ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis.

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl].

Low plasma magnesium concentration and future abdominal aortic calcifications in moderate chronic kidney disease.

BACKGROUND: Higher plasma magnesium concentrations are associated with reduced cardiovascular disease risk in chronic kidney disease (CKD) patients. The importance of plasma magnesium concentration for vascular calcification in earlier stages of CKD remains underexplored. This study investigated whether plasma magnesium is a determinant for the presence and severity of vascular calcification in moderate CKD. METHODS: Retrospective analysis was performed using abdominal aortic calcification (AAC) scores in 280 patients with stage 3 and 4 CKD enrolled in the MASTERPLAN trial. Lateral abdominal X-ray was used to evaluate AAC. Plasma magnesium concentration were measured over time. A zero-inflated Poisson model determined the association between plasma magnesium concentration and AAC. RESULTS: 79 out of 280 patients did not have AAC, and in patients with AAC the median calcification score was 3.5 (interquartile range: 0.0-8.6). The mean plasma magnesium concentration was 0.76 ± 0.10 mmol/L at baseline. A 0.1 mmol/L higher plasma magnesium concentration was associated with lower AAC of 0.07 point (95% CI -0.28 - 0.14). A 0.1 mmol/L higher plasma magnesium lowered the odds of detecting any AAC by 30% (OR = 0.63; 95% CI 0.29-1.37). After 1 year and 4 years (at time of X-ray) of follow-up this association was attenuated (OR = 0.93; 95% CI 0.61-1.43 and 0.93; 95% CI 0.60-1.45, respectively). None of these associations reached statistical significance. CONCLUSIONS: Plasma magnesium concentration at baseline is not associated with the risk for future AAC. Interventions increasing magnesium to avoid vascular calcification may have greatest potential in early CKD stages prior to onset of vascular calcification.

Prognostic models for chronic kidney disease: a systematic review and external validation.

BACKGROUND: Accurate risk prediction is needed in order to provide personalized healthcare for chronic kidney disease (CKD) patients. An overload of prognosis studies is being published, ranging from individual biomarker studies to full prediction studies. We aim to systematically appraise published prognosis studies investigating multiple biomarkers and their role in risk predictions. Our primary objective was to investigate if the prognostic models that are reported in the literature were of sufficient quality and to externally validate them. METHODS: We undertook a systematic review and appraised the quality of studies reporting multivariable prognosis models for end-stage renal disease (ESRD), cardiovascular (CV) events and mortality in CKD patients. We subsequently externally validated these models in a randomized trial that included patients from a broad CKD population. RESULTS: We identified 91 papers describing 36 multivariable models for prognosis of ESRD, 50 for CV events, 46 for mortality and 17 for a composite outcome. Most studies were deemed of moderate quality. Moreover, they often adopted different definitions for the primary outcome and rarely reported full model equations (21% of the included studies). External validation was performed in the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners trial (n = 788, with 160 events for ESRD, 79 for CV and 102 for mortality). The 24 models that reported full model equations showed a great variability in their performance, although calibration remained fairly adequate for most models, except when predicting mortality (calibration slope >1.5). CONCLUSIONS: This review shows that there is an abundance of multivariable prognosis models for the CKD population. Most studies were considered of moderate quality, and they were reported and analysed in such a manner that their results cannot directly be used in follow-up research or in clinical practice.

Worldwide Disparity in the Relation Between CKD Prevalence and Kidney Failure Risk.

INTRODUCTION: The incidence of kidney replacement therapy (KRT) for kidney failure varies internationally much more than chronic kidney disease (CKD) prevalence. This ecologic study investigated the relation of CKD prevalence to KRT and mortality risks by world region. METHODS: We used data from Global Burden of Disease and KRT registries worldwide with linear models to estimate the percentages of variance in KRT incidence and all-cause mortality explained by age-adjusted prevalence of CKD stages 3 to 5, overall and by gender, in 61 countries classified in 3 regions: high income (n = 28), Eastern and Central Europe (n = 15), and other (n = 18). RESULTS: The incidence of KRT ranged from 89 to 378 per million population in high-income regions, 32 to 222 per million population in Central and Eastern Europe, and 22 to 493 per million population in the other region; age-adjusted CKD prevalence ranged from 5.5% to 10.4%, 7.6% to 13.7%, and 7.4% to 13.1%, respectively. The relation between these indicators was positive in high-income countries, negative in Central and Eastern Europe, and null in the other region. Age-adjusted CKD prevalence explained 40% of the variance in KRT incidence (P < 0.001) in high-income countries. The explained variance of age-adjusted mortality was close to 0 in high-income countries and positive at 19% (P = 0.10) in Central and Eastern Europe and at 11% (P = 0.17) in the other region. Results were consistent by gender. CONCLUSION: This study raises awareness on the significant part of the gaps in KRT incidence across countries not explained by the number of individuals with CKD, even in high-income countries where access to KRT is not limited.

