Diabetes Management in Chronic Kidney Disease: Synopsis of the KDIGO 2022 Clinical Practice Guideline Update.

DESCRIPTION: The KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease is an update of the 2020 guideline from Kidney Disease: Improving Global Outcomes (KDIGO). METHODS: The KDIGO Work Group updated the guideline, which included reviewing and grading new evidence that was identified and summarized. As in the previous guideline, the Work Group used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of recommendations and expert judgment to develop consensus practice points. New evidence led to updating of recommendations in the chapters Comprehensive Care in Patients With Diabetes and CKD (Chapter 1) and Glucose-Lowering Therapies in Patients With T2D and CKD (Chapter 4). New evidence did not change recommendations in the chapters Glycemic Monitoring and Targets in Patients With Diabetes and CKD (Chapter 2), Lifestyle Interventions in Patients With Diabetes and CKD (Chapter 3), and Approaches to Management of Patients With Diabetes and CKD (Chapter 5). RECOMMENDATIONS: The updated guideline includes 13 recommendations and 52 practice points for clinicians caring for patients with diabetes and chronic kidney disease (CKD). A focus on preserving kidney function and maintaining well-being is recommended using a layered approach to care, starting with a foundation of lifestyle interventions, self-management, and first-line pharmacotherapy (such as sodium-glucose cotransporter-2 inhibitors) demonstrated to improve clinical outcomes. To this are added additional drugs with heart and kidney protection, such as glucagon-like peptide-1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonists, and interventions to control risk factors for CKD progression and cardiovascular events, such as blood pressure, glycemia, and lipids.

Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (CKD) represents a focused update of the KDIGO 2020 guideline on the topic. The guideline targets a broad audience of clinicians treating people with diabetes and CKD. Topic areas for which recommendations are updated based on new evidence include Chapter 1: Comprehensive care in patients with diabetes and CKD and Chapter 4: Glucose-lowering therapies in patients with type 2 diabetes (T2D) and CKD. The content of previous chapters on Glycemic monitoring and targets in patients with diabetes and CKD (Chapter 2), Lifestyle interventions in patients with diabetes and CKD (Chapter 3), and Approaches to management of patients with diabetes and CKD (Chapter 5) has been deemed current and was not changed. This guideline update was developed according to an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence, and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, and areas for which additional research is needed are presented.

Diabetes Management in Chronic Kidney Disease: Synopsis of the 2020 KDIGO Clinical Practice Guideline.

DESCRIPTION: The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed a clinical practice guideline in 2020 for the management of patients with diabetes and chronic kidney disease (CKD). METHODS: The KDIGO Work Group (WG) was tasked with developing the guideline for diabetes management in CKD. It defined the scope of the guideline, gathered evidence, determined systematic review topics, and graded evidence that had been summarized by an evidence review team. The English-language literature searches, which were initially done through October 2018, were updated in February 2020. The WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of the recommendations. Expert judgment was used to develop consensus practice points supplementary to the evidence-based graded recommendations. The guideline document underwent open public review. Comments from various stakeholders, subject matter experts, and industry and national organizations were considered before the document was finalized. RECOMMENDATIONS: The guideline includes 12 recommendations and 48 practice points for clinicians caring for patients with diabetes and CKD. This synopsis focuses on the key recommendations pertinent to the following issues: comprehensive care needs, glycemic monitoring and targets, lifestyle interventions, antihyperglycemic therapies, and educational and integrated care approaches.

Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.

THE KIDNEY DISEASE: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease represents the first KDIGO guideline on this subject. The guideline comes at a time when advances in diabetes technology and therapeutics offer new options to manage the large population of patients with diabetes and chronic kidney disease (CKD) at high risk of poor health outcomes. An enlarging base of high-quality evidence from randomized clinical trials is available to evaluate important new treatments offering organ protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. The goal of the new guideline is to provide evidence-based recommendations to optimize the clinical care of people with diabetes and CKD by integrating new options with existing management strategies. In addition, the guideline contains practice points to facilitate implementation when insufficient data are available to make well-justified recommendations or when additional guidance may be useful for clinical application. The guideline covers comprehensive care of patients with diabetes and CKD, glycemic monitoring and targets, lifestyle interventions, antihyperglycemic therapies, and self-management and health systems approaches to management of patients with diabetes and CKD.

