Fernanda Ortiz

Predictors of Renal Allograft Histologic Damage Progression

The objective of this study was to analyze factors that are involved in the progression of renal allograft damage in the first 6 mo after transplantation. Donor and 6-mo protocol biopsies of 83 patients who received a renal transplant were classified using the Chronic Allograft Damage Index (CADI). Histologic changes were compared and correlated to clinical parameters at transplantation, at 6 mo, and annually over 2 yr. All CADI components increased significantly in the 6-mo posttransplantation period, except chronic vascular changes and the percentage of glomerulosclerosis. Total cholesterol and LDL- cholesterol at the time of biopsy correlated positively with mesangial matrix increase, and HDL cholesterol correlated negatively with vascular intima increase. High BP at biopsy was associated with tubular atrophy. Diastolic BP at biopsy correlated with 6-mo CADI (CADI-6). Patients with diastolic BP > or =85 mmHg at biopsy had a higher difference between CADI score in protocol biopsies and CADI score in donor biopsies (DeltaCADI) and higher creatinine at 1 and 2 yr. CADI in donor biopsies (CADI-0) >1 was more frequently found in older (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01 to 1.14) and nontraumatic dead donors (OR, 3.89; 95% CI, 1.13 to 13.33). CADI-6 >3 was more frequently found in those with CADI-0 >1 (OR, 3.82; 95% CI, 1.19 to 12.21), older donors (OR, 1.05; 95% CI, 1.01 to 1.10), and number of AB mismatches (OR, 2.36; 95% CI, 1.09 to 5.10). CADI-0, CADI-6, and DeltaCADI correlated significantly with serum creatinine at hospital discharge, at 6 mo, and at 2 yr. DeltaCADI was affected by initial percentage of glomerulosclerosis (OR, 1.10; 95% CI, 1.02 to 1.19) and creatinine at hospital discharge (OR, 1.01; 95% CI, 1.00 to 1.02). Donor-related as well as nonimmunologic factors, such as hypertension and dyslipidemia, are associated with increased risk for renal allograft damage progression.

IgA nephropathy recurs early in the graft when assessed by protocol biopsy

BACKGROUND The recurrence of IgA nephropathy (IgAN) in the allograft is common. Factors related to IgA recurrence are unclear. The aims of this study were to determine the incidence of IgAN recurrence as assessed by protocol biopsies and to identify predictive factors for recurrence. METHODS We identified 65 protocol biopsies taken before the second year post-transplantation in patients with IgAN as primary renal disease. Diagnosis of recurrence of IgA was based on the detection of at least 1+ mesangial deposits of IgA. Pathological findings and clinical characteristics were retrospectively compared between recurrent and non-recurrent cases. RESULTS IgAN recurrence rate was 32%. Mesangial C3 was detected in 83% of recurrent cases versus 17% in non-recurrent patients (P < 0.001). Normal urinalysis was observed in 52%. Non-recurrent patients had arteriolar hyalinosis in 31% of the cases versus none in IgAN recurrence (P = 0.006). Seventy-nine per cent of cyclosporine users were free of recurrence, whereas 45% of the patients without cyclosporine experienced recurrence (P = 0.03). The odds ratio (OR) for IgAN recurrence in patients using cyclosporine was 0.3 (confidence interval 0.1-0.9). Zero HLA-DR mismatch was associated with non-recurrence (P < 0.01). The OR for IgA recurrence was 6.7 if any degree of DR mismatch was present. IgAN recurrent patients had better glomerular filtration rate, but after censoring delayed graft function, the differences disappeared. Graft loss due to IgA recurrence was only 3%. CONCLUSIONS IgAN recurrence rate was 32%. The histological diagnosis was not accompanied by abnormalities in the urinalysis in one-half of the patients. Full DR match and cyclosporine were associated with non-recurrence.

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial

BACKGROUND IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. METHODS We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. FINDINGS Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). INTERPRETATION TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. FUNDING Pharmalink AB.

Health-related quality of life after kidney transplantation: who benefits the most?

The influence of dialysis modalities on HRQoL before and after kidney transplantation (KT) and the role of adherence to medication on HRQoL have not been fully studied. Sixty four dialysis patients who answered the 15D HRQoL survey during dialysis were surveyed again after KT. Adherence and employment were also investigated. The mean 15D score was highest among home hemodialysis patients (HHD) and lowest among in‐center hemodialysis patients (icHD). After KT, the mean 15D score improved significantly in 78.6% of peritoneal dialysis patients (PD), 47.6% of HHD, and 53.8% of icHD. Then, mean 15D score remained unchanged in 28.6% of HHD and in 23.1% of icHD patients. A deterioration in the 15D score occurred in 14.3% of PD, 23.1% of icHD, and 23.8% of HHD patients, and this was influenced by the number of pills (P = 0.04). Adherence to medication was the lowest in PD, timing being the most challenging task showing a connection to higher creatinine concentration (never forgot 1.41 mg/dl vs. forgot 2.08 mg/dl P = 0.05). Employed patients had a higher mean 15D score. The icHD and PD patients benefited the most from KT and HHD the least. Low pill burden and employment were linked to a better HRQoL.

Polyomavirus BK and JC infections in well matched Finnish kidney transplant recipients

Since 2003, only one case of polyomavirus‐associated nephropathy (PVAN) has occurred in our clinic despite screening protocols. In contrast to BK virus, the role of JC virus in PVAN is unclear. We studied the incidence and impact of polyomavirus BK and JC viruria and PVAN in well‐matched Finnish kidney transplant recipients. All Helsinki University Hospital kidney transplant recipients between 2004 and 2006 were prospectively followed (n = 163). Patients with a 12‐month protocol‐biopsy taken and polyomavirus urinary secretion screened by PCR were studied (n = 68). Cyclosporine‐based triple‐drug immunosuppression was usually used. BK or JC viruria was detected in 18 (27%) and 14 (21%) patients after transplantation respectively. Persistent BK or JC viruria was found in 5 (7%) and 9 (13%) patients. No cases of PVAN were diagnosed from protocol biopsies or from biopsies taken for clinical indications. A positive BK or JC viruria or persistent viruria was not associated with reduced renal function at follow‐up, histopathologic changes in 12‐month protocol biopsies, or acute rejections. The incidence of BK and JC viruria was similar to what has been previously reported, but no cases of polyomavirus‐associated nephropathy were seen in our well‐matched kidney transplant population.

Impact of glucose metabolism abnormalities on histopathological changes in kidney transplant protocol biopsies.

The impact of post‐transplant diabetes (PTDM) on kidney transplant histopathology has been poorly described. We examined the association of glucose metabolism abnormalities on the progression of histopathological changes in serial protocol biopsies. Helsinki University Hospital kidney transplant recipients during 2004–2006 were followed up. Patients with pre‐existing diabetes or 2‐h oral glucose tolerance test (OGTT) performed at 3 months, and protocol biopsies taken at 0 and 12 months were analyzed (n = 76). Diabetes was defined according to WHO/ADA. Histology was analyzed with chronic allograft damage index (CADI). Altogether 32 patients had pre‐existing diabetes. In OGTT at 3 months, four showed PTDM, eight impaired glucose tolerance (IGT), two impaired fasting glucose, and 30 normal glucose tolerance. Patients with impaired glucose metabolism were older (P = 0.005), received grafts from older donors (P = 0.04), and had reduced renal function at 12 months (P = 0.003). In patients with IGT or PTDM, 2‐h postload glucose values in OGTT correlated with CADI at 12 months (R = 0.84, P = 0.001) and with the change in CADI score between 0 and 12 months (R = 0.67, P = 0.025). Graft survival was reduced in patients with pre‐existing diabetes (P = 0.01). Glucose abnormalities were associated with the progression of histopathological changes, especially in patients with already compromised kidneys, supporting the harmful role of PTDM to the kidney allograft.

