When to Suspect Non-diabetic Kidney Disease in a Diabetic Patient?

The diagnosis of non-diabetic kidney disease (NDKD) in a diabetic patient has significant therapeutic and prognostic implications. There are certain proven clinical predictors of NDKD, which, when present in an appropriate clinical setting, would warrant a kidney biopsy. Herein, we describe four cases of NDKD diagnosed in rather unusual clinical settings, which add to the list of clinical predictors of NDKD. The first case was a “parainfectious glomerulonephritis” diagnosed in a 50-year-old diabetic woman who presented with persistent renal dysfunction despite successful treatment of urinary tract infection. The second case was “membranous nephropathy” diagnosed in a 43-year-old man with long-standing type 1 diabetes, which was associated with other microvascular complications. In this case, the only predictor was disproportionately low serum albumin. The third case was “amyloid light chain (AL) amyloidosis” diagnosed in an elderly diabetic who presented with progressive anasarca over six months. In this case, the only clinical predictor was a disassociation observed between urine dipstick and 24-hour protein estimation. In the fourth case, an elderly diabetic woman without underlying diabetic retinopathy presented with sudden onset nephrotic syndrome. A kidney biopsy was suggestive of diffuse nodular glomerulosclerosis. Immunofluorescence and electron microscopic evaluation were diagnostic of “gamma heavy chain deposition disease.” In all four cases, diagnosis of NDKD led to major therapeutic changes and attainment of renal remission. We have extensively reviewed all major biopsy cohorts of NDKD and have formulated an approach to the diagnosis of NDKD.


Case Presentation Case 1: superimposed infection-related glomerulonephritis (IRGN) on DKD
A 50-year-old woman with a long-standing history of type 2 diabetes mellitus (DM) presented with complaints of dysuria, oliguria, and anasarca of 10 days duration. On examination, her blood pressure (BP) was 160/90 mmHg, she had pitting pedal edema, and there was no renal angle tenderness. Her initial laboratory parameters were as follows: hemoglobin (Hb) of 10 g/dL, total leucocyte count of 15,600 cells/mm³, serum creatinine of 3.5 mg/dL, and serum albumin of 2.5 g/dL. Urine microscopy revealed protein at 1+, RBC at 15/HPF, WBC at 120/HPF, and 24-hour urine protein was 1.6 g/day. Urine culture grew Escherichia coli with >10 5 CFU/ml. Non-contrast CT of the kidney, ureter, and bladder showed normal-sized kidneys with no features of pyelonephritis. She was treated with parenteral antibiotics and diuretics for 10 days. She improved symptomatically, though she needed two anti-hypertensives for BP control. Her repeat laboratory parameters after completion of the antibiotic course showed persistent renal dysfunction (serum creatinine of 5 mg/dL), microhematuria, sub-nephrotic proteinuria, hypocomplementemia (low C3 and normal C4), and sterile urine culture. She underwent a kidney biopsy with clinical suspicion of NDKD. Light microscopy (LM) showed features of diabetic nephropathy with superimposed endocapillary proliferation composed of neutrophil exudate. There was no neutrophil-rich interstitial infiltration suggestive of pyelonephritis. On immunofluorescence (IF), there were granular mesangial and capillary wall deposits of IgG (3+) and C3 (3+) in a "starry-sky pattern." The ultrastructural evaluation showed the presence of electron-dense sub-epithelial humps ( Figure 1). She was treated with a short course (six weeks) of oral prednisolone (1 mg/kg/day) with rapid tapering. After six weeks of treatment, her renal function improved (serum creatinine 1.5 mg/dL), complement levels normalized, and she was off anti-hypertensives.

Case 2: membranous nephropathy (MN)
A 43-year-old man with type 1 DM since the age of 20 years presented with anasarca, which was progressive over 12 months. His parameters were as follows: serum creatinine of 0.62 mg/dL, Hb of 14.4 g/dL, and albumin of 1.7 g/dL. Urine routine microscopy showed protein at 4+, RBC at 3-4/HPF, WBC at 3-4/HPF, 24hour urine protein at 11.5 g/day, C3 at 116 mg/dL, and C4 at 24 mg/dL. Though he had an underlying proliferative diabetic retinopathy, he underwent a kidney biopsy in view of disproportionately low serum albumin. On LM, there was mesangial expansion and hypercellularity with global capillary wall thickening. On IF, there was diffuse granular capillary wall staining for IgG (4+), C3 (1+), kappa (3+), and lambda (1+). Electron microscopy (EM) showed electron-dense sub-epithelial deposits characteristic of MN ( Figure 2). He was treated with rituximab infusions and attained partial remission over a period of six months.

