Ziad M. El-Zoghby

Identifying Specific Causes of Kidney Allograft Loss

The causes of kidney allograft loss remain unclear. Herein we investigated these causes in 1317 conventional kidney recipients. The cause of graft loss was determined by reviewing clinical and histologic information the latter available in 98% of cases. During 50.3 ± 32.6 months of follow‐up, 330 grafts were lost (25.0%), 138 (10.4%) due to death with function, 39 (2.9%) due to primary nonfunction and 153 (11.6%) due to graft failure censored for death. The latter group was subdivided by cause into: glomerular diseases (n = 56, 36.6%); fibrosis/atrophy (n = 47, 30.7%); medical/surgical conditions (n = 25, 16.3%); acute rejection (n = 18, 11.8%); and unclassifiable (n = 7, 4.6%). Glomerular pathologies leading to failure included recurrent disease (n = 23), transplant glomerulopathy (n = 23) and presumed nonrecurrent disease (n = 10). In cases with fibrosis/atrophy a specific cause(s) was identified in 81% and it was rarely attributable to calcineurin inhibitor (CNI) toxicity alone (n = 1, 0.7%). Contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or CNI toxicity. Glomerular pathologies cause the largest proportion of graft loss and alloinmunity remains the most common mechanism leading to failure. This study identifies targets for investigation and intervention that may result in improved kidney transplantation outcomes.

Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: A Simple Model for Selecting Patients for Clinical Trials

The rate of renal disease progression varies widely among patients with autosomal dominant polycystic kidney disease (ADPKD), necessitating optimal patient selection for enrollment into clinical trials. Patients from the Mayo Clinic Translational PKD Center with ADPKD (n=590) with computed tomography/magnetic resonance images and three or more eGFR measurements over ≥6 months were classified radiologically as typical (n=538) or atypical (n=52). Total kidney volume (TKV) was measured using stereology (TKVs) and ellipsoid equation (TKVe). Typical patients were randomly partitioned into development and internal validation sets and subclassified according to height-adjusted TKV (HtTKV) ranges for age (1A-1E, in increasing order). Consortium for Radiologic Imaging Study of PKD (CRISP) participants (n=173) were used for external validation. TKVe correlated strongly with TKVs, without systematic underestimation or overestimation. A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients. When 1A-1E classifications were used instead of log2HtTKV, eGFR slopes were significantly different among subclasses and, except for 1A, different from those in healthy kidney donors. The equation derived from the development set predicted eGFR in both validation sets. The frequency of ESRD at 10 years increased from subclass 1A (2.4%) to 1E (66.9%) in the Mayo cohort and from 1C (2.2%) to 1E (22.3%) in the younger CRISP cohort. Class and subclass designations were stable. An easily applied classification of ADPKD based on HtTKV and age should optimize patient selection for enrollment into clinical trials and for treatment when one becomes available.

Recurrent Idiopathic Membranous Nephropathy: Early Diagnosis by Protocol Biopsies and Treatment with Anti‐CD20 Monoclonal Antibodies

Membranous nephropathy (MN) recurs posttransplant in 42% of patients. We compared MN recurrence rates in a historical cohort transplanted between 1990 and 1999 and in a current cohort diagnosed by protocol biopsies, we analyzed the progression of the disease and we assessed the effects of anti‐CD20 antibodies (Rituximab) on recurrent MN. The incidence of recurrent MN was similar in the historical (53%) and the current cohorts (41%), although in the later the diagnosis was made earlier (median, 4[2–21] months vs. 83[6–149], p = 0.002) and the disease was clinically milder. Twelve out of 14 patients (86%) with recurrent MN in the current cohort had progressive increases in proteinuria. Eight recipients were treated with Rituximab after their proteinuria increased from median, 211 mg/day (64–4898) at diagnosis to 4489 (898–13 855) (p = 0.038). Twelve months post‐Rituximab, 75% of patients had either partial (PR) or complete remission (CR). After 24 months 6/7 (86%) had PR/CR and one patient relapsed. Posttreatment biopsies showed resorption of electron dense immune deposits in 6/7 cases and were negative for C3 (4/7) and IgG (3/7). Protocol biopsies allow early diagnosis of subclinical recurrent MN, which is often progressive. Treatment of recurrent MN with Rituximab is promising and should be evaluated in a prospective randomized controlled trial.

Autogenous versus prosthetic vascular access for hemodialysis: a systematic review and meta-analysis.

