Induction of diabetes by Tacrolimus in a phenotypic model of obesity and metabolic syndrome.

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.

Renal Disease in Metabolic Syndrome: the Hidden Role of Intrarenal Ischemia.

Introduction: The pathogenesis of renal disease in obesity and metabolic syndrome (MS) is mostly unknown. This is in part because of the limited information about renal morphological changes in these conditions. We evaluated renal histology in subjects with MS and those without MS, who are participants in the European Nephrectomy Biobank (ENBiBA) project. Methods: MS was defined with at least 3 of the following criteria: (i) body mass index (BMI) ≥27 kg/m2; (ii) prediabetes: fasting glucose of 100-125 mg/dl or HbA1c >5.7%; (iii) systolic or diastolic blood pressure >140/90 mm Hg or the use of medications; and (iv) triglycerides >150 mg/dl or high-density lipoprotein cholesterol <40 (in men) or 50 mg/dl (in women). The absence of these criteria defined patients without MS. Exclusion criteria were diabetes or known causes of renal disease. Results: A total of 157 cases were evaluated: 49 without and 108 with MS. Those with MS were older (54 ± 16 vs. 66 ± 11, P < 0.0001), had more prevalent chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] <60 ml/min): 24% (23%) versus 4% (8%) (P = 0.02), and had higher albumin-to-creatinine ratio (10 [4-68] vs. 4.45 [0-27], P = 0.05) than those without MS. Global sclerosis (3% [1-7] vs. 7% [3-13], P < 0.0001), nodular sclerosis, mesangial expansion, glomerulomegaly; moderate + severe hyalinosis, and arteriosclerosis were more frequent in those with MS than in those without (88 [82] vs. 29 [59]; 83 [77] vs. 30 [61]; P < 0.05). These vascular changes were independent of differences in age. Conclusion: In MS, ischemic renal disease may play a role in renal disease. In addition, some patients may develop lesions compatible with diabetic nephropathy such as increased mesangial expansion and nodular sclerosis. Further analyses are needed to study the consequences of the pandemic of obesity on renal health.

Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making.

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

International consensus on post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

Therapeutic Exercise on Metabolic and Renal Outcomes in Patients with Chronic Kidney Disease: A Narrative Review.

BACKGROUND: Chronic kidney disease (CKD) affects 11-13% of the world population. The main risk factors for CKD include diabetes, hypertension, and obesity. Metabolic syndrome (MS) is associated with the onset of CKD in the nondiabetic population. Obesity and MS are also risk factors for a worse progression of established CKD. Therapeutic exercise is an effective option to treat and manage obesity, MS, and diabetes in the general population. However, the evidence on the effect of exercise on patients with CKD, obesity, and MS is scarce. SUMMARY: We evaluated available evidence on the effect of therapeutic exercise in patients with CKD, excluding dialysis, particularly in improving the metabolic risk factors and main renal outcomes: renal function loss and albuminuria/proteinuria. This review includes prospective studies and clinical trials. A total of 44 studies were analysed in 1,700 subjects with renal disease (2-5), including patients with renal transplantation. Most studies did not prove a major effect of exercise on albuminuria/proteinuria, glomerular filtration rate (GFR), obesity, or MS. These results are intriguing and deserve attention. The exploratory nature of most studies, including a low number of cases and short follow-up, might explain the lack of efficacy of exercise in our analysis. Specific aspects like the type of exercise, frequency, intensity, duration, accommodation during follow-up, individualization, safety, and adherence are crucial to the success of therapeutic exercise. The beneficial role of exercise in patients with CKD remains to be determined. KEY MESSAGES: Key messages of this review are as follows. (1) The effect of therapeutic exercise on renal and metabolic outcomes in patients with CKD remains to be determined. (2) According to the evidence selected, therapeutic exercise seems to be safe to treat patients with CKD. (3) Most studies are exploratory by nature, with results that need further investigation. (4) Therapeutic exercise is a complex procedure that must be specifically designed to treat patients with CKD.