Performance of creatinine-based equations for estimating glomerular filtration rate changes over time.

BACKGROUND: Glomerular filtration rate (GFR) is commonly used to monitor chronic kidney disease (CKD) progression, but its validity for evaluating kidney function changes over time has not been comprehensively evaluated. We assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis. METHODS: In the NephroTest cohort study, we measured GFR 5324 times by chromium 51-labeled ethylenediamine tetraacetic acid renal clearance in 1955 adult patients with CKD Stages 1-4 referred to nephrologists (Stages 1-2, 19%) and simultaneously estimated GFR with both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations for isotope dilution mass spectrometry traceable creatinine; absolute and relative GFR slopes were calculated using a linear mixed model. RESULTS: Over a median follow-up of 3.4 [interquartile range (IQR) 2.0-5.6] years, the decline in mean absolute and relative measured GFR (mGFR) and CKD-EPI and MDRD estimated GFR (eGFR) was 1.6 ± 1.2, 1.5 ± 1.4 and 1.3 ± 1.3 mL/min/1.73 m2/year and 5.9 ± 5.3, 5.3 ± 5.3 and 4.8 ± 5.2%/year, respectively; 52% and 55% of the patients had MDRD and CKD-EPI eGFR slopes within 30% of mGFR slopes. Both equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and mGFR versus eGFR slope. Other patient characteristics and specific CKD diagnoses had little effect on the performance of the equations in estimating associations. CONCLUSIONS: This study shows little bias, but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. Importantly, bias strongly varied with age, possibly due to variations in muscle mass over time, with implications for clinical care and research.

CKD: A Call for an Age-Adapted Definition.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Predicting kidney failure from longitudinal kidney function trajectory: A comparison of models.

RATIONALE & OBJECTIVE: Early prediction of chronic kidney disease (CKD) progression to end-stage kidney disease (ESKD) currently use Cox models including baseline estimated glomerular filtration rate (eGFR) only. Alternative approaches include a Cox model that includes eGFR slope determined over a baseline period of time, a Cox model with time varying GFR, or a joint modeling approach. We studied if these more complex approaches may further improve ESKD prediction. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: We re-used data from two CKD cohorts including patients with baseline eGFR >30ml/min per 1.73m2. MASTERPLAN (N = 505; 55 ESKD events) was used as development dataset, and NephroTest (N = 1385; 72 events) for validation. PREDICTORS: All models included age, sex, eGFR, and albuminuria, known prognostic markers for ESKD. ANALYTICAL APPROACH: We trained the models on the MASTERPLAN data and determined discrimination and calibration for each model at 2 years follow-up for a prediction horizon of 2 years in the NephroTest cohort. We benchmarked the predictive performance against the Kidney Failure Risk Equation (KFRE). RESULTS: The C-statistics for the KFRE was 0.94 (95%CI 0.86 to 1.01). Performance was similar for the Cox model with time-varying eGFR (0.92 [0.84 to 0.97]), eGFR (0.95 [0.90 to 1.00]), and the joint model 0.91 [0.87 to 0.96]). The Cox model with eGFR slope showed the best calibration. CONCLUSION: In the present studies, where the outcome was rare and follow-up data was highly complete, the joint models did not offer improvement in predictive performance over more traditional approaches such as a survival model with time-varying eGFR, or a model with eGFR slope.

Graft intolerance syndrome requiring graft nephrectomy after late kidney graft failure: can it be predicted? A retrospective cohort study.

