Jan A.J.G. van den Brand

Epidemiology of Contrast Material–induced Nephropathy in the Era of Hydration

PURPOSE To evaluate the incidence of contrast material-induced nephropathy (CIN) in patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m(2) who received intravenous contrast media and underwent treatment in accordance with current guidelines and to determine risk factors associated with CIN. MATERIALS AND METHODS The research ethics committee waived the requirement for informed consent for this prospective cohort study. All nonhospitalized patients with an eGFR of less than 60 mL/min/1.73 m(2) were seen at a special outpatient clinic. Patients were stratified for the risk of CIN. They were classified as having high or low risk for CIN on the basis of absolute glomerular filtration rate (Modification of Diet in Renal Disease formula result multiplied by body surface area divided by 1.73 m(2)) and the presence of risk factors. Patients at high risk were hydrated with 1000 mL of isotonic saline before and after contrast material exposure. Serum creatinine level was measured 3-5 days later, and CIN was defined as an increase of 25% of more from the baseline level. Risk factors were recorded and compared between patients with CIN and those without CIN by using forward stepwise multiple logistic regression analysis. RESULTS A total of 944 procedures in 747 patients were evaluated. Mean age was 71.3 years ± 10 (standard deviation), and 42.9% of patients were female. In 511 procedures (54.1%), patients were hydrated. CIN developed after 23 procedures (2.4%). No patient needed hemodialysis treatment. Heart failure (odds ratio, 3.0), body mass index (BMI) (odds ratio, 0.9), and repeated contrast material administration (odds ratio, 2.8) were found to be independent predictors of CIN. CONCLUSION Heart failure, low BMI, and repeated contrast material administration were identified as risk factors for CIN under the current treatment strategy. The low incidence of CIN supports the use of hydration as a preventive measure in patients at high risk for CIN.

Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population

BACKGROUND Chronic kidney disease (CKD) is defined as the presence of kidney damage, albuminuria or a reduction in glomerular filtration rate (GFR). A GFR <60 mL/min/1.73 m(2) alone is sufficient to diagnose CKD Stages III-V. Recently, the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation was introduced. It has been suggested to result in higher estimated glomerular filtration rates (eGFRs) than the Modification of Diet in Renal Disease (MDRD(4)) formula. Here, we assess consequences of introducing the CKD-EPI equation in a West European Caucasian population. METHODS Data were obtained from 6097 Caucasian participants of the Nijmegen Biomedical Study (2823 males and 3274 females). Serum creatinine values were determined using the Jaffe method, calibrated against mass spectrometry and were used to calculate eGFR(MDRD4) and eGFR(CKD-EPI). Demographic data, health status and information on medication use for all participants was obtained with a postal questionnaire. RESULTS The introduction of the CKD-EPI equation changed the curve of eGFR by age, with higher values in the younger age groups and a steeper decline of eGFR with ageing. As a consequence, younger people were more often classified to a higher GFR stage and older people, especially males, to a lower GFR stage. CONCLUSIONS In comparison with the MDRD(4) formula, the CKD-EPI equation leads to higher estimates of GFR in young people and lower estimates in the elderly. On a population level, this may lead to higher estimates of kidney function. However, in routine clinical practice where the population is predominantly elderly, the opposite may be true. The introduction of eGFR(CKD-EPI) necessitates reconsidering the definition of CKD. We suggest introducing age-dependent threshold values and/or the use of urinary albumin excretion to improve risk stratification.

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.

High urinary excretion of kidney injury molecule-1 is an independent predictor of end-stage renal disease in patients with IgA nephropathy

