A novel PKD1 variant demonstrates a disease-modifying role in trans with a truncating PKD1 mutation in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of Polycystic Kidney Disease (PKD) and occurs at a frequency of 1/800 to 1/1000 affecting all ethnic groups worldwide. ADPKD shows significant intrafamilial phenotypic variability in the rate of disease progression and extra-renal manifestations, which suggests the involvement of heritable modifier genes. Here we show that the PKD1 gene can act as a disease causing and a disease modifier gene in ADPKD patients. METHODS: Clinical evaluation of a family with ADPKD was performed to diagnose and assess disease progression in each individual. PKD1 was genotyped in each individual by targeted sequencing. RESULTS: Targeted screening analysis showed that the patients with ADPKD in the family had the PKD1: p.Q2243X nonsense mutation. A more severe disease phenotype, in terms of estimated Glomerular Filtration Rate (eGFR) and total kidney volume, was observed in two patients where in addition to the mutation, they carried a novel PKD1 variant (p.H1769Y). Other patients from the same family carrying only the (p.Q2243X) mutation showed milder disease manifestations. CONCLUSION: ADPKD shows significant intrafamilial phenotypic variability that is generally attributed to other modifier genes. In this rare case, we have shown that a variant at PKD1, in trans with the PKD1 mutation, can also act as a modifier gene in ADPKD patients. Understanding the molecular mechanism through which the gene exerts its disease modifying role may aid our understanding of the pathogenesis of ADPKD.

The genetic landscape of autosomal dominant polycystic kidney disease in Kuwait.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal monogenic disease, characterized by bilateral accumulation of renal fluid-filled cysts leading to progressive renal volume enlargement and gradual impairment of kidney function, often resulting in end-stage renal disease. Kuwait could provide valuable genetic insights about ADPKD, including intrafamilial phenotypic variation, given its large household size. This study aims to provide a comprehensive description of the pathogenic variants linked to ADPKD in the Kuwaiti population using multiple genetic analysis modalities and to describe and analyse the ADPKD phenotypic spectrum in terms of kidney function, kidney volume and renal survival. Methods: A total of 126 ADPKD patients from 11 multiplex families and 25 singletons were recruited into the study. A combination of targeted next-generation sequencing (tNGS), long-range polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification were utilized for genetic diagnosis. Clinical evaluation was conducted through renal function testing and ultrasonographic kidney volume analysis. Results: We identified 29 ADPKD pathogenic mutations from 36 families achieving an overall molecular genetic diagnostic rate of 112/126 (88.9%), including 29/36 (80.6%) in families. A total of 28/36 (77.8%) families had pathogenic mutations in PKD1, of which 17/28 (60.7%) were truncating, and 1/36 (2.8%) had a pathogenic variant in the IFT140 gene. A total of 20/29 (69%) of the identified ADPKD mutations were novel and described for the first time, including a TSC2-PKD1 contiguous syndrome. Clinical analysis indicated that genetically unresolved ADPKD cases had no apparent association between kidney volume and age. Conclusion: We describe for the first time the genetic landscape of ADPKD in Kuwait. The observed genetic heterogeneity underlining ADPKD along with the wide phenotypic spectrum reveal the level of complexity in disease pathophysiology. ADPKD genetic testing could improve the care of patients through improved disease prognostication, guided treatment and genetic counselling. However, to fulfil the potential of genetic testing, it is important to overcome the hurdle of genetically unresolved ADPKD cases.

Estimating GFR using serum beta trace protein: accuracy and validation in kidney transplant and pediatric populations.