Graft nephrectomy is recommended in case of early graft failure. When the graft fails more than 3-6 months after transplantation, it is current practice to follow a wait-and-see policy. A common indication for graft removal is the graft intolerance syndrome. We aimed to create a risk prediction model for the occurrence of graft intolerance resulting in graft nephrectomy. We collected data of kidney transplantations performed in our center between 1980 and 2010 that failed at least 6 months after transplantation. We evaluated the association between baseline characteristics and the occurrence of graft nephrectomy because of graft intolerance using a competing risk regression model. Prognostic factors were included in a multivariate prediction model. In- and exclusion criteria were met in 288 cases. In 48 patients, the graft was removed because of graft intolerance. Donor age, the number of rejections, and shorter graft survival were predictive factors for graft nephrectomy because of the graft intolerance syndrome. These factors were included in a prediction rule. Using donor age, graft survival, and the number of rejections, clinicians can predict the need for graft nephrectomy with a reasonable accuracy.

Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy.

Guidelines recommend steroid plus cyclical cyclophosphamide (St-Cp) therapy for patients with idiopathic membranous nephropathy at high risk of progression to ESRD. Rituximab (Rtx) may be a safer alternative. In this retrospective, observational cohort study, we compared time to any adverse event (primary outcome); serious or nonserious events; partial and complete remission of the nephrotic syndrome; and a composite of doubling of serum creatinine, ESRD, or death between 100 Rtx-treated patients and 103 patients who received daily St-Cp We monitored patients with standardized protocols and adjusted for baseline characteristics by Cox regression. Over a median follow-up of 40 months, the Rtx group had significantly fewer adverse events than the St-Cp group (63 versus 173; P<0.001), both serious (11 versus 46; P<0.001) and nonserious (52 versus 127; P<0.001). Cumulative incidence of any first (35.5% versus 69.0%; P<0.001), serious (16.4% versus 30.2%; P=0.002), or nonserious (23.6% versus 60.8%; P<0.001) event was significantly lower with Rtx Adjusted hazard ratios (95% confidence intervals) between Rtx and St-Cp groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events. Although the cumulative incidence of partial remission was lower in the Rtx group, rates of complete remission and the composite renal end point did not differ significantly between groups. Because of its superior safety profile, we suggest that Rtx might replace St-Cp as first-line immunosuppressive therapy in patients with idiopathic membranous nephropathy and nephrotic syndrome.

Cost-effectiveness of eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome.

Background: Kidney transplantation in patients with atypical haemolytic uraemic syndrome (aHUS) is frequently complicated by recurrence of aHUS, often resulting in graft loss. Eculizumab prophylaxis prevents recurrence, improving graft survival. An alternative treatment strategy has been proposed where eculizumab is administered upon recurrence. We combined available evidence and performed a cost-effectiveness analysis of these competing strategies. Methods: A cost-effectiveness analysis using a decision analytical approach with Markov chain analyses was used to compare alternatives for aHUS patients with end-stage renal disease (ESRD): (i) dialysis treatment, (ii) kidney transplantation, (iii) kidney transplantation with eculizumab therapy upon recurrence of aHUS, (iv) kidney transplantation with eculizumab induction consisting of 12 months of prophylaxis and (v) kidney transplantation with lifelong eculizumab prophylaxis. We assumed that all patients received a graft from a living donor and that recurrence probability was 28.4% within the first year of transplantation. Results: At 8.34 quality-adjusted life years (QALYs) gained and a cost of €402 412, kidney transplantation without eculizumab was the least costly alternative. By comparison, dialysis was more costly and resulted in fewer QALYs gained. Eculizumab upon recurrence resulted in 9.55 QALYs gained at a cost of €425 097. The incremental cost-effectiveness ratio (ICER) was €18 748 per QALY. Both eculizumab induction and lifelong eculizumab were inferior to eculizumab upon recurrence, as both resulted in fewer QALYs gained and higher costs. Conclusions: Kidney transplantation is more cost effective than dialysis to treat ESRD due to aHUS. Adding eculizumab treatment results in a substantial gain in QALYs. When compared with eculizumab upon recurrence, neither eculizumab induction nor lifelong eculizumab prophylaxis resulted in more QALYs, but did yield far higher costs. Therefore, eculizumab upon recurrence of aHUS is more acceptable.

Copeptin, a surrogate marker for arginine vasopressin, is associated with disease severity and progression in IgA nephropathy patients.

