Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

Estimating risks of de novo kidney diseases after living kidney donation.

De novo post donation renal diseases, such as glomerulonephritis or diabetic nephropathy, are infrequent and distinct from the loss of GFR at donation that all living kidney donors experience. Medical findings that increase risks of disease (e.g. microscopic hematuria,borderline hemoglobin A1C) often prompt donor refusal by centers. These risk factors are part of more comprehensive risks of low GFR and end-stage renal disease (ESRD) from kidney diseases in the general population that are equally relevant. Such data profile the ages of onset, rates of progression, prevalence and severity of loss of GFR from generically characterized kidney diseases. Kidney diseases typically begin in middle age and take decades to reach ESRD, at a median age of 64. Diabetes produces about half of yearly ESRD and even more lifetime near-ESRD. Such data predict that (1) 10- to 15-year studies will not capture the lifetime risks of post donation ESRD; (2)normal young donors are at demonstrably higher risk than normal older candidates; (3) low-normal predonation GFRs become risk factors for ESRD when kidney diseases arise and (4) donor nephrectomy always increases individual risk. Such population-based risk data apply to all donor candidates and should be used to make acceptance standards and counseling more uniform and defensible.

'Normal for now' or 'at future risk': a double standard for selecting young and older living kidney donors.

Transplant centers medically evaluate potential living kidney donors in part to determine their baseline remaining lifetime risk for end stage renal disease (ESRD). If baseline risk is increased by the presence of a risk factor for ESRD, donation is often refused. However, as only about 13% of ESRD occurs in the general population by age 44, a normal medical evaluation cannot be expected to significantly reduce the 7% lifetime risk for a 'normal' 25-year-old black donor or the 2-3% risk for a similar white donor. About half of newly diagnosed ESRD in the United States occurs by age 65, and about half of that is from diabetic nephropathy, which takes about 25 years to develop. Therefore, the remaining baseline lifetime risk for ESRD is significantly lower in the normal, nondiabetic 55-year-old donor candidate. Some older donors with an isolated medical abnormality such as mild hypertension will be at lower or about the same overall baseline lifetime risk for ESRD as are young 'normal' donor candidates. Transplant centers use a 'normal for now' standard for accepting young donors, in place of the long-term risk estimates that must guide selection of all donors.

Glomerular hemodynamics in rats with chronic sodium depletion. Effect of saralasin.

In chronic sodium depletion the glomerular filtration rate may be reduced, and alterations in proximal tubular function may contribute to the maintenance of antinatriuresis. Measurements were made by micropuncture technique in superficial nephrons of the Munich-Wistar rat of (a) the determinants of glomerular filtration rate, (b) peritubular capillary hydrostatic and oncotic pressure, and (c) proximal tubular fractional and absolute reabsorption in both a control group (group 1, n = 12) and a group of chronically sodium-depleted rats (group 2, n = 12). Single nephron filtration rate (sngfr) was 37.2+/-1.2 in group 1 and 31.6+/-1.0 nl/min/g kidney wt (P < 0.05) in group 2. Of the factors potentially responsible for the observed reduction in sngfr, there was no change in systemic oncotic pressure or the transglomerular hydrostatic pressure gradient. Sngfr was lower in group 2 because of both a reduced single nephron plasma flow (rpf) (128+/-6 vs. 112+/-5 nl/min per g kidney wt, P < 0.05) and additionally to a decrease in the glomerular permeability coefficient, L(p)A, from a minimum value of 0.105+/-0.012 in group 1 to 0.054+/-0.01 nl/s per g kidney wt per mm Hg (P < 0.01) after chronic sodium depletion. There was no difference in fractional proximal tubular reabsorption between group 1 and group 2. Absolute proximal reabsorption (APR) was reduced from 20.8+/-1.3 in group 1 to 16.3+/-0.9 nl/min per g kidney wt in group 2. The role of angiotensin II (AII) in maintaining glomerular and proximal tubular adaptations to chronic sodium depletion was assessed in subsets of groups 1 and 2 by the infusion of the AII antagonist Saralasin at a rate of 1 mug/kg per min. In group 1 rats, Saralasin had no effect on sngfr, rpf, or L(p)A, because animals remained at filtration pressure equilibrium. In group 2 rats, AII blockade was associated with an increase in sngfr from 31.6+/-1.0 to 37.1+/-1.7 nl/min per g kidney wt (P < 0.01). Rpf increased during Saralasin infusion solely as a result of a decrease in afferent arteriolar resistance from 21.7+/-2.3 to 15.2+/-2.3 10(9) dyn-s-cm(-5) (P < 0.01). Saralasin infusion did not affect the reduced L(p)A in group 2, as L(p)A remained 0.056+/-0.02 nl/s per g kidney wt per mm Hg and rats remained disequilibrated. In spite of the increase in sngfr in group 2, AII antagonism further decreased APR to 13.1+/-1.5 (P < 0.01). Distal delivery therefore, increased from a control value of 15.3+/-1.3 to 24.3+/-1.5 nl/min per g kidney wt (P < 0.01). In conclusion, both a decrease in L(p)A and a reduction in rpf were major factors mediating the decrease in glomerular filtration rate observed in chronic sodium depletion. Saralasin infusion revealed a significant effect of AII on rpf and afferent arteriolar resistance in chronic sodium depletion, but no effect of AII on either efferent arteriolar resistance or the decrease in L(p)A could be demonstrated. Saralasin had no effect in rats that were not chronically sodium depleted. In group 2 rats AII antagonism reduced APR even though sngfr increased, suggesting an influence of AII on proximal reabsorption. The marked changes observed during Saralasin infusion in the chronically sodium-depleted rat reveal important modifying effects of endogenously generated AII on both the glomerulus and proximal tubule.