The Role of Gender Differences and Menopause in Obesity-Related Renal Disease, Renal Inflammation and Lipotoxicity.

The pathogenesis of obesity-related-renal disease is unknown. Menopause can promote renal disease in obese women, but this interaction is unclear. In a previous study, we observed that obese male and female mice developed albuminuria, hyperfiltration, and glomerulomegaly, and these changes were more severe in those obese ovariectomized females. In this study, we also evaluated renal inflammation and lipotoxicity in that animal model. For six months, 43 males and 36 females C57BL6/J mice were randomized to standard diet (SD) or high fat diet (HFD). A group of female animals on SD or HFD was ovariectomized to simulate menopause. We evaluated cytokines: NF-κß p65, IL-1ß, MCP-1, TNF-α, total lipid content, lipid classes, and fatty acid profile in total lipid and individual lipid classes in renal tissue and urine. We found that obese males and females showed higher NF-kß p-65, TNF-α and MCP-1 in renal tissue, and obese females ovariectomized had higher IL-1ß and TNF-α compared with not-ovariectomized. Also, obese animals showed lower proinflammatory and higher anti-inflammatory fatty acids in kidney total lipids, while obese females ovariectomized had a more exacerbated pattern. In brief, obesity induces inflammation and an unbalanced lipidic profile in renal tissue. This pattern seems to be enhanced in obesity after menopause.

Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone target gene expression.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel ß and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-ß-hydroxysteroid-dehydrogenase 2 (11ßHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process.NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.

Inflammation on the Waiting List Is a Risk Factor for New-Onset Prediabetes and Post-Transplant Diabetes Mellitus: A Prospective Study.

INTRODUCTION: Inflammation is a risk factor for diabetes in the general population. The role of inflammation in prediabetes or post-transplant diabetes mellitus (PTDM) is not clear. We evaluated the association between inflammatory markers in patients on the waiting list for renal transplantation and the onset of prediabetes and PTDM 12 months after transplantation. METHODS: This is a post hoc analysis of a prospective study that included nondiabetic patients on the waiting list for kidney transplantation who underwent an oral glucose tolerance test (OGTT) and were followed up to 12 months after transplantation. At this time, those patients without PTDM underwent another OGTT. At pre-transplantation, five cytokines: TNFα, IL6, IL1ß, CRP, MCP1 were determined. The association between inflammation and prediabetes/PTDM was evaluated using multiple regression models. RESULTS: 110 patients on the waiting list were enrolled: 74 had normal glucose metabolism and 36 had prediabetes or occult diabetes. At 12 months, 53 patients had normal glucose metabolism, 25 prediabetes, and 32 PTDM. In multiple regression analysis, pre-transplant inflammation was not a risk factor for prediabetes or PTDM. This was attributed to the high interrelation between obesity, prediabetes, and inflammation: about 75% of the cases had these conditions. In a sub-analysis, we analyzed only patients without prediabetes and occult diabetes on the waiting list and found that TNFα levels and BMI at pre-transplantation were independently associated with the onset of prediabetes or PTDM 1 year after transplantation. CONCLUSIONS: Pre-transplant inflammation and BMI are risk factors for prediabetes and PTDM in patients without glucose metabolism alterations.

