Prospective Kidney Donors Research Articles

Glomerular filtration rate what is the rationale and justification of normalizing GFR for body surface area?

80 ml/min/1.73 m 2 and 75 ml/min/1.73 m 2 respectively for a 55-year-old prospective kidney donor. The 9.1 ml/min difference between the absolute GFR and the GFR indexed for BSA prompted further consideration of the validity and rationale for indexing GFR to BSA. There are several formulae that estimate BSA from measures of height and weight in the literature and in this man, with height 1.65 m and weight 86 kg, we found that the application of six previously published height–weight formulae to estimate BSA [3–8] gave a range of indexed GFR of 72.0 to 77.9 ml/min/1.73 m 2 . In other words, indexing GFR for BSA in this man reduced the value for GFR by between 9.1 and 15 ml/min depending on which BSA formula was used and greatly influenced the decision about his suitability as a kidney donor. Several authors have questioned the validity of indexing GFR for BSA and the generalizability of the supporting studies from the last century to the increasingly obese population [9–12]. The purpose of this review is to explore the physiological plausibility of using BSA as an appropriate way to index measured GFR, the validity of the methods that

Accepting prospective kidney donors with asymptomatic urinary abnormalities: Are we shooting in the dark?

Accepting prospective kidney donors with asymptomatic urinary abnormalities: Are we shooting in the dark?

Occult Nephrolithiasis in Prospective Kidney Donors: A Source for Hematuria

In their report, Koushik et al. (1) identified causes for persistent, asymptomatic, microscopic hematuria in a series of 512 prospective kidney donors in Minnesota. Fourteen of these had hematuria, of whom two had a urinary tract infection, one had multiple renal arteries, one a renal cyst, two normal kidney biopsies (one with renal cysts), and eight had biopsies with varied findings. We wish to highlight another important cause for hematuria in this population: occult nephrolithiasis. In all, 192 prospective kidney donors underwent evaluation at our center between February 2002 and May 2005 that included renal imaging. Seventy-six were eventually excluded for medical or surgical reasons. Out of those excluded, eight were found to have one or more kidney stones by ultrasound (two patients) or computed tomography (CT) scan (six patients). No patient gave a previous history of hypertension, nephrolithiasis or visible hematuria. Kidney size was 11±0.7 cm, with average asymmetry 0.3 cm. Stone size varied from 1 to 7 mm in diameter with up to three in one kidney; two patients had bilateral stones. Ureteric stones, bladder stones, or renal cysts were not detected in any patient. Their age was 43±13 years, three were male, four were white, three Asian, and one Native American and BMI was 27.1±3. Their fasting and two-hour post 75 gram glucose load blood sugar levels and hemoglobin were normal, but one patient had hypercholesterolemia. All patients had a normal 24-hour urine protein excretion rate or random urine microalbumin-to-creatinine ratio, as well as a normal 24-hour urine creatinine clearance (120±21 ml/min). Although the average blood pressure was normal (124/70 mm Hg by 24-hour ambulatory BP monitoring), seven were nocturnal nondippers. Four out of these eight patients had persistent microscopic hematuria. Seven patients provided a 24-hour urine collection to evaluate for metabolic abnormalities favorable to stone formation. Three had significant hypercalciuria (9.2–16.3 mmol/d, N 0–7.5), three had hypocitraturia (0.4–1.0 mmol/d, N >1.6), two had hyperuricosuria (5.5–5.9 mmol/ d, N 2–4), and two had hyperoxaluria (508–814 μmol/d, N 190–480). Three patients had more than one metabolic abnormality. Nephrolithiasis can cause microscopic hematuria without other clinical manifestations. In one study (2), 195 of 906 subjects with asymptomatic hematuria were found to have renal calculi by ultrasound. Twenty-four of these subsequently required urological management (2). Hypercalciuria and hyperuricosuria may also cause microscopic hematuria in adults, which can resolve with appropriate therapy such as thiazides and allopurinol (3). In addition, hypercalciuria, hyperuricosuria, and nephrolithiasis are associated with thin basement membrane nephropathy, a glomerular disease (4). Although we typically decline these individuals as kidney donors, we agree with Koushik et al. that clear guidelines for managing young and healthy adults with microscopic hematuria are lacking. In summary, in addition to the list provided by Koushik et al., occult nephrolithiasis should be considered as a cause for microscopic hematuria in the prospective kidney donor population. This will enable appropriate diagnosis, counseling, referral, and management of these individuals independent of the transplantation process. G.V. Ramesh Prasad Philip A. McFarlane Division of Nephrology Department of Medicine University of Toronto Toronto, Ontario, Canada Renal Transplant Program St. Michael’s Hospital Toronto, Ontario, Canada