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes.

Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.

Multiple Mutations Detected Preoperatively May Predict Aggressive Behavior of Papillary Thyroid Cancer and Guide Management--A Case Report.

BACKGROUND: Multiple gene mutations in thyroid nodules are rare. The presence of several oncogenic mutations could be associated with aggressive biological behavior of tumors. PATIENT FINDINGS: A 60-year-old female presented to her physician after she felt a lump in her neck. On ultrasound, she was found to have a 1.4 cm × 0.8 cm × 1.3 cm nodule in the isthmus and a 0.5 cm × 0.6 cm × 0.6 cm nodule with irregular margins and hypoechogenicity in the right thyroid lobe, warranting fine-needle aspiration (FNA). Cytological examination of the smaller nodule yielded a diagnosis of atypia of undetermined significance (AUS/FLUS, Bethesda Category III). The aspirate was submitted for molecular testing using the next-generation sequencing ThyroSeq(®) v2 panel. The test revealed four distinct mutations: BRAF (p.V600E), TERT (C228T), PIK3CA (p.H1047R), and AKT1 (p.E17K). Presence of multiple oncogenic mutations in the FNA specimen was highly indicative of cancer, and suggestive of a cancer with propensity toward more aggressive biological behavior. Four weeks after the FNA results were available, the patient underwent total thyroidectomy. This was followed by radioactive iodine ablation after the final pathology revealed a 0.5 cm papillary thyroid carcinoma (PTC) with extrathyroidal extension and positive resection margins (pT3 stage). SUMMARY: Herein, the first case of four mutations preoperatively detected in a subcentimeter thyroid nodule that was confirmed to be a PTC with aggressive biological behavior is reported. CONCLUSIONS: The judicious indication of FNA and use of molecular screening can potentially help in predicting aggressive behavior of small-sized thyroid cancers and in identifying patients who may benefit from early and more extensive therapy.

Podocyte structural parameters do not predict progression to diabetic nephropathy in normoalbuminuric type 1 diabetic patients.

BACKGROUND: Podocyte injury has been implicated in diabetic nephropathy (DN) ranging from normoalbuminuria to proteinuria in both type 1 and type 2 diabetes. METHODS: To determine whether podocyte structural parameters predict DN risk in initially normoalbuminuric long-standing type 1 diabetic patients, we performed a nested case-control study in sex and diabetes duration-matched progressors (progression to proteinuria or ESRD, n = 10), non-progressors (normoalbuminuric at follow-up, n = 10), and non-diabetic controls (n = 10). RESULTS: HbA1c and diastolic blood pressure were higher in progressors versus non-progressors. Podocyte number per glomerulus, numerical density of podocyte per glomerulus, and foot process width were not different among groups. The glomerular basement membrane width was greater in progressors versus non-progressors or controls, and in non-progressors versus controls. As expected, the mesangial fractional volume was greater in progressors and non-progressors versus controls, with no differences between progressors and non-progressors. CONCLUSION: This study does not indicate that podocyte structural changes are preconditions for later DN progression in initially normoalbuminuric type 1 diabetic patients. However, this does not preclude an important role for podocyte injury at a later stage of DN.

Differential Response to High Glucose in Skin Fibroblasts of Monozygotic Twins Discordant for Type 1 Diabetes.

