Abstract
In a classical paper published in 1936, Kimmelstiel and Wilson for the first time described mesangial expansion and nodular glomerulosclerosis in diabetic kidney disease (DKD). We have since learned much more about DKD lesions, although natural history of progression of these lesions is better known in type 1 diabetes, while majority of patients with DKD suffer from type 2 diabetes, calling for further studies in the latter population. The pathology of DKD is also more homogeneous in type 1 diabetes, and there is some controversy if all kidney lesions observed in type 2 are attributable to diabetes or they may be related to concurrent conditions such as aging, hypertension, and atherosclerosis which are commonly present in type 2 diabetic patients. For these reasons, we will initially discuss pathology of DKD in type 1 diabetic patients and then provide comparisons with type 2 diabetes. Then, we move to the natural history of DKD progression and relationships between structural changes, renal dysfunction, and diabetes duration. Finally, reversal of DKD lesions following long-term normoglycemia after pancreas transplantation and animal models of DKD are discussed.
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Introduction
In a classical paper published in 1936, Kimmelstiel and Wilson for the first time described mesangial expansion and nodular glomerulosclerosis in diabetic kidney disease (DKD) [1]. We have since learned much more about DKD lesions, although natural history of progression of these lesions is better known in type 1 diabetes, while majority of patients with DKD suffer from type 2 diabetes, calling for further studies in the latter population. The pathology of DKD is also more homogeneous in type 1 diabetes, and there is some controversy if all kidney lesions observed in type 2 are attributable to diabetes or they may be related to concurrent conditions such as aging, hypertension, and atherosclerosis which are commonly present in type 2 diabetic patients. For these reasons, we will initially discuss pathology of DKD in type 1 diabetic patients and then provide comparisons with type 2 diabetes.
DKD in Type 1 Diabetic Patients
The most characteristic features of DKD occur in the glomeruli and include thickening of glomerular basement membrane (GBM), accumulation of mesangial matrix, and arteriolar hyalinosis , which typically occurs in both afferent and efferent arterioles. Evolution of these changes has a well-defined sequence. Using morphometric methods, thickening of GBM is identifiable within 2 years of onset of diabetes. There is a direct and linear relationship between thickness of GBM and duration of diabetes [2]. In early stages of DKD, when the patients are normoalbuminuric, there is substantial overlap between GBM thickness in persons with diabetes and nondiabetic individuals which in part may be related to inter-individual variability in the rate of progression of basement membrane thickening or in baseline values of GBM thickness, which is typically unknown [3]. In a study of identical twins who were discordant for type 1 diabetes, all diabetic siblings had thicker GBM and greater mesangial expansion, estimated by the fraction of the volume of glomerulus occupied by mesangium [Vv(Mes/glom)] compared with their nondiabetic siblings. Of note, some of the values for the diabetic subjects were within the “normal range” [4]. Thus, assuming that identical twins had similar GBM thickness and Vv(Mes/glom) values at the onset of diabetes, without a knowledge about the baseline values, these changes would have not been appreciated in diabetic siblings. Age and gender should be taken into account when interpreting GBM thickness values. Ramage et al. showed that GBM thickness in nondiabetic children increases with age, from an average of about 190 nm at 1 year to 300 nm at 11 years, with a reduced rate of increase after the age of 11 years [5], and no difference between males and females in pediatric population. In adulthood, GBM becomes thicker in nondiabetic males averaging about 370 nm in nondiabetic males and 325 nm in females with slight increase in thickness observed up to the fourth decade of life and some decline afterward [6]. In comparison, in normoalbuminuric young type 1 diabetic patients with an average age of 17 years and 8 years of diabetes, the average GBM thickness was 428 nm with a direct relationship with diabetes duration which was not affected by gender [7]. In an older group of type 1 diabetic patients with an average age of about 38 years and about 25 years of diabetes, the average GBM thickness ranged from 465 nm in normoalbuminuric to 700 nm in macroalbuminuric patients [3], where only rare microalbuminuric and virtually no macroalbuminuric patients showed GBM thickness values within the normal range. When examined by transmission electron microscopy, GBM is composed of three distinct components, namely, the lamina rara externa (immediately underneath the foot processes), lamina densa (in the middle and more electron dense), and lamina rara interna (subendothelial). Thickening of GBM in DKD is primarily due to expansion of lamina densa and occurs in a diffuse and uniform fashion. However, especially in advanced DKD, rare glomerular capillaries with thin GBM can be seen. This phenomenon is hypothesized to result from new capillary formation. The hallmark of DKD is accumulation of extracellular matrix, either in the form of thickening of basement membranes or accumulation of mesangial matrix (Fig. 8.1) [8, 9]. This accumulation is related to an imbalance between synthesis, controlled by transcription and translation, and degradation of matrix components, regulated by the interplay between matrix metalloproteinases and their inhibitors [10]. GBM thickening is associated with increased densities of α3 and α4 chains of type IV collagen, as hyperglycemia increases production of these molecules by podocytes [11,12,13].
