Diabetes mellitus (DM) is a metabolic/endocrinological disorder with an increasing global prevalence and incidence. The disease is characterized by hyperglycemia resulting directly from insulin resistance or inadequate insulin secretion. Type 1 DM is an autoimmune disorder leading to the destruction of pancreatic beta cells. Type 2 DM, which is much more common, is primarily a problem of progressively impaired glucose regulation due to a combination of dysfunctional pancreatic beta cells and insulin resistance. Kidney disease is one of the most important long-term complications of DM and is a leading cause of renal failure throughout the world. The purpose of this article was to review the long historical journey toward understanding the cause of DM and to present the pathophysiology, histopathology, and differential diagnosis of diabetic kidney disease (DKD).
UNDERSTANDING DM: HISTORICAL PERSPECTIVE
The first recorded reference to DM is found in an Egyptian papyrus (1550 BC) that mentions a rare disease that causes the patient to lose weight rapidly and urinate frequently. Indian physicians around the same time identified the disease and classified it as madhumeha or honey urine noting that the urine would attract ants. The creation of the term “diabetes” is credited to Apollonius of Memphis (250 BC), who refers to a disease that drains patients of more fluid than they can consume. The Greek word “diabetes” means to flow out or siphon. Type 1 and type 2 DM were identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400-500 AD, with one type associated with youth and the other with obesity. Persian polymath Avicenna (980-1037) published “The Canon of Medicine” in 1025, providing a detailed account of DM. The sweet urine of patients with diabetes is described, as is abnormal appetite, diabetic gangrene, and sexual dysfunction.1–5 The term “mellitus” or “from honey” was added by Thomas Willis (London) in the late 1600s to separate the condition from diabetes insipidus, which is also associated with frequent urination. Paul Langerhans, a German medical student (1869), discovered that the pancreas contains 2 types of cells, of which one type is arranged in tiny cell islands. These were later named as Islets of Langerhans, but their function and role in DM remained unknown at that time.1–5 In 1889, Von Mering and Minkowski6 found that removing the pancreas from dogs led them to develop diabetes and die shortly afterward. In 1910, Sir Edward Albert Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas; he proposed calling this substance insulin, from the Latin insula, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas.1–5 Frederick Banting (Toronto Canada) conducted critical experiments linking the pancreas and diabetes. Banting and Best (1921) demonstrated that administering the Islets of Langerhans from healthy dogs to dogs that have had their pancreases removed can treat high blood sugar levels.7 Collip working with Banting purified insulin, and it was successfully used for the first time (1922) to treat a human diabetic patient. The first synthetic human insulin was produced in 1980 using recombinant DNA techniques. Before this development, insulin manufacturers had to stockpile pancreatic tissue from animals. The synthetic insulin is identical to the structure of human insulin and has the advantage of being less likely to lead to allergic reactions than animal insulin.8,9
KIDNEY DISEASE: FROM CAUSE OF DM TO COMPLICATION OF DM
Beginning in antiquity, polyuria attracted considerable attention and was recorded as a disease, and most medical texts from that era devoted sections of variable length and detail to its description and treatment. Although polyuria is a symptom of varied etiology, it may be reasonable to presume that many of the patients with polyuria mentioned in the ancient texts were indeed diabetic, and several of the descriptions given in these texts are arguably consistent with DM. Aretaeus of Cappadocia (early 2nd century AD) describes it as an affliction in which the kidneys and bladder never stop making water. His more famous contemporary Roman physician, Galen (129-200 AD) considered diabetes as a disease of the kidneys. Galen’s authority and opinion on this issue became widely accepted, and the concept of diabetes as a disease of the kidney prevailed and remained a dominant viewpoint over the next 1500 years. Avicenna (980-1037), termed the disease “zalkh el kuliah” or diarrhea of the kidneys, terms that Galen and others had also used earlier.10 The first extant treatise dedicated to diabetes written by Abdel Latif el Baghdadi (1162-1231) in 1225 was entitled: Diabetes: A Disease of the Kidneys?
