Bing Ho

Rituximab Failed to Improve Nephrotic Syndrome in Renal Transplant Patients With Recurrent Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) recurs in 30% of patients with FSGS receiving a first renal transplant and in over 80% of patients receiving a second transplant after a recurrence. Recurrence often leads to graft failure. The pathogenesis remains unknown and may involve a circulating permeability factor that initiates injury to the glomerular capillary. There are anecdotal reports of pediatric patients with posttransplant lymphoproliferative disorder (PTLD) and recurrent FSGS who have had remission of proteinuria after treatment with rituximab. These observations have prompted speculation that B cells may play a role in the pathogenesis of recurrent FSGS. We report four consecutive adult patients with early recurrent FSGS refractory or dependent on plasmapheresis who received rituximab (total dose 2000–4200 mg). None of the patients treated with rituximab achieved remission in proteinuria, and one patient experienced early graft loss. In these four adult renal transplant patients with recurrent FSGS, rituximab failed to diminish proteinuria.

Effects of aging on glomerular function and number in living kidney donors

To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.

Perception versus reality ?: Virtual crossmatch - How to overcome some of the technical and logistic limitations

The goal of this work was to evaluate concordance between (a) actual flow cytometric crossmatch (FCXM) that is performed by the OPO laboratory servicing our transplant center and (b) virtual XM (vXM) prediction based on antibody identification by solid‐phase methods performed in our laboratory.

Outcomes and Native Renal Recovery Following Simultaneous Liver-Kidney Transplantation

With the increase in patients having impaired renal function at liver transplant due to MELD, accurate predictors of posttransplant native renal recovery are needed to select candidates for simultaneous liver–kidney transplantation (SLK). Current UNOS guidelines rely on specific clinical criteria for SLK allocation. To examine these guidelines and other variables predicting nonrecovery, we analyzed 155 SLK recipients, focusing on a subset (n = 78) that had post‐SLK native GFR (nGFR) determined by radionuclide renal scans. The 77 patients not having renal scans received a higher number of extended criteria donor organs and had worse posttransplant survival. Of the 78 renal scan patients, 31 met and 47 did not meet pre‐SLK UNOS criteria. The UNOS criteria were more predictive than our institutional criteria for all nGFR recovery thresholds (20–40 mL/min), although at the most conservative cut‐off (nGFR ≤ 20) it had low sensitivity (55.3%), specificity (75%), PPV (67.6%) and NPV (63.8%) for predicting post‐SLK nonrecovery. On multivariate analysis, the only predictor of native renal nonrecovery (nGFR ≤ 20) was abnormal pre‐SLK renal imaging (OR 3.85, CI 1.22–12.5). Our data support the need to refine SLK selection utilizing more definitive biomarkers and predictors of native renal recovery than current clinical criteria.

Imprecision of Creatinine-Based GFR Estimates in Uninephric Kidney Donors

BACKGROUND AND OBJECTIVES To ensure long-term safety of living kidney donors, it is now recommended that they be followed for at least 2 years after donation and that serum creatinine levels be monitored. Such levels are often subjected by clinical laboratories to estimating equations and are reported as estimated GFR (eGFR). The accuracy of such equations in uninephric living donors has yet to be validated. This is especially important in older living donors, who often have senescence-related depression of GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared urinary creatinine clearance, four-variable Modification of Diet in Renal Disease estimating equation (eGFR), and the recently reported CKD-EPI GFR estimating equation with true GFR measured by the urinary iothalamate clearance (iGFR) in 64 subjects after kidney donation. RESULTS Creatinine clearance overestimated iGFR. Both creatinine-based estimating equations were poorly correlated with and underestimated iGFR. More than half of kidney donors had eGFR <60 ml/min per 1.73 m(2) after donation, a level that categorized them as having stage 3 chronic kidney disease by our current laboratory reporting, whereas only 25% had iGFR <60 ml/min per 1.73 m(2). This misclassification disproportionately affected older donors age > or =55 years, of whom 80% had eGFR <60 ml/min per 1.73 m(2). Neither significant albuminuria nor hypertension was observed. CONCLUSIONS The current practice of reporting eGFR after donation commonly leads to a misclassification of chronic kidney disease, particularly in older donors. To ensure long-term well-being of living kidney donors, more precise estimates of GFR are required, particularly among older potential donors.

