Fig. 8.1
Survival probabilites of kidney donors from six large studies
Significant limitations regarding the selection of controls for comparison to carefully screened kidney donors have been a major concern regarding the long-term survival of kidney donors. It is possible that validity of studies addressing improved survival in kidney donors may reflect the overall excellent health of kidney donors, the meticulous medical screening and the use of general population controls as opposed to better matched controls.
Risk of Progression and Proteinuria
Garg et al. reported on 5,048 donors with a mean follow-up of 7 years post donation [20]. They demonstrated a pooled incidence of proteinuria of 12 % (95 % CI 8–16 %) and an average 24 h urine protein of 154 mg/dL. The pooled risk of albuminuria in 67 donors was 3.9 % (95 % CI 1.2–12.6 %) in comparison to controls. In regard to GFR, the level reported depended heavily on the proportion of missing data; studies with more data missing reported a larger decrement in GFR. The average GFR reported was 86 mL/min and 78.8 % of donors had a GFR >60 ml/min. Okamoto et al. showed that 3.1 % of their donors developed proteinuria and 0.7 % had a serum creatinine above 2 mg/dL [13]. Ibrahim et al. measured urinary albumin excretion rate and iohexol GFR (iGFR) in 255 randomly selected kidney donors [14]. Mean donor age was 41.1 ± 11.0 years at the time of donation and 53.2 ± 10.0 years at the time of GFR measurement. Women comprised 61.6 % of the donors and 98.8 % were white. Time since donation was 12.1 ± 9.2 years. Those donors <10 years from donation comprised 56.9 %; 21.6 % of the donors were 11–20 years from donation and 15.3 % were 21–30 years from donation. Only 6.2 % were 31–45 years from donation. Serum creatinine at the time of donation was 0.90 ± 0.2 mg/dL and eGFR was 84.0 ± 13.8 mL/min/ 1.73 m2. iGFR measurement revealed serum creatinine of 1.10 ± 0.20 mg/dL and eGFR was 63.7 ± 11.9 mL/min/1.73 m2 at the time of donation. Donors with the greatest compensatory increase in eGFR were more likely to be younger at the time of donation. The majority of donors (85.5 %) had an iGFR >60 mL/min/1.73 m2 with only 0.8 % having an iGFR of 30–45 mL/min/1.73 m2 and 14.5 %, 46–60 mL/min/1.73 m2, and none had a measured iGFR <30 mL/min/1.73 m2. A total of 87.3 % were normoalbuminuric, 11.5 % were microalbuminuric, and only 1.2 % were macroalbuminuric. None of the donors had both a measured GFR <45 mL/min/1.73 m2 and albuminuria. The results of this study are reassuring in that previously published studies may have demonstrated changes in proteinuria due to the method of assessment and of adjustment for BMI. The risk of having a GFR <60 mL/min/1.73 m2 was associated with older age, OR = 1.15 (95 % CI, 1.08–1.21), p < 0.0001; higher BMI, OR = 1.12 (95 % CI, 1.02–1.23); and female gender (p = 0.03). Time from donation was associated with the development of albuminuria with an OR = 1.12 (95 % CI, 1.05–1.20), p = 0.0004, and women were less likely to develop albuminuria [14].