Studies of Paracelsus (1493-1541) represent the first significant change in the conceptual evolution of diabetes. He describes diabetes as a constitutional disease that “irritates the kidneys” and provokes excessive urination.10 In 1776, Dobson11 showed that the sweetness of urine is caused by sugar, which he quantified and showed that its appearance in the urine is preceded and accompanied by an accumulation of sugar in the blood. Diabetes now came to be viewed as a disorder of nutrition in which sugar accumulates in the blood and is excreted in the urine. The sugar in the blood and urine was identified as glucose in 1815 by Michel Eugene Chevreuil (1786-1889). Efforts to quantify glucose in the urine continued to be refined, and, by the second half of the 19th century, the disease could be diagnosed from the examination of the urine. Although diabetes was now thought of as a disease of blood composition, it continued to be considered a disease of the kidneys, which were thought to have decreased retentive powers resulting in the passage of sugar. The source of increased glucose absorption in the gastrointestinal tract continued to be the focus of much debate and investigation unti1 1855 when Claude Bernard (1813-1878) showed the glycogenic properties of the liver and established glucose as the first internal secretion. It was this observation that, over the next 50 years, led to the discipline of endocrinology and thereby paved the way to the discovery of the role of the pancreas as the source of insulin. Thus, after >3 millennia, the concept of the origin of DM evolved from a disease of the kidney to a disease of the pancreas.10
For a disease long considered to originate in the kidneys, attempts to find an explanatory pathologic abnormality in the kidneys had been slow in coming. The larger size and increased vascularity of the kidneys are recorded in several earlier texts. Initial microscopic studies of the kidneys also did not shed much light on the subject other than to confirm enlarged glomeruli and vessels that were engorged with blood. In 1881, Wilhelm Ebstein reported subnuclear vacuolation of tubular epithelial cells due to the accumulation of glycogen in diabetic kidneys and acknowledged their prior recognition by Armanni in 1875. This finding was later called Armanni-Ebstein lesion and came to be considered pathognomonic of diabetes.12,13 The real breakthrough in our understanding of the renal pathology in diabetic patients came in 1936 when Kimmelstiel and Wilson14 reported on the presence of peculiar hyaline masses in the glomerular lobules of 8 diabetic patients, which they termed intercapillary glomerulosclerosis. What is critical in their report, however, is the correlation of histologic findings with accompanying symptom complex of diabetes, proteinuria, hypertension, nephrotic edema, and impaired kidney function. Interestingly, in 1934, MacCallum15 had described glomerular lesions resembling Kimmelstiel-Wilson lesions; however, he failed to make the connection to diabetes and ascribed this to “the ageing process of the glomerulus.” Other reports confirmed these findings and showed a closer association with diffuse, rather than nodular glomerulosclerosis, whose severity was increased with the duration of diabetes.16–23 Thus, kidney disease is no longer considered a cause of DM but is now recognized as one of the many complications of this multisystem disease. This syndrome complex soon termed diabetic nephropathy is now recognized as one of the leading causes of chronic kidney dysfunction and end-stage renal disease throughout the world. The term diabetic nephropathy has also been used as synonymous with DKD.