Exercise and Prediabetes After Renal Transplantation (EXPRED-I): A Prospective Study.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) beyond 12 months (late PTDM) is a severe complication after renal transplantation. Late PTDM develops mostly in subjects with prediabetes. Although exercise may have a potential role in preventing late PTDM, there are no previous data on the effect of exercise in patients with prediabetes. MATERIAL AND METHODS: The design was a 12-month exploratory study to test the capacity of exercise in reverting prediabetes in order to prevent late-PTDM. The outcome was the reversibility of prediabetes, assessed every 3 months with oral glucose tolerance tests (OGTT). The protocol included an incremental plan of aerobic and/or strength training as well as an active plan for promoting adherence (telephone calls, digital technology, and visits). A priori, a sample size cannot be calculated which makes this an exploratory analysis. Based on previous studies, the spontaneous reversibility of prediabetes was 30% and the reversibility induced by exercise will account for another 30%, a total reversibility of 60% (p value < 0.05, assuming a potency of 85%). Ad interim analysis was performed during follow-up to test the certainty of this sample calculation. Patients beyond 12 months after renal transplantation with prediabetes were included. RESULTS: The study was interrupted early due to efficacy after the evaluation of the follow-up of 27 patients. At the end of follow-up, 16 (60%) patients reverted to normal glucose levels at fasting (from 102.13 mg/dL ± 11 to 86.75 ± 6.9, p = 0.006) and at 120 min after the OGTTs (154.44 mg/dL ± 30 to 113.0 ± 13.1, p = 0.002) and 11 patients had persistent prediabetes (40%). Also, insulin sensitivity improved with the reversibility of prediabetes, compared to those with persistent prediabetes: 0.09 [0.08-0.11] versus 0.04 [0.01-0.07], p = 0.001 (Stumvoll index). Most needed at least one increment in the prescription of exercise and compliance. Finally, measures aimed at the improvement of compliance were successful in 22 (80%) patients. CONCLUSION: Exercise training was effective to improve glucose metabolism in renal transplant patients with prediabetes. Exercise prescription must be conducted considering both the clinical characteristics of the patients and pre-defined strategy to promote adherence. The trial registration number of the study was NCT04489043.

Pretransplant evaluation and the risk of glucose metabolic alterations after renal transplantation: a prospective study.

BACKGROUND: Post-transplant prediabetes (PreDM) and diabetes (PTDM) are common and have an impact on cardiovascular events. We sought to investigate the pathogenesis and best approach for prediction. METHODS: We prospectively studied 115 waitlisted patients from a single center without manifest diabetes. An oral glucose tolerance test (OGTT) was performed yearly until transplantation and 12 months later. Insulin secretion, insulin sensitivity (IS) and disposition index (DI) were derived from the OGTT. RESULTS: PreDM and PTDM were observed in 27% and 28.6% of patients, respectively. Pretransplant age, body mass index (BMI), 120 min glucose, IS, DI, and prediabetes or undiagnosed diabetes were significantly associated with these alterations. In multivariate analysis, pretransplant age [odds ratio (OR) 1.5; 95% confidence interval (CI) 1.04-2.1], BMI (OR 1.16; 95% CI 1.04-1.3) and cumulative steroids (OR 1.5; 95% CI 1.02-2.2) were predictors of PreDM or PTDM. Receiver operating characteristic curve analysis showed that pretransplant BMI and 120 min glucose had the highest area under the curve (0.72; 95% CI 0.62-0.8; and 0.69; 95% CI 0.59-0.79, respectively). The highest discrimination cut-off for BMI (≥28.5 kg/m2) and 120 min glucose (≥123.5 mg/dL) yielded a similar number needed to diagnose (2.5). CONCLUSIONS: PreDM or PTDM develops in waitlisted patients with an ineffective insulin secretion and BMI shows a similar diagnostic capacity to OGTT. Pretransplant interventions may reduce post-transplant glucose alterations.

Post-transplant diabetes mellitus and renal cell cancer after renal transplantation.

