Insights into the Role of Renal Biopsy in Patients with T2DM: A Literature Review of Global Renal Biopsy Results

Analysis of the results of the 40 studies on renal biopsy results and pathological NDKD lesions in T2DM patients (Table 1) showed that the prevalence rate of DN alone ranges from 8.2 to 62.7%, with an average of 41.3%, which is similar to the T2DM rate of about 40% reported by Alicic et al. [1]. The overall prevalence of NDKD (including the mixed form) is 58.7%, which is consistent with the reported prevalence of NDKD in T2DM patients ranging from 8 to 93.5% [55]. The prevalence of isolated NDKD ranges from 0 to 68.6%, with an average of 40.6%, and the prevalence of DN plus NDKD ranges from 0 to 45.5%, with an average of 18.1%. As shown in Table 1, the prevalence and pathological types of isolated NDKD or DN plus NDKD are quite variable, which can be explained by the following:

As illustrated in Table 2, the proportion of NDKD cases identified in renal biopsy performed on patients with T2DM is not insignificant. In all continents, with the exception of Europe and Oceania, the proportion of patients with NDKD exceeds that with DN. These studies may overestimate the true prevalence of NDKD in T2DM patients, as indications for biopsy favor atypical cases, such as nephrotic syndrome, abnormal urine sediment, rapid decline of renal function or other NDKD indicators. On the other hand, in clinical practice, patients with T2DM rarely undergo diagnostic renal biopsy. In the absence of renal biopsy, the registry usually identifies patients with DM plus CKD as having DKD, resulting in an increase in the reported prevalence of DKD and a decrease that of NDKD [62]. In Asia, Africa (specifically Morocco and Tunisia) and Europe, the most commonly isolated NDKD pathological type is MN (Table 2), possibly associated with the increasing incidence of MN worldwide in the past decades. According to the literature [63], the incidence of MN in China increased from 6.48% in 1997–1999 to 22.79% in 2009–2011, while in Korea, idiopathic MN (IMN) was identified in 12.0% of all renal biopsies. Similar to Asia, the prevalence of IMN increased from 11.2 to 29.4% in Europe. A large-scale data study by Xu et al. [64] explained the high incidence of MN in China in the past decades in the context of environmental pollution (especially the increase in PM 2.5 levels). In areas with PM 2.5 > 70 μg/m³, for every 10 μg/m³ increase in concentration, the risk of developing MN was noted to increase by 14% (odds ratio 1.14, 95% confidence interval 1.10–1.18), while the effect in areas with PM 2.5 < 60 μg/ m³ was much lower. In support of this explanation, the prevalence of other major glomerular diseases remained relatively stable with increasing air pollution in China over the past decades, leading the authors to conclude that patients with long-term exposure to high levels of PM 2.5 may be more prone to MN than to other kidney diseases in a nonlinear pattern. In North America (specifically the USA), FSGS is the primary pathological type in patients with isolated NDKD (22%) (Table 2), which may be also related to the high incidence of FSGS. Consistent with previously published data [65], FSGS has always represented the primary pathological lesion in the USA, reported to be an average of 25.3% from 1986 to 2015.

Table 2 also illustrates the high rate of tubulointerstitial disease in the mixed group (21.7%), with the most common types being acute interstitial nephritis (AIN) (9.3%), followed by acute tubular necrosis (ATN) (9.0%). This high rate of tubulointerstitial disease may be associated with ischemic injury caused by diabetic vascular disease combined with other complex factors, such as susceptibility to infection, direct tubulointerstitial damage due to alterations in extracellular matrix synthesis and metabolism under the influence of glucose and/or the use of non-steroidal anti-inflammatory drugs, antibiotics, among others. These factors together lead to tubulointerstitial injuries. In conclusion, the high frequency of tubulointerstitial disease in patients with DKD may be related to the increased susceptibility of the kidney to ischemia and toxic injury [36].

The natural history of progression of T2DM/DKD to ESRD is not as clear as that of T1DM/DKD to ESRD. In addition, the clinical manifestations of this progression are varied. As such, many researchers have focused on trying to identify clinical indicators to distinguish DKD, single NDKD or a combination of the two in T2DM patients. Relevant clinical indicators include proteinuria, hematuria, duration of diabetes, diabetic retinopathy (DR), hypertension, hemoglobin, glycated hemoglobin (HbA1c), serum creatinine, serum cystatin C (CysC), C3, immunoglobulin, among others (Table 3)

As illustrated in Table 3, DR is an important clinical indicator predicting DKD or NDKD [18, 19, 21, 22, 24, 29, 31, 32, 37‐40, 44, 46, 48, 51, 53, 54, 69‐77, 80]. The presence of DR strongly suggests DKD, and the absence of DR is a major indicator to predict NDKD. In a multi-variate analysis, the overall diagnostic efficiency of DR was found to be quite significant [75, 76, 80]. In the study by Castellano et al. [51], the presence of retinopathy had a predictive value of 100% for DN. However, in a meta-analysis by Liang et al. [72], 23.6% of patients with biopsy-proven DKD did not have DR and there was no evidence of co-existence of DN and DR in 17.6% of patients. In summary, the absence of DR can predict NDKD, but DKD cannot be ruled out. Similarly, even if DR is present, NDKD can also occur (DKD plus NDKD). As such, Zwi et al. [81] suggest that biopsy should be performed to exclude interstitial nephritis and FSGS even in the presence of retinopathy. Jiang et al. [77] also found that the severity of DR was not related to the presence of DKD.