The limitations of estimates of glomerular filtration rate (GFR) based only on serum creatinine measurements have spurred an interest in more sensitive markers of GFR. Beta-trace protein (BTP), a low-molecular-weight glycoprotein freely filtered through the glomerular basement membrane and with minimal non-renal elimination, may be such a marker. We have recently derived two GFR estimation equations based on BTP. To validate these equations, we measured BTP and the plasma clearance of (99)mTc-DTPA in 92 adult kidney transplant recipients and 54 pediatric patients with impaired kidney function. GFR was estimated using the serum creatinine-based Modification of Diet in Renal Disease (MDRD) Study equation for adults, the Schwartz and updated Schwartz equations in children, and 4 novel BTP-derived equations (our 2 equations and 2 proposed by Poge). In adults, our BTP-based equations had low median bias and high accuracy such that 89-90% of estimates were within 30% of measured GFR. In children, the median bias of our 2 equations was low and accuracy was high such that 78-83% of estimates were within 30% of measured GFR. These results were an improvement compared to the MDRD and Schwartz equations, both of which had high median bias and reduced accuracy. The updated Schwartz equation also performed well.

Effect of clinical variables and immunosuppression on serum cystatin C and beta-trace protein in kidney transplant recipients.

BACKGROUND: Cystatin C and beta-trace protein (BTP) are low-molecular-weight proteins that have generated interest as alternative endogenous markers of glomerular filtration rate (GFR). Studies examining the effect of demographic, biometric, clinical, and biochemical variables on cystatin C levels have yielded conflicting results, perhaps because of the reliance on inferior methods of GFR determination. The aim of this study is to examine the independent effect of various clinical parameters on serum concentrations of creatinine, cystatin C, and BTP in kidney transplant recipients. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 207 kidney transplant recipients with stable kidney function. PREDICTORS: GFR, age, race, sex, body mass index, albumin level, proteinuria, smoking status, prednisone, and calcineurin inhibitor and mycophenolate mofetil use. OUTCOMES & MEASUREMENTS: Multiple linear regression analysis was used to examine the relationship between predictor variables and cystatin C, BTP, and creatinine levels. GFR was measured by using technetium 99m-radiolabeled diethylenetriaminepentaacetic acid clearance. RESULTS: After adjusting for GFR, cystatin C and BTP levels were significantly lower in women compared with men. Greater albumin concentration was associated with significantly lower cystatin C and BTP concentrations. There was a statistically significant, but clinically small, association between body mass index and cystatin C level, but no association between the other demographic variables or medications analyzed. LIMITATIONS: Predominantly white population; results may not be applicable to other racial groups. CONCLUSION: Important nonrenal factors can influence BTP and cystatin C concentrations and need to be considered when interpreting BTP and cystatin C values in kidney transplant patients.

PKD1 Duplicated regions limit clinical Utility of Whole Exome Sequencing for Genetic Diagnosis of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic renal disease characterised by the accumulation of clusters of fluid-filled cysts in the kidneys and is caused by mutations in PKD1 or PKD2 genes. ADPKD genetic diagnosis is complicated by PKD1 pseudogenes located proximal to the original gene with a high degree of homology. The next generation sequencing (NGS) technology including whole exome sequencing (WES) and whole genome sequencing (WGS), is becoming more affordable and its use in the detection of ADPKD mutations for diagnostic and research purposes more widespread. However, how well does NGS technology compare with the Gold standard (Sanger sequencing) in the detection of ADPKD mutations? Is a question that remains to be answered. We have evaluated the efficacy of WES, WGS and targeted enrichment methodologies in detecting ADPKD mutations in the PKD1 and PKD2 genes in patients who were clinically evaluated by ultrasonography and renal function tests. Our results showed that WES detected PKD1 mutations in ADPKD patients with 50% sensitivity, as the reading depth and sequencing quality were low in the duplicated regions of PKD1 (exons 1-32) compared with those of WGS and target enrichment arrays. Our investigation highlights major limitations of WES in ADPKD genetic diagnosis. Enhancing reading depth, quality and sensitivity of WES in the PKD1 duplicated regions (exons 1-32) is crucial for its potential diagnostic or research applications.

Chronic kidney disease management: comparison between renal transplant recipients and nontransplant patients with chronic kidney disease.

