1) ABO incompatible kidney transplantation
While the transplant community has largely accepted ABO incompatible (ABOi) kidney transplantation as a viable option based on the ‘excellent’ early results, we haven’t given due importance to the concerns raised by the recent registry data. RCTs evaluating outcomes of ABOi kidney transplantation are impossible to conduct. Here is a paper in Lancet by Scurt et al -probably the best data published so far.
In this systematic review and meta-analysis involving 7098 recipients of ABOi kidney transplants from 49 studies (1 involving children), most outcomes of interests were inferior in these patients when compared to ABO compatible kidney transplantation: significantly higher mortality at 1 year (OR 2∙17 [1∙63–2∙90], p<0∙0001), 3 years (OR 1∙89 [1∙46–2∙45], p<0∙00012), and 5 years (OR 1∙47 [1∙08–2∙00], p=0∙010). Death-censored graft survival was lower with ABOi kidney transplantation than with ABO compatible kidney transplantation at 1 year (OR 2∙52 [1∙80–3∙54], p<0∙0001) and 3 years (OR 1∙59 [1∙15–2∙18], p=0∙0040), and remained lower at 5 year although at this time the difference wasn’t statistically significant.
Higher mortality could be a result of an over-suppressed immune system following the desensitization with the emergence of life-threatening infections of bacterial (sepsis) and viral origin (eg, cytomegalovirus). Moreover, risk of bleeding events and surgical revisions was higher in ABOi KTR.
Given the observational nature of the most studies in the analysis, data on important determinants like recipient comorbidities, donor characteristics, various desensitization methods used were not available. So what do we take away from this important and revealing data? It is imperative to maximize other options like paired exchange and deceased donor KTR, and consider ABOi as the last resort after a careful discussion of the risks and benefits with the recipients. All ABOi transplant are not the same in terms of immunological risk (low isoagglutinin titres, A2 blood groups) may pose a lower rejection risk, require less intense immunosuppression and may fare better. A simple question to ask ourselves is: do we have a fully functional swap transplant program? If not, work for it before breaching the blood group barrier.
2) No need to deprive of water for evaluation of polyuria
14 years ago, when I performed water deprivation test successfully for the first time on a young college girl, I received a pat on the back from my MD teacher, an endocrinologist. It was surely a pain in the neck for us residents and patients alike. The procedure is tedious, sometimes risky and needs close monitoring . Interpretation is often challenging. Here is good news (albeit 12 years late for me): you can reach the diagnosis of diabetes insipidus (DI) with a simple blood test.
Arginine stimulates release of various pituitary hormones and is useful in the evaluation of growth hormone deficiency. It turns out that it can similarly work in cases of defective ADH secretion in diabetes insipidus. ADH itself is difficult to measure but copeptin-a degradation product of the C terminal peptide precursor of ADH-can be assayed easily. In this multi center diagnostic study, 52 patients from a center with polyuria due to central complete or partial DI and primary polydipsia were enrolled alongside 52 healthy controls.
Serial measurements (at baseline and 30, 45, 60, 90, and 120 min) of plasma copeptin concentration after arginine stimulation were measured. At 60 minutes, plasma copeptin level of less than 3·8 pM gave an excellent sensitivity (93%, 95% CI 86–98) and specificity 92% (95% CI 84–100). The test was safe and well tolerated. This is going to simplify the diagnosis of polyuria greatly. Time to wave goodbye to water deprivation-a test based on data of only 36 patients and a diagnostic accuracy of just 70%!
3 New(er) chapters in renoprotection in diabetes
The dust hasn’t settled after the publication of CREDENCE yet. After all the excitement CREDENCE trial brought about, here are a few new chapters in renoprotection in diabetes.
In an exploratory analysis of the renal endpoint among the REWIND trial participants, composite renal endpoint (first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or ESRD) was lower in patients treated with dulaglutide [ 848 (17·1%) participants in the dulaglutide group and in 970 (19·6%) in the placebo group HR 0·85, 95% CI 0·77–0·93; p=0·0004].
Most of this benefit was driven by occurrence of new macroalbuminuria with a between the group difference of 1-2 percentage points. Such effects have also been reported previously in at least half dozen trials of GLP 1 analogues (LEADER, LIRA-RENAL, SUSTAIN6, ELIXA, EXSCEL, AWARD 7). Being a secondary analysis, these results can’t be considered definitive and need to be further studied in RCTs with meaningful renal endpoints over and above albuminuria.
After Canagliflozin, other SGLT2i are all set to prove equivalence in terms of renoprotection. A prespecified secondary analysis of DECLARE–TIMI 58 trial evaluating dapagliflozin demonstrated a lesser likelihood of composite renal endpoint of sustained 40% eGFR reduction, ESRD or confirmed sustained eGFR <15mL/min [HR for the renal-specific
outcome was 0·53 (0·43–0·66; p<0·0001)]. The participants had creatinine clearance >60 ml/min at the time of enrollment. Once again the results should be interpreted with caution given the secondary nature of the endpoints and very few renal events (number of events of ESRD are in single digits for a trial involving thousands of patients!). Nonetheless, against the backdrop of CREDENCE, a class effect of SGLT2i looks more promising (than that of GLP1 analogues).
