Nadia Stucchi

Performance of Different Prediction Equations for Estimating Renal Function in Kidney Transplantation

Numerous formulas have been developed to estimate renal function from biochemical, demographic and anthropometric data. Here we compared renal function derived from 12 published prediction equations with glomerular filtration rate (GFR) measurement by plasma iohexol clearance as reference method in a group of 81 renal transplant recipients enrolled in the Mycophenolate Mofetil Steroid Sparing (MY.S.S.) trial. Iohexol clearances and prediction equations were carried out in all patients at months 6, 9 and 21 after surgery. All equations showed a tendency toward GFR over‐estimation: Walser and MDRD equations gave the best performance, however not more than 45% of estimated values were within ±10% error. These formulas showed also the lowest bias and the highest precision: 0.5 and 9.2 mL/min/1.73 m2 (Walser), 2.7 and 10.4 mL/min/1.73 m2 (MDRD) in predicting GFR. A significantly higher rate of GFR decline ranging from −5.0 mL/min/1.73 m2/year (Walser) to −7.4 mL/min/1.73 m2/year (Davis–Chandler) was estimated by all the equations as compared with iohexol clearance (−3.0 mL/min/1.73 m2/year). The 12 prediction equations do not allow a rigorous assessment of renal function in kidney transplant recipients. In clinical trials of kidney transplantation, graft function should be preferably monitored using a reference method of GFR measurement, such as iohexol plasma clearance.

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.

Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients.

Background: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is now routinely used as immunosuppressant in solid organ transplantation in a fixed daily dose regimen (2 g/d) in association with cyclosporine (CsA) and steroids. However, no correlation has been shown between fixed MMF dose and clinical outcome. 
Methods: Here we examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring in 46 stable kidney transplant recipients. MPA plasma concentration profiles were measured by a reverse‐phase high‐performance liquid chromatography method 6–9 months after transplantation and related with routine laboratory analysis tests. Since MPA is extensively bound to serum albumin and only the free fraction is pharmacologically active, in a subgroup of 23 patients free plasma MPA was also determined. 
Results: Despite a comparable MMF dose, a large interindividual variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.1–99.8 μg/mL · h) and in trough levels (range 0.24–7.04 μg/mL) was found. Patients with AUC >40 μg/mL · h showed a better (p<0.05) renal function than patients with lower AUC (creatinine clearance 85.7±23.2 versus 64.5±17.5 mL/min), despite no difference in CsA dose, CsA AUC and blood CsA trough level. The percentage of free plasma MPA but not total MPA correlated with the red blood cell and leukocyte count. 
Conclusions: Therapeutic MMF drug monitoring might contribute to a better management of kidney transplant recipient with the goal of optimizing drug dosing and limiting the risk of MMF‐related toxicity.

The GFR and GFR decline cannot be accurately estimated in type 2 diabetics

There are no adequate studies that have formally tested the performance of different estimating formulas in patients with type 2 diabetes both with and without overt nephropathy. Here we evaluated the agreement between baseline GFRs, GFR changes at month 6, and long-term GFR decline measured by iohexol plasma clearance or estimated by 15 creatinine-based formulas in 600 type 2 diabetics followed for a median of 4.0 years. Ninety patients were hyperfiltering. The number of those identified by estimation formulas ranged from 0 to 24:58 were not identified by any formula. Baseline GFR was significantly underestimated and a 6-month GFR reduction was missed in hyperfiltering patients. Long-term GFR decline was also underestimated by all formulas in the whole study group and in hyper-, normo-, and hypofiltering patients considered separately. Five formulas generated positive slopes in hyperfiltering patients. Baseline concordance correlation coefficients and total deviation indexes ranged from 32.1% to 92.6% and from 0.21 to 0.53, respectively. Concordance correlation coefficients between estimated and measured long-term GFR decline ranged from -0.21 to 0.35. The agreement between estimated and measured values was also poor within each subgroup considered separately. Thus, our study questions the use of any estimation formula to identify hyperfiltering patients and monitor renal disease progression and response to treatment in type 2 diabetics without overt nephropathy.

Predicting cisplatin-induced acute kidney injury by urinary neutrophil gelatinase-associated lipocalin excretion: a pilot prospective case-control study.