These findings may not be representative of other ethnic groups, however. Parasuraman et al. demonstrated a greater loss of eGFR in 54 African American donors compared to Caucasian donors 2–3 years after donation (39.8 vs. 30.4 mL/min, p = 0.001) [21]. Predonation eGFR <100 mL/min and age at time of donation were associated with eGFR <60 mL/min in African American donors. With over 50 years of experience in kidney donation, the question regarding whether an increased risk of ESRD after donation lingers. This has stemmed mainly from the lack of routine follow up of kidney donors, analogous to what we do for recipients, and perhaps due to the commonly held belief that donors do indeed do well and are not at increased risk for ESRD or excess mortality. Three large single center studies, two large US registry-based studies and a more recent study from Canada have affirmed the belief regarding any adverse outcomes for kidney donors [1–6]. In addition, kidney donors do not appear to be at high risk for the complications seen in those with CKD such as fractures, kidney stones or acute kidney injury requiring dialysis [7, 8]. The study of Mjoen et al. challenges our convictions regarding donor outcomes in the domains of ESRD, overall mortality and also cardiovascular mortality [9]. Before commenting specifically about this study, it is worth pointing out two other recent observations that have also suggested increased risk of ESRD in donors. Muzaale et al. matched a cohort of 96,217 US donors who underwent nephrectomy between 1994–2011 with NHANES controls matched on age, gender, race, education, BMI, systolic blood pressure and also smoking history [10]. ESRD incidence at 15 years was 0.31 % vs. 0.04 % in controls; a 15 fold higher risk. This excess risk was consistent across different racial groups. More recently, Reese et al. matched 3,368 donors who were above 50 years of age at the time of donation to healthy controls drawn from the National Institutes of Health sponsored Health and Retirement Study. After a mean follow up of 7.8 years, 20 donors developed ESRD; a 7.4 fold increase in risk compared to controls. Both groups, however, enjoyed a similar survival. The study of Mjoen et al. is at great odds with all other previous studies as it is the first study to ever demonstrate both excess risk of ESRD and mortality in kidney donors [9]. In this study 1901 donors were matched with 32,621 healthy controls and follow up duration was 15.1 years in donors and 24.9 years in controls. Donors incurred a 30 % increase in risk of death, a 40 % increase risk of death from cardiovascular disease and an over an 11 fold increase in the risk of ESRD. In total, 9 donors developed ESRD. These data should be considered seriously as an ideal study to really answer the question of ESRD and mortality risk is yet to be done as single center data has longer follow up but less events and registry based data has more events but are certainly plagued by their short follow up.
Does Donation Place the Kidney Donor at Higher Cardiovascular Risk?
The association of reduced renal function as a consequence of donor nephrectomy and cardiovascular disease without the clustering of known risk factors that are common in CKD is unknown. Go et al. and many others reported an inverse relationship in GFR and hazard ratio of death and cardiovascular disease [22]. Donor nephrectomy and loss of glomerular mass as a result of surgery may not impart similar risk on kidney donors, however. Mjøen et al. followed 2,269 Norwegian donors for a median of 14.3 years and found that overall mortality, as well as cardiovascular mortality, was lower in donors than the general population matched for age and gender [15]. Garg et al. reported on long-term outcomes with healthy matched controls. Using registry data beginning in 1991 and applying extensive exclusion criteria, the authors attempted to select for the “healthiest” segment of the population in Ontario, Canada. A total of 2,028 kidney donors were matched to population controls with exhaustive exclusion criteria applied. Prior conditions that would have otherwise eliminated kidney donation were excluded as controls. Through diagnostic and procedural codes for visits related to hypertension, cancer, cardiovascular disease, pulmonary disease, liver disease, and rheumatologic and genitourinary disease, the authors were able to include patients as controls representing a potentially healthier control group. They also were able to obtain data on the number of physician visits as a method of establishing access to care. This criterion resulted in exclusion of approximately 85 % of the population in question. The remaining controls were matched to living donors in a 10:1 ratio. Median follow-up was 6.5 years with a maximum of 17.7 years of follow-up time. Using outcomes of both first cardiovascular event and mortality, the observed event rates were lower in donors. In addition, there appeared to be no difference in major cardiovascular event in both donors and controls when censored for death. Together, these studies provide compelling data to show that survival in donors is excellent, when compared to carefully selected controls.
Special Donor Situations
Older Kidney Donors
While it is known that there is some, though not universal, loss of kidney function with aging, the consequences of donor nephrectomy in the elderly are unknown. Efforts to expand the live donor kidney pool have included use of “nonideal” donors including those with hypertension, increased body mass, and older age. Studies reviewing the use of donors aged greater than 70 years old have yielded mixed results. Some studies have suggested that these particular allografts perform as well as ones from younger donors but others have shown increased rates of chronic allograft dysfunction. Berger et al. analyzed a large cohort of data from the Scientific Registry of Transplant Recipients (SRTR), that included older donors, predominantly women, with increased prevalence of hypertension, and more often white. The authors compared graft loss and death in a competing risk model. The 1-, 5-, and 10-year risks of graft failure among recipients of kidneys from live donors greater than 70 years of age were 7.4, 14.9, and 33.3 %, whereas the 1-, 5-, and 10-year graft failure rates from live donors between the ages 50 and 59 years old were 5.0, 12.0, and 21.6 %. Importantly, graft failure rates of those recipients of older donors were similar to non-ECD donors. These results were significant in that there were higher rates of allograft failure from donors ≥70 years of age in comparison to matched controls ages 50–59 years old. Interestingly there was no difference in graft failure rates for donors ≥65 years old [23].