CLINICAL FEATURES OF DKD
DKD was originally characterized by Mogensen in the 1980s as a progressive disease that began with the loss of small amounts of albumin into the urine (30 to 300 mg/d), known as microalbuminuria, which indicated occult or incipient nephropathy. As progressively larger amounts of albumin were lost in the urine, and albuminuria became detectable by dipstick urinalysis (>300 mg/d), the term macroalbuminuria indicating overt nephropathy was used (Fig. 1). This presentation was then classically followed by a slow but relentless decline in kidney function, ultimately leading to end-stage renal disease.24 This paradigm has proved useful in clinical studies, especially in type 1 DM, for identifying patients at increased risk of adverse outcomes. Proteinuria, however, represents a continuous variable, and any boundary between stages is artificial, as there is no specific cutoff in quantity at which the mechanisms of albuminuria may differ. Furthermore, some patients with microalbuminuria do not develop a progressive increase in their urinary albumin excretion, as in the classic paradigm, and treatment-induced and spontaneous remission of albuminuria may be observed.24,25
Approximately half of all patients with type 2 DM and one third with type 1 DM will develop chronic kidney disease, which is clinically defined by the presence of impaired renal function or elevated urinary albumin excretion, or both. The incidence of chronic kidney disease in type 1 DM is less than that observed in type 2 DM. This difference is mostly because subjects with type 1 DM are generally younger and healthier at diagnosis and carry fewer comorbid conditions. In contrast, patients with type 2 DM fare worse because of other contributors to renal dysfunction, including hypertension, dyslipidemia, obesity, intrarenal vascular disease, acute kidney injury, atherosclerosis, renal ischemia, and age-related nephron loss.26,27
PATHOLOGY OF DKD
The changes in kidney structure caused by diabetes are fairly specific, creating a pattern generally not seen in other renal diseases, and the severity of diabetic nephropathy is related to diabetes duration, degree of glycemic control, and genetic factors. The risk of developing nephropathy is ∼25% to 40% and is essentially similar in patients with type 1 and type 2 DM but may take 10 to 20 years to manifest. There are no substantial differences between patients with type 2 and those with type 1 DM with respect to the basic pathophysiological mechanisms leading to nephropathy.28
Glomeruli are composed of a network of capillaries supported by a framework of mesangial tissue. In diabetic nephropathy, the major structural abnormality seen by light microscopy is mesangial matrix expansion. This increase in mesangial tissue is initially due to both cell proliferation and increased matrix deposition. As the disease progresses, however, matrix accumulation is the predominant mesangial change. The lesions can be identified as either diffuse or nodular. The diffuse glomerular lesion appears as an expansion of the mesangial matrix that gradually encroaches upon the capillary lumina, thus reducing the area available for glomerular filtration (Fig. 2). The Kimmelsteil-Wilson nodule is a well-demarcated lesion located in central regions of peripheral glomerular lobules. It is primarily composed of mesangial matrix and is generally acellular, but there may be a few mesangial cells located at the periphery (Fig. 3). The Kimmelsteil-Wilson nodule is present in 20% to 67% of patients with diffuse lesions. Microaneurysms of glomerular capillaries are often seen along with mesangiolysis (Fig. 4). A solitary mesangial nodule may develop in association with microaneurysm and may reveal a laminated architecture on Jones silver stain (Fig. 5). Diffuse thickening of the glomerular basement membranes (GBMs) is a consistent feature of DKD but is not recognizable by light microscopic examination during the earlier stages of the disease, although it is quite apparent in advanced disease. Segmental glomerulosclerosis, especially at the tubular outlet (ie, tip lesion), is common in later stages of diabetic nephropathy (Fig. 6). Subendothelial lipohyaline deposits may be present within the glomerular tuft, and there may be similar deposits under the parietal epithelial cells (capsular drop) (Figs. 7, 8). Glomerular enlargement is a recognized feature of DKD and occurs both early and late in the disease process. It could be an adaptive response to loss of filtration surface or simply a direct result of expanding mesangium. Hyalinized glomeruli of both ischemic and solid type, and atubular glomeruli, may be seen in variable numbers depending on the severity and duration of the disease.28–30
Arteriolar lesions are prominent in diabetes, with lipohyaline material progressively replacing the entire wall. Hyalinosis of afferent and efferent arterioles is common and, although not specific for DKD, is rare in other conditions (Fig. 9).