OBJECTIVES The autogenous arteriovenous access for chronic hemodialysis is recommended over the prosthetic access because of its longer lifespan. However, more than half of the United States dialysis patients receive a prosthetic access. We conducted a systematic review to summarize the best available evidence comparing the two accesses types in terms of patient-important outcomes. METHODS We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and SCOPUS) and included randomized controlled trials and controlled cohort studies. We pooled data for each outcome using a random effects model to estimate the relative risk (RR) and its associated 95% confidence interval (CI). We estimated inconsistency caused by true differences between studies using the I(2) statistic. RESULTS Eighty-three studies, of which 80 were nonrandomized, met eligibility criteria. Compared with the prosthetic access, the autogenous access was associated with a significant reduction in the risk of death (RR, 0.76; 95% CI, 0.67-0.86; I(2) = 48%, 27 studies) and access infection (RR, 0.18; 95% CI, 0.11-0.31; I(2) = 93%, 43 studies), and a nonsignificant reduction in the risk of postoperative complications (hematoma, bleeding, pseudoaneurysm and steal syndrome, RR 0.73; 95% CI, 0.48-1.16; I(2) = 65%, 31 studies) and length of hospitalization (pooled weighted mean difference -3.8 days; 95% CI, -7.8 to 0.2; P = .06). The autogenous access also had better primary and secondary patency at 12 and 36 months. CONCLUSION Low-quality evidence from inconsistent studies with limited protection against bias shows that autogenous access for chronic hemodialysis is superior to prosthetic access.

Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T.

Patients waiting for a kidney transplant have high mortality despite careful preselection. Herein, we assessed whether cardiac troponin T (cTnT) can help stratify risk in patients selected for kidney transplantation. cTnT levels were measured in all kidney transplant candidates but the results were not used for patient selection. Among 644 patients placed on the kidney waiting list from 9/2004 to 12/2006, 61% had elevated cTnT levels (>0.01 ng/mL). Higher levels related to diabetes, longer time on dialysis, history of cardiovascular disease and low serum albumin. High cTnT also related to cardiac anomalies, including left ventricular hypertrophy (LVH), wall motion abnormalities and stress‐inducible ischemia by dobutamine echo (DSE). However, 54% of patients without these cardiac findings had elevated cTnT. Increasing cTnT levels were associated with reduced survival (HR = 1.729, CI (1.25–2.39), p = 0.01) independently of low serum albumin (0.449 (0.24–0.83), p = 0.011) and history of stroke (3.368 (1.47–7.73), p = 0.0004). The results of the DSE and/or coronary angiography did not relate significantly to survival. However, high cTnT identified patients with abnormal echo findings and poor survival. Wait listed patients with normal cTnT have excellent survival irrespective of other factors. In contrast, high cTnT levels are strongly predictive of poor survival in the kidney transplant waiting list.

Urolithiasis and the Risk of ESRD

BACKGROUND AND OBJECTIVES The contribution of urolithiasis, if any, to the development of ESRD is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All stone formers in Olmsted County, Minnesota, first diagnosed between 1984 and 2008 were identified by diagnostic codes with up to four controls matched on age and sex. Charts were reviewed to validate symptomatic stone formers in a random subset. Incident ESRD events were identified by the US Renal Data System. RESULTS Altogether, 51 stone formers and 75 controls developed ESRD among 6926 stone formers and 24,620 matched controls followed for a mean of 9 years. Stone formers had an increased risk of ESRD after adjusting for diabetes, hypertension, dyslipidemia, gout, and CKD (hazard ratio: 2.09; 95% confidence interval: 1.45-3.01). This increased risk of ESRD remained in the subset of 2457 validated symptomatic stone formers (hazard ratio: 1.95; 95% confidence interval: 1.09-3.49). The attributable risk of ESRD from symptomatic urolithiasis was 5.1% based on a prevalence of 5.4% for stone formers. For stone formers versus controls who developed ESRD, there was an increased likelihood of past hydronephrosis (44% versus 4%), recurrent urinary tract infections (26% versus 4%), acquired single kidney (15% versus 3%), neurogenic bladder (12% versus 1%), and ileal conduit (9% versus 0%), but not diabetes (32% versus 49%) or hypertension (44% versus 52%). CONCLUSIONS Symptomatic stone formers are at increased risk for ESRD independent of several cardiovascular risk factors. Other urological disease is relatively common among stone formers who develop ESRD.

Surveillance of arteriovenous hemodialysis access: A systematic review and meta-analysis

OBJECTIVES Hemodialysis centers regularly survey arteriovenous (AV) accesses for signs of dysfunction. In this review, we synthesize the available evidence to determine to what extent proactive vascular access monitoring affects the incidence of AV access thrombosis and abandonment compared with clinical monitoring. METHODS We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, and SCOPUS) and sought references from experts, bibliographies of included trials, and articles that cited included studies. Two reviewers independently assessed trial quality and extracted data. We used random effects meta-analysis to estimate the pooled relative risk (RR) and 95% confidence interval (CI) across studies and conducted subgroup analyses to explain heterogeneity. The I(2) statistic was used to assess heterogeneity of treatment effect among trials. RESULTS Nine studies (1363 patients) compared a strategy of surveillance vs clinical monitoring. A vascular intervention to maintain or restore patency was provided to both groups if needed. Surveillance followed by intervention led to a nonsignificant reduction of the risk of access thrombosis (RR, 0.82; 95% CI, 0.58-1.16; I(2) = 37%) and access abandonment (RR, 0.80; 95% CI, 0.51-1.25; I(2) = 60%). Three studies (207 patients) compared the effect of vascular interventions vs observation in patients with abnormal surveillance result. Vascular interventions after an abnormal AV access surveillance led to a significant reduction of the risk of access thrombosis (RR, 0.53; 95% CI, 0.36-0.76) and a nonsignificant reduction of the risk of access abandonment (RR, 0.76; 95% CI, 0.43-1.37). CONCLUSION Very low quality evidence yielding imprecise results suggests a potentially beneficial effect of AV access surveillance followed by interventions to restore patency. This inference, however, is weak and will require randomized trials of AV access surveillance vs clinical monitoring for rejection or confirmation.