BACKGROUND The variable course of immunoglobulin A nephropathy (IgAN) warrants accurate tools for the prediction of progression. Urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are markers for the detection of early tubular damage caused by various renal conditions. We evaluated the prognostic value of these markers in patients with IgAN. METHODS We included patients (n = 65, 72% male, age 43 ± 13 years) with biopsy-proven IgAN, who were evaluated for proteinuria. Urinary KIM-1 and NGAL were measured by enzyme-linked immunosorbent assay. We analysed data using Cox regression for the outcome end-stage renal disease (ESRD). RESULTS Median serum creatinine was 142 μmol/L and proteinuria 2.2 g/day. During follow-up (median 75 months), 23 patients (35%) developed ESRD. In patients with IgAN median urinary KIM-1 excretion was 1.7 ng/min and NGAL excretion was 47 ng/min, both significantly higher than in healthy controls. KIM-1 and NGAL were correlated with proteinuria (r = 0.40 and 0.34, respectively, P < 0.01) and each other (r = 0.53, P < 0.01) but not with estimated glomerular filtration rate (eGFR). Interestingly, KIM-1 was not significantly correlated with the excretion of α(1)-microglobulin (α(1)m) and β(2)-microglobulin (β(2)m), known markers of tubular injury. Univariate analysis showed that baseline serum creatinine and urinary excretion of total protein, α(1)m, β(2)m, immunoglobulin G, KIM-1 and NGAL were significantly associated with ESRD. By multivariate analysis, serum creatinine and KIM-1 excretion proved to be significant independent predictors of ESRD. CONCLUSION KIM-1 and NGAL excretion are increased in patients with IgAN and correlate with proteinuria but not with eGFR. Baseline serum creatinine and urinary KIM-1, but not proteinuria, are independent predictors of ESRD.

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.

Long-Term Outcomes in Idiopathic Membranous Nephropathy Using a Restrictive Treatment Strategy

Recently published Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend limiting the use of immunosuppressive drugs in idiopathic membranous nephropathy to patients at the highest risk of kidney failure. However, recommendations are based on natural history rather than direct assessment of a restrictive treatment strategy. Here, we describe the long-term outcomes of treating a large cohort of patients with idiopathic membranous nephropathy according to a restrictive treatment policy. We analyzed data for 254 patients who visited our outpatient clinic between 1995 and 2009. All patients were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Immunosuppressive therapy was recommended in cases of deteriorating renal function or untreatable nephrotic syndrome. Primary outcomes for the present study were renal replacement therapy and death. Secondary outcomes included adverse events during follow-up and remission of proteinuria. In total, 124 patients (49%) received immunosuppressive therapy, which predominantly consisted of cyclophosphamide combined with steroids. Ten-year cumulative incidence rates were 3% for renal replacement therapy and 10% for death. Partial remission rates were 39%, 70%, and 83% after 1, 3, and 5 years, respectively; complete remission rates were 5%, 24%, and 38% at 1, 3, and 5 years, respectively. A serious adverse event occurred in 23% of all patients. The most notable complications were infections (17%), leukopenia (18%), cardiovascular events (13%), and malignancies (8%). In conclusion, the use of a restrictive treatment strategy in this cohort of patients with idiopathic membranous nephropathy yielded favorable outcomes while limiting the number of patients exposed to toxic drugs. These results support current KDIGO guidelines.

Validation of the kidney failure risk equation in European CKD patients

BACKGROUND Patients with chronic kidney disease (CKD) are at risk for progression to kidney failure. Using data of Canadian CKD patients, Tangri et al. recently developed models to predict the progression of CKD stages 3-5 to kidney failure within 5 years. We validated this kidney failure risk equation (KFRE) in European CKD patients. METHODS We selected non-transplanted patients with CKD stages 3-5 who participated in the MASTERPLAN study, a randomized controlled trial in patients with CKD. Kidney failure was defined as the initiation of chronic dialysis or kidney transplantation within 5 years. Patients who died before kidney failure were censored. Patients followed for <5 years, who did not develop kidney failure and did not die, were excluded. The 5-year kidney failure risk was predicted using three different models developed by Tangri et al. and compared with the actual kidney failure rate in MASTERPLAN. Model performance was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), the net reclassification index (NRI) and by comparing the observed and predicted rates of kidney failure. RESULTS A total of 595 patients were included; 114 developed kidney failure. (Overall observed kidney failure risk in our cohort was 5% lower than in the Canadian validation cohort.) Discrimination of the eight-variable model [including age, sex, estimated glomerular filtration rate (eGFR), albuminuria, calcium, phosphate, bicarbonate, albumin] was similar to that of the four-variable model (including age, sex, eGFR, albuminuria) and the three-variable model (including age, sex, eGFR); ROC-AUCs were 0.89 [95% confidence interval (CI) 0.86-0.92], 0.88 (95% CI 0.85-0.91) and 0.88 (95% CI 0.85-0.92), respectively. Using the NRI, the eight-variable model slightly outperformed the four-variable model (NRI 6.5%) and the three-variable model (NRI 12.4%). The mean differences between the observed and predicted kidney failure risk were -4.0, -7.1 and -7.4% for the eight-, four-, and three-variable model, respectively. CONCLUSIONS The KFRE accurately predicted the progression to kidney failure in European CKD patients. Discrimination of the three models was similar. Calibration of the eight-variable model was slightly better than that of the simpler models. We question whether this outweighs its added complexity.