Tubulointerstitial damage, a consistent feature of DKD, is not simply the aftermath of glomerular injury. Indeed, tubular cells may be primary targets for various pathophysiological influences. Pathologic changes seen in diabetic nephropathy are interstitial inflammation, thickening of the tubular basement membrane (Fig. 10), tubular atrophy, and interstitial fibrosis. Although there is a correlation between interstitial changes and mesangial expansion, interstitial inflammation and fibrosis along with tubular atrophy may be seen independent of glomerular changes. In type 1 DM, interstitial fibrosis and tubular atrophy (IFTA) follow glomerular lesions and may be less severe or proportional to diabetic glomerulopathy. In type 2 DM, in which arteriosclerosis is commonly present, the lesions are more heterogeneous, and chronic tubulointerstitial injury may be more severe than the diabetic glomerulopathy primarily due to accompanying microvascular and macrovascular disease.31
Immunofluorescence microscopy reveals diffuse linear accentuation of the GBM and tubular basement membrane with immunoglobulin (Ig) G and kappa and lambda light chains and albumin. In approximately one third of cases, similar staining for IgM and C3 may also be seen, although it is usually of lesser intensity. Faint staining of the mesangial areas, and of the mesangial nodules as well, may occasionally be seen. Nonspecific segmental staining of hyaline deposits or glomerular sclerotic regions for IgM, C3, and C1q is common in advanced disease. Vascular hyalinosis lesions also reveal a similar staining pattern.28,30
On electron microscopy, diffuse thickening of the GBM is demonstrable in almost all diabetic patients, irrespective of whether they have nephropathy (Fig. 11). It is usually the earliest structural change and can be demonstrated by electron microscopy as early as 2 years after the diagnosis of type 1 DM. Mesangial regions are expanded, predominantly due to the accumulation of mesangial matrix (Fig. 11). There are no immune-complex deposits. Podocytes show variable foot process effacement, especially in advanced stages of the disease. Tubular basement membranes of nonatrophic tubules are also thickened.28,30
The Renal Pathology Society proposed a histologic classification system for diabetic nephropathy in 2010, which can be used for both type 1 and type 2 DM.32,33 On the basis of the presence and severity of glomerular lesions, 4 classes are proposed:
- Class I, Mild or nonspecific changes on light microscopy and confirmed GBM thickening proven by electron microscopy: >395 nm in female individuals, and >430 nm in male individuals.
- Class II, diffuse mesangial expansion
- IIa, Mild mesangial expansion in >25% of the observed mesangium; area of mesangial expansion<area of the capillary cavity.
- IIb, Severe mesangial expansion in >25% of the observed mesangium. Area of mesangial expansion>area of the capillary cavity.
- Class III, nodular sclerosis (Kimmelstiel-Wilson lesions)—At least 1 Kimmelstiel-Wilson lesion and none of the changes described in class IV, with no >50% globally sclerosed glomeruli on biopsy.
- Class IV, advanced diabetic glomerulosclerosis—>50% globally sclerosed glomeruli on biopsy, with clinical or pathologic evidence indicating that the sclerosis stems from diabetic nephropathy.
The severities of interstitial and vascular lesions were also assigned scores:
- A score of 0 was assigned if the interstitium had no areas of IFTA; scores of 1, 2, or 3 were assigned if areas of IFTA <25%, 25% to 50%, or >50%, respectively, were present.
- A score of 0 was assigned if no T lymphocyte or macrophage infiltrate was present. Scores of 1 or 2 were assigned if the infiltrate was limited to the area surrounding atrophic tubules, or if the infiltrate was not limited, respectively.
- Scores of 0, 1, or 2 were assigned if no arteriolar hyalinosis, 1 arteriole, or >1 arteriole with hyalinosis was present. In addition, the most severely affected arteriole was assigned a score of 0, 1, or 2 if there was no intimal thickening, intimal thickening<thickness of media, or if there was intimal thickening>thickness of the media.
PATHOPHYSIOLOGY OF DKD
DKD is associated with significant changes in the composition of the filtration barrier formed by the peripheral capillary loops. Each capillary loop consists of a GBM lined by fenestrated endothelial cells and covered by interdigitating cell processes called foot processes, which are derived from visceral epithelial cells or podocytes. The foot processes from adjacent podocytes are separated by filtration slits or pores that are spanned by slit diaphragm, a specialized intercellular junction primarily composed of nephrin with several other proteins. The fenestrae of the endothelial cells are coated in a 200 to 400 nm thick endothelial surface layer, which comprises a membrane-bound glycocalyx composed of proteoglycans glycosaminoglycans and glycoproteins. These provide the endothelium with an anionic charge and thus a barrier to macromolecules (Fig. 13). Filtration of plasma occurs via the endothelial fenestrae, across the basement membrane, and through the filtration slits into the urinary space. The filtration barrier acts as a type of molecular sieve, allowing only small molecules that lack a high negative charge to pass through.34,35
It is likely that alterations to all components of the filtration barrier play a part in the development of DKD. There is a change in the composition of the GBM—there is an increase in type IV collagen and a decrease in both laminin and heparan sulfate proteoglycan. The latter provides the GBM with most of its anionic charge; therefore, the loss of this charge from the GBM is likely to be a major factor in allowing the permeation of albumin across the filtration barrier. Endothelial fenestration is decreased in diabetic patients, and there is evidence that the glycocalyx may be decreased (Fig. 12).