Studies on the tubulo-glomerular feedback system in the rat. The mechanism of reduction in filtration rate with benzolamide.

The specific mechanism whereby superficial nephron glomerular filtration rate (sngfr) is reduced after the administration of benzolamide, a carbonic anhydrase inhibitor with a primary inhibitory effect in the proximal tubule, have been examined by measuring pertinent pressures, flows, and glomerular permeabilities in the hydropenic Munich-Wistar rat, a strain with surface glomeruli. Because benzolamide decreases absolute proximal reabsorptive rate, the rate of delivery of tubular fluid to the distal nephron should be at least transiently increased and may reduce sngfr by activating the tubulo-glomerular feedback system. Sngfr fell from 29.2+/2.0 to 2.1+/3.1 nl/min (P less than 0.01) after benzolamide (group 1), a percentage reduction equal to kidney glomerular filtration rate and similar to sngfr obtained in collections from distal tubules. Separate studies (group 2) revealed that if transient increases in distal nephron delivery were prevented by insertion of a long oil block in proximal tubules before control, the decrease in sngfr was prevented (30.3+/1.0 vs. 30.3+/1.8 nl/min, P greater than 0.9). In paired "unblocked" nephrons in the same rats, sngfr fell in group 2 (33.0+/1.0 vs. 25.2+/2.3 nl/min, P less than 0.01). In "blocked" nephrons in which sngfr reduction was prevented, the rate of fluid leaving the proximal tubule increased from 16.9+/ to 23.1+/1.0 nl/min (P less than 0.01). In group 1 studies in which sngfr fell and transient increases in flow out of the last segment of the proximal tubule (distal delivery) (approximately equal to 8 nl/min) were not prevented, steady-state distal delivery was unchanged by benzolamide (13.9+/1.1 vs. 14.2+/2.2 nl/min). Also, sngfr returned toward control, pre-benzolamide values, when a proximal oil block was placed for 15 min and the rate of distal delivery reduced after benzolamide administration, which suggests that this activation was reversible. These data suggest that activation of tubulo-glomerular feedback by transient increases in distal delivery was responsible for decreases in sngfr. Analysis of all determinants of glomerular ultra-filtration revealed that the efferent mechanism leading to reduced sngfr after benzolamide was decreased nephron plasma flow (101+/13 vs. 66+/13 nl/min, P less than 0.01). Hydrostatic pressure and the glomerular permeability coefficient did not contribute to reductions in sngfr with benzolamide. Because the rate of distal delivery remained constant in spite of large changes in both sngfr and absolute proximal reabsorptive rate, it is suggested that the rate of distal delivery may be the physiologic entity that is regulated by the tubulo-glomerular feedback system via alterations in sngfr.

Characteristics of the hematocrit response to continuous ambulatory peritoneal dialysis.

Markedly heterogeneous increases in hematocrit readings were noted in a group of nine patients who previously had undergone hemodialysis, none of whom had polycystic disease. They had been receiving continuous ambulatory peritoneal dialysis (CAPD) for at least one year. There was no correlation between change in Hct reading and serum urea nitrogen, creatinine, total protein, or albumin levels. Respective contributions of blood transfusions and venipuncture were likewise negligible. The increase in Hct reading in several patients was gradual and still ongoing at one year of CAPD. Other patients, two of whom had a decrease in transfusion requirement with CAPD, had either no increase in Hct reading or a small increase that was not sustained. A return to hemodialysis (or, in one case, discontinuation of all dialysis with partial return of renal function) lowered Hct readings in patients who had initially responded to CAPD. The individual response in Hct reading to CAPD maintenance therapy is highly variable and is not predictable from clinically available measurements.

Glomerular hemodynamics in moderate Goldblatt hypertension in the rat.