CONTEXT: Most epigenetic studies in diabetes compare normal cells in "high glucose" (HG) to cells in "normal glucose" (NG) and cells returned from HG to NG. Here we challenge this approach. OBJECTIVE: The objective was to determine whether there were differences in gene expression in skin fibroblasts of monozygotic twins (MZT) discordant for type 1 diabetes (T1D). DESIGN: Skin fibroblasts were grown in NG (5.5 mmol/L) and HG (25 mmol/L) for multiple passages. SETTING: This study was conducted at the University of Minnesota. PATIENTS: Patients were nine MZT pairs discordant for T1D. MAIN OUTCOME MEASURE(S): Gene expression was assessed by mRNA-Seq, using the Illumina HiSeq 2000 instrument. Pathway analysis tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: A total of 3308 genes were differentially expressed between NG and HG in T1D MZT vs 889 in non-T1D twins. DNA replication, proteasome, cell cycle, base excision repair, homologous recombination, pyrimidine metabolism, and spliceosome pathways had overrepresented genes with increased expression in T1D twins with P values ranging from 7.21 × 10(-10) to 1.39 × 10(-4). In a companion article, we demonstrate that these pathway changes are related to diabetic nephropathy risk. There were no pathways statistically significant differently expressed in nondiabetic twins in HG vs NG. CONCLUSIONS: In vivo exposure to diabetes alters cells in a manner that markedly changes their in vitro responses to HG. These results highlight the importance of using cells directly derived from diabetic patients for studies examining the effects of HG in diabetes.

Differential Gene Expression in Diabetic Nephropathy in Individuals With Type 1 Diabetes.

CONTEXT: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States. OBJECTIVE: The aim of this study was to determine whether there were skin fibroblast gene expression differences between subjects with type 1 diabetes (T1D) with or without DN. SETTING: This was a cross-sectional study conducted in the University of Minnesota. PATIENTS: Study volunteers were 100 former participants of Genetics of Kidneys in Diabetes: 40 were diabetic nephropathy (DN) Controls, normoalbuminuric after ≥ 15 years of T1D; and 60 were DN Cases, 25 with proteinuria and 35 with ESRD. INTERVENTION(S): Skin fibroblasts were grown in high glucose (HG) for five passages (approximately 6 weeks). MAIN OUTCOME MEASURE(S): SF gene expression was assessed by transcriptome sequencing using the Illumina HiSeq 2000 platform. Pathway analyses tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: Eight pathways, all related to cell cycle and repair, were up-regulated in the DN Controls vs the DN Cases. These pathways markedly overlapped with the pathways up-regulated by HG in T1D monozygotic twins (MZT), but not in their non-T1D MZT. DN Cases showed statistical trends toward up-regulation of these pathways vs non-T1D MZT, but much less so than the DN Controls. CONCLUSIONS: Together, these data suggest that SF from T1D patients undergo epigenetic modifications resulting in increased expression of genes in healing and repair pathways. These responses, much more robust in patients protected from DN, suggest that epigenetic factors are important in DN risk.

Renal lesions predict progression of diabetic nephropathy in type 1 diabetes.

Whether early glomerular, tubulointerstitial, vascular, and global glomerulosclerotic lesions can predict progression of diabetic nephropathy is not well defined. Here, we sought to determine whether renal structural parameters predict the development of proteinuria or ESRD after long-term follow-up. We measured several renal structures in kidney biopsies from 94 normoalbuminuric patients with longstanding type 1 diabetes using unbiased morphometric methods. Greater width of the glomerular basement membrane and higher levels of glycated hemoglobin were independent predictors of progression to diabetic nephropathy in this normoalbuminuric cohort. Moreover, none of these patients with type 1 diabetes who had glomerular basement membrane widths within the normal range developed proteinuria and/or ESRD. In conclusion, careful quantitative assessment of kidney biopsies in normoalbuminuric patients with type 1 diabetes adds substantially to the prediction of progression to clinical diabetic nephropathy.

Viper venom for diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. Renin-angiotensin-aldosterone system (RAAS) blockers are thought to have a specific renoprotective effect in diabetes. Hirst et al. report the results of randomized clinical trials assessing the effects of RAAS inhibitors on urinary albumin excretion levels in diabetic patients. Although reductions in urinary albumin excretion were observed, whether RAAS inhibitors offer additional protection over other antihypertensive agents is unclear.

Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes.