Persistent, Asymptomatic, Microscopic Hematuria in Prospective Kidney Donors

Asymptomatic, microscopic hematuria is seen in 8-21% of the general population, has a good prognosis, and is generally not an indication for kidney biopsy. But whether it should preclude kidney donation is unclear. Of 512 consecutive prospective donors, 14 (2.7%) continued to have asymptomatic, microscopic hematuria over 1 month. If the medical history, physical examination, and computerized tomographic angiography were unremarkable, and if they still wished to donate, a kidney biopsy was performed. In two prospective donors, hematuria resolved after treatment for urinary tract infection; two others declined donation and were referred to their primary care provider. Kidney biopsy in the remaining 10 showed: two normal; four thin basement membrane nephropathy (TBMN); one nonhomogeneous basement membrane abnormalities; one IgA nephropathy, 5 of 16 glomeruli globally sclerotic; one in a patient with a family history of Schimke's Syndrome, 7 of 30 glomeruli globally sclerotic; and one TBMN and early hypertensive changes without systemic hypertension. Only 4 of the 10 who underwent kidney biopsy donated (two normal, two TBMN). Kidney abnormalities are common in young, otherwise healthy, prospective kidney donor candidates with persistent, asymptomatic, microscopic hematuria. A kidney biopsy is often abnormal and aids in the decision-making process.

Body mass index is associated with altered renal hemodynamics in non-obese healthy subjects

Weight excess is associated with increased renal risk. Data in overt obesity suggest a role for altered renal hemodynamics. Whether body mass index (BMI) is also relevant to renal function in non-obese subjects is unknown. We studied the relation between BMI and renal hemodynamics in 102 healthy, non-obese (BMI <30 kg/m2) subjects [59 males, 43 females, mean age 39 (18-69) years] in a post-hoc analysis of subjects evaluated as prospective kidney donors or as healthy volunteers in renal hemodynamic studies. Mean (+/-SD) BMI was 24.0 +/- 2.8 kg/m2, mean arterial pressure (MAP) 93 +/- 11 mm Hg, glomerular filtration rate (GFR, iothalamate clearance) 111 +/- 19 mL/min/1.73 m2, effective renal plasma flow (ERPF, hippuran clearance) 458 +/- 108 mL/min/1.73 m2, FF (GFR/ERPF) 0.25 +/- 0.04. On univariate analysis, BMI correlated negatively with ERPF/1.73 m2 body surface area (BSA) (r=-0.46; P < 0.001), GFR/1.73 m2 BSA (r=-0.24, P= 0.013) and positively with FF (r= 0.45, P < 0.001), and age (r= 0.47, P < 0.001). On multivariate analysis both BMI and age were independent predictors of ERPF/1.73 m2 BSA (negative) and FF (positive, all P < 0.05). Age was the only predictor of GFR/1.73 m2 BSA (negative). Analyzed for renal function indexed for height (h), BMI correlated negatively with ERPF/h (r=-0.274, P= 0.005), but not with GFR/h (r= 0.13, P= 0.899). On multivariate analysis both BMI (positive) and age (negative) were independent predictors for GFR/h (both P < 0.001). Age was the only predictor for ERPF/h (negative). Predictors for FF (BMI and age, both positive) were by definition unaltered. The impact of BMI on renal function is not limited to overt obesity, as in subjects with BMI <30 kg/m2 a higher BMI is associated with higher FF, that is, a higher GFR relative to ERPF. This suggests an altered afferent/efferent balance and higher glomerular pressure (i.e., a potentially unfavorable renal hemodynamic profile) that may confer enhanced renal susceptibility when other factors, such as hypertension or diabetes are superimposed.

Living donors: options and meanings.

Both the phenomenologic study by Lennerling and colleagues and the case study by Dwyer raise interesting moral issues. Lennerling et al.'s finding that prospective kidney donors understood their decisions as "the only option" invites further examination into how donors understand this phrase, because, as ordinarily construed, it seems false; other options do exist for patients undergoing renal failure. Dwyer's case challenges our moral understanding of transplantation at an even deeper level, presenting us with a possible example of an instance of organ provision, not as a "gift" to the recipient, but as a "shield" for a third party. There is no existing moral consensus that surgeons or other health professionals may gravely worsen the health and threaten the lives of healthy people on the grounds that someone other than their patients may be benefited.

Induction of immune alterations and successful renal transplantation with a simplified method of donor-specific blood transfusion.

We developed a new and simplified donor-specific blood transfusion (DSBT) protocol for prospective kidney transplant recipients from one-haplotype-mismatched related donors. Prospective kidney donors gave 450 ml of blood in a quad-pack unit, and the blood was stored in a blood bank. Twenty-five patients were transfused with 100 ml of the respective donor's whole blood at 1, 8, and 15 days after its storage. After DSBT, only three (12%) developed donor-specific lymphocytotoxic antibodies. Following DSBT, donor-specific mixed lymphocyte culture (MLC) was significantly suppressed, without any accelerated (secondary-type) response in early MLC. In addition, sera obtained after DSBT also suppressed donor-specific MLC significantly. Sixteen recipients subsequently received a kidney transplant from the donor, and all had functioning grafts at three months, but one lost the graft thereafter (graft survival rate: 94% at 12 months). This study indicates that (1) 100 ml of stored whole-blood DSBT three times at weekly intervals is a practical, less immunizing, and effective approach to enhance graft survival in recipients of a one-haplotype-mismatched graft; and (2) immune consequences of DSBT include induction of donor-specific cellular and humoral adaptive responses that might be conducive to successful graft outcome.