DELIGHT trial evaluated albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin at a short term follow up of 6 month among patients with CKD and diabetes (UACR >30 and eGFR 25-75) and showed promising effect of dapagliflozin.
It’s time to consider renaming CKD G3a/A1 as ‘clinical trialist CKD’-most DKD trials relate to this class of kidney disease. Many elderly diabetics in real life would get this label due to age related GFR decline. Microalbuminuria in these patients with multiple CV risk factors may not necessarily be a marker of progression of CKD.
4 Hematuria evaluation
Should CT be performed for all the patients with hematuria?
Guideline recommendations vary, reflecting the uncertainty of scientific evidence. AUA guideline recommend it for all patients over 35, others [Dutch, Canadian Urological Association (CUA), Kaiser Permanente (KP)] don’t . HRI (Hematuria Risk Index) recommends risk stratification: none for low-risk, cystoscopy and ultrasonography for moderate-risk, and cystoscopy and CT for high-risk patients. Multiphase CT imaging of the abdomen and pelvis has been associated with the highest median radiation dose and, in turn, the highest adjusted lifetime-attributable risk for cancer among common CT protocols. Although absolute risk is low, approximately 1 fatal cancer can be avoided for every 2,000 abdominal CT scan avoided.
Against this backdrop, in a microsimulation modeling study of a hypothetical cohort of 100 000 adults with hematuria, uniform computed tomography scanning (as under AUA guideline) appeared to be associated with more than 500 secondary cancers from imaging-associated radiation exposure and was approximately twice the cost of alternative approaches.
The AUA guideline missed detection for the fewest number of cancers. It detected 82 [2.3%] cancers compared to the detection rate of the HRI (116 [3.3%]) and KP (130 [3.7%]) guidelines. However, the simulation model projected 108 (95% CI, 34-201) radiation-induced cancers under the KP guidelines, 136 (95% CI, 62-229) under the HRI guidelines, and 575 (95% CI, 184-1069) under the AUA guidelines per 100 000 patients.
Can’t agree more with this conclusion of authors: well-intentioned efforts may lead to the widespread dissemination of clinical practices before their safety and effectiveness are clearly understood. This model-based comparison of 5 different guidelines for the diagnostic evaluation of hematuria suggests that, in addition to its substantial costs, the potential harms of the intensive application of uniform CT urography may outweigh the advantages of early diagnosis of urinary tract malignant neoplasms.
5 Urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery
Troponins fascinate nephrologists, who keep talking about possibility of a ‘renal troponin’ for early detection of ‘renal angina’ or ‘kidney attack’. Several of such ‘renal troponins’ have appeared and disappeared from the literature before ever making to the bedside.
Here is a news for biomarker enthusiasts: urinary dickkopf-3 (DKK3 sounds better) predicted not only the AKI but also subsequent CKD in patients undergoing cardiac surgery according to this observational cohort study. This involved 733 participants in the derivation cohort and 216 participants in validation cohort from RenalRIP trial [this showed a reduced AKI and RRT risk after cardiac surgery with remote ischemic preconditioning(RIP)]. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08–3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67–26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50–122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less.
AKI risk and dialysis dependency was only observed in the patients who didn’t receive RIP. After publication of this 2017 cochrane review on RIP, I thought it has no place in AKI prevention-results of this study seems to be putting new life into RIP.
Transplantation of Kidneys From Hepatitis C Infected Donors To Hepatitis C Negative Recipients
In a single-center retrospective study, Molnar et al studied short-term outcome of deceased donor renal transplant recipients who received kidneys from HCV NAT positive donors. They accepted HCV NAT positive and/or HCV antibody-positive donors who were younger than 45 years old and had a donor biopsy showing less than 10% glomerular sclerosis. They offered these organs to recipients who previously agreed to accept HCV infected donor kidneys.
All 53 recipients became viremic after transplantation. Treatment with a direct-acting antiviral regimen (DAA) regimen was initiated when HCV RNA was detected. The time between transplant and treatment initiation was 76 days (IQR:68 -88 days). One patient developed fibrosing cholestatic hepatitis with complete resolution. All recipients completed antiviral treatment and 100% were HCV -RNA negative and achieved 12 -week sustained virologic response. There were no graft losses or patient deaths during the study period. Thirty four percent recipients had BK viremia and 60% had CMV viremia, which is concerning.
Overall the results look encouraging. However, the risks need to be discussed in details with the waitlisted patients.
In the same journal, Kapila et al present two cases of HCV negative recipients who underwent kidney transplantation from viremic donors and developed fibrosing cholestatic hepatitis (FCH).
Fibrosing cholestatic hepatitis is characterized by the rapid development of inflammation, cholestasis, hepatocyte ballooning, and advanced fibrosis with the potential for hepatic injury and death. Although DAAs have improved the outcome of this potentially fatal condition, we need to have a high index of suspicion to diagnose and treat FCH early.
Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100,000,000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs.
Every decision we make has various possible outcomes. The papers discussed above emphasize the importance of shared decision-making in medicine.
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