BACKGROUND: Diabetes is a risk factor for cancer in the general population. However, few data are available on the association between post-transplant diabetes mellitus (PTDM) and cancer after transplantation. METHODS: We analyzed this issue in a Spanish cohort of patients without diabetes before transplantation. PTDM was diagnosed with consensus criteria at 12 months after transplantation and 12 months before the diagnosis of cancer. The association between PTDM and cancer (overall and specific types) was evaluated with regression analysis. RESULTS: During a follow-up of 12 years (interquartile range 8-14), 85 cases of 603 developed cancer (829/100 000/year) and 164 (27%) PTDM. The most frequent cancers were renal cell cancer (RCC) n = 15, 146/cases/100 000/year), lung (n = 12, 117/cases/100 000/year), colon (n = 9, 88/cases/100 000/year) and prostate (n = 9, 88/cases/100 000/year). In logistic regression, PTDM was not associated with cancer. Eight of the 164 patients with PTDM (4.9%) vs 7 of the 439 without PTDM developed RCC (1.6%) (P = .027). In multivariate analysis, PTDM was independently associated with RCC [odds ratio (OR) 2.92, confidence interval (CI) 1.03-8.27], adjusting for smoking (OR 4.020, 95% CI 1.34-12.02) and other covariates. PTDM was not associated with other types of cancer. CONCLUSIONS: Patients with PTDM must be considered a population at risk for RCC and accordingly, the subject of active surveillance.

Evaluation of commercially available glucagon receptor antibodies and glucagon receptor expression.

Glucagon is a major regulator of metabolism and drugs targeting the glucagon receptor (GCGR) are being developed. Insight into tissue and cell-specific expression of the GCGR is important to understand the biology of glucagon and to differentiate between direct and indirect actions of glucagon. However, it has been challenging to localize the GCGR in tissue due to low expression levels and lack of specific methods. Immunohistochemistry has frequently been used for GCGR localization, but antibodies targeting G-protein-coupled-receptors may be inaccurate. We evaluated all currently commercially available GCGR antibodies. The antibody, ab75240 (Antibody no. 11) was found to perform best among the twelve antibodies tested and using this antibody we found expression of the GCGR in the kidney, liver, preadipocytes, pancreas, and heart. Three antibody-independent approaches all confirmed the presence of the GCGR within the pancreas, liver and the kidneys. GCGR expression should be evaluated by both antibody and antibody-independent approaches.

Obesity and Metabolic Traits after High-Fat Diet in Iberian Pigs with Low Birth Weight of Placental Origin.

Intrauterine growth restriction (IUGR) and later obesity and metabolic disorders have classically been associated with maternal malnutrition, but most cases of IUGR are related to placental insufficiency. The current study, using a swine model for IUGR and obesity, aimed to determine the interaction of birth weight (categorized as low birth weight [LBW] or normal birth-weight [NBW]) and postnatal diet (categorized as maintenance diet [MD] or fattening diet [FD]) on body weight, adiposity and metabolic traits. FD induced higher body weight and adiposity (both p < 0.0001), with higher fructosamine levels (p < 0.005) and a trend toward higher HOMA-ß index (p = 0.05). NBW pigs remained heavier than LBW pigs during the early juvenile period (p < 0.005), but there were no differences at later stages. There were no differences in metabolic traits during juvenile development, but there were differences in adulthood, when LBW pigs showed higher glucose and lower insulin levels than NBW pigs (both p < 0.05). These results suggest that (a) FD allows LBW offspring to achieve similar obesity in adulthood as NBW offspring, and (b) glucose metabolism is more compromised in obese LBW than obese NBW pigs. The comparison of our data with previous studies highlights significant differences between offspring with LBW induced by maternal malnutrition or placental insufficiency, which should be considered when studying the condition.

A High-Fat Diet Modifies Brain Neurotransmitter Profile and Hippocampal Proteome and Morphology in an IUGR Pig Model.