BACKGROUND/AIM: Renal transplant recipients (RTR) and patients with native chronic kidney disease (CKD) have similar complications. It is not known how the management of CKD in RTR differs from that of patients with native CKD. This study compares the management of complications related to CKD between RTR and patients with native CKD. METHODS: Cross-sectional study of all RTR with stage 4 or 5 CKD (n = 72). The control group consisted of 72 native CKD patients matched by glomerular filtration rate (within 2 ml/min/1.73 m(2)). Multivariate logistic regression analysis was performed to account for potential confounding variables. RESULTS: Multivariate analysis revealed RTR to more likely have uncontrolled hypertension (adjusted odds ratio AOR 3.8; 95% confidence interval CI 1.3-10.7), less likely to be on angiotensin-converting enzyme inhibitors (AOR 0.11; 95% CI 0.04-0.32), more likely to be anemic and not be on erythropoietin (AOR 6.4; 95% CI 0.99-41.9), and more likely to have dyslipidemia and not be on statin (AOR 4.3; 95% CI 1.4-13.4). CONCLUSIONS: This study suggests that the management of non-RTR in a multidisciplinary CKD clinic differs significantly from the CKD management in a traditional transplant clinic. A disease management approach like a multidisciplinary clinic may be an appropriate model for the future.

Utilizing Estimated Creatinine Excretion to Improve the Performance of Spot Urine Samples for the Determination of Proteinuria in Kidney Transplant Recipients.

BACKGROUND: Agreement between spot and 24-hour urine protein measurements is poor in kidney transplant recipients. We investigated whether using formulae to estimate creatinine excretion rate (eCER), rather than assuming a standard creatinine excretion rate, would improve the estimation of proteinuria from spot urine samples in kidney transplant recipients. METHODS: We measured 24 hour urine protein and albumin and spot albumin:creatinine (ACR) and spot protein:creatinine (PCR) in 181 Kidney transplant recipients." We utilized 6 different published formulae (Fotheringham, CKD-EPI, Cockcroft-Gault, Walser, Goldwasser and Rule) to estimate eCER and from it calculated estimated albumin and protein excretion rate (eAER and ePER). Bias, precision and accuracy (within 15%, 30% and 50%) of ACR, PCR, eAER, ePER were compared to 24-hour urine protein and albumin. RESULTS: ACR and PCR significantly underestimated 24-hour albumin and protein excretion (ACR Bias (IQR), -5.9 mg/day; p< 0.01; PCR Bias, (IQR), -35.2 mg/day; p<0.01). None of the formulae used to calculate eAER or ePER had a bias that was significantly different from the 24-hour collection (eAER and ePER bias: Fotheringham -0.3 and 7.2, CKD-EPI 0.3 and 13.5, Cockcroft-Gault -3.2 and -13.9, Walser -1.7 and 3.1, Goldwasser -1.3 and -0.5, Rule -0.6 and 4.2 mg/day respectively. The accuracy for ACR and PCR were lower (within 30% being 38% and 43% respectively) than the corresponding values estimated by utilizing eCER (for eAER 46% to 49% and ePER 46-54%). CONCLUSION: Utilizing estimated creatinine excretion to calculate eAER and ePER improves the estimation of 24-hour albuminuria/proteinuria with spot urine samples in kidney transplant recipients.

Zopiclone-induced acute interstitial nephritis.

Zopiclone, a relatively new nonbenzodiazepine short-acting hypnotic medication is prescribed frequently for insomnia. The authors report a case of zopiclone-induced acute interstitial nephritis in a young, otherwise healthy man. The patient presented with anuric acute renal failure requiring hemodialysis. Kidney biopsy results showed acute interstitial nephritis with a prominent eosinophilic infiltrate in the interstitium. He recovered his renal function after stopping the medication and receiving corticosteroids.

Single nucleotide polymorphisms at erythropoietin, superoxide dismutase 1, splicing factor, arginine/serin-rich 15 and plasmacytoma variant translocation genes association with diabetic nephropathy.

