Impact of donor kidney biopsy on kidney yield and posttransplant outcomes.

Procurement biopsy is performed to determine kidney quality, but evidence supporting such association is poor. We investigated the impact of glomerulosclerosis percentage (GS%) on kidney yield and patient outcomes. Information on deceased kidney donors from July 1, 2017, to June 30, 2019, was collected. Association between GS% and kidney yield (number of kidneys procured per donor) and posttransplant graft and patient outcomes were studied. Maximal GS% and minimal GS% were calculated to determine the relationship between GS% and kidney yield; minimal GS% only for correlation with posttransplant outcomes. Multinomial logistic regression and Cox models with least absolute shrinkage and selection operator were used to analyze the association of GS% with kidney yield and posttransplant outcomes, respectively. The kidney yield was 1.63 when maximal GS% and minimal GS% were <5%, but was 0.88 when both GS% were >20%. The hazard ratio for graft failure 1 year after transplant was 1.05 when minimal GS% was 16% to 20%, but was 1.3 for GS% of >20%. The hazard ratio for mortality increased from 1 to 1.2 when minimal GS% reached >20%. In summary, higher GS% was associated with lower kidney yield and inferior posttransplant outcomes. Incorporation of GS% into Scientific Registry of Transplant Recipients models may reassure organ procurement organizations and transplant centers pursuing kidneys with relatively high GS% levels, thereby reducing kidney discard rates.

Are dialysis patients too frail to exercise?

Clinical manifestations of functional and morphological muscular abnormalities in dialysis patients are muscle weakness and low exercise capacity, possibly leading to a sedentary life style with low physical activity. Low cardiorespiratory fitness and muscle atrophy and weakness contribute to the development of frailty and affect patients' ability to physically navigate their environment. While many dialysis patients may appear too frail to participate in moderate-to-vigorous aerobic exercise training, those who can complete such programs appear to derive substantial benefit. Less vigorous aerobic exercise, resistance training, and alternative forms of exercise can also be beneficial. Most patients on dialysis are not too frail to perform resistance exercise of adequate intensity to achieve increases in muscle size and strength, therefore, frailty should not be considered a contraindication to exercise.

Polycystic kidney disease and cancer after renal transplantation.

Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease (PKD), is a disorder with characteristics of neoplasia. However, it is not known whether renal transplant recipients with PKD have an increased risk of cancer. Data from the Scientific Registry of Transplant Recipients, which contains information on all solid organ transplant recipients in the United States, were linked to 15 population-based cancer registries in the United States. For PKD recipients, we compared overall cancer risk with that in the general population. We also compared cancer incidence in PKD versus non-PKD renal transplant recipients using Poisson regression, and we determined incidence rate ratios (IRRs) adjusted for age, sex, race/ethnicity, dialysis duration, and time since transplantation. The study included 10,166 kidney recipients with PKD and 107,339 without PKD. Cancer incidence in PKD recipients was 1233.6 per 100,000 person-years, 48% higher than expected in the general population (standardized incidence ratio, 1.48; 95% confidence interval [95% CI], 1.37 to 1.60), whereas cancer incidence in non-PKD recipients was 1119.1 per 100,000 person-years. The unadjusted incidence was higher in PKD than in non-PKD recipients (IRR, 1.10; 95% CI, 1.01 to 1.20). However, PKD recipients were older (median age at transplantation, 51 years versus 45 years for non-PKD recipients), and after multivariable adjustment, cancer incidence was lower in PKD recipients than in others (IRR, 0.84; 95% CI, 0.77 to 0.91). The reason for the lower cancer risk in PKD recipients is not known but may relate to biologic characteristics of ADPKD or to cancer risk behaviors associated with ADPKD.

A Pkd1-Fbn1 genetic interaction implicates TGF-ß signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-ß binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-ß signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-ß signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-ß. Our data link the interaction of two important diseases to a fundamental signaling pathway.

The medicinal use of water in renal disease.

Although water is essential for life, its use for medicinal purposes is not universally accepted. We performed a comprehensive review of the literature to determine where the evolving state of knowledge lies regarding the benefits of water as a therapy for renal diseases. In the past two decades, water has emerged as a potential therapeutic agent in nephrolithiasis, chronic kidney disease (CKD), and polycystic kidney disease (PKD) in particular. In nephrolithiasis, the benefit of drinking water beyond that demanded by thirst is a cornerstone of therapy for both primary and secondary disease. In CKD, recent observational studies suggest a strong, direct association between preservation of renal function and fluid intake. In PKD, increased water intake slows renal cyst growth in animals via direct vasopressin suppression, and pharmacologic blockade of renal vasopressin-V2 receptors has recently been shown to be efficacious in retarding cyst growth in PKD patients. Although evidence is lacking to support increased water intake in the general population, available evidence indicates that individuals who are at risk for nephrolithiasis as well as those with CKD and PKD may benefit from 3 to 4 l of urine output each day, a level of excretion that is likely to be safe.