Clinical studies suggest metabolic memory to hyperglycemia. We tested whether diabetes leads to persistent systematic in vitro gene expression alterations in patients with type 1 diabetes (T1D) compared with their monozygotic, nondiabetic twins. Microarray gene expression was determined in skin fibroblasts (SFs) of five twin pairs cultured in high glucose (HG) for ∼6 weeks. The Exploratory Visual Analysis System tested group differences in gene expression levels within KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. An overabundance of differentially expressed genes was found in eight pathways: arachidonic acid metabolism (P = 0.003849), transforming growth factor-ß signaling (P = 0.009167), glutathione metabolism (P = 0.01281), glycosylphosphatidylinositol anchor (P = 0.01949), adherens junction (P = 0.03134), dorsal-ventral axis formation (P = 0.03695), proteasome (P = 0.04327), and complement and coagulation cascade (P = 0.04666). Several genes involved in epigenetic mechanisms were also differentially expressed. All differentially expressed pathways and all the epigenetically relevant differentially expressed genes have previously been related to HG in vitro or to diabetes and its complications in animal and human studies. However, this is the first in vitro study demonstrating diabetes-relevant gene expression differences between T1D-discordant identical twins. These SF gene expression differences, persistent despite the HG in vitro conditions, likely reflect "metabolic memory", and discordant identical twins thus represent an excellent model for studying diabetic epigenetic processes in humans.

Benefits of Renin-Angiotensin blockade on retinopathy in type 1 diabetes vary with glycemic control.

OBJECTIVE: Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo. RESULTS: A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P < 0.001). There was no beneficial effect of RAS blockade (P = 0.92) in patients with baseline A1C ≤7.5%. In contrast, 30 of 112 (27%) patients on the active treatment arms with A1C >7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group (P = 0.03). CONCLUSIONS: RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C ≤7.5% will require long-term studies of much larger cohorts.

Glomerulopathy in spontaneously obese rhesus monkeys with type 2 diabetes: a stereological study.

BACKGROUND: Animal models could provide insights into the diabetic nephropathy pathogenesis; however, available rodent models do not mirror the heterogeneity of lesions in type 2 diabetic patients, and do not progress to end-stage renal disease. Previous studies showed that spontaneously obese type 2 diabetic rhesus monkeys develop many of the features of human diabetic glomerulopathy, and may progress to end-stage renal disease. Here, in order to further characterize diabetic glomerulopathy in this model, we used electron microscopic stereology. METHODS: Renal biopsies from 17 diabetic, 17 pre-diabetic/metabolic syndrome and 11 non-diabetic monkeys were studied. Fractional volumes of mesangium [Vv(Mes/glom)], mesangial matrix [Vv(MM/glom)] and mesangial cells [Vv(MC/glom)], glomerular basement membrane width and peripheral glomerular basement membrane surface density per glomerulus [Sv(PGBM/glom)] were estimated. Glomerular filtration and albumin excretion rates were measured in a limited number of animals. Glomerular structural and biochemical/metabolic data were compared among the groups. RESULTS: Compared to non-diabetic monkeys, diabetic rhesus monkeys showed classic diabetic nephropathy changes, including glomerular basement membrane thickening (p = 0.001), increased fractional volumes of mesangium (p = 0.02), and reduced peripheral glomerular basement membrane surface density per glomerulus (p = 0.03) compared to non-diabetic monkeys. Increased fractional volumes of mesangium was primarily due to increased mesangial matrix (p = 0.03). Glomerular structural parameter inter-relationships in diabetic monkeys mirrored those of human diabetic glomerulopathy. Albumin excretion rate was greater (p = 0.03) in diabetic vs. non-diabetic monkeys. There was trend for a positive correlation between albumin excretion rate and fractional volumes of mesangium. CONCLUSIONS: This rhesus primate model shares many features of human diabetic glomerulopathy. Mesangial expansion in this model, similar to human diabetic nephropathy and different from available rodent models of the disease, is primarily due to increased mesangial matrix.

Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with Type 1 diabetes.