Classical biopsy findings in DKD. (a) A glomerulus with nodular glomerulosclerosis or Kimmelstiel-Wilson nodules (asterisks) and mesangial expansion due predominantly to increased mesangial matrix and microaneurysm formation (m); Jones methenamine silver stain. (b) Thickening of glomerular basement membrane (GBM) and increased mesangial matrix (mm); transmission electron microscopy. (c) Thickening of tubular basement membranes (TBM); transmission electron microscopy
The earliest lesion of DKD which is appreciable by light microscopy, especially by periodic acid-Schiff stain, is mesangial expansion. Using morphometry, increased Vv(Mes/glom) can be detected as early as 4–5 years after the onset of diabetes [14]. In contrast to thickening of GBM which is more or less linear with increasing diabetes duration, progression of mesangial expansion is slower in the first few years after the onset of diabetes and becomes faster with increased duration of diabetes [15]. Expansion of mesangium in DKD is due primarily to increased mesangial matrix [7]. Even in the earlier stages when Vv(Mes/glom) is still within the normal range, the fraction of mesangium which is matrix [Vv(MM/glom)], as opposed to mesangial cells, is increased compared to nondiabetic subjects [15]. As mesangium expands, it protrudes into peripheral capillary walls within the subendothelial space, the so-called mesangial interposition. This leads to reduced filtration surface area. Thus, an inverse relationship exists between Vv(Mes/glom) and peripheral GBM filtration surface density [Sv(PGBM/glom)] (Fig. 8.2) [8, 16]. On the other hand, this reduction in Sv(PGBM/glom) is at least partially compensated by increased glomerular volume, preserving the total filtration surface area. Mesangial expansion can be diffuse or nodular. Fraying of the mesangial matrix leads to unfolding of the GBM, conjoining of adjacent capillary loops, and formation of microaneurysms or nodular glomerulosclerosis (so-called Kimmelstiel-Wilson nodules ). The accumulated mesangial matrix in the nodules is hypocellular and may show a distinctive lamellated appearance which is best appreciated by Jones methenamine silver stain. The nodules are often surrounded by patent glomerular capillaries or microaneurysms. The microaneurysms may become sclerotic, creating large scarred nodules. Although nodular lesions typically occur in advanced DKD and at least 15 years after the onset of T1D [17, 18], occasional nodular lesions can be seen in earlier stages of DKD when the overall mesangial expansion is mild and diffuse. Therefore, in contrast to the classification proposed by Tervaert et al., the presence of nodular glomerulosclerosis does not always indicate severe DKD. It is noteworthy that nodular glomerulosclerosis is not pathognomonic to DKD and can also be seen in other conditions, perhaps again as a consequence of mesangiolysis, such as light chain deposition disease, immune complex processes, idiopathic nodular glomerulosclerosis, and chronic thrombotic microangiopathy [19].
Relationship of percentage total mesangium and S/V of the peripheral capillary surface. r = -0.86, P < 0.0005. (Figure reproduced from Ref. [8] with permission of the publisher)
Another group of characteristic lesions of DKD result from accumulation of hyaline and are referred to as exudative lesions. These include arteriolar hyalinosis, fibrin caps, and capsular drops (Fig. 8.3). Concomitant hyalinosis of afferent and efferent arterioles is almost specific to DKD and can be seen within 3–5 years after the onset of diabetes [20]. Hyalinosis starts in the subendothelial space but can expand to replace the entire media of arterioles. Some glomeruli may show multiple efferent arterioles at the vascular pole [21]. Fibrin cap, a misnomer which would more appropriately be called “hyaline cap,” refers to accumulation of hyaline in glomerular capillary subendothelial spaces. Accumulation of hyaline under parietal epithelial cell lining of Bowman’s capsule is called “capsular drop .”
Exudative lesions of DKD. (a) Arteriolar hyalinosis (arrow). (b) Fibrin cap in a glomerular capillary (asterisk). (c) Capsular drop (arrowhead). Jones methenamine silver stain
While DKD is primarily defined by accumulation of extracellular matrix and its exudative lesions, there is a body of evidence that podocyte injury plays a crucial role in progression of the diseases and kidney prognosis in diabetic patients. About 1/3 of diabetic patients with normal urine albumin excretion rate show increased nephrin excretion in the urine, indicative of early podocyte injury even before the onset of microalbuminuria [22]. Similarly, foot process effacement, commonly regarded as an evidence of podocyte injury, is detectable in normoalbuminuric diabetic patients [23] and becomes more severe as albuminuria increases [24]. Various mechanisms are proposed for podocyte injury in diabetes, including reduced expression of α3β1 integrin [25], apoptosis, glucose-induced oxidative stress, and autophagy [26, 27]. Electron microscopy studies show evidence of detachment of podocytes from GBM in normoalbuminuric patients. Similar to foot process effacement, detachment becomes more severe as albuminuria increases (Fig. 8.4) [24]. Podocyte loss and reduced density of podocytes in the glomeruli lead to secondary focal and segmental glomerulosclerosis (FSGS). Notably, FSGS is a relatively late finding in type 1 diabetic patients, when patients are commonly macroalbuminuric. There is a distinct predilection for FSGS lesions to occur at the glomerulotubular junction. A serial section study showed that over half of the FSGS lesions occur at or adjacent to the glomerular tubular outlet, consistent with tip lesion [28, 29]. Thus, it is important to realize that tip lesion is not limited to a subset of primary FSGS and can be seen in various proteinuric conditions, including DKD. A combination of increased shear stress to podocytes at the tubular pole of the glomerular tuft [30] and injury to tubular epithelial cells secondary to the tubulotoxic effect of proteinuria might be involved in predilection of FSGS to this region in conditions with heavy proteinuria [31]. Bowman’s capsule thickening and duplication is a common finding at the FSGS site, perhaps reflecting direction of part of the glomerular ultrafiltrate through into Bowman’s capsule, leading to dissection of the capsular basement membrane. This dissection can extend into the glomerulotubular junction, leading to stricture and occlusion of the glomerular tubular outlet and eventually creation of atubular glomeruli (Fig. 8.5), or extend into the proximal tubule [28, 29].