Background: Besides its essential role for water homeostasis, arginine vasopressin (AVP) may have deleterious effects on the kidney. Copeptin, a surrogate marker for AVP, has been shown to be related to renal outcome in patients with diabetic nephropathy and polycystic kidney disease. We investigated the association of copeptin with disease severity and progression in immunoglobulin A nephropathy (IgAN). Methods: We included a prospective cohort of 59 patients with biopsy proven IgAN. Urinary excretion of α1 microglobulin (α1m), ß 2 microglobulin (ß2m), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and total protein were measured at baseline. Plasma copeptin was determined from stored baseline serum samples. Cox regression was performed for the composite renal outcome defined as doubling of serum creatinine, end-stage renal disease (ESRD) or start of immunosuppressive therapy, and for the individual components during 5-year follow-up. Results: In IgAN patients [male: 72%, age: 42 ± 13 years, mean arterial pressure (MAP): 101 ± 12 mmHg, proteinuria: 1.4 (0.7-2.3) g/day, estimated glomerular filtration rate (eGFR): 48 ± 21 mL/min/1.73 m 2 ] median copeptin was 9.4 (5.3-18.4) pmol/L. At baseline, copeptin was associated with α1m [standardized beta (St. ß) = 0.34, P = 0.009], ß2m (St. ß = 0.33, P = 0.01) and proteinuria (St. ß = 0.36, P = 0.053), adjusted for sex and eGFR. During follow-up, the highest tertile of baseline copeptin was positively associated with the incidence of the composite renal outcome as well as with the individual components of doubling of creatinine, ESRD and start of immunosuppressive therapy. In Cox regression models, copeptin showed prognostic value over MAP, proteinuria and eGFR for the composite renal outcome. Conclusions: Copeptin is associated with disease severity and prognosis in IgAN patients and may have additional prognostic value besides established risk markers.

Statistical significance versus clinical relevance.

In March this year, the American Statistical Association (ASA) posted a statement on the correct use of P-values, in response to a growing concern that the P-value is commonly misused and misinterpreted. We aim to translate these warnings given by the ASA into a language more easily understood by clinicians and researchers without a deep background in statistics. Moreover, we intend to illustrate the limitations of P-values, even when used and interpreted correctly, and bring more attention to the clinical relevance of study findings using two recently reported studies as examples. We argue that P-values are often misinterpreted. A common mistake is saying that P < 0.05 means that the null hypothesis is false, and P ≥0.05 means that the null hypothesis is true. The correct interpretation of a P-value of 0.05 is that if the null hypothesis were indeed true, a similar or more extreme result would occur 5% of the times upon repeating the study in a similar sample. In other words, the P-value informs about the likelihood of the data given the null hypothesis and not the other way around. A possible alternative related to the P-value is the confidence interval (CI). It provides more information on the magnitude of an effect and the imprecision with which that effect was estimated. However, there is no magic bullet to replace P-values and stop erroneous interpretation of scientific results. Scientists and readers alike should make themselves familiar with the correct, nuanced interpretation of statistical tests, P-values and CIs.

Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry.

Background: Upcoming KDIGO guidelines for the evaluation of living kidney donors are expected to move towards a personal risk-based evaluation of potential donors. We present the age and sex-specific lifetime risk of renal replacement therapy (RRT) for end-stage renal disease in 10 European countries. Methods: We defined lifetime risk of RRT as the cumulative incidence of RRT up to age 90 years. We obtained RRT incidence rates per million population by 5-year age groups and sex using data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry, and used these to estimate the cumulative incidence of RRT, adjusting for competing mortality risk. Results: Lifetime risk of RRT varied from 0.44% to 2.05% at age 20 years and from 0.17% to 1.59% at age 70 years across countries, and was twice as high in men as in women. Lifetime RRT risk decreased with age, ranging from an average of 0.77% to 0.44% in 20- to- 70-year-old women, and from 1.45% to 0.96% in 20- to- 70-year-old men. The lifetime risk of RRT increased slightly over the past decade, more so in men than in women. However, it appears to have stabilized or even decreased slightly in more recent years. Conclusions: The lifetime risk of RRT decreased with age, was lower in women as compared with men of equal age and varied considerably throughout Europe. Given the substantial differences in lifetime risk of RRT between the USA and Europe, country-specific estimates should be used in the evaluation and communication of the risk of RRT for potential living kidney donors.

Uremic Solutes in Chronic Kidney Disease and Their Role in Progression.

BACKGROUND: To date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated. METHODS: Patients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated. RESULTS: In total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time. CONCLUSIONS: Elevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated.

Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology.

The uremic solutes p-cresyl sulfate (pCS) and p-cresyl glucuronide (pCG) accumulate in patients with chronic kidney disease (CKD), and might contribute to disease progression. Moreover, retention of these solutes may directly be related to renal tubular function. Here, we investigated the role of the efflux transporters Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) in pCS and pCG excretion, and studied the impact of both solutes on the phenotype of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC). Our results show that p-cresol metabolites accumulate during CKD, with a shift from sulfation to glucuronidation upon progression. Moreover, pCS inhibited the activity of MRP4 by 40% and BCRP by 25%, whereas pCG only reduced MRP4 activity by 75%. Moreover, BCRP-mediated transport of both solutes was demonstrated. Exposure of ciPTEC to pCG caused epithelial-to-mesenchymal transition, indicated by increased expression of vimentin and Bcl-2, and diminished E-cadherin. This was associated with altered expression of key tubular transporters. In conclusion, BCRP is likely involved in the renal excretion of both solutes, and pCG promotes phenotypical changes in ciPTEC, supporting the notion that uremic toxins may be involved in CKD progression by negatively affecting renal tubule cell phenotype and functionality.

Impact of fractional phosphate excretion on the relation of FGF23 with outcome in CKD patients.

BACKGROUND: Cardiovascular risk is increased in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) has emerged as an important, independent predictor of outcome in CKD patients. High FGF23 may, however, be a reflection of renal tissue resistance to its actions, reflected by low fractional excretion of phosphate (FePi). We evaluated the modifying effect of FePi on the association between FGF23 and outcome in patients with CKD stage 3-4. METHODS: An analysis was performed in a subset of 166 adult patients of two participating centers of the MASTERPLAN trial of whom urine samples at baseline were available to calculate FePi. Outcome was defined as a composite of death, renal failure (defined as need for renal replacement therapy or doubling of serum creatinine) and cardiovascular events (myocardial infarction, cerebrovascular accident, percutaneous transluminal coronary angioplasty or coronary artery bypass graft. Patients were categorized by FGF23 and FePi. A product term was added to Cox regression and RERIs were calculated. RESULTS: Patients had a median estimated glomerular filtration rate (eGFR) of 36 ml/min/1.73 m(2) [interquartile range (IQR) 27-44], serum phosphate 1.04 mmol/l (IQR 0.92-1.20), FGF23 140 RU/ml (IQR 81-236) and FePi 0.32 (IQR 0.25-0.44). A total of 96 events occurred during 5 years of follow up. LnFGF23 was a significant, independent predictor for the composite outcome [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.53-2.95]. FePi did not modify the relation between FGF23 and outcome in these patients with CKD. CONCLUSIONS: Our study shows that FGF23 itself, but not its renal tissue resistance as reflected by FePi, is an important risk factor for clinical events in subjects with CKD stage 3-4.

Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.

BACKGROUND AND OBJECTIVES: Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer. RESULTS: Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively. CONCLUSION: Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.

Nurse practitioner care improves renal outcome in patients with CKD.

Treatment goals for patients with CKD are often unrealized for many reasons, but support by nurse practitioners may improve risk factor levels in these patients. Here, we analyzed renal endpoints of the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners (MASTERPLAN) study after extended follow-up to determine whether strict implementation of current CKD guidelines through the aid of nurse practitioners improves renal outcome. In total, 788 patients with moderate to severe CKD were randomized to receive nurse practitioner support added to physician care (intervention group) or physician care alone (control group). Median follow-up was 5.7 years. Renal outcome was a secondary endpoint of the MASTERPLAN study. We used a composite renal endpoint of death, ESRD, and 50% increase in serum creatinine. Event rates were compared with adjustment for baseline serum creatinine concentration and changes in estimated GFR were determined. During the randomized phase, there were small but significant differences between the groups in BP, proteinuria, LDL cholesterol, and use of aspirin, statins, active vitamin D, and antihypertensive medications, in favor of the intervention group. The intervention reduced the incidence of the composite renal endpoint by 20% (hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.98; P=0.03). In the intervention group, the decrease in estimated GFR was 0.45 ml/min per 1.73 m(2) per year less than in the control group (P=0.01). In conclusion, additional support by nurse practitioners attenuated the decline of kidney function and improved renal outcome in patients with CKD.