A number of genes have been identified in diabetic nephropathy. Association between diabetes-associated nephropathy and polymorphisms in the erythropoietin (EPO) gene, variants in the superoxide dismutase 1 (SOD1) gene and plasmacytoma variant translocation 1 (PVT1) gene have been identified. The EPO, SOD1:SFRS15 and PVT1 genes were genotyped using the single nucleotide polymorphism (SNP) technique in 38 diabetic nephropathy patients (Group 1) compared with 64 diabetic type 2 subjects without nephropathy (Group 2) at the Mubarak Alkabeer Hospital, Kuwait. The frequency of the risk allele T of the EPO (rs1617640) gene was high in both groups (0.96 in Group 1 and 0.92 in Group 2). Similarly, SNPs of the PVT1 (rs2720709) gene showed a higher frequency of the risk allele G in both groups (0.70 in the Group 1 and 0.68 in Group 2). Although the frequency of the risk allele A was higher than the frequency of the non-risk allele C of the SOD1:SFRS15 gene in both groups, the lowest probability value was observed in those gene SNPs (P = 0.05). We observed that the A allele of the SOD1:SFRS15 gene (rs17880135) was more frequently present in Group 1 (0.75) compared with Group 2 (0.62). Susceptibility to diabetes-associated nephropathy is partially mediated by genetic predisposition, and screening tests may open the gate for new therapeutic approaches.

Can continuous venovenous hemofiltration prevent contrast-agent induced nephropathy in patients with advanced chronic kidney disease after coronary angiography?

To determine whether contrast induced nephropathy (CIN) post coronary angio-graphy procedure can be prevented in chronic kidney disease (CKD) patients by continuous venovenous hemofiltration (CVVH), we evaluated 98 CKD patients [52 (53.1%) were males, the mean age was 60.7 ± 11.0 years] who underwent coronary angiography from January 2004 to December 2006. Serum creatinine (Cr) before the procedure was 411 ± 79.9 µmol/L and crea-tinine clearance (Cr Cl) was 18.04 ± 4.26 mL/min. All patients underwent post procedure CVVH for 21.34 ± 2.12 hours. The mean time interval between the procedure and the start of CVVH was 44.3 ± 18.8 min. The mean serum Cr at discharge was 403 ± 88.4 µmol/L (Cr Cl 18.5 ± 4.61 mL/min) and was 423 ± 88.9 µmol/L (Cr Cl17.6 ± 4.27 mL/min) 15 days after the procedure. One patient (1.02%) developed worsening of renal functions that required repeated CVVH during hospitalization and ended up on regular hemodialysis. There was no in-hospital mortality. We conclude that CVVH is effective in preventing CIN after coronary angiography in CKD patients.

Clinical and histopathological spectrum of IgA nephropathy in Kuwait.

BACKGROUND: Little is known about the nature and the course of IgA nephropathy (IgAN) in Arab countries. The aim of this work was to study the spectrum of clinical presentation and histopathological findings at our institution. DESIGN AND SETTING: Retrospective review, all renal biopsies at the Mubarak Al Kabeer Hospital between January 2000 and December 2004. METHODS: Cases of IgA nephropathy were selected, and their medical records and biopsy findings were reviewed. RESULTS: Eighty patients (9.2% of all native kidney biopsies) were diagnosed to have IgAN nephropathy. Sixty-nine biopsies were included in the study;11 were excluded. Forty-three (62.3%) patients were male and 26 (37.7) patients were female. Fifty (72.5%) patients were below the age of 40 years. Mean (SD) duration of follow-up was 3.6 (1.3) years. The first presentation included nephritic-range proteinuria (49.3%) and renal impairment (50.7%). During the follow-up period, 56 (81.2%) patients were stable or improved. Hass classification of biopsies showed 36.2% had class I, 27.5% had class II, 13.0% had class III, 5.8% had class IV, and 17.4% had class V IgAN. Females had milder forms of the disease than males. Macroscopic hematuria and renal impairment at presentation were seen more in patients with class IV and V IgAN. The presenting serum creatinine and uric acid values were higher in those with Hass classes III to V. Deterioration of renal function during the follow-up period was more significant in the presence of hypertension, renal impairment, or macroscopic hematuria at the time of biopsy . CONCLUSION: The prevalence of IgAN in Kuwait is about 9.2%. Renal impairment or macroscopic hematuria at presentation was seen in patients with more aggressive renal lesions and contributed to poor outcome.

Acute renal failure in pediatric patients: etiology and predictors of outcome.