Podocyte (PC)-GBM interfaces (arrowheads) are classified into areas with intact foot processes (a), areas with no foot process coverage (b), and areas with a mixture of intact and detached foot processes (c). *Capillary lumen. (Figure reproduced from Ref. [24] with permission of the publisher)
(a) A glomerulus attached to a normal tubule (NT). * Glomerulotubular junction. (b) (i) A glomerulus attached to a short atrophic tubule (SAT), with a tip lesion at glomerulotubular junction. PAS-stained; magnification, ×630. (ii) A higher-magnification view of the tip lesion, allowing better appreciation of a dilated loop (*), with foam cells within the tip lesion and flat epithelial cells (arrow) covering the very beginning of the proximal tubule. (c) An atubular glomerulus (AG). The glomerular tuft is indistinguishable from other glomeruli. Bowman’s capsule is markedly thickened and wrinkled at a site opposite to the vascular pole, where a tubular connection is expected. ↔, reduplicated Bowman’s capsule; arrowhead, a spindle-shape cell within the reduplicated Bowman’s capsule; arrow, atrophic tubules adjacent to the atubular glomerulus; * periglomerular fibrosis. PAS-stained; magnification, ×630. (Figure reproduced from Ref. [29] with permission of the publisher)
Thickening of tubular basement membranes (TBM) parallels GBM thickening and is an early finding in DKD (Fig. 8.1) [4, 9]. TBM thickening related to diabetes is diffuse and homogeneous with a different appearance from the nonspecific TBM thickening in atrophic tubules where basements become irregular, corrugated, and duplicated and frequently associated with deposition of cellular debris. Supportive of this difference, TBM width in diabetic patients correlates strongly with GBM width and Vv(Mes/glom) but only weakly with the volume fraction of renal cortex that is interstitium [Vv(Int/cortex)] [9]. Moreover, tubulointerstitial fibrosis follows glomerulopathy in T1D patients. In fact, as a result of tubular hypertrophy, Vv(Int/cortex) initially reduces [32]. Expansion of cortical interstitium is initially due primarily to an increase in the cellular component, while increased interstitial fibrillar collagen deposition occurs relatively late, when GFR decline is already present [32].
Using immunofluorescence microscopy, GBM and TBM commonly show modest linear staining with IgG (polytypical) and albumin in diabetic patients. This finding is related to diabetes, regardless of the presence or absence of DKD. The exact cause of this phenomenon remains unclear, although alterations in chemical properties of extracellular matrix, immunoglobulins, or both might be involved. A recent study suggested an association between the intensity of IgG staining and renal outcomes, but this finding requires further validation, especially given the absence of a proper way to precisely standardize fluorescent intensity of IgG staining [33].
Structural-Functional Relationships of DKD in T1D
The natural history of DKD in T1D patients is characterized by an initial long period of normal or high GFR and normoalbuminuria, during which the disease has a slow progression rate. This initial period is followed by a more rapid pace of increasing albuminuria and GFR loss [34]. The structural-functional relationship models of DKD follow a similar course. Initially, when the patients are normoalbuminuric, classical DKD glomerular structural parameters, including GBM width, Vv(Mes/glom), and Sv(PGBM/glom), may be within the normal range. As progression of DKD leads to microalbuminuria and macroalbuminuria, GBM thickness and Vv(Mes/glom) increase, and Sv(PGBM/glom) reduces. These parameters show considerably less overlap with normal values in microalbuminuric patients and almost no overlap in macroalbuminuric patients [3]. Persistent microalbuminuria is associated with progression of the lesions and increased risk for developing macroalbuminuria [3]. Vv(Mes/glom) and GBM width directly and Sv(PGBM/glom) inversely correlate with urine albumin excretion rate (AER) from normoalbuminuria to macroalbuminuria (Fig. 8.6). Importantly, increased GBM width can predict progression of DKD in T1D patients from normoalbuminuria to microalbuminuria or even to macroalbuminuria and ESRD [35]. In a longitudinal study, none of the normoalbuminuric patients with long-standing T1D and normal GBM width progressed to proteinuria or ESRD after an average follow-up of 11 years [35]. Vv(Mes/glom), fractional volume of mesangial matrix per glomerulus [Vv(MM/glom)], and GBM width are inversely and Sv(PGBM/glom) is directly related to GFR (Fig. 8.7) [3]. In fact, there is a direct correlation between the total peripheral capillary filtration surface area and GFR from hyperfiltration to renal insufficiency.