Post hoc analyses: after the facts.

Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.

Simulation modeling of the impact of proposed new simultaneous liver and kidney transplantation policies.

Background Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. Methods A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the United Network for Organ Sharing policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. Results When 1-week pretransplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pretransplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. This change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist because of the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. Conclusion Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment.

Comparative effectiveness of liver transplant strategies for end-stage liver disease patients on renal replacement therapy.

There are complex risk‐benefit tradeoffs with different transplantation strategies for end‐stage liver disease patients on renal support. Using a Markov discrete‐time state transition model, we compared survival for this group with 3 strategies: simultaneous liver‐kidney (SLK) transplantation, liver transplantation alone (LTA) followed by immediate kidney transplantation if renal function did not recover, and LTA followed by placement on the kidney transplant wait list. Patients were followed for 30 years from the age of 50 years. The probabilities of events were synthesized from population data and clinical trials according to Model for End‐Stage Liver Disease (MELD) scores (21‐30 and >30) to estimate input parameters. Sensitivity analyses tested the impact of uncertainty on survival. Overall, the highest survival rates were seen with SLK transplantation for both MELD score groups (82.8% for MELD scores of 21‐30 and 82.5% for MELD scores > 30 at 1 year), albeit at the cost of using kidneys that might not be needed. Liver transplantation followed by kidney transplantation led to higher survival rates (77.3% and 76.4%, respectively, at 1 year) than placement on the kidney transplant wait list (75.1% and 74.3%, respectively, at 1 year). When uncertainty was considered, the results indicated that the waiting time and renal recovery affected conclusions about survival after SLK transplantation and liver transplantation, respectively. The subgroups with the longest durations of pretransplant renal replacement therapy and highest MELD scores had the largest absolute increases in survival with SLK transplantation versus sequential transplantation. In conclusion, the findings demonstrate the inherent tension in choices about the use of available kidneys and suggest that performing liver transplantation and using renal transplantation only for those who fail to recover their native renal function could free up available donor kidneys. These results could inform discussions about transplantation policy. Liver Transpl 20:1034‐1044, 2014.

Acute Renal Failure and Severe Hypertension from a Page Kidney Post-Transplant Biopsy

Page kidney refers to a clinical picture characterized by acute onset of hypertension due to external compression of the kidneys from hematoma, tumor, lymphocele, or urinoma. Hypertension is believed to result from renin-angiotensin-aldosterone activation triggered by renal hypoperfusion and microvascular ischemia. Renal failure, in addition to hypertension, may occur in the setting of a single functional kidney or a diseased contralateral kidney. We report a case of a patient who had a transplant kidney biopsy complicated by a subcapsular perinephric hematoma. The patient presented with an acute increase in blood pressure and a rapid rise in serum creatinine following a transplant kidney routine biopsy. He underwent emergent evacuation of the perinephric hematoma, with consequent decrease of his blood pressure and return of serum creatinine back to his baseline level. Early recognition and rapid intervention are needed in order to correct hypertension and reverse acute renal failure in Page kidney occurring in renal transplant recipients.

Should Both UNOS and CMS Provide Regulatory Oversight in Kidney Transplantation

Since publication of the Centers for Medicare and Medicaid Services (CMS) Conditions of Participation Final Rule in 2007, there has been dual regulation of transplant centers by the Organ Procurement and Transplantation Network (OPTN) contractor the United Network for Organ Sharing (UNOS) and CMS. Herein, we summarize the environment leading to the development of the present regulatory framework and identify significant and unintended consequences of the current regulations.