Intrauterine Growth Restriction (IUGR) hinders the correct growth of the fetus during pregnancy due to the lack of oxygen or nutrients. The developing fetus gives priority to brain development ("brain sparing"), but the risk exists of neurological and cognitive deficits at short or long term. On the other hand, diets rich in fat exert pernicious effects on brain function. Using a pig model of spontaneous IUGR, we have studied the effect on the adult of a long-term high-fat diet (HFD) on the neurotransmitter profile in several brain areas, and the morphology and the proteome of the hippocampus. Our hypothesis was that animals affected by IUGR (born with low birth weight) would present a different susceptibility to an HFD when they become adults, compared with normal birth-weight animals. Our results indicate that HFD affected the serotoninergic pathway, but it did not provoke relevant changes in the morphology of the hippocampus. Finally, the proteomic analysis revealed that, in some instances, NBW and LBW individuals respond to HFD in different ways. In particular, NBW animals presented changes in oxidative phosphorylation and the extracellular matrix, whereas LBW animals presented differences in RNA splicing, anterograde and retrograde transport and the mTOR pathway.

Early glomerular filtration rate changes in living kidney donors and recipients: an example of renal plasticity.

Background: In living kidney transplantation there are two different individuals, a healthy donor and a renal transplant recipient. This is an excellent human model to study factors that influence kidney function in the context of reduced renal mass and the adaptation of two comparable kidneys to different metabolic demands. Methods: We analyzed the changes in measured glomerular filtration rate (GFR, iohexol) from pretransplantation to 12 months after transplantation in 30 donor-recipient pairs. Each donor was compared with his/her recipient. We defined a priori three different groups based on GFR differences at 12 months: donor > recipient (Group A; 78 ± 8 versus 57 ± 8 mL/min), donor < recipient (Group B; 65 ± 11 versus 79 ± 11 mL/min) and donor ≈ recipient (Group C; 66 ± 7 versus 67 ± 7 mL/min). Other factors like donor/recipient mismatches in body mass index (BMI), surface area and gender were evaluated. Results: In Group A donors were mostly male and recipients were female (75% each). Donors had a higher baseline weight than their recipients. During follow-up, weight remained stable in donors but increased 7% in recipients. In Group B donors were mostly female (60%) and recipients male. At baseline, donors had a lower weight than recipients. At 12 months, weight was stable in donors but increased in recipients. In Group C donors were mostly (75%) female and recipients male. At baseline, donors had a higher BMI than their recipients. At 12 months, BMI was stable in donors but increased 14% in recipients. In multivariable analysis, higher GFR at 12 months was associated with higher baseline weight and GFR in donors and with male gender and higher baseline weight in recipients. Conclusions: Kidneys from living donors are more 'plastic' than originally thought and respond to metabolic demands and weight changes of their new host. These changes should be taken into account when assessing GFR outcomes in this population.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1-4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed. METHODS: We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment. RESULTS: No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min. CONCLUSIONS: The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.

Estimating Renal Function Following Lung Transplantation.

BACKGROUND: Patients undergoing lung transplantation (LTx) experience a rapid decline in glomerular filtration rate (GFR) in the acute postoperative period. However, no prospective longitudinal studies directly comparing the performance of equations for estimating GFR in this patient population currently exist. METHODS: In total, 32 patients undergoing LTx met the study criteria. At pre-LTx and 1-, 3-, and 12-weeks post-LTx, GFR was determined by 51Cr-EDTA and by equations for estimating GFR based on plasma (P)-Creatinine, P-Cystatin C, or a combination of both. RESULTS: Measured GFR declined from 98.0 mL/min/1.73 m2 at pre-LTx to 54.1 mL/min/1.73 m2 at 12-weeks post-LTx. Equations based on P-Creatinine underestimated GFR decline after LTx, whereas equations based on P-Cystatin C overestimated this decline. Overall, the 2021 CKD-EPI combination equation had the lowest bias and highest precision at both pre-LTx and post-LTx. CONCLUSIONS: Caution must be applied when interpreting renal function based on equations for estimating GFR in the acute postoperative period following LTx. Simplified methods for measuring GFR may allow for more widespread use of measured GFR in this vulnerable patient population.

Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random.

BACKGROUND: The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. METHODS: We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. RESULTS: Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. CONCLUSIONS: Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.