(a) GBM width in 88 normoalbuminuric (NA), 17 microalbuminuric (MA), and 19 proteinuric (P) patients with type 1 diabetes. The hatched area represents the mean ± 2 SD in a group of 76 age-matched normal control subjects. All groups are different from control subjects. (b) Vv(Mes/glom) in 88 normoalbuminuric (NA), 17 microalbuminuric (MA), and 19 proteinuric (P) patients with type 1 diabetes. The hatched area represents the mean ± 2 SD in a group of 76 age-matched normal control subjects. All groups are different from control subjects. (Figure reproduced from Ref. [3] with permission of the publisher)
(a) Correlation between Vv(Mes/glom) and AER in 124 patients with type 1 diabetes. ⧫, Normoalbuminuric patients; ▪, microalbuminuric patients; ▵, proteinuric patients. r = 0.75, P < 0.001. (b) Correlation between GBM width and AER in 124 patients with type 1 diabetes. ⋄, Normoalbuminuric patients; ▪, microalbuminuric patients; ▵, proteinuric patients. r = 0.63, P < 0.001. (c) Correlation between Sv(PGBM/glom) and GFR in 125 patients with type 1 diabetes. ⋄, Normoalbuminuric patients; ▪, microalbuminuric patients; ▵, proteinuric patients. r = 0.48, P < 0.001. (Figure reproduced from Ref. [3] with permission of the publisher)
T1D patients are fairly homogeneous in regard to DKD structural-functional relationship models, and such models have been shown to be robust [36]. Current models can better predict AER than GFR. About 70% of AER and only about 20–30% of GFR variances are explainable by structural-functional relationship models developed by multiple regression analysis based on glomerular lesions alone. However, models developed by piecewise linear regression analysis can explain much larger fraction of AER and GFR variances, approaching prediction of over 80% of AER and over 65% of GFR variances. Piecewise linear regression analysis examines if the relationships can be explained by two regression lines of different slopes, intersecting at a breakpoint. Thus, the improved predictability of the piecewise linear regression analysis models mirrors the natural history of DKD with an initial slow progression prior to a breakpoint and fast progression thereafter. Importantly, the breakpoints found in two separate studies one based on a small cohort and another based on a larger cohort of T1D patients were both in the microalbuminuric and normal GFR ranges [28, 36], suggesting that the shift from a slow to a fast progression phase occurs relatively early and during the initial clinically silent phase. In addition, these results indicate that glomerular lesions alone can explain a major proportion of AER and GFR variance in T1D patients. In fact, predictability of these models showed relatively minor improvements by adding Vv(Int/cortex) and glomerulotubular junction abnormalities as other predictor variables [28]. In contrast to these results, some studies have suggested that GFR decline in DKD is primarily driven by interstitial fibrosis, rather than diabetic glomerulopathy [37, 38]. However, as pointed out earlier, increased Vv(Int/cortex) in DKD in T1D patients is seen in later stages when diabetic glomerulopathy becomes more advanced. Moreover, appreciation of contribution of glomerular lesions in GFR loss requires careful measurement of glomerular structural parameters using morphometric techniques. The importance of vascular lesions in advancement of chronic injury in DKD should not be underestimated. An autopsy study showed that the sclerotic glomeruli in T1D patients are more often clustered in the plane vertical to the renal capsule, indicative of the importance of vascular lesions and chronic ischemia in glomerulosclerosis [39].
There is a large body of evidence about podocyte injury and progression of DKD. Foot process width, a parameter that is commonly regarded a sign of podocyte injury, was directly correlated with AER and inversely with GFR across a wide range of albuminuria [24]. Another study showed that the density of podocytes per glomerular volume [Nv(Podo/glom)] was inversely related to AER in normotensive proteinuric T1D patients [40]. Such association was not found between AER and total number of podocytes per glomerulus, perhaps signifying the importance of imbalance between the number of podocytes and glomerular volume as suggested in other glomerulopathies. Of note, relationship between AER and Nv(Podo/glom) was not seen in microalbuminuric T1D patients. Moreover, another study showed that podocyte structural parameters did not predict progression to proteinuria or ESRD during long-term follow-up in normoalbuminuric T1D patients [36], suggesting that podocyte injury may play a more critical role in progression of DKD in later stages of the disease or, alternatively, the role of podocyte injury may become evident only after a certain fraction of podocytes are lost [41].
The endothelial cells develop structural changes in DKD. There is a reduction in glomerular endothelial fenestration in normoalbuminuric patients which persists in micro- and macroalbuminuria [24]. Although endothelial glycocalyx cannot be observed using routing electron microscopy techniques, it has been shown that DKD is associated with increased heparanase activity that leads to reduced endothelial glycocalyx, a change that can contribute into albuminuria and infiltration of macrophages into the kidney [42].
DKD in Type 2 Diabetic Patients
The frequency of DKD among clinical biopsies, regardless of the status of diabetes, has progressively increased over the last three decades in the USA, currently approaching ~20% [43, 44]. This is while an autopsy study showed that ~19% of diabetic patients with obvious DKD lesions did not present with clinical manifestations of DKD, suggesting that DKD may be underdiagnosed based on indication biopsies [45]. Although type 2 diabetes is by far the most common etiology of ESRD, there are more studies available describing the natural history of DKD lesions in type 1 compared to type 2 diabetes. In general, similarities between DKD lesions in T1D and T2D patients are substantial. Classical glomerular lesions of DKD, including GBM thickening , mesangial expansion , and reduced glomerular filtration surface area, similar to type 1 diabetes, are present and progress with diabetes duration [46]. Studies performed on adults who develop type 2 diabetes later in life when hypertension and atherosclerotic vascular lesions are already present suggest that pathologic findings are more heterogeneous in T2D compared to type 1 diabetic patients [9, 47,48,49]. Fioretto et al. identified three different patterns or categories of lesions in kidney biopsies from microalbuminuric and macroalbuminuric Northern Italian T2D patients: category I with almost normal biopsies (35% of microalbuminuric and 10% of proteinuric patients) (Fig. 8.8), category II with classical lesions of DKD similar to T1D (30% of microalbuminuric and 55% of proteinuric patients), and category III with disproportionately advanced tubulointerstitial fibrosis, arteriolar hyalinosis, arteriosclerosis, or global glomerulosclerosis, despite minor diabetic glomerulopathy [9]. Of note, these categories correlated with some clinical phenotypes. Thus, the presence of classical DKD lesions (category II) was associated with longer duration of diabetes, poorer glycemic control, faster GFR decline, and retinopathy [50, 51]. In contrast, retinopathy was rare in patients exhibiting category I or II on biopsies [52]. In contrast, biopsy studies performed in Pima Indians who generally develop type 2 diabetes at a younger age suggest that the relationships between albuminuria and DKD structural changes are more similar to those seen in type 1 diabetic patients [53], reflecting more homogeneity in DKD lesions in these younger type 2 diabetic patients.