Glomerular hemodynamics were studied by micropuncture technique in the unclipped kidney in rats in which modest two kidney Goldblatt hypertension was maintained for 4 weeks and in normotensive controls. Both groups ingested less than 2 mEq Na+/day. In hypertensive rats at micropuncture, mean hydrostatic pressure was elevated both systematically (128 +/- 5 vs 113 +/- 3 mm Hg, p less than 0.05) and within glomerular capillaries (55 +/- 2 vs 48 +/- 1 mm Hg, p less than 0.05), resulting in an increase in the transglomerular hydrostatic pressure gradient (40 +/- 2 vs 33 +/- 1 mm Hg, p less than 0.05). The glomerular capillary permeability coefficient, however, was decreased in the hypertensive rats (0.063 +/- 0.017 vs 0.115 +/- 0.011 nl/s/g kw/mm Hg, p less than 0.05), resulting in no change in nephron filtration rate 38.9 +/- 2.3 vs 39.0 +/- 2.5 nl/min/g kw). Nephron plasma flow also remained unchanged (154 +/- 10 vs 140 +/- 7 ml/min/g kw). In separate studies in this model of hypertension, saralasin infusion demonstrated a peripheral effect of circulating angiotensin II which was increased over controls. Kidney mass and GFR were not different between clipped and unclipped kidneys. No consistent abnormalities were observed by light or electron microscopy either in glomeruli or in vessels in the unclipped kidney. This study demonstrates that glomerular hemodynamics may be altered early in the course of modest hypertension in this model without altering blood flow or filtration rate. The decrease in glomerular capillary area and/or permeability (LpA) in the hypertensive rats could be either a result of the increased effect of circulating angiotensin II or the direct effect of glomerular capillary hypertension.

Interpreting the fractional excretion of sodium.

In most normal subjects, the fractional excretion of sodium is usually less than 1 percent but may be raised with an increase in salt intake. In acutely azotemic patients, a low fractional excretion of sodium usually indicates a prerenal process that is responsive to volume repletion. However, such a low fractional excretion of sodium also can be seen with azotemia due to hepatic or cardiac failure, as well as acute glomerulonephritis, pigment nephropathy, contrast nephrotoxicity, polyuric renal failure associated with burns, acute obstruction, renal transplant rejection, and occasionally non-oliguric acute renal failure, none of which is a volume-responsive process. A fractional excretion greater than 1 percent in acutely azotemic patients usually indicates intrinsic renal injury, but is consistent with volume depletion in patients receiving diuretics or in some patients with chronic renal insufficiency. Similarly, a low quotient in acute renal parenchymal injury is usually interpreted to indicate widespread tubular integrity, but is consistent with several different pathophysiologic processes. The fractional excretion of sodium must be interpreted in light of the specific clinical setting and other laboratory data to be useful in patient management.

A technique for presenting risk and outcome data to potential living renal transplant donors.

BACKGROUND: Transplant centers have become increasingly interested in living donor kidney transplantation and have always had the obligation to counsel these donors fairly. Counseling techniques vary markedly among centers and can include overly qualitative or unintentional but covertly prescriptive presentation of risk and benefit. METHODS: We describe a simple technique using preprinted fields of stick figures for presenting important risk and benefit data to potential renal donors. We also suggest an approach to formulating basic statistics for donor counseling. RESULTS: Risk and benefit statistics can be presented visually and quantitatively in a way that minimizes the need for donor sophistication and also displays the "all or nothing" nature of adverse events in donor and recipient populations, as opposed to using of percentages or prescriptive phrases by the donor counselor. CONCLUSION: Such stick figure field counseling for living renal transplant donors accurately provides information to both donor and center, appropriately facilitates center impartiality, and may increase the center's and the donor's confidence in the counseling process.

Effect of daily oral vitamin D and calcium therapy, hypophosphatemia, and endogenous 1-25 dihydroxycholecalciferol on parathyroid hormone and phosphate wasting in renal transplant recipients.

Ten stable, normocalcemic renal transplant patients with good allograft function, hyperparathyroidism, and variable hypophosphatemia were treated for 2 to 9 months with oral calcium carbonate and replacement doses of vitamin D analogues. Parathyroid hormone levels (PTH) and renal phosphate wasting were not autonomous or fixed but decreased with therapy. Although serum 1-25(OH)2D3 levels could be shown to rise appropriately during oral vitamin D therapy and fall afterwards, a separate study in a larger group of patients showed no effect of elevated parathyroid hormone or hypophosphatemia to increase endogenous 1-25(OH)2D3 levels. Some 42% of patients with elevated carboxy-terminal PTH, had elevated N-terminal PTH, which was closely associated with more severe phosphate wasting. Aggressive oral calcium and vitamin D supplementation in certain normocalcemic renal transplant patients may decrease endogenous PTH levels, improve hypophosphatemia, and provide a physiologic increase in levels of 1-25(OH)2D3.

Pentoxifylline does not prevent the cytokine-induced first dose reaction following OKT3--a randomized, double-blind placebo-controlled study.