Impact of Donor Liver Macrovesicular Steatosis on Deceased Donor Yield and Posttransplant Outcome.

BACKGROUND: The Scientific Registry of Transplant Recipients (SRTR) had not traditionally considered biopsy results in risk-adjustment models, yet biopsy results may influence outcomes and thus decisions regarding organ acceptance. METHODS: Using SRTR data, which includes data on all donors, waitlisted candidates, and transplant recipients in the United States, we assessed (1) the impact of macrovesicular steatosis on deceased donor yield (defined as number of livers transplanted per donor) and 1-y posttransplant graft failure and (2) the effect of incorporating this variable into existing SRTR risk-adjustment models. RESULTS: There were 21 559 donors with any recovered organ and 17 801 liver transplant recipients included for analysis. Increasing levels of macrovesicular steatosis on donor liver biopsy predicted lower organ yield: ≥31% macrovesicular steatosis on liver biopsy was associated with 87% to 95% lower odds of utilization, with 55% of these livers being discarded. The hazard ratio for graft failure with these livers was 1.53, compared with those with no pretransplant liver biopsy and 0% to 10% steatosis. There was minimal change on organ procurement organization-specific deceased donor yield or program-specific posttransplant outcome assessments when macrovesicular steatosis was added to the risk-adjustment models. CONCLUSIONS: Donor livers with macrovesicular steatosis are disproportionately not transplanted relative to their risk for graft failure. To avoid undue risk aversion, SRTR now accounts for macrovesicular steatosis in the SRTR risk-adjustment models to help facilitate use of these higher-risk organs. Increased recognition of this variable may also encourage further efforts to standardize the reporting of liver biopsy results.

A CD3+ count-based thymoglobulin induction regimen permits delayed introduction of calcineurin inhibitors in kidney transplantation.

BACKGROUND: Withholding calcineurin inhibitors (CNIs) can be considered when graft function is inadequate following kidney transplantation (KT). Thymoglobulin (rATG) can be used to prevent acute rejection while CNIs are being withheld. Here, we report our results of a novel CNI-sparing induction protocol, which utilizes a CD3+ cell count-based rATG treatment regimen when delayed graft function (DGF) develops in the immediate postoperative period. METHODS: In a cohort of 153 consecutive deceased-donor KT recipients, all received a single intraoperative dose of basiliximab; 84 subsequently developed DGF and therefore received rATG (rATG+ group), while 69 demonstrated immediate graft function and received CNIs (rATG- group). RESULTS: In the rATG+ group, mean duration of therapy was 8.5±6.0 d, permitting CNI initiation to be delayed until postoperative day 10.3±6.2. Cumulative dose of rATG was only 5.1±4.5 mg/kg while targeting CD3+ counts of ≤30 cells/mm3. CD3+ counts were reduced to a mean of 16.7±17.0 cells/mm3 during therapy. At one yr, patient and graft survival rates were 97.6% and 92.9%, respectively, while the frequency of infections and malignancies were not significantly increased compared to the rATG- group. CONCLUSION: A unique induction regimen successfully delayed CNI initiation by using modest doses of rATG to deplete CD3+ cells, while yielding excellent long-term graft outcome without increased risk of infection or malignancy.

Sexual Dysfunction Among Patients With Chronic Kidney Disease.

Sexual dysfunction (SD) in patients with chronic kidney disease is common and negatively impacts quality of life. SD is often under-appreciated because of overall low awareness. Diagnosis of SD is subjective, and manifestations can be different among men and women. Causes of SD are multifactorial, including psychological disorders, hormonal imbalances, vascular disorders, neurological disorders, and medication side effects. Non-specific approaches to improving sexual function include addressing underlying psychological disorders, promoting lifestyle modifications, optimizing dialysis care, and facilitating successful kidney transplantation, whereas treatment with phosphodiesterase type 5 inhibitor, hormone replacement, and mechanical devices can be offered to patients with specific indications.

Association of Slow Graft Function with Long-Term Outcomes in Kidney Transplant Recipients.