(a) Glomeruli from a patient in category C I. Glomerular structure is near normal with minimal mesangial expansion (PAS). (b) Glomerulus from a patient in category C II, with well-established diabetic nephropathology. Diffuse mesangial expansion, advanced arteriolar hyalinosis, and mild interstitial fibrosis are present (PAS). (c) Glomerulus from a patient in category C III (a), with near-normal glomerular structure and tubular basement membrane thickening, tubular atrophy, and severe interstitial fibrosis (PAS). (d) Glomerulus from a patient in category C III (b), with mild mesangial expansion and severe arteriolar hyalinosis, affecting both afferent and efferent glomerular arterioles (PAS). (e) Glomeruli from a patient in category C III (c). Glomerular structure is near normal in one glomerulus, while the adjacent shows global glomerular sclerosis (PAS). (Figure reproduced from Ref. [18] with permission of the publisher)
Structural-Functional Relationships in T2D Patients
There is substantial similarity in structural-functional relationships of DKD between type 1 and type 2 diabetes, albeit these relationships may be less precise in type 2 diabetes, which may be at least partly related to the heterogeneity of lesions in older type 2 diabetic patients. A study on 47 Caucasian adults (average age about 60 years) with type 2 diabetes and proteinuria showed direct relationships between Vv(Mes/glom), Vv(MM/glom), and GBM width and proteinuria and inverse relationships between Vv(Mes/glom), Vv(MM/glom), Vv(Int/cortex), and GFR [54]. A longitudinal study in Japanese type 2 diabetic patients found GBM width and Vv(Mes/glom) as predictors of progression of albuminuria after 6 years of follow-up [55]. Another longitudinal study performed on Northern Italian type 2 diabetic patients showed that GBM width and Vv(Mes/glom) predicted GFR decline after follow-up for 4 years [50]. Importantly, even in patients who were normoalbuminuric at the baseline, these lesions predicted GFR loss at follow-up. More recently, a study performed on a large cohort of Pima Indians with type 2 diabetes suggested that both glomerular and tubulointerstitial lesions were significant contributors into GFR loss. On one hand, glomerular parameters, including Vv(Mes/glom), percentage of global glomerular sclerosis, nonpodocyte (mesangial and endothelial) cell number per glomerulus, GBM width, mean glomerular volume, and podocyte foot process width; lower Sv(PGBM/glom); and fewer endothelial fenestrations were each associated with GFR decline after adjustment for main clinical parameters [56]. Moreover, a composite glomerulopathy index, reflecting the combined effects of the statistically significant morphometric variables listed above, was strongly associated with GFR loss. On the other hand, when GFR slope was modeled as a threshold, only Vv(Int/cortex) was associated with the slope. Importantly, these relationships between biopsy structural parameters and GFR loss were even present when the baseline GFR was normal or elevated, suggesting that the deteriorating impact of these lesions on renal function starts at very early stages of DKD when the disease is clinically silent.
Podocyte injury starts early in type 2 diabetic patients. Normoalbuminuric patients with type 2 diabetes show increased urine nephrin and/or podocin mRNA compared to nondiabetic persons [57]. Injured podocytes can detach from the GBM and fall into the urine. In fact, microalbuminuric and proteinuric type 2 diabetic patients show increased shedding of podocytes into the urine (podocyturia) [58]. Since podocytes do not regenerate efficiently, podocyte loss is generally regarded as a cumulative insult to the glomerulus and in time leads to podocyte depletion in the glomeruli. The number of podocytes in a glomerulus can be assessed either in relative (to glomerular volume), i.e., podocyte number density per glomerular volume, or absolute (i.e., podocyte number per glomerulus) terms. It has been shown that both number and number density of podocytes per glomerulus are reduced in microalbuminuric and macroalbuminuric type 2 diabetic patients [53, 59, 60]. Podocyte loss increases with diabetes duration, and as expected this is associated with increased AER [46, 59]. Once podocyte loss is severe enough, it ensues into segmental and eventually global glomerulosclerosis . Importantly, Meyer et al. found that podocyte number per glomerulus in microalbuminuric Pima Indian persons with type 2 diabetes was not only the strongest predictor of AER increase but also predicted progression to overt nephropathy [61].
Nondiabetic Renal Disease in Diabetic Patients
Currently, indication biopsies in diabetic patients are performed if the clinical history raises suspicion for a nondiabetic renal disease (NDRD), including [62] nephrotic-range proteinuria or kidney failure in the absence of diabetic retinopathy, with diabetes duration less than 5 years or with normal GFR, reduced GFR with diabetes duration less than 5 years, unexplained microscopic hematuria or acute kidney injury, or rapidly worsening kidney function in patients with previously stable kidney function. Therefore, it is not surprising to find a high incidence of NDRD in clinical biopsies from diabetic patients [63,64,65,66,67,68]. Given the prevalence of diabetes, up to 25% of all clinical renal biopsies are done in diabetic patients [69]. The prevalence of NDRD in biopsies from diabetic patients is variable in the literature and ranges from 10% to 85% [70,71,72,73]. However, the incidence of NDRD in research or protocol biopsies is remarkably lower than in clinical biopsies [74]. The likelihood of finding NDRD in indication biopsies from diabetic patients is affected by the criteria and biopsy threshold used, as well as ethnic and geographic factors. In a study performed at Columbia University, of all indication biopsies from diabetic patients, 37% had DKD alone, 36% had NDRD alone, and 27% had DKD plus NDRD [69]. In the NDRD alone group, the most common diagnosis was FSGS (22%), followed by hypertensive nephrosclerosis, acute tubular injury, IgA nephropathy, membranous nephropathy, and pauci-immune glomerulonephritis. In the DKD plus NDRD group, however, acute tubular injury was the most common finding (43%), followed by hypertensive nephrosclerosis, FSGS, and IgA nephropathy. Diabetes duration ≥12 years was found to be the best predictor of DKD alone.