Acute renal failure (ARF) is the acute loss of kidney function over hours or days, the etiology of which varies in different countries. The data on the etiology and outcome of ARF in Arab children is limited. Our objective was to define the causes and predictors of outcome of ARF in Kuwaiti children, and the variables determining their fitness for dialysis. A total of 32 children with ARF were evaluated regarding their demographic and clinical data, the cause of ARF and the co-morbidities. Data were analyzed to find the independent variables determining fitness for dia-lysis and outcome. Males comprised 62.5% of the study children; 46.9% of ARF cases were due to sepsis and 56.2% underwent renal replacement therapy (RRT). Univariate analysis showed that age, hemodynamic instability, use of vasopressors, multi-organ failure (MOF), and mechanical venti-lation contributed to fitness for dialysis. However, MOF was the only independent variable affecting fitness for dialysis. The overall mortality was 43.8%. Univariate analysis showed that age below 24-months, hemodynamic instability, use of vasopressors, fluid overload, need for mecha-nical ventilation, MOF and late referral to the nephrologist were associated with poor outcome. However, multivariate analysis documented MOF, and the time of nephrologists' intervention as independent prognostic indicators. Our study suggests that sepsis was the major cause of pediatric ARF. RRT is the optimal treatment, and the only factor determining child's fitness for dialysis is MOF.

Renal biopsy in patients with type 2 diabetes mellitus: indications and nature of the lesions.

BACKGROUND AND OBJECTIVES: The prevalence of non diabetic renal disease (NDRD) among patients with type 2 diabetes mellitus varies widely depending on the selection criteria and the populations being studied. The aim of this study was to evaluate the renal biopsies performed on type 2 diabetic patients for suspicion of NDRD and to correlate the pathological with the clinical and laboratory findings. SUBJECTS AND METHODS: We selected and reviewed biopsies performed on type 2 diabetics for clinically suspected NDRD from January 2006 to December 2008 at a single hospital. Clinical and laboratory data were analyzed in relation to the histopathology findings. Patients were grouped into either group I with isolated DGS or group II with NDRD on top of DGS. RESULTS: Thirty-one biopsies were performed on type 2 diabetic patients; Seventeen patients (54.8%) were males. Mean age was 50.68 (11.29) years. The mean duration of diabetes was 9.33 (3.6) years. Renal biopsy showed that among the studied group 14 patients (45.2%) showed NDRD on top of DGS. Crescentic glomerulonephritis was the commonest finding seen in 3 cases (21.4% of group II cases) followed by acute tubulointerstitial nephritis and hypertensive changes each was seen in 2 cases (14.4%). Other findings included IgA nephropathy, primary focal segmental glomerulosclerosis, rhabdomyolysis, membranoproliferative glomerulonephritis each of them was seen in one case (7.1%). Group I had a significantly higher level of proteinuria 4.97 (2.08) gm/24 hrs urine than group II 2.72 (1.09) gm/24 hrs urine (P=.003). There was no significant difference between the two groups in age, duration of diabetes, gender, presence of hypertension, hematuria, serum creatinine or glomerular filtration rate. CONCLUSION: The present study showed that crescentic glomerulonephritis is the commonest NDRD among diabetic patients. A higher level of proteinuria was reported among those with NDRD superimposed on DGS. So, Renal biopsy should be performed in diabetics when the clinical scenario is atypical.

Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations.

BACKGROUND: Current clinical guidelines recommend that renal transplant recipients (RTRs) be classified into chronic kidney disease (CKD) stage using a creatinine-based estimate of glomerular filtration rate (GFR). However, creatinine-based equations are inaccurate in RTRs leading to frequent CKD stage misclassification. It is not known whether the classification of CKD stage would be improved using a cystatin C-based estimate of GFR. METHODS: We measured (99m)Tc-DTPA GFR, cystatin C and creatinine in 198 stable RTRs. GFR was estimated using cystatin C-based equations (Filler, Le Bricon and Rule) and four creatinine-based equations. We determined the proportion, overall and by CKD stage, that were classified correctly by each equation as compared to the (99m)Tc-DTPA GFR. RESULTS: The Filler equation correctly classified 76% of patients compared to only 65% with the abbreviated modification of diet in renal disease (MDRD) equation and 69% with the Cockcroft-Gault equation. In CKD stages two and four, the Filler equation correctly classified 77% and 60% of patients whereas the abbreviated MDRD equation correctly classified 46% and 93% of patients. The area under the curve by receiver operating curve analysis for overall stage classification was uniformly poor for all equations (0.52-0.56). CONCLUSIONS: The cystatin C-based Filler and Le Bricon GFR estimates classified slightly more patients into the correct CKD stage than the standard creatinine-based equations in stable RTRs although the overall diagnostic accuracies were similar. The differences are modest and prospective studies will be needed to determine if the adoption of these equations for classification would lead to improved recognition of CKD complications or patient care.

