Severe podocyte loss is characteristic of advanced diabetic nephropathy evaluated by scanning EM

Scanning electron microscope (SEM) is not routinely used in diagnostic renal pathology. However, SEM can provides insight into pathophysiology of certain renal disease. Progression of diabetic nephropathy is clinically measured by amount of albuminuria, from microalbuminuria in the early to overt proteinuria in late disease. By using SEM, Conti et al. demonstrated that the state of proteinuria reflect morphological alteration of visceral epithelial cells (podocytes). Biopsy in patient with early DN who had no microalbuminuria showed largely intact podocytes without injury. Patients with advanced DN showed near total podocyte loss.

https://doi.org/10.1038/s41598-018-23244-2

Collapsing glomerulopathy superimposed on diabetic nephropathy: insights into etiology of an under-recognized, severe pattern of glomerular injury

Collapsing glomerulopathy (CG) can be primary or secondary to a number of conditions such as HIV infection. It is commonly agreed that the podocyte injury is the underlying etiology, hence the name podocytopathy. Salvatore et al. studied this lesion in patients with diabetic nephropathy (DN). There were CG in 30 of 534 biopsies with diabetic nephropathy. The patients with DN and CG had higher level of proteinuria and were more likely to progress to end stage renal disease than patients with DN only. The podocytes in patients with CG showed absence or decrease of maturation markers such as WT-1, synptopodin. Severe arteriosclerosis and arteriolar hyalinosis were noted in this group of patients. The authors suggested ischemic injury to podocytes as the cause of CG in DN.

Renal prognosis a long time after renal biopsy on patients with diabetic nephropathy

Kimmelstiel-Wilson nodule characteristic of class III lesion

Mise et al. retrospectively studied correlation between histologic parameters and renal
survival in patients with diabetic nephropathy. They found that histologic classification (Tervaert's), tubular atrophy/interstitial fibrosis and arterial lesions correlated with renal survival.
This is the first validation study of diabetic nephropathy histologic classification in which its association with renal outcome was shown.  

Renal biopsy in diabetic patients

Diabetic nephropathy with superimposed postinfectious GN

The reason for renal biopsy in diabetic patients is mainly due to clinical suspicion of renal diseases other than diabetic nephropathy (DN). Most common causes of concern are sudden increase in proteinuria and rising serum creatinine. With increased proportion of diabetic patients being biopsied, Sharma et al. performed the largest study of renal biopsies in diabetic patients (N = 620). Almost one quarters of their biopsies came from diabetic patients. 384 of 611 (63%) had other renal diseases with or without DN.

The renal diseases found in non-DN group are the usual suspects: FSGS, hypertensive nephrosclerosis, IgA nephropathy, etc. The surprising finding is acute tubular necrosis (ATN) as the most common disease in DN group with other diseases. The explanation is that the functional and hemodynamic compromise in DN coupled with the drug angiotensin converting enzyme inhibitor make the kidneys vulnerable to ATN.
The best predictor of patients having DN alone is the longer duration of diabetes before biopsy (>12 years). The shorter duration and lower degree of proteinuria suggest non-DN renal diseases alone. Active urine sediment is more associated with DN with other diseases than DN alone.

Idiopathic nodular glomerulosclerosis

Nodular glomerulosclerosis can be seen in diabetic nephropathy
and idiopathic nodular glomerulosclerosis

Idiopathic nodular glomerulosclerosis (ING) is a recently recognized entity in renal Nasr and D'Agati described pathogenesis of the disease. ING is found mainly in elderly with a long history of smoking and/or hypertension. Their predominant clinical presentation is renal failure.
pathology.
The central player in the pathogenesis is advanced glycation end product (AGE) which is increased in smokers in similar way to hyperglycemia in diabetic patients. Other participating factors include oxidative stress, sympathetic activation, hypoxia and nicotine. The later two involve angiogenesis while AGE and oxidative stress involve increased extracellular matrix production. ING can also be found in non-smoking, hypertensive patients.
The main concern for renal pathologists is that ING has a morphology of nodular glomerulosclerosis identical to diabetic nephropathy. This is not surprising because AGE involves in the pathogenesis of both. Clinical history of diabetes must be established in order for pathologist to call the lesion diabetic nephropathy.

Diabetic nephropathy with crescents

Crescent in a diabetic glomerulus

Diabetic nephropathy (DN) do not usually require kidney biopsy for diagnosis. The history of diabetes and the presence of diabetic retinopathy are suffice. However, when other glomerular disease is suspected, the biopsy is performed. These diabetic patients usually have sudden onset of nephrotic syndrome and/or hematuria. Add-on glomerular diseases such as membranous nephropathy, acute postinfectious glomerulonephritis were found in biopsies from these patients. Hower, no lesion other than DN were found in a lot of them.

When crescents are identified in biopsy with well-defined features of DN, the pathologist will search for evidence of glomerular disease superimposing on DN. Similar to biopsies without diabetic changes, the usual suspects for crescentic glomerulonephritis can be found in diabetic kidneys. Immunofluorescence can identify immune complex disease such as IgA nephropathy or acute postinfectious glomerulonephritis and anti-glomerular basement membrane (Goodpasture) disease. The real problem is pauci-immune (ANCA-associated) glomerulonephritis in which no or minimal amount of immune complex is detected by immunofluorescence or electron microscope. When clinical findings such as extrarenal manifestations of the disease and the serological evidence of ANCA are present, the diagnosis of ANCA-associated GN can be made. In the absence of clinical and serological findings, it is difficult to make this diagnosis. The situation is rather different in non-diabetic kidney with crescents, the pathologist may be more comfortable to call it pauci-immune GN though no clinical or serological findings are present.

Otani et al. demonstrated a case of diabetic nephropathy with crescents. No immune complex, ANCA or its extrarenal manifestations were found. The authors argued for the link between microvascular injury in DN and crescent formation and suggested further investigation to establish this link.

Proteomic study of diabetic nephropathy

Pathogenesis of diabetic nephropathy (DN) is undoubtedly complex with elements of genetic disposition, hemodynamic changes and various cytokines orchestrated by prolonged hyperglycemia. Nakatani et al. used proteomic technique to study glomeruli from deceased patients who had DN. These glomeruli were laser microdissected from archived autopsy tissue preserved in formalin-fixed paraffin-embedded blocks. Among many overexpressed proteins related to urinary system diseases, nephronectin was identified for immunohistochemical study.

Environmental factors in glomerular diseases

The advances in genomics identify genetics as a contributing factor of glomerular diseases. The most prominent one is focal and segmental glomerulosclerosis (FSGS) in which a number of podocyte genes are responsible for abnormal structural proteins.
However, it becomes increasingly common to view pathogenesis of diseases as an interplay between genetics and environment. Nelson and Alpers summed up progress in identifying environmental factors contributing to pathogenesis of the three common glomerular diseases.