It is noteworthy that some lesions listed among the most commonly reported forms of NDRD in biopsies from diabetic patients, e.g., focal and segmental glomerulosclerosis and hypertensive nephrosclerosis, can reflect processes secondary to DKD, rather than independent concurrent diseases. There is no general consensus on how to report such lesions. Therefore, studies on NDRD made based on extracting data from pathology reports may well be affected by reporting routines of one center vs. another. Another example would be the presence of interstitial eosinophilic aggregates that are commonly regarded as an allergic reaction to presumptive drugs. However, Dai et al. showed that this finding, which can be seen in about 40% of indication biopsies from diabetic patients, does not correlate with a clinical history of drug allergy or the number of medicines used by patients and instead it correlates with the severity of chronic injury in renal parenchyma [75].
DKD Classification of Pathologic Lesions
Classification of pathologic lesions facilitates uniform reporting of biopsy findings and reproducibility of data generated from biopsy studies. Tervaert et al. [76] proposed a pathologic classification for DKD mainly based on the glomerular lesions. The classification consists of four progressive classes, including GBM thickening (class I), mesangial expansion (class II which is divided into classes IIa if mild and IIb if severe), presence of Kimmelstiel-Wilson nodules (class III), and extensive global glomerulosclerosis (class IV). Vascular and tubulointerstitial lesions are included in a separate scoring system. An et al. in a large study performed on type 2 diabetic patients showed that the severity of glomerular and interstitial lesions inversely impacts renal prognosis [77]. Another study showed that progression of glomerular, tubulointerstitial, and vascular lesions evaluated by this classification was associated with poor renal prognosis [33]. On the other hand, some studies have challenged the prognostic significance of glomerular lesions according to this classification [78, 79]. Whether this classification has any predictive value in early stages of DKD, when treatments are more likely to affect outcomes, remains to be validated. In an effort to study the net cumulative effect of various DKD lesions on renal prognosis, Hoshino et al. proposed a D-score calculated by summing the scores of all components in Tervaert classification which led to improvement in prediction of renal outcome, with a D-score ≤14 predicting excellent outcomes [80]. However, it should be noted that all studies confirming a prognostic value for this classification so far basically have reported that more severe glomerular or tubulointerstitial lesions portend worse outcomes, which is not surprising and does not help identifying patients at greater risk of progression at earlier stages. In addition, some other important aspects of DKD with predictive value for renal dysfunction, such as heterogeneity of patterns of renal injury in T2D [70], and some other morphologic features with predictive value for renal dysfunction, such as podocyte loss [53], glomerulotubular junction abnormalities [28], or endothelial fenestration [56], are not included in this classification.
Are DKD Lesions Reversible?
It has been shown that kidney lesions developed in diabetic murine models are reversible following normoglycemia. Islet transplantation in STZ-induced diabetic rats normalizes blood glucose and leads to reversal of diabetic kidney lesions in 2 months [81]. BTBR ob/ob diabetic mice, a model of type 2 diabetes with kidney lesions mimicking those seen in human DKD, show reversal of diabetic lesions after 6 weeks of leptin replacement-associated normoglycemia [82]. However, as explained earlier in this chapter, human DKD lesions in contrast to murine models gradually develop in a long time. Similarly, long-term normoglycemia is required for human DKD lesions to improve or reverse. Fioretto et al. showed that after 10 years of normoglycemia following pancreas transplantation, marked reversal of diabetic glomerulopathy lesions can be seen in type 1 diabetic patients with a diabetes duration of approximately 20 years, while 5 years of normoglycemia after pancreas transplantation was not enough to lead to appreciable changes [83]. Most strikingly, Kimmelstiel-Wilson nodules had completely disappeared in the 10-year biopsies. GBM and TBM width, Vv(Mes/glom), and Vv(MM/glom) were all reduced at 10 years compared with the baseline and 5-year values, and these parameters in some patients returned to the normal at 10-year biopsies (Fig. 8.9) [9]. Reversal of diabetic glomerulopathy was also associated with improvement of tubulointerstitial lesions and reduction in total cortical interstitial collagen [28].
Thickness of the glomerular basement membrane, thickness of the tubular basement membrane, mesangial fractional volume, and mesangial-matrix fractional volume at baseline and 5 and 10 years after pancreas transplantation. The mesangial fractional volume is the proportion of the glomerulus occupied by the mesangium; the mesangial-matrix fractional volume is the proportion of the glomerulus occupied by mesangial matrix. The shaded areas represent the normal ranges obtained in the 66 age- and sex-matched normal controls (means ±2 SD). Data for individual patients are connected by lines. (Figure reproduced from Ref. [9] with permission of the publisher)
Given the limited regeneration capacity of podocytes and the role of podocyte loss in progression of DKD lesions (see above), it is important to find out if podocyte regeneration is needed for reversal of DKD. Animal models have suggested that progenitor cells on Bowman’s capsule may be involved in replacing lost podocytes in the glomerular tuft [82, 84,85,86,87]. Pichaiwong et al. showed that leptin treatment of BTBR ob/ob mice not only led to reversal of renal diabetes lesions but also was associated with podocyte regeneration in the glomeruli [82]. Evidence as to whether or not that is the case in reversal of DKD lesions in humans is scanty. In one study that addresses this issue, Andeen et al. showed that early DKD in clinical biopsies was associated with increased number of parietal cells with a podocyte phenotype (Fig. 8.10), indicative of the potential for podocyte restoration [19].
