Esteban Porrini

Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes

OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: −0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease.

The global increase in chronic kidney disease (CKD) parallels the obesity epidemic. Obesity conveys a gradual but independent risk of progression of CKD that seems irrespective of the underlying nephropathy. Obesity has been associated with a secondary focal segmental glomerulosclerosis coined obesity-related glomerulopathy (ORG). Pathways through which obesity might cause renal disease are not well understood, and early clinical biomarkers for incipient ORG or renal relevant obesity are currently lacking. Recent human and experimental studies have associated ectopic lipid accumulation in the kidney (fatty kidney) with obesity-related renal disease. There is enough growing insight that ectopic lipid--the accumulation of lipid in non-adipose tissue--is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells to propose the development of ORG as a maladaptive response to hyperfiltration and albuminuria. Recent advances in metabolic imaging might validate ectopic lipid as a biomarker and research aid, to help translate novel therapeutics from experimental models to patients.

Proceedings From an International Consensus Meeting on Posttransplantation Diabetes Mellitus: Recommendations and Future Directions

A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney‐centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new‐onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion‐based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion‐based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin–angiotensin–aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.

Measurable Urinary Albumin Predicts Cardiovascular Risk among Normoalbuminuric Patients with Type 2 Diabetes

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 μg/min was significantly associated with increased risk compared with albuminuria <1 μg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes

Largely on the basis of data from patients with type 1 diabetes, the natural history of diabetic renal disease has been classified as a sequence of three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Progressive decline of glomerular filtration rate (GFR) was thought to parallel the onset of macroalbuminuria (overt nephropathy), whereas glomerular hyperfiltration was deemed a hallmark of early disease. However, researchers have since shown that albuminuria is a continuum and that GFR can start to decline before progression to overt nephropathy. In addition to proteinuria, other risk factors might contribute to GFR deterioration including female sex, obesity, dyslipidaemia (in particular hypertriglyceridaemia), hypertension, and glomerular hyperfiltration, at least in a subgroup of patients. This phenomenon could explain why patients with type 2 diabetes can have renal insufficiency even before the onset of overt nephropathy, and might also suggest why the heterogeneous phenotype of type 2 diabetic renal disease does not necessarily associate with typical histological lesions of diabetic renal disease, unlike in type 1 diabetic renal disease. Patients with renal insufficiency but without albuminuria are usually excluded from randomised clinical trials in overt nephropathy, thus optimum treatment for this group of patients is unknown. The wide inter-patient variability of the disease probably needs individually tailored intervention.

Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study.

Background. Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established. Methods. In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria. Results. Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004–1.14), pretransplant body mass index (OR: 1.3, CI: 1.09–1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05–1.9) were independent risk factors for prediabetes. Conclusion. One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression.

Background. Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown. Methods. This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups. Results. A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57±12, 65.2±20, 73.5±27 ml/min, P=0.044), the Jelliffe-2 (51.5±16, 56±19, 59.4±19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53±17, 58.5±20, 61.6±22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008). Conclusions. Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.

Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research : a review. Part 1 How to measure glomerular filtration rate with iohexol?

While there is general agreement on the necessity to measure glomerular filtration rate (GFR) in many clinical situations, there is less agreement on the best method to achieve this purpose. As the gold standard method for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtration markers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFR marker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, but multiple-sample protocols may be more accurate in specific situations. In low GFRs one or more late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method.

Early association of low-grade albuminuria and allograft dysfunction predicts renal transplant outcomes.

Background. Data on the combined associations of albuminuria and estimated glomerular filtration rate (eGFR) with renal transplant outcomes are limited. Our objective was to explore how renal transplant outcomes could be predicted by a combined variable of early low-grade albuminuria and allograft dysfunction. Methods. We studied a cohort of adult deceased-donor kidney transplant recipients who were subdivided into four groups according to median albuminuria (100 mg/day, interquartile range, 0–470 mg/day) and median eGFR (60 mL/min/1.73 m2; interquartile range, 30–73 mL/min/1.73 m2) at third month posttransplantation as follows: group I (albuminuria <100 and eGFR >60, n=238); group II (albuminuria ≥100 and eGFR >60, n=151); group III (albuminuria <100 and eGFR ⩽60; n=167); and group IV (albuminuria ≥100 and eGFR ⩽60, n=228). Results. Death-censored graft survival was significantly lower in group IV compared with the rest (P<0.0001). Multivariate Cox regression analysis using fixed and time-dependent covariates showed that the combination of low-grade albuminuria and lower eGFR was associated with graft failure (hazard ratio, 2.2, 95% confidence interval, 1.3–3.7; P=0.003). Likewise, but to a lesser extent, the risk of mortality was increased for group IV (hazard ratio, 1.7, 95% confidence interval, 1.01–2.8; P=0.042). Conclusions. Early association of low-grade albuminuria and allograft dysfunction represents an important risk factor of graft failure and mortality. This additive effect should be considered to identify individuals at risk for adverse kidney transplantation outcomes.