Changes in the epithelial side of the glomerular filtration barrier have been demonstrated in patients with DKD and correlate with proteinuria. There is widening or “effacement” of the podocyte foot processes, with a decrease in filtration slit length, a change that becomes more marked as the disease progresses. Podocyte foot process effacement is caused by changes in the actin cytoskeleton and this, together with structural alterations to the slit diaphragm, results in proteinuria (Fig. 12). Podocyte foot process effacement may be reversible if the podocytes themselves remain intact. Extensive podocyte damage, however, will eventually lead to podocyte loss, and, in diabetic patients, there is a gradual reduction in the number of podocytes as the disease progresses. Podocytes are incapable of regenerative replication, and loss of podocytes for any reason would not be replaced, resulting in areas of bare GBM. These areas of denuded GBM would then become attached to the parietal epithelial cells and the Bowman capsule, resulting in segmental glomerulosclerosis.34–39
Hyperglycemia is the main initiator of DKD. Interaction between high intracellular sugar levels and the free amino groups on proteins, lipids, and nucleic acids results in dysfunction through the formation of advanced glycation end products. These chemically heterogeneous compounds induce many of the pathogenic changes such as extracellular matrix production, reduce the expression and activity of degradative matrix metalloproteinases, and significantly interact with the renin-angiotensin system. Advanced glycation products also result in the expression and activation of several transcription factors implicated in the development of DKD, most important of which is transforming growth factor (TGF) β1, which induces the production of extracellular matrix proteins in several types of glomerular cells and plays a major role in the expansion of the mesangial matrix and in the diffuse thickening of the tubular and glomerular capillary basement membranes. The TGFβ system in the podocytes promotes apoptosis, stimulates matrix production by contributing to GBM thickening, and decreases integrin expression, which can lead to podocyte detachment and podocytopenia. In diabetic kidneys, TGFβ1 expression is also associated with increased tubular cell apoptosis, which leads to tubular degeneration and atrophy. Increased oxidative stress, inflammation, and aberrant growth factors are all implicated as mechanisms of injury. Many factors have been reported to be involved, including prostanoids, nitric oxide, vascular endothelial growth factor A among others.40–42
In persons with either type 1 or type 2 DM, hyperglycemia has been shown to be a major determinant of the progression of diabetic nephropathy. The evidence is best reported for type 1 DM wherein intensive therapy has been shown to partially reverse glomerular hypertrophy and hyperfiltration, delay the development of microalbuminuria, and stabilize or even reverse microalbuminuria. Results from pancreatic transplant recipients in whom normal glycemic level is restored suggest that strict glycemic and metabolic control may slow the progression rate of renal injury even after the development of overt dipstick-positive proteinuria. Glomerular changes of DKD may also be reversible over a span of several years.43–45 The impact of strict glycemic control in patients with type 2 DM is more complex and controversial. In the Diabetes Control and Complications Trial, reduction in microvascular complications was of smaller magnitude in patients with type 2 DM receiving intensive insulin therapy than in patients with type 1 DM.46–50 In an outcome and cost-effective analysis of the United Kingdom Prospective Diabetes Study (UKPDS), the authors concluded that the extra expense involved in intensive blood glucose control in patients with DKD was justified, as it slowed down the progress of the disease and delayed its complications, thus sparing extra expense.46 Other studies have shown that it increases the risk of cardiovascular complications and mortality rates in these patients.51
MORPHOLOGIC DIFFERENTIAL DIAGNOSIS OF DKD
The differential diagnosis of diffuse diabetic glomerulosclerosis includes a variety of conditions including immune-complex glomerulonephritis such as IgA nephropathy/IgA vasculitis, membranoproliferative glomerulonephritis (MPGN), and membranous glomerulonephritis. Most of these conditions are readily distinguished from diabetic nephropathy by light microscopy, immunofluorescent microscopy, and ultrastructural evaluation of the glomerular lesions. In addition, arteriolar hyalinosis may be absent or less severe than in DKD, and, when present, it affects the afferent arterioles with sparing of the efferent arterioles. In DKD, on the other hand, both afferent and efferent arterioles may be affected.33,52