Immunophenotypic alterations in podocyte and parietal epithelial cells in diabetic nephropathy (DN). (a–d) Cells marking as podocytes were present in parietal epithelial cell locations and significantly increased in histologically early DN (a, b), with a nonsignificant increase in advanced DN (c, d) compared with controls (original magnification ×400). (e–g) Synaptopodin highlighted a significantly increasing percentage of staining of cells lining Bowman’s capsules from controls (e) to early (f) to advanced DN, including areas of segmental adhesions (original magnification ×400). (h–j) Ki-67-expressing cells were identified on the glomerular tuft and Bowman’s capsule in morphologically early (i) and advanced (j) DN but only rarely in controls (h) (original magnification ×400). (k–m) Claudin-1/PAS revealed claudin-1-positive cells in areas of increased mesangial matrix in early DN (k), in areas of “capping” of segmentally sclerotic regions (l), and having a variable glomerular distribution in advanced DN (m) (original magnification ×400). (Figure reproduced from Ref. [19] with permission of the publisher)
The effect of pharmaceutical intervention to reverse DKD or reduce its progression has also been explored in limited studies. Five years of RAAS blockade by losartan or enalapril in normotensive normoalbuminuric type 1 diabetic patients did not prevent progression of DKD lesions but reduced progression of retinopathy [88]. On the other hand, 6 years of treatment with losartan slowed progression of mesangial expansion in microalbuminuric Pima Indian patients with type 2 diabetes [89].
Animal Models of DKD
Animal models have been widely used to explore the pathogenesis of DKD [90, 91]; however, in general, they do not faithfully replicate human DKD. A detailed discussion of models of DKD in several animal species is presented in Chapter 13 of this book. Most murine models show only the earliest features of human DKD, and an ideal model is yet to be developed. In response to this need, the nephropathy subcommittee of the Animal Models of Diabetic Complications Consortium (AMDCC) sets validation criteria for rodent models of DKD based on the clinical and pathological features of human DKD [92], including [1] >50% decrease in renal function, [2] >10-fold increase in albuminuria, and [3] pathological features including advanced mesangial matrix expansion with or without nodules, thickening of the GBM, arteriolar hyalinosis, and tubulointerstitial fibrosis.
Common rodent models used for type 1 diabetes include streptozotocin (STZ)-induced diabetic mice, Akita mice , OVE26 FVB mice , and nonobese diabetic (NOD) mice. STZ is a chemical toxin for pancreatic β cells. Therefore, injection of sufficient dose of STZ can make virtually any pre-existing model diabetic, although it should be noted that susceptibility to develop diabetic DKD varies among different strains [92]. For example, C57BL/6J mice in general are resistant to the development of kidney injury, including DKD [92]. It should be noted that STZ, especially if used at high doses (150–200 mg/kg), is nephrotoxic [93]. Multiple injections of low doses can avoid this problem to some degree [94]. Diabetic C57BL/6J mice develop mesangial expansion and some thickening of GBM, but not nodular glomerulosclerosis or tubulointerstitial fibrosis [92]. STZ-induced diabetes has been tried on other mouse strains such as DBA/2, CD1, and 129/Sv and also in rats [95]. Multiple genetic models for type 1 diabetes have also been developed. Akita mice have an Ins2+/C96Y mutation (a single nucleotide substitution in the Ins2 gene) [96], which leads to abnormal folding of the insulin protein with subsequent toxic injury to pancreatic β cells and development of diabetes. It has been shown that the genetic background of Akita mutation mice affects the severity of albuminuria and histological changes. Although Ins2+/C96Y mutation causes comparable hyperglycemia in C57BL/6, DBA/2, and 129/SvEv mice, the DBA/2-Ins2+/C96Y mice develop more severe albuminuria, but C57BL/6 and 129/SvEv mice develop more prominent increase in mesangial matrix [97]. However, Akita mice, regardless of the background strain, do not develop advanced DKD lesions, such as mesangiolysis, nodular glomerulosclerosis, or tubulointerstitial fibrosis. Thus, these mice can be considered for modeling early to moderate DKD [95]. Moreover, C57BL/6-Ins2+/C96Y mice develop diffuse granular mesangial IgA deposits starting at 20 weeks of age, which is a confounding factor for analysis of the contribution of diabetes to the mesangial injury that may develop [98]. Another model of type 1 diabetes is the OVE26 FVB mice with transgenic overexpression of calmodulin in pancreatic β cells with subsequent deficiency in insulin production within the first week of life [99]. This model develops progressive albuminuria, starting by 2 months of age. GFR increases from 2 to 3 months of age, followed by a subsequent decline from 5 to 9 months, with increased systolic and diastolic blood pressures. Diabetic OVE26 FVB mice develop glomerulomegaly, GBM thickening, podocyte loss, mesangial matrix increase, nodular glomerulosclerosis, and tubulointerstitial fibrosis [100]. Therefore, this model exhibits some of the features of advanced DKD in humans. The nonobese diabetic (NOD) mouse, which develops type 1 diabetes through autoimmune destruction of islet cells, is similar to humans [101, 102]. However, this model faces some disadvantages to others including the complex genetic background required for development of disease, the inconsistent timeline for onset of hyperglycemia, and the development of autoimmunity including deposition of immune complexes in glomeruli [103]. Perhaps for the same reasons, the extent of diabetic kidney injury in NOD mice has not been well characterized.