Case 3: amyloid light chain (AL) amyloidosis
A 69-year-old man with a history of type 2 DM for 10 years presented with anasarca, which was progressive over six months. On examination, he had a BP of 100/70 mmHg and pitting edema on both legs. His laboratory values were as follows: serum creatinine of 1.74 mg/dL, Hb of 15.2 g/dL, and albumin of 2.7 g/dL. Urine routine microscopy showed albumin trace, RBC at 3-4/HPF, WBC at 1-2/HPF, 24-hour urine protein at 4.8 g/day, and serum protein electrophoresis showed no M spike. He underwent a kidney biopsy due to disassociation observed between urine dipstick and 24-hour urine protein estimation. There was marked mesangial expansion by pale amorphous eosinophilic deposits on LM. These deposits were periodic acid-Schiff (PAS) pale, silver negative, and congophilic with apple green birefringence on polarized microscopy. IF showed lambda restricted smudgy staining (3+) within the glomerular mesangium, arterial wall, and focal interstitium. Bone marrow biopsy showed an arteriole with scanty intramural congophilic deposits with apple green birefringence ( Figure 3). Serum immunofixation electrophoresis showed IgG lambda monoclonality. He was initiated on a "CyBorD" (cyclophosphamide, bortezomib, and dexamethasone) induction regimen and attained a very good partial response (VGPR) at six months.

Case 4: gamma heavy chain deposition disease (HCDD)
A 61-year-old woman with a history of diabetes for four years presented with sudden onset anasarca. Her initial laboratory parameters were as follows: Hb of 8.7 g/dL, serum creatinine of 2.8 mg/dL, albumin of 2.7 g/dL, and normal serum protein electrophoresis. Urine routine microscopy showed protein at 3+, RBC at 2-3/HPF, WBC at 2-3/HPF, and 24-hour urine protein was 14.3 g/day. She underwent a kidney biopsy due to the absence of retinopathy, well-controlled glycemic status, and a sudden onset of nephrotic syndrome. On LM, there was a mesangial expansion with diffuse nodular glomerulosclerosis involving all the glomeruli. These nodules were PAS positive, silver negative, and Congo negative. IF showed strong linear staining for IgG (4+) along the tubular basement membrane and blood vessels along with smudgy mesangial staining for IgG (4+), C3 (2+), and C1q (3+). There was only trace capillary wall staining for kappa and lambda. On EM, fine powdery deposits were also seen along the lamina rara interna of the glomerular basement membrane and within the mesangium ( Figure 4). Bone marrow biopsy showed mild CD138-positive plasmacytosis (15-20%) with no light chain restriction seen on immunohistochemistry. She was initiated on a "CyBorD" induction regimen and attained partial remission of proteinuria within three months of therapy.

Discussion
DKD occurs in 30-40% of patients with more than 10 years duration of DM. Clinically, these patients progress slowly over years from an initial stage of hyperfiltration (increase in estimated glomerular filtration rate (eGFR)) to microalbuminuria (now termed as moderately increased proteinuria) to macroalbuminuria (now termed as severely increased proteinuria) to overt nephropathy and finally progress to kidney failure. The histological features of DKD include thickening of the glomerular capillary wall, mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson lesions), diffuse glomerulosclerosis, hyaline arteriosclerosis, and exudative lesions like fibrin caps, capsular drops, and hyaline thrombi [1]. Most of these lesions are irreversible and current therapies include only strategies to slow down the progression by tight control of blood sugars and blood pressure. Antiproteinuric measures like renin-angiotensin-aldosterone blockers and sodium-glucose cotransporter inhibitors have proven efficacy in reducing the rate of disease progression [12].
Kidney biopsy is the most crucial tool to diagnose NDKD. However, with an unrestricted biopsy policy, 50% will have pure DKD, whereas, with a restricted biopsy policy based on clinical indications, two-thirds of patients will have pure NDKD [15]. This signifies the relevance of knowing the clinical predictors of NDKD and how to apply them in an appropriate clinical setting ( Table 2).

Low complement levels
Positive serological markers like ANA or ANCA Persistent renal dysfunction despite eradication of infection source (8) Suspicion of monoclonal gammopathy [10,11] Discrepancy between urine dipstick and 24-hour urine protein estimation Detectable circulating monoclonal immunoglobulin by serum protein electrophoresis, immunofixation electrophoresis, or serum free light chain assay (9) Atypical nodular glomerulosclerosis on kidney biopsy [1] Nodules are uniformly distributed within all glomeruli PAS positive, silver negative, and Congo red negative (MIDD) PAS positive, silver negative, and Congo red positive (amyloidosis) The most significant predictor of NDKD is the absence of diabetic retinopathy [2,[5][6][7][8]. This retinal-kidney bond in diabetes is due to common underlying risk factors for the development of both nephropathy and retinopathy [16]. The positive predictive value for NDKD in type 2 DM patients with and without retinopathy is 54% and 87%, respectively [2]. The combination of absent retinopathy with nephrotic range proteinuria (NRP) or microhematuria is a stronger predictor of NDKD [2,6]. Another important predictor of NDKD is the short duration (< five years) of diabetes. NDKD is highly unlikely with a duration of diabetes >12 years [10]. Though some studies have shown microhematuria as a predictor of NDKD [5,8,9], 33-50% of patients with DKD may also have microhematuria [17]. Sudden onset NRP (without going through stages of micro and macroalbuminuria) should raise the suspicion of underlying podocytopathy. Renal dysfunction without significant proteinuria in a diabetic patient should raise suspicion of renal artery stenosis. The