BACKGROUND Whether slow graft function (SGF) represents an intermediate phenotype between immediate graft function (IGF) and delayed graft function (DGF) in kidney transplant recipients is unknown. MATERIAL AND METHODS In a retrospective cohort analysis of 1,222 kidney transplant recipients, we classified patients as having IGF, SGF, and DGF using two different schemas. SGF was defined as serum creatinine (Cr) ≥3.0 mg/dL by postoperative day 5 in Schema 1, and in Schema 2, SGF was defined as Cr >1.5 mg/dL plus a creatinine reduction ratio <20% between postoperative days 1 and 3. A complementary log-log model was used to examine the association of graft function with graft survival and patient survival. RESULTS Mean age of study patients was 51.5±13.3 years, 59.9% were male, and 66.7% were white. In Schema 1, SGF and DGF were associated with comparable increases in risk of graft failure compared to IGF (hazard ratio (HR) 1.46, 95% confidence intervals (CI) 1.02-2.10 for SGF and HR 1.56, CI 1.11-2.22 for IGF); estimates were similar for Schema 2 (HR 1.52, CI 1.05-2.20 for SGF and HR 1.54, CI 1.10-2.17 for IGF). However, for mortality, outcomes for SGF were similarly to IGF, both SGF and IGF were associated with lower risk relative to DGF (HR 0.54, CI 0.36-0.80 for SGF in Schema 1; HR 0.58, CI 0.39-0.85 for SGF in Schema 2). CONCLUSIONS These findings suggest that SGF may be a marker for graft failure but not for mortality, and SGF may therefore represent a phenotype separate from IGF and DGF.

Old versus new: Progress in reaching the goals of the new kidney allocation system.

As demand for kidney transplant continues to grow faster than organ availability, appropriate allocation of deceased donor kidneys is an acute priority. Increased longevity matching is central to this effort. To foster equitable and efficient utilization of deceased donor kidneys, a new kidney allocation system (KAS) was introduced in December 2014. Major achievements in the 1year after its implementation include a reduction in age-mismatch and an increase in access to transplant for historically disadvantaged candidates, such as those with very high levels of panel-reactive antibodies or long dialysis duration. However, the rate of discarded kidneys has not decreased, and an increase in A2/A2B transplants has yet to be realized. Organs are now shared more often at the regional and national levels, with some regions experiencing an increase in transplants and other a decrease. While implementation of the KAS has been associated with the attainment of key goals, the kidney transplant community must remain vigilant about potential untoward consequences, including reductions in transplant rates for specific groups such as pediatric patients. More time is required before firm conclusions about the long-term effects of the new KAS can be rendered.

Donor-specific antibodies present at the time of kidney transplantation in immunologically unmodified patients increase the risk of acute rejection.

BACKGROUND: Human leukocyte antigens (HLA) class II donor-specific antibodies (DSAs) are associated with microcirculation inflammation, transplant glomerulopathy and ultimately graft loss. There is however no data on allograft outcomes in deceased donor kidney transplant recipients who have not received any desensitization prior to transplantation. METHODS: We prospectively evaluated the association of HLA DR and DQ DSAs on rejection and short-term graft survival in patients who did not receive desensitization prior to transplantation. On the basis of their cumulative strength of HLA DR and/or DQ DSA, the patients were dichotomized into: 1) median fluorescence intensity (MFI)<1000 and 2) MFI≥1000. RESULTS: In the two year study period, 50 consecutive patients with HLA DR and/or DQ sensitization were transplanted in our two centers. Post-transplantation, the incidence of acute rejection was significantly greater in the MFI≥1000 group (35%; 8/22) compared to the MFI<1000 group (7%; 2/28) (p<0.001). There were two graft losses, both in the MFI≥1000 group. CONCLUSION: The strength of DR and/or DQ DSA at the time of renal transplantation influences the risk of rejection in non-desensitized recipients with HLA class II DSA.

Water prescription in autosomal dominant polycystic kidney disease: a pilot study.

BACKGROUND AND OBJECTIVES: In animal models of polycystic kidney disease, the ingestion of large amounts of water promotes diuresis by suppressing plasma levels of arginine vasopressin (AVP) and renal levels of cAMP, slowing cyst progression. Whether simple water ingestion is a potential therapeutic strategy for individuals with autosomal dominant polycystic kidney disease (ADPKD) is unknown. In this study, a simple method to quantify the amount of water to achieve a specific mean urine osmolality target in patients with ADPKD was developed and tested. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In eight ADPKD patients eating typical diets, osmolality and volume were measured in 24-hour urine collections. The amount of additional ingested water required daily to achieve a mean urine osmolality of 285 ± 45 mosm/kg was determined. Participants were instructed to distribute the prescribed water over waking hours for each of 5 days. Blood chemistries, 24-hour urine collections, BP, and weight were measured before and after the period of supplemental water intake. RESULTS: Five patients achieved the 285 mosm/kg urine target without difficulty. Mean urine osmolality decreased and mean urine volume increased; serum sodium, weight, and BP were unchanged. Daily osmolar excretion remained constant, indicating a stable ad lib dietary intake of solutes and protein over the 2-week study period. CONCLUSIONS: The amount of additional water needed to achieve a urine osmolality target can be approximated from the urine osmolar excretion in ADPKD patients eating typical diets, providing a quantitative method to prescribe supplemental water for such individuals.