Obesity
As the prevalence of obesity increases, the number of obese candidate donors is likely to increase as well. The association between obesity and end-stage kidney disease in non-donors has been demonstrated. Screening over 175,000 subjects in California over a period of 1964–1973, Hsu et al. demonstrated that there is an increasing association with obesity and end-stage kidney disease beginning at a BMI >25 kg/m2, with those subjects whose BMIs ≥35 kg/m2 having the highest relative risk of ESKD at 4.39 (95 % CI; 3.38–5.70) [24]. In addition to the association of obesity with various health consequences, there are also significant structural and functional consequences to the kidney [25]. Data from Kambham et al. reveal a possible increase in glomerular volume and findings of focal segmental glomerulosclerosis [26].
There are surgical considerations as well. Heimbach et al. demonstrated that laparoscopic donor nephrectomy to be generally safe; however donors with BMI >35 kg/m2 may experience both slightly longer operative times and higher percentage of procedure related surgical outcomes. In addition, obese donors demonstrated no difference in renal function or the prevalence of albuminuria at 6–12 months [27]. In a small, single-center study, O’Brien et al. reviewed the outcomes of seven donor nephrectomies in morbidly obese patients (BMI >40 kg/m2). There did not appear to be any significant differences in mean operation time, blood loss, or hospital stay. There was also no significant changes in kidney function during follow-up (mean 20 months) [28]. Young et al. performed a systematic review of kidney donors with isolated medical abnormalities (IMA). Their analysis included information from ten studies on outcomes in obese kidney donors. Only two of the ten studies reviewed included long-term follow-up and the information reported regarding GFR decline was conflicting [29].
Hypertension
Hypertension is a risk factor for end-stage kidney disease. In addition, inadequately controlled blood pressure is associated with adverse cardiovascular events. Current recommendations require clinic blood pressure evaluation of potential donors on two separate occasions. Textor et al. evaluated patients undergoing donor nephrectomy between January 2001 and December 2002 [3]. Only 24 of the 148 living donors reviewed were found to be hypertensive after approximately 10 months of follow-up. There was no change in ambulatory blood pressure monitoring while awake, and blood pressure in hypertensive donors actually improved by 10 mmHg systolic and 5 mmHg diastolic blood pressure with both non-pharmocologic and drug therapy. Although starting at a lower estimated GFR, there was no effect of blood pressure for predicting GFR before and after nephrectomy in hypertensive donors, adjusted for age [3]. In addition there was no difference in protein excretion on hypertensive donors. There is a paucity of data regarding long-term follow-up of hypertensive kidney donors likely related to the exclusion of candidates with hypertension, and while these results are encouraging, it is important to remember that this is a highly selected population of patients with no evidence of proteinuria, generally preserved GFR, and only have modest hypertension. Young and colleagues reported on the significant heterogeneity including the definitions of hypertension used as well as length of follow-up in hypertensive kidney donors [29]. Of the long-term follow-up studies, one demonstrated an increase in serum creatinine of 14 μmol/L in hypertensive patients versus normotensive patients. One study reported on blood pressure assessment 1 year post donation revealing that there was a decrease in systolic and diastolic blood pressure of 5 and 6 mmHg in hypertensive donors [29].
These findings have significant implications in the evaluation of possible kidney donors. In most transplant centers, donors with hypertension are generally excluded donation however donors with well-controlled hypertension may be considered for kidney donation. Importantly, there appear to be a large number of patients who may have elevated clinic blood pressure alone. In a recent study of 178 potential kidney donors utilizing ambulatory blood pressure monitoring, 62 % of those patients characterized as having hypertension by clinical assessment were found to have “white-coat hypertension” [30]. In addition, approximately 17 % of donors with normal clinic blood pressure were found to have “masked” hypertension [30].
Recommendations from the Amsterdam Forum on the Care of the Live Kidney Donor regarding hypertension include [31]:
1.
Patients with a blood pressure >140/90 by ambulatory blood pressure should generally not be accepted as donors; the preferred method of measurement is ambulatory blood pressure monitoring particularly in those aged >50 years and/or with high office blood pressure readings.
2.
Those candidate donors with controlled hypertension may be considered if age >50 years, GFR ≥80 mL/min, and no evidence of proteinuria defined as urinary albumin of <30 mg/day.