Endoglin is an accessory receptor molecule that, in association with transforming growth factor beta (TGF-beta) family receptors Types I and II, binds TGF-beta1, TGF-beta3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulating TGF-beta dependent cellular responses. Relevant to diabetic nephropathy, endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts, and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of this study was to evaluate endoglin expression in cultured skin fibroblasts from patients with Type 1 diabetes with and without diabetic nephropathy. Kidney and skin biopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastest rate of mesangial expansion (estimated by electron microscopy) and proteinuria ("fast-track") and the 20 with the slowest rate and normoalbuminuria ("slow-track"), along with 20 controls were studied. Endoglin mRNA expression was assessed by microarray and quantitative real-time polymerase chain reaction (QRT-PCR) and protein expression by Western blot. Age and sex distribution were similar among groups. Diabetes duration was similar (20+/-8 vs. 24+/-7 years), hemoglobin A1c lower (8.4+/-1.2% vs. 9.4+/-1.5%), and glomerular filtration rate higher (115+/-13 vs. 72+/-20 ml/min per 1.73 m2) in slow-track vs. fast-track patients. Microarray endoglin mRNA expression levels were higher in slow-track (1516.0+/-349.9) than fast-track (1211.0+/-274.9; P=.008) patients or controls (1223.1+/-422.9; P=.018). This was confirmed by QRT-PCR. Endoglin protein expression levels correlated with microarray (r=0.59; P=.044) and QRTPCR (r=0.61; P=.034) endoglin mRNA expression. These studies are compatible with the hypothesis that slow-track Type 1 diabetic patients, strongly protected from diabetic nephropathy, have distinct cellular behaviors that may be associated with reduced ECM production.

Having one kidney does not accelerate the rate of development of diabetic nephropathy lesions in type 1 diabetic patients.

OBJECTIVE: Reduced nephron number is hypothesized to be a risk factor for chronic kidney disease and hypertension. Whether reduced nephron number accelerates the early stages of diabetic nephropathy is unknown. This study investigated whether the rate of development of diabetic nephropathy lesions was different in type 1 diabetic patients with a single (transplanted) kidney compared with patients with two (native) kidneys. RESEARCH DESIGN AND METHODS: Three groups of volunteers were studied: 28 type 1 diabetic kidney transplant recipients with 8-20 years of good graft function, 39 two-kidney patients with duration of type 1 diabetes matched to the time since transplant in the one-kidney group, and 30 age-matched normal control subjects. Electron microscopic morphometry was used to estimate glomerular structural parameters on 3.0 +/- 1.4 glomeruli per biopsy. RESULTS: In the one- versus two-kidney diabetic subject groups, respectively, serum creatinine (means +/- SD 1.3 +/- 0.4 vs. 0.9 +/- 0.2 mg/dl; P < 0.001), systolic blood pressure (133 +/- 13 vs. 122 +/- 11 mmHg; P < 0.001), and albumin excretion rate (median [range] 32.1 microg/min [2-622] vs. 6.8 microg/min [2-1,495]; P = 0.006) were higher. There were no differences in the one- versus two-kidney diabetic subject groups, respectively, in glomerular basement membrane width (median [range] 511 nm [308-745] vs. 473 nm [331-814]), mesangial fractional volume (mean +/- SD 0.30 +/- 0.06 vs. 0.27 +/- 0.07), mesangial matrix fractional volume (0.16 +/- 0.05 vs. 0.16 +/- 0.06), and mesangial matrix fractional volume per total mesangium (0.61 +/- 0.07 vs. 0.64 +/- 0.09). However, these glomerular structural parameters were statistically significantly higher in both diabetic subject groups compared with normal control subjects. Results were similar when patients receiving ACE inhibitors were excluded from the analyses. CONCLUSIONS: Reduced nephron number is not associated with accelerated development of diabetic glomerulopathy lesions in type 1 diabetic patients.

Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy.

The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy. We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium [S(S)(Fenestrated/cap)] and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r = -0.71, P = 0.001) and directly with AER (r = 0.66, P = 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects (P = 0.001), normoalbuminuric patients (P = 0.0002) and microalbuminuric patients (P = 0.04) and correlated with renal structural and functional parameters, including AER (r = -0.52, P = 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. S(S)(Fenestrated/cap) was reduced in normoalbuminuric (P = 0.03), microalbuminuric (P = 0.03), and proteinuric (P = 0.002) patients versus control subjects. S(S)(Fenestrated/cap) correlated with mesangial fractional volume per glomerulus (r = -0.57, P = 0.01), IFP (r = 0.61, P = 0.007), and FPW (r = -0.58, P = 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy.