Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood

Mutations in HNF1B are responsible for a dominantly inherited disease with renal and nonrenal consequences, including maturity-onset diabetes of the young (MODY) type 5. While HNF1B nephropathy is typically responsible for bilateral renal cystic hypodysplasia in childhood, the adult phenotype is poorly described. To help define this we evaluated the clinical presentation, imaging findings, genetic changes, and disease progression in 27 adults from 20 families with HNF1B nephropathy. Whole-gene deletion was found in 11 families, point mutations in 9, and de novo mutations in half of the kindred tested. Renal involvement was extremely heterogeneous, with a tubulointerstitial profile at presentation and slowly progressive renal decline throughout adulthood as hallmarks of the disease. In 24 patients tested, there were cysts (≤5 per kidney) in 15, a solitary kidney in 5, hypokalemia in 11, and hypomagnesemia in 10 of 16 tested, all as characteristics pointing to HNF1B disease. Two patients presented with renal Fanconi syndrome and, overall, 4 progressed to end-stage renal failure. Extrarenal phenotypes consisted of diabetes mellitus in 13 of the 27 patients, including 11 with MODY, abnormal liver tests in 8 of 21, diverse genital tract abnormalities in 5 of 13 females, and infertility in 2 of 14 males. Thus, our findings provide data that are useful for recognition and diagnosis of HNF1B disease in adulthood and might help in renal management and genetic counseling.     

HNF1B-associated clinical phenotypes: the kidney and beyond

Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer. The most commonly identified mutation, in approximately 50 % of patients, is an entire gene deletion occurring in the context of a 17q12 chromosomal microdeletion that also includes several other genes. Some of the associated phenotypes, especially the neurologic ones, appear to occur only in the context of this microdeletion and thus may not be directly linked to HNF1B. Here we review the spectrum of associated phenotypes and discuss potential implications for clinical management.     

Dialysis,kidney transplantation,or pancreas transplantation for patients with diabetes mellitus and renal failure: a decision analysis of treatment options

Patients with type 1 diabetes mellitus and end-stage renal disease may remain on dialysis or undergo cadaveric kidney transplantation, living kidney transplantation, sequential pancreas after living kidney transplantation, or simultaneous pancreas-kidney transplantation. It is unclear which of these options is most effective. The objective of this study was to determine the optimal treatment strategy for type 1 diabetic patients with renal failure using a decision analytic Markov model. Input data were obtained from the published medical literature, the United Network for Organ Sharing registry, and patient interviews. The outcome measures were life expectancy (in life-years [LY]) and quality-adjusted life expectancy (in quality-adjusted life-years [QALY]). Living kidney transplantation was associated with 18.30 LY and 10.29 QALY; pancreas after kidney transplantation, 17.21 LY and 10.00 QALY; simultaneous pancreas-kidney transplantation, 15.74 LY and 9.09 QALY; cadaveric kidney transplantation, 11.44 LY and 6.53 QALY; dialysis, 7.82 LY and 4.52 QALY. The results were sensitive to the value of several key variables. Simultaneous pancreas-kidney transplantation had the greatest life expectancy and quality-adjusted life expectancy when living kidney transplantation was excluded from the analysis. These data indicate that living kidney transplantation is associated with the greatest life expectancy and quality-adjusted life expectancy for type 1 diabetic patients with renal failure. Treatment strategies involving pancreas transplantation should be considered for patients with frequent metabolic complications of diabetes and for those patients who favor kidney-pancreas transplantation over kidney transplantation alone. For patients without a living donor, simultaneous pancreas-kidney transplantation is associated with the greatest life expectancy.     

Simultaneous pancreas-kidney transplant: a single-center long-term outcome

BACKGROUND: In patients with type 1 diabetes mellitus and end-stage renal disease, simultaneous pancreas-kidney transplantation is associated with increased survival when compared with solitary deceased kidney transplant or dialysis. We consider that the analysis of our long-term program (based in a single center) of simultaneous pancreas-kidney transplantation would provide valuable information for this therapeutic approach regarding patient and organ survival. METHODS: The outcome of 57 consecutive pancreas-kidney transplants patients was analyzed. The analysis included characteristics of the donor and recipient and survival rates of patients and both grafts. We also analyzed age and modality of renal replacement treatment as possible mortality risk factors. RESULTS: Ten-year patient, kidney and pancreas graft survival rates were 75.8%, 57.2% and 42.7%, respectively. Censoring for patient death, the results for 10-year kidney and pancreas survival were 78.5% and 58%, respectively. CONCLUSION: Our results add evidence to support the notion that the double and simultaneous pancreas-kidney transplantation is in fact the treatment of choice in selected patients with end-stage renal failure due to type 1 diabetes mellitus.     

Transplantation in Diabetic Kidney Failure Patients: Modalities,Outcomes, and Clinical Management

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre‐emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre‐existent DM or NODAT involves a multi‐pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re‐transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.     

An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study

Transplant options for patients with type 1 diabetes and end‐stage renal disease (ESRD) include deceased donor kidney, live donor kidney (LDK) and simultaneous pancreas‐kidney (SPK) transplantation. The aim of this study was to compare outcomes between LDK and SPK for patients with type 1 diabetes and ESRD in the UK. Data on all SPK (n = 1739) and LDK (n = 385) transplants performed between January 2001 and December 2014 were obtained from the UK Transplant Registry. Unadjusted patient and kidney graft survival were calculated using the Kaplan–Meier method. Multivariate analysis of kidney graft and patient survival was performed using Cox proportional hazards regression. There was no significant difference in patient (P = 0.435) or kidney graft survival (P = 0.204) on univariate analysis. On multivariate analysis there was no association between LDK/SPK and patient survival [HR 0.71 (0.47–1.06), P = 0.095]. However, LDK was associated with an overall lower risk for kidney graft failure [HR 0.60 (0.38–0.94), P = 0.025]. SPK recipients with a functioning pancreas graft had significantly better kidney graft and patient survival than LDK recipients or those with a failed pancreas graft. SPK transplantation does not confer an overall survival advantage compared to LDK. However, those SPK recipients with a functioning pancreas have significantly better outcomes.     

Kidney-pancreas transplantation: single-center experience at a university hospital in Turkey

INTRODUCTION: One treatment option for patients with type 1 diabetes mellitus with end-stage nephropathy is combined pancreas-kidney transplantation, which can be performed either simultaneously (SPK) or following kidney transplantation (PAK). PATIENTS AND METHODS: Between February 2003 and November 2004, 14 patients, including 10 males and 4 females of overall mean age of 31.3 +/- 6.1 years (range, 23-44 years), presented with end-stage renal disease secondary to type 1 diabetes mellitus. Five patients (35.7%) received SPK; 7 patients (50%) received PAK; and 2 patients (14.3%) received simultaneous pancreas and living-related kidney (SPLK) transplantations. RESULTS: Two among 14 pancreas grafts were lost in the early postoperative period secondary to venous thrombosis despite anticoagulation including 1 with poor portal drainage. Insulin therapy was reinitiated in 1 patient after a second rejection episode in the seventh postoperative month. By the ninth median follow-up month (range, 1-21 months), all kidney grafts were functioning. CONCLUSION: Our single-center short-term experience with 14 consecutive kidney-pancreas transplantations suggests that while the pancreas transplant is effective and safe to reestablish normoglycemia, this transplant creates additional surgical and immunosuppressive stresses on the patient.     

A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry

Variants in hepatocyte nuclear factor (HNF)-4alpha cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.     

Morbidity of pancreas transplantation during cadaveric renal transplantation.

Simultaneous transplantation of the pancreas is an option for diabetic patients undergoing kidney transplantation to attempt to halt progression of diabetic complications, but the additional risk imposed by the procedure is unclear. Our aim was to determine the morbidity attributable to pancreas transplantation during simultaneous pancreas and kidney transplantation. We compared the first posttransplant year of 18 consecutive recipients of combined pancreas and kidney transplantation to 18 consecutive recipients of kidney transplantation alone. All patients received cadaver donor allografts between 1986 and 1989, and had type I diabetes mellitus with chronic renal failure. There were no differences in patient survival (94% both groups) or satisfactory renal allograft function (89% pancreas/kidney group, 83% kidney group) up to 18 months after transplantation. Eighty-eight percent of pancreas allografts were functioning satisfactorily at 18 months. There was a mean (+/- SD) of 1.5 +/- 1.0 acute rejection episodes per patient for the pancreas/kidney group compared to 0.8 +/- 6 for the kidney-only group (P less than 0.02). Cytomegalovirus infection and wound complications were each encountered more often after pancreas/kidney transplantation than kidney transplantation alone, and together with rejection accounted for a difference in days of hospitalization during the first year (71 +/- 34 vs. 27 +/- 13, P less than 0.001). We conclude that simultaneous pancreas transplantation during cadaver donor kidney transplantation accounted for more frequent rejection episodes, CMV infections, and wound complications. These complications resulted in more hospitalization for patients undergoing simultaneous pancreas/kidney transplantation than kidney transplantation alone.