3.
Donors with hypertension should be regularly followed up by a physician.
Nephrolithiasis
Potential donors with evidence of bilateral nephrocalcinosis on imaging of the abdomen and those with a known history of kidney stones that have high recurrence potential such as cystine stones, hyperoxaluria-related stones, renal tubular acidosis, or infectious stones are generally excluded from donation. Subjects with a history of a single kidney stone in the absence of the previously mentioned conditions may be considered for donation. Those donors with asymptomatic nephrolithiasis during evaluation may be allowed to donate in the presence of a favorable urinary stone profile, as well as favorable stone size profile, namely, <15 mm. Recently, Rule et al. reviewed the association between symptomatic stone formers and CKD using a population-based historical cohort and matched controls. Using both diagnostic codes and increased creatinine values for a period of ≥3 months as criteria, they demonstrated a 51–68 % increased risk for CKD by diagnosis codes and a 25–44 % increased risk for CKD using creatinine-based criteria [32]. Furthermore, this increased risk of development of CKD was not explained by comorbidities including diabetes, hypertension, and obesity [32]. An association between nephrolithiasis and ESKD was recently demonstrated as well. El-Zoghby et al. demonstrated that an increased risk of ESKD in stone formers was observed over a 9-year period after adjustment for diabetes, hypertension, hyperlipidemia, gout, and CKD with an HR of 2.09; (95 % CI 1.45–3.01) [33]. Therefore, accepting those with stones as kidney donors should be considered when other options are exhausted.
Malignancy
As part of the screening process for kidney donation, screening for a history of malignancy in the donor as well as a family history of malignancy is performed. Candidate donors should undergo age- and gender-appropriate malignancy screening tests. This includes a chest X-ray, flexible sigmoidoscopy, or colonoscopy for those above 50. Mammography and a pelvic exam for females above the age of 20 should also be done. If the donor has a history of malignancy, oncologic evaluation may be considered. Importantly, a prior history of malignancy may exclude kidney donation in certain circumstances. Those donors with a history of melanoma, testicular cancer, hematologic malignancy, renal cell carcinoma, choriocarcinoma, bronchial cancer, breast cancer, or monoclonal gammopathy should generally be excluded from donation unless 2–5 years of remission has elapsed. Prior history of treated or cured malignancy, thereby decreasing potential transmission to the recipient including early-stage colon cancer, nonmelanoma skin cancer, or carcinoma in situ of the cervix, may be considered for donation.
Hematuria
Workup for microscopic hematuria in donors is similar to the general population. Urine dipstick testing should be performed on two occasions to confirm the presence of microscopic hematuria. Positive results should be confirmed with analysis of the urinary sediment. Evidence of dysmorphic red cells, as well as proteinuria, casts, or decreased kidney function may be an indication of a glomerular pathology warranting further workup and potential kidney biopsy.
While current recommendations for workup of hematuria include a full urologic workup and screening for malignancy, Loo et al. used risk factors for the development of urothelial malignancy to develop a risk index as a means to stratify patients as high or low risk for malignancy detection [34]. Using a prospective cohort of 2,630 patients evaluated for hematuria, 2.1 % had a neoplasm detected and 1.9 % had histopathologic confirmation of a urothelial tract malignancy. Predictive factors including age >50 years, recent gross hematuria, and male gender were used to develop a Hematuria Risk Index. The risk index was then validated in 1,784 patients. Of the patients identified as low risk (32 %), 0.2 % had a detected neoplasm. Fourteen percent were identified as high risk, with 11.1 % found to have a malignancy [34]. The results indicate that extensive testing and additional cost may be avoided through use of the proposed risk index. Persistent microscopic hematuria (>3 months duration) may be present in up to 3 % of the general population and may have important implications in the development of ESKD. In over one million Israeli adults screened for entry into military service, Vivante et al. demonstrated an increased risk of ESKD. Adjusting for age, sex, paternal country of origin, year of enrollment, BMI, and BP at baseline revealed a hazard ratio of 18.5 (95 % CI, 12.4–27.6) [35]. ESKD attributed to glomerular disease for individuals with isolated microscopic hematuria occurred with incidence rates of 19.6 versus 0.55 per 100,000 person-years (HR: 32.4, 95 % CI, 18.9–55.7).
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Urologic Issues in the Renal Transplant Patient
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