Effect of Blood Transfusion on Renal Allograft Survival: Immunologic Considerations

DETERMINATION of immunologic factors relevant to renal allograft survival may allow identification of high risk potential recipients who will experience poor allograft survival. These factors may include histocompatibility matching, determination of recipient anti donor immune responsiveness and finally, the general, nonspecific state of recipient immunocompetence. Well matched cadaveric grafts, in recipients with no known donor alloantigen pre sensitivity , may be rejected because the recipient is a high-risk strong immune responder. 1 We cannot yet determine whether these recipients are strong responders to all alloantigens or whether they are presensitized to a donor antigen not tested for, such as kidney specific or enothelial antigens. For recipients of living related donor (LRD) organs a high donor specific mixed lymphocyte culture (MLC) stimulation index (SI) is a risk factor. As has been reported by the UCSF transplant group and others, graft survival, in haplotype matched related renal allograft recipients with a high MLC SI, is comparable to the results of cadaveric transplantation with a l-yr graft survival rate of 45%-55%.2 The data imply that high MLC responders are at risk when they receive the LRD organ. Potential recipients of LRD grafts, with strong donor specific MLC responsiveness, may be relegated to receive a cadaveric allograft as one alternative. A second alternative is to be transplanted with the LRD graft and to be treated with adjunctive immunosuppressive medications postoperatively, such as antithymocyte globulin (ATG) or cyclosporin A, to dampen the potentially destructive immune response. These medications may modify the immune response and improve strong immune responder graft survivals so that they are comparable to weak MLC LRD graft survivals. 1 However, the patient morbidity and mortality attendant with the use of these medications is still to be determined. A third alternative is for the strong MLC responder recipient to be treated with purposeful blood transfusions from the prospective kidney donor prior to transplant. Transfused recipients who do not respond by developing deleterious anti-Tor B antibodies can be transplanted and a clear cut positive influence on allograft survival has been reported. 3•4 However, before recommending wholesale donor specific transfusions (DST) of strong responder recipients of LRD grafts, a detailed examination of the protocol is necessary to determine the appropriateness of such a protocol to other patients and to compare these data with data obtained from random donor transfusions in cadaveric transplantation. It is possible that consideration of these points may result in an appreciation of what has been accomplished, arid more significantly, may direct our attention to improving graft survival for those positive responders who are excluded from receiving an LRD graft following transfusion and for recipients of cadaveric grafts. Since initiating the DST protocol, the UCSF transplant team has reported that approximately 30% of the transfused patients developed donor specific anti-T or B antibodies, which was taken as a contraindication to transplantation. Recipients v.'ith a negative cross-match who received a kidney from their blood donors had approximately a 95% graft survival. 3.4 As indicated, the mechanism(s) operative in the DST protocol may be: (1) selection and segregation of responders from nonresponders by antibody development; or (2) modification of the host immune response by the development of suppressor cells or the development of antiidiotypic (enhancing) antibodies. As reported, approximately 65% of the patients receiving DST also received random donor transfusions. 3 It is now widely accepted that increasing numbers of random pretransplant transfusions can improve cadaveric allograft survival. 5 Moreover, haplotype matched recipients of LRD

Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfuions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

Plasma levels and hepatic extraction of renin and aldosterone in alcoholic liver disease

Arterial plasma levels and hepatic extraction of renin and aldosterone (ALDO) were measured in 24 patients with alcoholic liver disease and in 14 normal subjects being evaluated as prospective kidney donors. Patients with liver disease had higher plasma concentrations and lower fractional hepatic extractions of both renin and ALDO than the normal subjects. The quantity of renin extracted by the liver was highly correlated with plasma renin in both normal subjects and patients. Plasma ALDO concentration was positively correlated with plasma renin (p < 0.001) but not with serum sodium, potassium or albumin concentration, inferior vena cava pressure, corrected hepatic venous wedge pressure, plasma volume or sulfobromophthalein storage or transport. Sixteen patients were restudied after one month. Six had received 40 mg/day of prednisolone, and the remaining 10 had received a placebo. Neither group had a change in plasma volume, corrected hepatic venous wedge pressure, plasma concentration or hepatic extraction of renin or ALDO. Serum albumin concentration increased and inferior vena cava pressure decreased with prednisolone therapy. These studies document high plasma levels and impaired hepatic extraction of renin and ALDO in patients with liver disease that are not corrected by short-term prednisolone therapy.

Prelusive skin grafts in live-donor kidney transplantation.

In recipients receiving oral azathioprine (50 mg. a day) the fate of skin grafts taken from live human prospective kidney donors correlates well with the outcome of kidney transplantation from the same donors. Correlation between the fate of skin grafts and HL-A serotyping is not nearly as good except in the case of complete HL-A identity. There is little or no correlation between the mixed-lymphocyte-culture test and the fate of skin grafts and the outcome of kidney transplantation. When the degree of compatibility does not exceed one haplotype the results of live human-kidney transplantation can be significantly improved if the fate of a preliminary skin graft from the prospective kidney donor is used as an index.