The differential diagnosis of nodular diabetic glomerulosclerosis includes diverse conditions such as chronic idiopathic and secondary MPGN, dense deposit disease, monoclonal Ig deposition disease, amyloidosis, fibrillar and immunotactoid glomerulopathies, fibronectin glomerulonephritis, and idiopathic nodular glomerulosclerosis. These entities can usually be easily distinguished from diabetic nodular glomerulosclerosis by clinicopathologic correlation with a history of DM. Difficult cases require meticulous histopathologic examination and the utilization of immunofluorescence and electron microscopy. MPGN is characterized by the lobular accentuation of glomeruli, diffuse and global mesangial expansion, marked endocapillary proliferation, double contouring of the peripheral capillary loops along with mesangial interposition that is readily identified on periodic acid–Schiff (PAS), and methenamine silver stains. Immunofluorescent microscopy shows diffuse granular glomerular capillary loop and mesangial deposition of C3, with or without Igs. On electron microscopy, extensive mesangial and subendothelial electron-dense deposits are present. In cases of dense deposit disease, the light microscopic and immunofluorescence microscopy features may resemble MPGN, but, ultrastructurally, the disease is characterized by large, intramembranous, often discontinuous nonimmune complex-type electron-dense deposits. Similar deposits may also be seen within the mesangium and along the Bowman capsule and tubular basement membranes.52
Renal monoclonal Ig deposition disease is characterized by tissue deposition of light chains, heavy chains, or mixed light and heavy chain deposition. In the kidney, these deposits may be seen within the glomerulus, renal thin basement membrane (TBM), and blood vessels. By light microscopy, all subtypes share similar histologic features. The most common histologic finding is nodular glomerulosclerosis and diffusely thickened peripheral capillary walls, indistinguishable from classic diabetic nodular glomerulosclerosis. In addition, the tubular basement membrane is thickened by a characteristic deposition of ribbon-like refractile, eosinophilic PAS-positive material. Immunofluorescent microscopy reveals diffuse, linear staining of the GBM and TBM with monoclonal Ig light or heavy (or mixed) chains. Ultrastructural examination shows a continuous band of electron-dense granular-powdery deposits along the subendothelial space of the peripheral capillary loops, within the mesangial nodules, and along the outer aspect of the tubular basement membranes.33,52,53
Renal amyloidosis is usually associated with systemic amyloidosis and is characterized by the deposition of acellular, eosinophilic proteinaceous material in the mesangium, peripheral capillary wall, tubulointerstitial spaces, and blood vessels. These deposits are Congo Red positive and show a characteristic apple-green birefringence under polarized light.
Fibrillar glomerulonephritis and immunotactoid glomerulonephritis are 2 closely related entities, characterized by Congo Red–negative glomerular deposits. Both diseases have diverse morphologic patterns and may present as a diffuse proliferative or MPGN and marked mesangial expansion with lobular accentuation and nodular glomerulosclerosis resembling nodular diabetic nephropathy. Immunofluorescence and electron microscopy are important for accurate diagnosis and to distinguish these entities from other causes of nodular sclerosis. Fibrillar glomerulonephritis is ultrastructurally characterized by the mesangial and capillary loop deposits composed of randomly oriented, nonbranching fibrils that range from 16 to 24 nm in diameter. In cases of immunotactoid glomerulopathy, these deposits are composed predominantly of tubular structures rather than fibrils, measuring 30 to 50 nm in diameter. On immunofluorescent microscopy, the deposits are found to be composed predominantly of polyclonal IgG, and C3.33,52,53
Fibronectin glomerulopathy is a rare autosomal dominant disease, characterized by marked mesangial expansion due to massive deposition of fibronectin, and prominent hypocellular lobular accentuation of the glomerular tufts. The glomerular nodules are PAS-positive, but silver and Congo Red stains are negative. Electron microscopy shows abnormal electron-dense deposits in the mesangium and subendothelial zone. The deposits may be finely granular or have a fibrillary substructure with randomly arranged, 12 to 16 nm fibrils. The diagnosis of fibronectin glomerulopathy is confirmed by intense immunohistochemical staining for fibronectin in the mesangium and along the glomerular capillary walls.33,52,53
Idiopathic nodular glomerulosclerosis is an unusual distinct clinicopathologic entity with light microscopic and ultrastructural features like those of nodular diabetic glomerulosclerosis, but without evidence of abnormal glucose metabolism. It is strongly associated with smoking, obesity, and long-standing hypertension. Absence of DM after a detailed clinical history and investigations, and the exclusion of other causes of nodular glomerulosclerosis, is prerequisite to diagnose this entity, as the morphologic findings are identical to those seen in diabetic nephropathy. These nodules react positive for PAS and silver stains and have no affinity for Congo Red dye, similar to the nodular lesions of diabetic nephropathy. Immunohistochemical staining for CD34, a marker of endothelial cells, highlighting an increased number of vascular channels within the nodules has been described in the literature, although the significance of this finding is not clear. Associated with glomerular changes, there may be mild to moderate tubular atrophy and interstitial fibrosis. Other changes such as diabetic nephropathy include thickening of the tubular basement membranes of both atrophic and intact tubules, arteriosclerosis, and arteriolar hyalinosis. Immunofluorescence findings include nonspecific linear staining of GBMs and TBMs with anti-IgG and antialbumin. Electron microscopy findings include prominent mesangial matrix deposition, diffuse thickening of GBMs, variable effacement of foot processes, thickening of tubular basement membranes, and absence of electron-dense immune deposits.54–59
A few cases of nodular glomerulosclerotic lesions resembling diabetic nodules secondary to Takayasu arteritis with renal artery stenosis, cyanotic congenital heart disease, and cystic fibrosis have been reported in the literature.60,61 The pathogenesis of the mesangial nodules in these states is not clearly understood; however, evolution of these lesions seems to suggest that mesangial cells may respond to a wide variety of stimuli, such as various growth factors, proinflammatory cytokines, immune deposits, or fragments of Ig chains—by producing excess extracellular matrix.
NONDIABETIC RENAL PATHOLOGY IN DIABETIC PATIENTS
Previous studies evaluating histologic findings in renal biopsies performed in diabetic patients have shown that approximately one third of the cases exhibit pure diabetic nephropathy, one third a nondiabetic condition only, and another third diabetic nephropathy with a superimposed disease. There is, however, a wide variation in the prevalence of the nondiabetic renal disease in patients with DM due to variable selection criteria for renal biopsy, and geographical differences. The indications for renal biopsy in type 1 DM have been somewhat established: microhematuria, absence of diabetic retinopathy, uncharacteristic change in renal function, or immunologic abnormalities. However, the indications are not as clear in patients with type 2 DM in whom renal involvement is frequently overlooked, and, when DKD is diagnosed, it is usually solely on the basis of clinical findings. The atypical clinical features that may suggest involvement by nondiabetic renal disease in diabetic patients are sudden onset of proteinuria, proteinuria in the absence of diabetic retinopathy, active urinary sediment, rapidly decreasing renal function, and short duration of diabetes. In several recent studies, renal biopsies from patients with DM and renal disease have revealed a heterogenous group of disease entities. Nondiabetic renal disease may include acute tubular injury, acute interstitial nephritis, and several types of glomerulopathies. A wide variety of glomerular diseases have been encountered, including IgA nephropathy, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA vasculitis (Henoch-Schönlein purpura), postinfectious glomerulonephritis (Fig. 13), MPGN (Fig. 14), TBM disease, collapsing glomerulopathy, pauci-immune crescentic glomerulonephritis, and lupus nephritis among others.62–72 Regional differences exist in the prevalence of different types of glomerulopathies. For example, chronic IgA nephropathy, which is usually a slowly progressive disease, is much more prevalent in East Asia. Renal survival can be prolonged with early initiation of disease-specific therapy in diabetic patients with nondiabetic renal disease; therefore, a swift and accurate diagnosis is crucial.