Patient Survival After Kidney Transplantation: Relationship to Pretransplant Cardiac Troponin T Levels

Assessing cardiovascular (CV) risk pretransplant is imprecise. We sought to determine whether cardiac troponin T (cTnT) relates to patient survival posttransplant. The study includes 603 adults, recipients of kidney transplants. In addition to cTnT dobutamine stress echography and coronary angiography were done in 45% and 19% of the candidates respectively. During 28.4 ± 12.9 months 5.6% of patients died or had a major cardiac event. cTnT levels were elevated (>0.01 ng/ml) in 56.2% of patients. Elevated cTnT related to reduced event‐free survival (hazard ratio (HR) = 1.81, CI 1.33–2.45, p < 0.0001) whether those events occurred during the first year or beyond. This relationship was statistically independent of all other variables tested, including older age, reduced left ventricular ejection fraction (EF) and delayed graft function. cTnT levels allowed better definition of risk in patients with other CV risk factors. Thus, event‐free survival was excellent in older individuals, patients with diabetes, low EF and those with preexisting heart disease if their cTnT levels were normal. However, elevated cTnT together with another CV risk factor(s) identified patient with very poor survival posttransplant. Pretransplant cTnT levels are strong and independent predictors of posttransplant survival. These results suggest that cTnT is quite helpful in CV risk stratification of kidney transplant recipients.

Cardiac Troponin T Before and After Kidney Transplantation: Determinants and Implications for Posttransplant Survival

Pretransplant cardiac troponin T(cTnTpre) is a significant predictor of survival postkidney transplantation. We assessed correlates of cTnT levels pre‐ and posttransplantation and their relationship with recipient survival. A total of 1206 adult recipients of kidney grafts between 2000 and 2010 were included. Pretransplant cTnT was elevated (≥0.01 ng/mL) in 56.4%. Higher cTnTpre was associated with increased risk of posttransplant death/cardiac events independent of cardiovascular risk factors. Elevated cTnTpre declined rapidly posttransplant and was normal in 75% of recipients at 3 weeks and 88.6% at 1 year. Elevated posttransplant cTnT was associated with reduced patient survival (cTnT3wks: HR = 5.575, CI 3.207–9.692, p < 0.0001; cTnT1year: 3.664, 2.129–6.305, p < 0.0001) independent of age, diabetes, pretransplant dialysis, heart disease and allograft function. Negative/positive predictive values for high cTnT3wks were 91.4%/50% respectively. Normalization of cTnT posttransplant was associated with reduced risk. Variables related to elevated cTnT posttransplant included pretransplant diabetes, older age, time on dialysis, high cTnTpre and lower graft function. Patients with delayed graft function and those with GFR < 30 mL/min at 3 weeks were more likely to have an elevated cTnT3wks and remained at high risk. When allografts restore sufficient kidney function cTnT normalizes and patient survival improves. Lack of normalization of cTnT posttransplant identifies a group of individuals with high risk of death/cardiac events.

Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease

BACKGROUND The autosomal dominant polycystic kidney disease (APDKD) genotype influences renal phenotype severity but its effect on polycystic liver disease (PLD) is unknown. Here we analyzed the influence of genotype on liver phenotype severity. METHODS Clinical data were retrieved from electronic records of patients who were mutation screened with the available liver imaging (n = 434). Liver volumes were measured by stereology (axial or coronal images) and adjusted to height (HtLV). RESULTS Among the patients included, 221 (50.9%) had truncating PKD1 (PKD1-T), 141 (32.5%) nontruncating PKD1 (PKD1-NT) and 72 (16.6%) PKD2 mutations. Compared with PKD1-NT and PKD2, patients with PKD1-T had greater height-adjusted total kidney volumes (799 versus 610 and 549 mL/m; P < 0.001). HtLV was not different (1042, 1095 and 1058 mL/m; P = 0.64) between the three groups, but females had greater HtLVs compared with males (1114 versus 1015 mL/m; P < 0.001). Annualized median liver growth rates were 1.68, 1.5 and 1.24% for PKD1-T, PKD1-NT and PKD2 mutations, respectively (P = 0.49), and remained unaffected by the ADPKD genotype when adjusted for age, gender and baseline HtLV. Females <48 years of age had higher annualized growth rates compared with those who were older (2.65 versus 0.09%; P < 0.001). After age 48 years, 58% of females with severe PLD had regression of HtLV, while HtLV continued to increase in males. CONCLUSIONS In contrast to the renal phenotype, the ADPKD genotype was not associated with the severity or growth rate of PLD in ADKPD patients. This finding, along with gender influence, indicates that modifiers beyond the disease gene significantly influence the liver phenotype.