The use of OKT3 as an immunosuppressive agent is accompanied by increased cytokine production and constellation of side effects collectively termed cytokine release syndrome (CRS). Pentoxifylline (PTF) inhibits synthesis of some cytokines, and has been shown to attenuate CRS when administered before OKT3. In this double-blinded, placebo-controlled study, 46 renal allograft recipients were randomized to receive either PTF (800 mg q 8 hr for at least 24 h) p.o. or placebo, along with methylprednisolone (7 mg/kg), diphenhydramine, and acetaminophen, prior to beginning OKT3 as therapy for acute rejection. Patients were observed, and symptoms scored semiquantitatively. Despite the presence of therapeutic PTF levels (721 +/- 726 ng/ml), the frequency and severity of side effects (fever, chills, headache, neurocortical symptoms, dyspnea, nausea, vomiting, diarrhea) did not differ between treatment groups. Likewise PTF did not affect renal function or immunologic response to OKT3, with similar graft and patient survival in both groups. Plasma levels of TNF alpha, IFN gamma, IL-6, and IL-8 increased as predicted following OKT3 administration, without significant differences between PTF and placebo groups. In this controlled, multicenter trial, pretreatment with oral PTF was ineffective in attenuating OKT3-related CRS in renal allograft recipients.

Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action.

BACKGROUND: Intravenous gammaglobulin (i.v.IG) contains anti-idiotypic antibodies that are potent inhibitors of HLA-specific alloantibodies in vitro and in vivo. In addition, highly HLA-allosensitized patients awaiting transplantation can have HLA alloantibody levels reduced dramatically by i.v.IG infusions, and subsequent transplantation can be accomplished successfully with a crossmatch-negative, histoincompatible organ. METHODS: In this study, we investigated the possible use of i.v.IG to reduce donor-specific anti-HLA alloantibodies arising after transplantation and its efficacy in treating antibody-mediated allograft rejection (AR) episodes. We present data on 10 patients with severe allograft rejection, four of whom developed AR episodes associated with high levels of donor-specific anti-HLA alloantibodies. RESULTS: Most patients showed rapid improvements in AR episodes, with resolution noted within 2-5 days after i.v.IG infusions in all patients. i.v.IG treatment also rapidly reduced donor-specific anti-HLA alloantibody levels after i.v.IG infusion. All AR episodes were reversed. Freedom from recurrent rejection episodes was seen in 9 of 10 patients, some with up to 5 years of follow-up. Results of protein G column fractionation studies from two patients suggest that the potential mechanism by which i.v.IG induces in vivo suppression is a sequence of events leading from initial inhibition due to passive transfer of IgG to eventual active induction of an IgM or IgG blocking antibody in the recipient. CONCLUSION: I.v.IG appears to be an effective therapy to control posttransplant AR episodes in heart and kidney transplant recipients, including patients who have had no success with conventional therapies. Vascular rejection episodes associated with development of donor-specific cytotoxic antibodies appears to be particularly responsive to i.v.IG therapy.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Ethical selection of living kidney donors.

Renal transplant centers vary markedly in their rates of living donor kidney transplantation. Recent surveys also document marked differences among centers in both appreciation of medical risk for donation and what constitutes ethical donor selection. Because of this marked variability, some donors likely are being inappropriately denied or others are being inappropriately accepted. In addition to defensible donor education about risk and benefit, three fundamental obligations of the center are identified: (1) to recognize that it is often ethical to participate in acts of individual risk and sacrifice that are performed to benefit others; (2) to not deny transplantation without good reason to donors and recipients who apply to the center; and (3) to neutralize, but not overreact to, center self-interest, which stems from the professional benefits of transplantation and the center's desire to help potential transplant recipients. The basic medical facts surrounding donation must be understood by all parties as part of ethical decision making. Donor risk can be presented quantitatively using US Renal Data System data as a baseline. Confirmation of accurate donor understanding of risks, benefits, and alternatives is always a fundamental center obligation. Donors should not be rejected except for the general reasons we identify, and when these reasons do not seem to apply, the decision to deny transplantation should be reconsidered.

Kidney transplantation in the cyclosporine era.

Seventy-seven patients underwent transplantation, using a cyclosporine-prednisone immunosuppression protocol. No recipients died, and graft survival at one year was 100% for living related donor (LRD) recipients and 84% for cadaver donor (CD) recipients. Nineteen percent of locally harvested, flush-cooled kidney recipients required dialysis, whereas imported kidneys had a 66% dialysis rate. Infectious complications occurred in 17% of patients. Mean hospitalization was 12.8 days for LRD recipients and 13.6 days for CD recipients. Twenty-eight patients required 37 readmissions, mostly for treatment of rejection and infections. Total two-year cost for LRD transplants was +21,400; for CD transplants, +23,900.