DKD IN RENAL ALLOGRAFT
Renal transplantation has been considered the therapy of choice in suitable patients with advanced DKD, as it confers a better survival benefit to these patients compared with renal dialysis.73 Despite renal transplantation addressing the problem of imminent renal failure, DKD remains prevalent among kidney-transplant patients, leading, in some cases, to allograft loss and contributing to overall patient mortality.74–76
DM in renal transplant recipients may represent a continuation of the preexisting condition resulting in recurrent DKD or can develop as de novo after kidney transplantation.
The reported incidence of new-onset DM after renal transplant is variable, ranging between 10% and 46%. In a study of 58 kidney-transplant recipients, 74.1% had a history of DM before kidney transplantation, and 25.9% had new-onset diabetes after transplantation. The duration of diabetes was similar in the 2 groups at the time of histologic findings of DKD (6.68±3.86 vs. 5.90±3.13 y, P=0.66).77
The pathologic findings of DKD after kidney transplantation are, in most part, like those of typical DKD in native kidneys. The thickening of GBM and the tubular basement membrane constitutes the first sign of DKD. Mesangial matrix expansion develops later. The extracellular matrix accumulates overtime and forms nodular mesangial changes that gradually lead to the compression of the associated glomerular capillaries, resulting in glomerular sclerosis and obliteration of capillary lumina. Hyalinosis in the afferent and efferent arteriolar occurs along with the glomerular lesions, leading also to tubulointerstitial chronic changes. These changes may be variably associated with vascular and tubulointerstitial changes caused by allograft rejection, viral infection, or calcineurin inhibitor nephrotoxicity.78
DKD IN NEPHRECTOMY SPECIMENS
The kidney can be involved in various pathologic processes, some of which may require surgical removal. Radical, simple, or partial nephrectomy is a common procedure in the surgical treatment of renal neoplasms. Simple nephrectomy may also be performed for irreversibly damaged kidney resulting from symptomatic chronic infections, obstruction, calculus disease, or severe traumatic injury.79 Whatever the indication may be, the evaluation of the surgical specimen in totality is extremely important. This becomes more relevant in cases of nephrectomies performed for cases of malignancy. In these situations, the surgical pathology report usually becomes limited to the evaluation of the tumor type, tumor grade evaluation of surgical resection margins, and renal sinus evaluation from the point of view of accurately staging the disease. Synoptic reports, such as those created by the College of American Pathologists, have been important in ensuring that all the important parameters are systematically evaluated and reported for every specimen. A modification of the College of American Pathologist kidney cancer protocol and checklist in January 2010 established the status of non-neoplastic kidney as a required parameter for reporting, which was an optional parameter before this date. Although this requirement is now in place, there are no data with regard to compliance with this specific parameter. Given that most kidney masses are stage 1 tumors, the status of the non-neoplastic kidney is arguably the most important pathologic parameter for these patients and may discover previously unrecognized kidney pathology, such as glomerular disease, interstitial fibrosis, diabetic nephropathy, and others. Pathologists have a unique opportunity and important responsibility to diagnose non-neoplastic kidney diseases, which are commonplace. Current surgical techniques provide adequate non-neoplastic tissue for pathologic evaluation. Routine inspection of the non-neoplastic parenchyma of complete or partial nephrectomy specimens should be performed, as it can alert the clinician to the presence subclinical renal disease, allowing for medical intervention.80
A large spectrum of changes may be noted, the most frequent of which are arterial nephrosclerosis with or without renal tissue scarring, and diabetic nephropathy, which may be present in a quarter of cases. The diabetic changes may be mild, characterized by mild global or segmental mesangial sclerosis and hypercellularity, or marked with severe mesangial changes, including Kimmelstiel-Wilson mesangial nodules, and thickened glomerular capillaries. Vascular changes, as in the case of arterial nephrosclerosis and hyalinosis, may involve afferent and efferent arterioles. Chronic tubulointerstitial changes are also frequent, which may be due to diabetes alone, the frequently associated hypertension, or both.80–84 Bijol and colleagues found that nodular glomerulosclerosis in tumor nephrectomy specimens was predictive of significantly decreased renal function within 6 months after surgery. Strict blood glucose control is the mainstay of therapy for both type 1 and type 2 DM. Long-term normoglycemia may halt the progression of DKD and possibly reverse the process of mesangial expansion.82 Thus, diagnosing DKD at any stage is important so that preventive measures or proper therapy can be administered.
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