Implications of donor disseminated intravascular coagulation on kidney allograft recipients.

BACKGROUND AND OBJECTIVES: Disseminated intravascular coagulation (DIC) is common in deceased kidney donors and is considered a relative contraindication to donation. The significance of donor DIC on recipient kidney function is poorly understood. Additionally, the significance of thrombocytopenia in recipients of kidneys from DIC-positive donors is understudied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a retrospective cohort of 162 kidney transplants, the presence of DIC in donors, the occurrence of thrombocytopenia in recipients, and risk factors for delayed or slow graft function (DGF/SGF) were assessed. The effects of DIC donor status on DGF/SGF in the study sample as a whole, and of thrombocytopenia on DGF/SGF in recipients of DIC-positive kidneys specifically, were examined using multiple logistic regression. RESULTS: DIC donor status was not associated with occurrence of DGF/SGF, but thrombocytopenia was significantly associated with DIC-positive donor status (P=0.008). Thrombocytopenia was independently associated with DGF/SGF only in the recipients of DIC-positive kidneys (P=0.005). Patient and graft survival at 1 year were not affected by donor DIC status or by thrombocytopenia status. CONCLUSIONS: Donor DIC was not associated with short-term suboptimal graft function, defined as DGF/SGF, nor with long-term patient or graft survival. However, thrombocytopenia appears to portend DGF/SGF in recipients of DIC-positive kidneys and may be a clinical sign on which the basis of therapeutic decisions could be undertaken.

Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension.

BACKGROUND: We previously reported that renal cortical cyclooxygenase (COX-2) expression increased following subtotal nephrectomy, and chronic treatment with a selective COX-2 inhibitor, SC58236, reduced proteinuria and retarded the development of glomerulosclerosis. The present studies were designed to examine the effects of COX-2 inhibition in a model of diabetic nephropathy. METHODS: Rats were divided into three groups: control, diabetic (streptozotocin-induced diabetic animals with superimposed DOCA/salt hypertension; right nephrectomy and DOCA treatment), and treated (administration of the selective COX-2 inhibitor, SC58236, to a subset of diabetic/DOCA/salt rats). Insulin was administered to maintain blood glucose in the 200 to 300 mg/dL range. RESULTS: Systolic blood pressure in the two diabetic groups was elevated within one week and remained elevated until sacrifice at six weeks (control, 108 +/- 2 mm Hg; diabetic, 158 +/- 4 mm Hg; treated, 156 +/- 7 mm Hg). When measured at six weeks, immunoreactive COX-2 expression in the renal cortex of the diabetic rats was 2.5 +/- 0.3-fold of control animals (N = 7). Immunohistochemical localization indicated increased expression in macula densa and surrounding cortical thick ascending limb of Henle (cTALH). The COX-2 inhibitor decreased COX-2 expression in diabetic rats to 1.3 +/- 0.1-fold control. In addition, SC58236 decreased expression of PAI-1 (diabetic vs. treated, 3.2 +/- 0.5 vs. 1.7 +/- 0.2-fold control, N = 7, P < 0.05), vascular endothelial growth factor (VEGF; 2.0 +/- 0.2 vs. 1.2 +/- 0.2; N = 7, P < 0.05), fibronectin (2.4 +/- 0.3 to 1.3 +/- 0.1; N = 7, P < 0.05) and transforming growth factor-beta (TGF-beta; 2.1 +/- 0.2 vs. 1.3 +/- 0.2; N = 7, P < 0.05). Proteinuria at six weeks was decreased in the SC58236-treated rats (149 +/- 8 vs. 92 +/- 8 mg/24 h; N = 7, P < 0.01). The mesangial sclerosis index, defined as increases in extracellular matrix within the mesangial space, was determined at six weeks; the control group had an index of 0.06 +/- 0.01, the diabetic group was 2.7 +/- 0.04 and the treated group was 0.6 +/- 0.03 (P < 0.0001 compared to the diabetic group). CONCLUSIONS: These results suggest that in an experimental model of diabetes and hypertension, inhibition of COX-2 expression decreases potential mediators of glomerular and tubulointerstitial injury and also decreases biochemical, functional and structural markers of renal injury.