Background/Aims: Nephrotoxicity is the major limitation to cisplatin therapy for solid tumors. We aimed at evaluating whether early increases in serum/urine levels of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage and regeneration, predict cisplatin-induced acute kidney injury (AKI). Methods: We compared changes in serum creatinine and serum/urine NGAL levels (ELISA assay) at 1 and 4 h and 1, 2, 3, 7 and 15 days after cisplatin infusion (70–80 mg/m2) versus baseline in 12 consecutive cancer patients (cases) with AKI (>25% serum creatinine increase vs. baseline) and 12 consecutive controls without AKI. Results: Baseline characteristics and posttreatment serum NGAL levels were similar in both groups. Urinary NGAL levels increased significantly more in cases than in controls at 1, 2, 3 and 15 days after cisplatin. The NGAL increase preceded AKI by 4.5 days and the NGAL increase at day 2 after cisplatin independently predicted AKI (p < 0.05). Six cases with residual kidney dysfunction at 15 days showed a trend to earlier and higher increase in urinary NGAL levels compared to cases with renal function recovery. Conclusion: An early increase in urinary NGAL excretion may help in identifying patients at risk of cisplatin-induced AKI who might benefit from innovative treatments to prevent cisplatin nephrotoxicity.

Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade: The ESPLANADE Trial

BACKGROUND AND OBJECTIVES This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. RESULTS During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. CONCLUSIONS In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Measuring and Estimating GFR and Treatment Effect in ADPKD Patients: Results and Implications of a Longitudinal Cohort Study

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m2 in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.

Renal Transplantation: Can We Reduce Calcineurin Inhibitor/Stop Steroids? Evidence Based on Protocol Biopsy Findings

How to combine antirejection drugs and which is the optimal dose of steroids and calcineurin inhibitors beyond the first year after kidney transplantation to maintain adequate immunosuppression without major side effects are far from clear. Kidney transplant patients on steroid, cyclosporine (CsA), and azathioprine were randomized to per-protocol biopsy (n = 30) or no-biopsy (n = 29) 1 to 2 yr posttransplant. Steroid or CsA were discontinued or reduced on the basis of biopsy to establish effects on drug-related complications, acute rejection, and graft function over 3 yr of follow-up. Serum creatinine, GFR (plasma clearance of iohexol), RPF (renal clearance of p-aminohippurate), CsA pharmacokinetics, and adverse events were monitored yearly. At the end, patients underwent a second biopsy. Per-protocol biopsy histology revealed no lesions (n = 5, steroid withdrawal), CsA nephropathy (n = 13, CsA discontinuation/reduction), or chronic rejection (n = 12, standard therapy). Reducing the drug regimen led to overall fewer side effects related to immunosuppression as compared with standard therapy or no-biopsy. Steroids were safely stopped with no acute rejection or graft loss. Complete CsA discontinuation was associated with acute rejection in the first four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml) never led to acute rejection or major renal function deterioration. Biopsy patients on conventional regimen had no acute rejection, one graft loss, no significant change in GFR, and significant RPF decline. No-biopsy controls: no acute rejection, one graft loss, significant decline of GFR and RPF. By serial biopsy analysis, severe lesions did not develop in patients with steroid discontinuation in contrast to patients on standard therapy over follow-up. CsA reduction did not adversely affect histology. Per-protocol biopsy more than 1 yr after kidney transplantation is a safe procedure to guide change of drug regimen and to lower the risk of major side effects.

Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial

BACKGROUND Macroalbuminuria predicts renal and cardiovascular events in patients with type 2 diabetes. We aimed to assess the albuminuria-lowering effects of salt restriction, paricalcitol therapy, or both, in this population. METHODS In this randomised, double-blind, placebo-controlled, crossover trial, we recruited adult patients with type 2 diabetes from six diabetology outpatient clinics in northern Italy, with 24 h albuminuria of more than 300 mg despite 100 mg per day losartan therapy, blood pressure of less than 140/90 mm Hg, serum creatinine concentration of less than 2 mg/dL, stable renal function on stable renin-angiotensin system inhibitor therapy with a fixed dose of losartan, parathyroid hormone concentration of 20 pg/mL to <110 pg/mL, serum calcium concentration of less than 9·5 mg/dL, and serum phosphate concentration of less than 5 mg/dL, who had been more than 80% compliant with placebo treatment during a 1 month placebo run-in. We allocated patients 1:1 with computer-generated randomisation to an open-label 3 month high-sodium (>200 mEq [4·8 g] per day) or low-sodium (<100 mEq [2·4 g] per day) diet and, within each diet group, to a 1 month double-blind treatment period of oral paricalcitol (2 μg per day) or placebo, followed by 1 month of placebo washout and then a further 1 month double-blind treatment period of paricalcitol or placebo in which patients crossed over to the opposite treatment period. The primary outcome was 24 h albuminuria (median of three consecutive measurements). Analyses were modified intention-to-treat (including all randomly allocated patients who took at least one dose of study drug and had an efficacy measurement after the first treatment period). Patients and investigators were masked to paricalcitol and placebo assignment. Those assessing outcomes were masked to both study drug and diet assignment. This study is registered with ClinicalTrials.gov, number NCT01393808, and the European Union Clinical Trials Register, number 2011-001713-14. FINDINGS Between Dec 13, 2011, and Feb 17, 2015, we randomly allocated 57 (50%) patients to a low-sodium diet (28 [49%] to paricalcitol then placebo and 29 [51%] to placebo then paricalcitol) and 58 (50%) to a high-sodium diet (29 [50%] to paricalcitol then placebo and 29 [50%] to placebo then paricalcitol). In the low-sodium group (30 mEq of daily sodium intake reduction, equivalent to approximately 1·7-1·8 g per day), 24 h albuminuria was reduced by 36·6% (95% CI 28·5-44·9) from 724 mg (441-1233) at baseline to 481 mg (289-837) at month 3 (p<0·0001), but no significant change occurred in the high-sodium group (from 730 mg [416-1227] to 801 mg [441-1365]; 2·9% [-16·8 to 16·4] increase; p=0·50). Changes between diet groups differed by 32·4% (17·2-48·8; p<0·0001) and correlated with changes in natriuresis (r=0·43; p<0·0001). On the high-sodium diet, paricalcitol reduced the salt-induced albuminuria increase by 17·8% (3·9-32·3) over the month of treatment compared with placebo (p=0·02), whereas on the low-sodium diet, paricalcitol did not have a significant effect versus placebo (increase of 4·1% [-9·3 to 21·6]; p=0·59). During placebo treatment, albuminuria decreased with the low-sodium diet (p=0·0002) and did not significantly change with the high-sodium diet, but changes were significantly different between diet groups (p=0·0004). Treatment was well tolerated and no patients withdrew from the study because of treatment-related effects. 67 adverse events occurred in 52 (45%) patients during paricalcitol treatment and 44 events occurred in 36 (31%) patients during placebo treatment. During paricalcitol therapy, 14 cases of hypercalciuria, six cases of hypercalcaemia, and five cases of hyperphosphataemia were reported in one patient each, all of which were possibly treatment related. One case of hypercalciuria was reported in one patient during the placebo treatment period. One stroke and one coronary event occurred during paricalcitol therapy. No patients died during the study. INTERPRETATION In patients with macroalbuminuria and type 2 diabetes, moderate salt restriction enhances the antialbuminuric effect of losartan, an effect that could be nephroprotective and cardioprotective in the long term. The finding that paricalcitol prevents a sodium-induced increase in albuminuria provides support for trials to test the long-term risk-benefit profile of paricalcitol add-on therapy in patients with type 2 diabetes and macroalbuminuria refractory to dietary salt restriction, including patients refractory to even moderate salt restriction. FUNDING AbbVie.

Safety of Iohexol Administration to Measure Glomerular Filtration Rate in Different Patient Populations: A 25-Year Experience

Background/Aim: In clinical research setting, accurate and precise measurement of glomerular filtration rate (GFR) is essential to overcome the limitations of GFR estimation with equations, which are often unreliable. In recent decades, a method for measuring GFR by plasma clearance of iohexol, a non-ionic radiocontrast agent, was developed. To evaluate the safety of the procedure, we aimed to review all immediate adverse reactions that could be related to iohexol administration in our group’s 25 years worth of experience. Methods: We retrospectively reviewed all GFR investigations in 2,891 patients, between 1992 and 2016, as part of 37 clinical trials coordinated by our group. Subjects with disparate renal diseases, kidney transplant recipients, and living donors – all with different renal function categories – were included in the surveyed clinical trials. Results: During 15,147 GFR measurements, only one treatment-related event of moderate intensity was identified. Flushing, urticaria, and itching were observed in a diabetic patient a few minutes after iohexol administration during the first GFR measurement. The event recovered without sequelae after intravenous injection of methylprednisolone sodium succinate. The patient was not hospitalized and the event was categorized as non-serious. Eight additional non-serious events observed closely following iohexol injection were considered as not related to treatment. Thus, independent of disease conditions and GFR categories, the overall rate of treatment-related events was 0.0066%. Conclusion: Iohexol administration for GFR measurement is a safe procedure, even in repeated investigations in the same subject, that should be adopted in clinical research and, when needed, also in clinical practice.