Biochemical pathways of breath ammonia (NH3) generation in patients with end-stage renal disease undergoing hemodialysis

Breath ammonia (NH3) has been proposed as a potential biomarker in monitoring hemodialysis (HD) adequacy, since a strong correlation between blood urea and mouth-exhaled breath NH3 has been observed in patients with end-stage renal disease (ESRD) undergoing HD. However, the biochemical pathways for breath NH3 generation from blood urea have not been demonstrated. In this study, we show a strong correlation (r s  =  0.77, p  <  0.001) between blood and salivary urea, indicating that salivary urea levels reflect blood urea levels. Salivary urea is in turn strongly correlated to salivary ammonia ([Formula: see text] + NH3) in most of the patients. This confirms that the hydrolysis of urea by urease generates ammonia in the oral cavity. A further strong correlation between salivary ammonia and breath NH3 indicates that salivary ammonia evaporates into gas phase and turns to breath NH3. Therefore, blood urea is a major biochemical source of breath NH3. Since breath NH3 is generated predominantly in the oral cavity, the levels of breath NH3 are influenced significantly by the patients oral condition including urease activity and salivary pH. Our results agree with previous studies that have shown a connection between salivary urea and breath NH3.

Simultaneous BK Polyomavirus (BKPyV)-associated nephropathy and hemorrhagic cystitis after living donor kidney transplantation

BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression.

Timing and value of protocol biopsies in well‐matched kidney transplant recipients – a clinical and histopathologic analysis

The role and timing of protocol biopsies after kidney transplantation are controversial. We changed our protocol biopsy policy and compared the predictive value of biopsies at different time‐points. Protocol biopsies at 6 months (n = 45) were obtained during 2001–2004, and at 3 and 12 months from 2004 (n = 41). Donor biopsy was available from 70 patients. Histopathologic changes were described with chronic allograft damage index (CADI) and Banff 1997. Follow‐up was for 18 months. Chronic allograft nephropathy (CAN) was present in 12%, 51%, and 34% and borderline or subclinical rejection in 9.8%, 8.9%, and 7.3% of patients at 3, 6, and 12 months. CAN at 6 and 12 months was associated with reduced graft function (P = 0.001). Semiquantitative CADI scores at all time‐points significantly correlated with glomerular filtration rate (GFR) at 18 months. Strongest correlation existed with CADI at 12 months (P < 0.001). Change in CADI between 0–6 and 0–12 months, but not between 0–3 and 3–12 months, correlated with GFR at 18 months (P = 0.03, P = 0.01). Subclinical rejections were rare and chronic changes mild at 3 months. In our well‐matched population, the predictive value of a biopsy at 3 months was inferior to biopsies at 6 or 12 months, both of which were effective in predicting long‐term graft function.

Oral Health and Mortality in Patients With Chronic Kidney Disease.

BACKGROUND Factors related to mortality of patients with chronic kidney disease (CKD) were investigated to find out whether oral disease inflammatory burden or different etiology (diabetes nephropathy vs. other etiologies) of CKD could be associated with mortality. METHODS This prospective cohort study comprised 144 adults at the predialysis stage. Clinical oral and radiologic examination was made from 2000 to 2005. Patients were followed up until August 2015 (complete follow-up time: 157 months). Cause of death could be verified from 62 of 65 patients. Clinical health data were combined with mortality records obtained from the Finland national statistics database. Number of teeth, total dental index (TDI), and periodontal inflammatory burden index were calculated to describe degree of oral inflammation. RESULTS Primary causes of death were cardiovascular diseases, infection, and cancer. There was a statistically significant difference in survival between diabetic nephropathy (23.8%) and other patients with CKD (59.9%; log-rank test P <0.001). A Cox regression model showed fewer teeth, higher age, and diabetes mellitus were statistically significant independent risk factors for death. Deceased patients had fewer teeth (P <0.001) and higher TDI (P <0.05). CONCLUSIONS Risk of death was higher among patients with diabetic nephropathy. The deceased had fewer teeth and more oral infections. However, indices used failed to show independent association with survival.