The most common type 2 diabetes murine models include db/db mice , KK-Ay mice, T2DN/Mcwi mice, eNOS−/− db/db mice, OVE26–TTrhRen double transgenic mice, BTBR ob/ob mice, Zucker diabetic fatty (ZDF) rats, Wistar fatty rats, Otsuka Long-Evans Tokushima fatty (OLETF) rats, and Goto-Kakizaki (GK) rats.
db/db mice have a deletion mutation in the leptin receptor (LepRdb/db) which causes abnormal splicing and results in a defective receptor for the adipocyte-derived hormone leptin [104]. Defected leptin signaling leads to abnormal hypothalamic responses, ensuing in hyperphagia, obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, and diabetes, which is more severe in male mice than in females. Male db/db mice become hyperglycemic at 6–10 weeks of age, followed by moderate to severe albuminuria at 8–25 weeks of age. Renal function declines at 15–18 weeks. db/db mice develop GBM thickening, podocyte loss, and moderate mesangial matrix expansion, but not mesangiolysis, nodular glomerulosclerosis, or severe tubulointerstitial fibrosis [26, 105]. KK mice develop mild insulin resistance and obesity, which is more severe in male animals [106, 107]. KK mice develop mild increase in mesangial matrix and GBM thickening. However, STZ-induced diabetic KK/H1J mice show more severe mesangial matrix expansion with nodular glomerulosclerosis and arteriolar hyalinosis [108]. The KK-Ay mouse was developed by transferring the yellow obese gene (Ay allele) into the KK mouse, which then becomes severely obese, hyperglycemic, and albuminuric. The kidneys of these mice show diffuse and moderate to severe mesangial matrix expansion with mesangial cell proliferation, segmental glomerulosclerosis, nodular glomerulosclerosis, and podocyte loss [109, 110]. The Zucker fatty (ZF) rat has a homozygous missense mutation (fatty, fa) in the leptin receptor gene (Lepr), resulting in obesity without diabetes. Zucker diabetic fatty (ZDF) rats are derived from the ZF strain. These rats are obese and develop progressive insulin resistance and diabetes [111, 112]. They are not hypertensive and show an initial increase in GFR which later on declines to normal level. Pathological changes include glomerulosclerosis, tubulointerstitial fibrosis, and inflammation [113]. The Wistar fatty (WF) rat is a congenic strain of the Wistar Kyoto (WKY) rat with a fa/fa homozygous missense mutation in the Lepr gene, resulting in obesity, hyperinsulinemia, and hyperlipidemia [114, 115]. Diabetes in the WF rats is milder than in the ZDF rats. However, the WF rats develop GBM thickening, foot process effacement, mesangial expansion, and tubulointerstitial inflammation. The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a robust model of type 2 diabetes. Almost all male OLETF rats develop diabetes by 25 weeks of age [116]. These rats develop albuminuria, proteinuria, and elevated GFR. Long-lasting diabetes in the OLETF rats is associated with glomerulomegaly, increased mesangial matrix, GBM thickening, nodular glomerulosclerosis, and tubulointerstitial fibrosis [117]. The Goto-Kakizaki (GK) rat is a nonobese model of type 2 diabetes, developed from a colony of Wistar rats through selection of rats with hyperglycemia [118]. The GK rats demonstrate impaired glucose tolerance test as early as 2 weeks of age, due to hypoplasia of pancreatic islet cells and insulin resistance [119]. GK rats develop type 2 diabetes by 12 weeks of age. However, they are relatively resistant to develop DKD [120], although some levels of GBM thickening and mild to moderate mesangial expansion have been reported in this model [121]. T2DN/Mcwi mice which are developed from a cross between GK and fawn-hooded hypertensive (FHH) rats [122] develop diabetes and progressive proteinuria, focal glomerulosclerosis, severe mesangial matrix expansion, and GBM thickening and later on nodular glomerulosclerosis and arteriolar hyalinosis [123].
Additional genetic stressors have been incorporated into some of the genetic models of DKD to accelerate progression of the lesions. The full knockout of endothelial nitric oxide synthase (eNOS) on the db/db C57BL/KsJ background results in eNOS−/− db/db mice which are hypertensive and develop marked albuminuria and reduced GFR with aging, extensive mesangial matrix expansion with nodules, mesangiolysis, increased GBM thickness, arteriolar hyalinosis, and tubulointerstitial fibrosis [124, 125]. Chronic activation of the renin-angiotensin system (RAS) in hyperreninemic transgenic (TTRhRen) mice is another approach to accelerate kidney lesions [126]. STZ injection to TTRhRen transgenic mice results in albuminuria and kidney lesions. OVE26–TTrhRen double transgenic mice develop very prominent albuminuria with glomerulosclerosis and interstitial fibrosis [126]. Combining the black and tan, brachyuric (BTBR) mouse strain with natural insulin resistance, with the ob/ob leptin mutation, results in BTBR ob/ob mice [127, 128]. These mice develop hyperglycemia and albuminuria with prominent mesangial matrix expansion, focal nodular glomerulosclerosis, mild GBM thickening and arteriolar hyalinosis and podocyte loss. Importantly, many of these lesions, including podocyte loss, can be reversed by administration of leptin [82]. However, the phenotype reported by some other labs has been milder than what was originally described, perhaps reflecting the impact of environmental factors on DKD in this model [129].
Characteristics of some of the discussed models are tabulated in Table 8.1. In summary, most currently studied mouse models of diabetes show early morphological changes of human DKD, such as mesangial matrix expansion and, in some cases, podocyte loss, including db/db and Akita mice. There are few models that exhibit features of both morphologically early and late DKD; of these, the eNOS−/− db/db mice, OVE26 FVB mice (a type 1 diabetes model), and BTBR ob/ob mice (modeling type 2 diabetes and obesity) appear to be the most robust. The BTBR ob/ob mouse model is particularly noteworthy for the relative rapidity in which lesions develop, making it well suited for studies of new therapeutics. Despite the plethora of diabetic mouse models, all models available to date possess important limitations in their practicality and/or fidelity in recapitulating all of the features of human disease. The tubulointerstitial and vascular lesions of DKD have been particularly challenging to model in the mouse. Designing better models of DKD that will allow identification of underlying mechanisms remains an important research objective, which in turn will facilitate testing of therapeutic interventions that can ameliorate or even reverse the structural alterations of DKD.
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Najafian, B., Alpers, C.E. (2019). Pathology of the Kidney in Diabetes. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_8
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