The duration of diabetes is an important predictor of DKD and NDKD according to many published reports [16, 21, 22, 24, 26, 29, 37, 41, 44, 48, 54, 69, 72, 74‐76, 80]. The major finding suggested by these reports is that a shorter duration of diabetes is suggestive of NDKD, while a longer duration is related to DKD. Some reports even provide a relatively specific time period: a duration of < 5 years from the time of diagnosing DM to developing a kidney disease is an independent predictor of NDKD [7, 16, 69, 75, 76], while a duration of > 10 years is an important indicator of DKD. More specifically, Yenigun et al. [ [37] and Sharma et al. 41] identified a duration of > 12 years as a predictor of DKD and NDKD with high sensitivity and specificity.

Hematuria is also a common predicting factor of DKD and NDKD [21, 26, 45, 48, 66, 74, 75]. Jiang et al. [82] further found dysmorphic erythrocytes were more valuable than microhematuria in the diagnosis of a nondiabetic lesion in T2DM with proteinuria. Lower HbA1c can also predict NDKD [16, 26, 32, 33, 53, 72]. Wang et al. [83] further pointed out that both the ratio of glycated albumin to HbA1c and glycated albumin were better biopsy-proven DKD indicators than HbA1c.

Other clinical predictors studied are proteinuria and serum CysC. Proteinuria as a predictor, most of the published literature suggest that sub-nephrotic range proteinuria is associated with the presence of NDKD, while nephrotic range proteinuria suggests DKD [20, 23, 37, 74, 80]. Ghani [34] also found that proteinuria level in patients with NDKD superimposed on diabetic glomerulosclerosis is typically higher; however, this finding needs to be supported by data from study with a large sample. Moreover, in a meta-analysis [67], researchers found that serum CysC was an early predictor of DN. Suzuki [78] also confirmed CysC can effectively detect grade 2 DN (urine albumin to creatinine ratio 30–300 mg/g) and will be especially useful for screening grade 2 CKD patients (K/DOQI–KDIGO [Kidney Disease Outcomes Quality Initiative–Kidney Disease Improving Global Outcomes] joint statement [3]).

Studies combining more than one predictor to distinguish DKD from NDKD have also been reported. Wong et al. [21] found that combination of absence of DR with hematuria or proteinuria (≥ 2 g/day) was the most sensitive indicator of a nondiabetic lesion, and Soni [29] considered that a short duration of diabetes and absence of retinopathy, especially when associated with nephrotic proteinuria, strongly predicts a nondiabetic lesion, consistent with results from a research paper from Australia [69]. Our analysis of the published literature revealed some contradictions. For example, in a study by Lin et al. [20], duration of DM of > 10 years and absence of DR failed to rule out NDKD, and in a study by Tone et al. [76] microscopic hematuria and granular casts had low specificity and sensitivity for NDKD. Furthermore, a study by Zhang et al. [68] showed that with different levels of proteinuria, low IgG and high C3 were independent indicators of NDKD in patients with T2DM, while Byun et al. [22] described an association between higher levels of IgG and NDKD, and Kanodia et al. [74] described an association of NDKD with low levels of C3 and/or C4. All of these contradictions require further study and verification by analysis of large-scale data.

Although single or combined indicators have resulted in higher sensitivity and specificity, most have been derived from single sample studies, which cannot exclude the effect of small sample size, selection bias and other such limitations. Christensen et al. [50] clearly pointed out that clinical or laboratory data could not be used to separate diabetes and nondiabetic glomerular lesions based on demographics. Clinically, if atypical DKD features are present, renal biopsy is still the only means to confirm the presence or absence of NDKD [2, 16‐20, 22, 24‐27, 31‐34, 37‐40, 46, 48, 50, 51, 69, 75, 80, 84]. To this end, we have divided these indicators from Table 3 into well-established indicators to NDKD and potential indicators to NDKD (Fig. 1). Whether potential indicators are able to predict NDKD requires more research data. However, when T2DM patients have the atypical DKD symptoms suggested by the above indicators, having kidney biopsy as early as possible to determine the presence and pathological type of NDKD is beneficial to the initiation of personalized treatment for patients.