 (17.2)	33 (20.1)	29 (13.2)
Hispanic	12 (5.3)	7 (4.3)	8 (3.6)
Asian	4 (1.8)	4 (2.4)	7 (3.2)
Other	2 (0.9)	0 (0.0)	2 (0.9)
DM type 1	9 (4.0)	5 (3.1)	2 (0.9)
Duration of DM (yr)	13 (8–17)	10 (7–18)	5 (3–10)
Serum creatinine (mg/dl)	2.3 (1.6–3.8)	3.1 (1.7–5.2)	2.3 (1.5–4.4)
eGFR (ml/min per 1.73 m2)	31.3 (17.5–55.2)	21.4 (12.5–46.6)	32.5 (14.3–60.0)
Proteinuria (g/d)	5.0 (2.8–8.8)	5.0 (2.0–8.0)	2.9 (1.4–7.1)

IgG4 related kidney disease: A new disease or an old disease raising its head?

I recently managed an elderly African American man who was admitted from the clinic for a renal biopsy. He was referred for proteinuria that had not been quantified by his PCP but had been present for over a decade. His creatinine had risen to 6.8mg/dl from 1.3mg/dl 8 months prior to referral. His admission UA had no casts, 1 rbc/hpf, 10 wbc/hpf and he had 1.2 g/24hr of proteinuria. This patient was well with no recent medication changes, NSAID use or allergies. He was normotensive and had no rash, organomegaly or lymphadenopathy. Work up was remarkable for slightly positive ANA (1:40), an amylase of 140U/l and elevated total IgG of 3000mg/dl. He also had elevated white cells with 79% lymphocytes. His renal ultrasound was normal. Hepatitis serology, HIV, complement and SPEP were all normal. He had a renal biopsy and a bone marrow biopsy. 

Biopsy findings.  In panel A (immunoperoxidase stain for IgG4), numerous immunoreactive cells are present (arrowhead).  There is also mild, patchy background staining, not seen in a serial negative control section (panel B); this may reflect the presence of interstitial IgG4 secreted by the infiltrating plasma cells.  The plasma cells are also seen in sections stained for CD138 (panel C) and with hematoxylin and eosin (panel D)(arrowheads).  In panel C, there is also staining for CD138 in the epithelium of proximal tubules (T), which are known to express the antigen. 

This patient was diagnosed with IgG4-Tubulointerstial Nephritis and also with CLL after his bone marrow biopsy. He was treated with 60mg of prednisone for his IgG4-TIN and his creatinine improved to 2.7mg/dl within a month. He was tapered off steroids over months and his eGFR remains at about 30ml/min/1.73m².

IgG4 related systemic disease was first described in pancreatic specimens that had been removed for suspected malignancy found on imaging. Now it is known that this inflammatory condition can affect many organs including the kidney. The most common renal lesion is infiltration of the interstitium with IgG4 positive plasma cells but other lesions such as membranous nephropathy can occur. Abnormal radiological findings in the kidney also occur. The full diagnostic criteria proposed by Raisson et al is shown here.

1. Histology: >10 IgG4 positive plasma cells/hpf in the most concentrated field (mandatory) and tubular basement membrane immune complex deposition by IF, IHC and/or EM (supportive, present in >80% of cases)
2. Imaging: Small cortical nodules, round or wedge lesions and/or enlargement of the kidneys
3. Serology: elevated serum IgG4 or total IgG
4. Other organ involvement such as autoimmune pancreatitis or lymphadenopathy

IgG4-TIN is diagnosed when (1) is present plus one of the features described in (2)-(4)

In this month’s KI issue Saeki et al report on the long term follow up of 43 patients with IgG4-related kidney disease (IgG4-TIN) from Japan. Follow up data on these cases is rare. 34 patients were treated with corticosteroids and followed for at least 12 months in this study. In summary, IgG4-TIN is usually responsive to corticosteroid treatment and response is rapid but not total. If eGFR was lower than 60 before treatment renal scaring is more likely to occur. Relapse occurs in about 20% but most are responsive to further steroid treatment. Serological markers and radiological features all improve with treatment for the most part.

There are no large-scale studies for this disorder that was first described with any frequency in Japan. This is a renal condition that is gaining more and more coverage in the renal literature and any budding nephrologist needs to be aware of it. Whether this is a new disease or a disease diagnosed more frequently with the advent of better immunohistochemical stains for IgG4 is unknown. My feeling is that it is the latter.  

Posted by Andrew Malone