A novel equation to estimate glomerular filtration rate using beta-trace protein.

BACKGROUND: Beta-trace protein (BTP) is a low molecular weight glycoprotein that is a more sensitive marker of glomerular filtration rate (GFR) than serum creatinine. The utility of BTP has been limited by the lack of an equation to translate BTP into an estimate of GFR. The objectives of this study were to develop a BTP-based GFR estimation equation. METHODS: We measured BTP and GFR by (99m)technetium-diethylenetriaminepentaacetic acid in 163 stable adult renal transplant recipients. Stepwise multiple regression models were created to predict GFR corrected for body surface area. The following variables were considered for entry into the model: BTP, urea, sex, albumin, creatinine, age, and race. RESULTS: BTP alone accounted for 75.6% of variability in GFR. The model that included all the predictor variables had the largest coefficient of determination (R(2)) at 0.821. The model with only BTP, urea, and sex had only a slightly lower R(2) of 0.81 and yielded the following equation: GFR mL . min(-1) . (1.73 m(2))(-1) = 112.1 x BTP(-0.662) x Urea(-0.280) x (0.88 if female). A 2nd equation (R(2) = 0.79) using creatinine instead of urea was also developed: GFR mL . min(-1) . (1.73 m(2))(-1) = 1.678 x BTP(-0.758) x creatinine(-0.204) x (0.871 if female). CONCLUSIONS: We have shown that BTP can be used in a simple equation to estimate GFR. Further study is needed in other populations to determine accuracy and clinical utility of this equation.

Estimating glomerular filtration rate in kidney transplantation: a comparison between serum creatinine and cystatin C-based methods.

Accurate measurement of GFR is critical for the evaluation of new therapies and the care of renal transplant recipients. Although not accurate in renal transplantation, GFR is often estimated using creatinine-based equations. Cystatin C is a marker of GFR that seems to be more accurate than creatinine. Equations to predict GFR based on the serum cystatin C concentration have been developed, but their accuracy in transplantation is unknown. GFR was estimated using four equations (Filler, Le Bricon, Larsson, and Hoek) that are based on serum cystatin C and seven equations that are based on serum creatinine in 117 adult renal transplant recipients. GFR was measured using radiolabeled diethylenetriaminepentaacetic acid (99mTc-DTPA), and the bias, precision, and accuracy of each equation were determined. The mean (99m)Tc-DTPA GFR was 58 +/- 23 ml/min per 1.73 m(2). The cystatin C-based equations of Filler and Le Bricon had the lowest bias (-1.7 and -3.8 ml/min per 1.73 m2), greatest precision (11.4 and 11.8 ml/min per 1.73 m2), and highest accuracy (87 and 89% within 30% of measured GFR, respectively). The cystatin C equations remained accurate even when the measured GFR was >60 ml/min per 1.73 m2. The creatinine-based equations were not as accurate, with only 53 to 80% of estimates within 30% of measured GFR. Cystatin C-based equations are more accurate at predicting GFR in renal transplant recipients than traditional creatinine-based equations. Further prospective studies with repetitive measurement of cystatin C are needed to determine whether cystatin C-based estimates of GFR will be sufficiently accurate to monitor long-term allograft function.

Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials.

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus-based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus-based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2-10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08-9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46-1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40-1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40-0.78, p = 0.0006). CNI withdrawal from sirolimus-based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow-up is needed to determine if these changes will result in a significant improvement in patient and graft survival.