Prognostic Value of Risk Score and Urinary Markers in Idiopathic Membranous Nephropathy

BACKGROUND AND OBJECTIVES Accurate prediction of prognosis may improve management of patients with idiopathic membranous nephropathy. This study compared the Toronto Risk Score and urinary low-molecular weight proteins. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS One hundred four patients with biopsy-proven idiopathic membranous nephropathy who presented between 1995 and 2008 with a well-preserved kidney function and nephrotic range proteinuria were included. Urinary β2-microglobulin and α1-microglobulin measurements were obtained by timed standardized measurements, and the Toronto Risk Score was calculated using data obtained from medical records. The endpoint was progression, which was defined as an increase in serum creatinine > 50% or > 25% with a concentration > 135 μmol/L. RESULTS Forty-nine patients showed progression. The area under the receiver-operating characteristics curve was 0.78 (95% confidence interval = 0.69-0.88) for the risk score versus 0.80 (0.71-0.89) and 0.79 (0.71-0.88) for urinary β2- and α1-microglobulin, respectively. Differences were not significant. Persistent proteinuria did not add accuracy to the Toronto Risk Score. Conversely, its accuracy was not reduced when data from the first 6 months of follow-up were used. Furthermore, a score based on GFR estimated with the six-variable Modification of Diet in Renal Disease equation, calculated in the first 6 months of follow-up, gave an area under the receiver-operating characteristics curve of 0.83 (0.74-0.92), which was not statistically different from other markers. CONCLUSIONS The prognostic accuracies of the Toronto Risk Score and urinary low-molecular weight proteins were not significantly different. The risk score can be calculated within 6 months of diagnosis, and a simplified risk score using estimated GFR-Modification of Diet in Renal Disease may be sufficient.

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.

Intra-individual variability of serum hepcidin-25 in haemodialysis patients using mass spectrometry and ELISA

BACKGROUND Measurement of serum hepcidin levels may provide a useful alternative to the current methods of determining iron status in chronic haemodialysis (HD) patients. However, the biological variability of this pivotal regulator of iron homeostasis is unclear, and the impact of inflammation, dialysis clearance and iron therapy on hepcidin variability has not been established. METHODS Two independent studies in chronic HD patients were conducted; serum hepcidin levels were measured at the start of dialysis sessions in 20 UK patients and in 43 Dutch patients by mass spectrometry (MS). Samples from UK patients were also analysed by a competitive enzyme-linked immunosorbent assay (cELISA). Coefficient of variance (CV(1)) was calculated and potential factors affecting CV(1) were also examined. RESULTS The median CV(1) (inter-quartile range) was 23% (17-28) for the UK MS, 26% (17-48) for the Dutch MS and 23% (17-39) for the UK cELISA. The CV(1) was similar in those patients receiving and those not receiving regular intravenous iron. The CV(1) was not associated with the degree of inflammation. Hepcidin levels were higher following an inter-dialytic period of 3 versus 2 days (P = 0.02). CONCLUSIONS These findings suggest considerable variability of serum hepcidin levels in HD patients. Inflammation and the use of iron did not impact on the degree of variability, and hepcidin levels were higher after an inter-dialytic period of 3 versus 2 days. These findings need to be taken into account in future studies assessing the utility of serum hepcidin as a guide to the use of iron or erythropoiesis-stimulating agents therapy.