Sequential genetic testing of living-related donors for inherited renal disease to promote informed choice and enhance safety of living donation.

Living kidney donors (LKDs) with a family history of renal disease are at risk of kidney disease as compared to LKDs without such history suggesting that some LKDs may be pre-symptomatic for monogenic kidney disease. LKDs with related transplant candidates whose kidney disease was considered genetic in origin were selected for genetic testing. In each case, the transplant candidate was first tested to verify the genetic diagnosis. A genetic diagnosis was confirmed in 12 of 24 transplant candidates (ADPKD-PKD1: 6, ALPORT-COL4A3: 2, ALPORT-COL4A5: 1: nephronophthisis-SDCCAG8: 1; CAKUT-HNF1B and ADTKD-MUC1: 1 each) and 2 had variants of unknown significance (VUS) in phenotype-relevant genes. Focused genetic testing was then done in 20 of 34 LKDs. 12 LKDs screened negative for the familial variant and were permitted to donate; seven screened positive and were counseled against donation. One, the heterozygous carrier of a recessive disorder was also cleared. Six of seven LKDs with a family history of ADPKD were under 30 years and in 5, by excluding ADPKD, allowed donation to safely proceed. The inclusion of genetic testing clarified the diagnosis in recipient candidates, improving safety or informed decision-making in LKDs.

Urine free light chains as a novel biomarker of acute kidney allograft injury.

BACKGROUND: We evaluated urine free light chains (FLC) as a potential biomarker for acute kidney allograft injury (AKAI). METHODS: Urine κ and λ FLC were compared with urine ß-2 microglobulin (ß2-M), retinol-binding protein (RBP), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and microalbuminuria (MAB) in biopsy-confirmed acute rejection (AR) and acute tubular necrosis (ATN). Healthy volunteers (normal) and transplant recipients with normal allograft function (control) were used as references. RESULTS: Compared with control or normal group (N = 15), urine FLC, MAB, and RBP were higher in ATN (N = 29) and AR (N = 41) groups (p < 0.05). There was no difference in KIM-1, NGAL, or ß2-M between four groups. In the AR group, urine κFLC demonstrated the highest predictive value with sensitivity of 95.12% and specificity of 87.5% (p < 0.0001). Urine κFLC also performed best with a sensitivity of 96.55% and specificity of 93.33% (p < 0.0001) in the ATN group. The area under the receiver operating characteristic (ROC) curves (AUC) by ROC analysis is greatest in urine RBP (100%) and FLC (99%), and lowest in KIM-1 (53.5%), then NGAL (71.5%) in the AR group. The AUC is also greatest in urine FLC (100%) and RBP (99%), and lowest in urine KIM-1 (55.6%) and NGAL (69.9%) in the ATN group. CONCLUSIONS: Urine FLC appears sensitive for both AR and ATN, and it may be a novel AKAI biomarker.

Antibody induction therapy in adult kidney transplantation: A controversy continues.

Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection (AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody (thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody (basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in most patients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.

Metabolic bone diseases in kidney transplant recipients.

Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients.