Urinary creatinine clearance 59 ml/min, DTPA GFR 75 ml (gates), 65 ml (plasma sampling), CKD-EPI 90 ml/min, CKD-EPI using cystatin C 102 ml/min–these are ‘GFR’ values by various methods for one of our perfectly healthy 58-year-old donor under evaluation. Which of these should I rely upon? This should probably be one of the top research priorities here and this NEJM article tells us a way how to. In this study of 1388 live donors, (mean age 44, 55% female), authors studied glomerular number (cortical volume of both kidneys by CT multiplied by glomerular density on kidney biopsy), single nephron GFR (measured GFR -mGFR-by iothalamate divided by glomerular number so actually esnGFR) and its determinants. Total mGFR and snGFR were 115 ml/min (SD 24) and 80 nl/min (SD 40) respectively. snGFR didn’t vary according to age (until <70), sex or body height (until< 190cm). High snGFR was associated with large nephrons, glomerulosclerosis, height >190cm, obesity, family history of ESRD. Predominantly white population, selection of healthy donors, and a possibility of variation in the glomerular volume distribution within the biopsy are important limitations of this study. Nevertheless, it is an important clinico-patho-physiological exercise telling us — estimating nephron number and snGFR measurement is feasible (even before death and without sacrificing animals), an increase in snGFR is an initial adaptive mechanism that precedes kidney disease. Also, the age-associated decline in GFR is a feature of normal nephron senescence and usually not accompanied by increased snGFR. Are we right then in assigning CKD status based on GFR alone in elderly? This makes case for age calibration in CKD definition and staging and this single intervention can potentially halt the epidemic of CKD! With serum creatinine, only the trend can give you the faintest idea of what’s happening to those 860,000±370,000 per kidney tiny filters. Why then the delusion “eGFR”? Especially, in populations where none of the estimating equations have been formally evaluated.
‘Pancreatic islets are like kidney, initial hyperfunction as an adaptive response becomes maladaptive to give rise to diabetes, similar to initial compensatory hyperfiltration by nephron’——Prof Hase taught us during internal medicine grand rounds a decade ago. Never imagined then that a drug would act along both of these pathways. CANVAS program (CANVAS+CANVAS R) compared Canagliflozin with placebo to assess the effect on CV outcomes in a randomized controlled trial involving 10,142 participants. While effect on primary CV outcome was modest (as compared to EMPA REG OUTCOME trial) , renal outcomes were significantly improved as assessed by :progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Significant improvement in renal end point was also demonstrated in a previous EMPA REG OUTCOME trial involving empagliflozin. Both reviewed in depth by NephJC here and here.
After the initial introduction of these drugs in the management of diabetes, my endocrine colleagues were worried that they will end up bothering nephrologists more often for urinary tract infections and AKI. Gears have shifted now, and they wonder ‘what Nephrologist are left to do’ with diabetic nephropathy after this ‘ breakthrough’?. Industry hailed it as the magic pill for nephropathy in diabetes– ‘Cure for diabetic nephropathy found’ read one of the headlines in an online medical news portal. The renoprotective benefit appears almost double than what could be achieved in pivotal RAAS inhibition trials (risk reduction 40% with Canagliflozin vs 16% with losartan in RENAAL, 20% with irbesartan in IDNT trial). These dramatic results are widely received with great optimism by the scientific community- NEJM reversing section title to ‘ basic implications of clinical research, and JAMA coining the term metabolodiuretic in praise. They will continue to influence journal editors and we will get to read a lot more speculations on how this class of drug saves heart and kidney. Before we sign off diabetic nephropathy to Boehringer Ingelheim, Eli Lilly, and Janssen, let’s have a closure look at the data to put results in perspective.
Both EMPA-REG OUTCOME and CANVAS studied renal outcomes as secondary endpoints which should only generate hypothesis and not conclusions. Renoprotection benefit in CANVAS R was largely driven by softer end points like microalbuminuria (or moderately increased albuminuria), and progression/regression of microalbuminuria- a marker that is not unique to CKD especially in patients with preserved GFR and other metabolic risks. Mean GFR at baseline was >70ml and <8% of the total study population had albuminuria >300mg/d. The risk of CANVAS population developing kidney failure in remaining lifespan is very low (0.03% at 5 yrs by this risk calculator). Hence, although relative risk reduction appears massive, absolute risk reduction is much smaller when compared to pivotal ARB trials [as baseline risk of renal failure there -RENAL/ IDNT- is about 600 times more(20.67% and 15.5% at 5yrs)]. So you need to treat 54 patients with losartan and 11 with irbesartan to prevent one adverse renal outcome versus 278 patient needing treatment with canagliflozin. Moreover, 31% discontinued treatment, reflecting challenge in handling these drugs in real life. Important safety issues are keto-acidosis (documented by this report telling us how important post-marketing data will be), amputations (1 per 346 patients treated), genitourinary infections (1 per 20 patients treated), hypovolemia (1 per 136 patients treated).
It’s not an easy trade-off and more colors are yet to be filled in this beautiful appearing CANVAS. I will wait for replication before application.
This review in KI reports data from Joslin Clinic on the rate of GFR decline in a cohort of 364 ESRD patients with T1DM. Almost half of these cases progressed at an extraordinarily rapid rate (GFR decline of 5-70ml/min/yr). No clue as to which of the kidney compartment (glomerulus, vessels, tubulointerstitium) is mediating this progression.Very fast and fast renal decline developed in a significant proportion of patients with only mild to moderate albuminuria.
Authors noted elevated levels of circulating TNFR1 and TNFR2 (TNF receptor) as strong predictors of fast renal decline to ESRD. Whether high levels of circulating TNFR1 and TNFR2 are causal factors or only markers of this course remains unknown. Kidney disease in diabetics is much more complex than we think; this highlights the fact that widely held -“normoalbuminuria->albuminuria->GFR loss”- theory of diabetic nephropathy progression may be too simple to be true in all the cases. This also raises questions whether albuminuria is a valid surrogate endpoint in nephropathy trials.
Rapid progression is rather underrecognized and less acknowledged feature of kidney disease type 2 diabetes as well. Every one of us must have also faced type 2 diabetics with a relentless decrease in kidney function in your clinic like this-I know how painful, helpless and embarrassing it can be.
HERAKLES is a multicentric German randomized trial evaluating the use of everolimus in kidney transplantation. 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid. Primary efficacy endpoint was the effect of everolimus conversion on eGFR at 12-month follow-up which was better by ~5ml/min in everolimus arms.
Authors conclude, “Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.” Although it didn’t bother Novartis and authors much, composite efficacy failure (biopsy-proven acute rejections, graft loss, death, drug discontinuation due to lack of efficacy or adverse events) was significantly more likely with everolimus. This is in line with previous 3 meta-analyses that showed increased risk of acute rejections, side effects necessitating discontinuation, graft loss and death associated with mTOR use and its tough to find a patient who will be willing to bear with such cost and risks. For what? a non-melanoma skin cancer which only rarely kills and few ml increase in that number called eGFR. Forget the nephron, spare the patient.
Novel Endovascular Access Trial (NEAT) is a prospective, single-arm, multicentre study evaluating endovascular approach (using everlinQ endoAVF System, TVA Medical) to create AV fistula for dialysis. Successful creation of AVF was possible in 98% of the cases, functional usability was 64% in those who received dialysis and 12-month primary patency rate was 69% -comparable to surgically created fistulas. Functional usability is much lower than previously reported by the authors in a pilot study (64% vs 96%) reflecting various challenges for success in real world settings (learning curve, patient comorbidities etc). Follow-up is limited to 12 months, and a significant number of patients were not yet on dialysis for whom clinical usability data isn’t available. Even then, results are encouraging and hopefully, this technique will offer an additional option for creation of the lifeline. Another interesting report in this month’s Indian J of Nephrology on an alternative approach to brachiocephalic AVF creation (sparing cephalic vein for future use) and commentary here.
While I was discussing this potential option of endoAVF creation by nephrologist with my interventional radiology colleague, he mocked me by saying,”what’s new there, nephrologists keep creating AVF in the neck while cannulating IJV, and in the kidney, while doing the biopsy!”. I said, “I can understand your pain.” I know few nephrology colleagues here who surgically create beautiful AVFs themselves (although they don’t call themselves Interventional Nephrologists). Given the interest and priorities of our surgery colleagues, this skill demands urgent multiplication among budding nephrologists. What’s the fun of being an Interventional Nephrologist if you can’t do an intervention (much simpler although less sexy than plasties and stenting) which can actually add years to patient’s life?
This excellent review in KI challenges our widely held beliefs on the relationship of salt, volume and blood pressure. We know kidney as central in the genesis of hypertension in response to high salt diet since ages, however relationship of dietary sodium intake and blood pressure may not be as simple. Authors review here human and experimental data supporting ‘’vasodysfunctioner” theory of salt-sensitive hypertension according to which mere increase in the ECF volume and cardiac output is not enough to elevate blood pressure. Normal physiological response to salt loading is, in fact, vasodilatation and failure of this vasodilation (or vasodysfunction) underly salt-induced increase in the blood pressure. They also review their previous seminal work challenging our simplistic belief about sodium balance i.e. salt excretion parallels intake and increased salt intake leads to increased thirst and so increased water intake. All these years we have completely neglected the third body compartment i.e. interstitial fluid which is now considered to be osmotically active. JCI paper by same authors is reviewed in detail by NephJC here. High salt diet increased urinary osmolyte (read urinary sodium) excretion but reduced free water clearance (meaning water was held back in the body). This extra water suppressed thirst leading to decreased water intake. So the water intake was actually least in the high salt intake phase. They also observed rhythmic mineralocorticoid and glucocorticoid surges. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. Higher salt intake elevated rhythmic glucocorticoid secretion and suppressed rhythmic mineralocorticoid excretion. These rhythmic patterns of mineralocorticoid and glucocorticoid secretion were not daily; they are weekly or half-weekly. In other words, if you collect a 24-hour sample to assess daily salt intake, you are probably wrong. It’s time to ask for a 7-day urine collection if you go by the book! This is really getting interesting.
What should guideline expert do when there is little or no evidence? They can ask their nephro friends for sure, who have developed an unique expertise in creating guidelines based upon imperfect evidence. The 2017 KDIGO clinical practice guideline update on CKD-MBD published last month has very little to add what we already know (or don’t know!) about the mineral bone disease in CKD. As was the case with the last version, most of the statements are either not graded or are 2C/2D. ISN webinar by Geoffrey Block explaining the basis of this update is here. What’s new: 1) BMD testing to assess the risk of fractures in patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis (2B) based on the observational data suggesting BMD predicts fracture risk across the spectrum of CKD. 2) In absence of data supporting benefits of maintaining phosphate in the normal range in CKD G3a–G4 patients and because of safety concerns with phosphate binders, the group suggests lowering elevated phosphate levels toward the normal range rather than attempting to maintain in the normal range. 3) As inorganic phosphate is a constituent of food preservatives, patients should be encouraged to have fresh and homemade foods, rather than processed foods, to avoid additives. About 40% to 60% of phosphate in animal proteins is absorbed, as against 20%–50% with plant-based phosphate, because of associated phytates. So, rigorous restriction of plant-based proteins may not be warranted and may not be possible without harmful protein restriction
A young adult coming with: blood pressure >200systolic, papilledema, subnephrotic proteinuria, markedly reduced kidney function, all for the first time in his life, is not an unusual case scenario here. ‘Malignant hypertension’ can give rise to thrombotic microangiopathy (TMA) that is evident only on kidney biopsy i.e. without other clinical features of TMA. In this interesting report, Timmermans et al hypothesize alternative complement pathway (AP) dysregulation as an unrecognized, but treatable cause of hypertension-associated TMA. To test this hypothesis, they analyzed AP in 9 patients with severe hypertension who had histological criteria of TMA on renal biopsy. Six out of nine patients had mutations in C3, CFI, CFH, and CD46 with complement activation evident in the plasma (raised C5b-9 level) and in the biopsy (deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall). Eight patients progressed to ESRD. Four patients received six allografts and TMA recurred in four allografts (patients with C3 and CFH mutations) -leading to the graft loss in three cases. Hypertension-induced shear stress possibly activates complement pathway leading to the formation of C5b-9 on activated endothelial cells. Eculizumab was started in one patient with CFI mutation who was on dialysis for three months and his renal function improved (estimated glomerular filtration rate: 38 ml/min) within a 12-month treatment period. These patients, for sure, fall in the spectrum of complement-mediated TMA. We do not routinely biopsy patients with severe hypertension, rising creatinine, and not-so-high proteinuria. Challenge is how to identify people who are likely to have complement dysregulation. Wider availability of tests to evaluate complement pathway and having a low threshold for kidney biopsy in such a case may be the way to go.
The prespecified subgroup analyses of outcomes in SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline CKD got published online ahead of print in JASN. 2646 participants (28.3%) had GFR <60 ml/min/1.73m2 at baseline. Primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (P values for interactions $0.30).
As expected, the intensive group had a higher incidence of ≥ 30% GFR loss in the first 6 months. However, the rate of change in eGFR using the values at 6 months after randomization as the baseline was slightly higher in the intensive group. [-0.47 ml/min per 1.73 m2 per year in the intensive group and -0.32 ml/min per 1.73 m2 per year in the standard group (P <0.03)]—SPRINT-CKD doesn’t tell us what is its implication after 3.3yrs. Hypokalemia, hyperkalemia and AKI were more often seen in the intensive group, but unlike the main study population, hypotension, syncope, hyponatremia and orthostatic hypotension were similar in the two groups.
The strength of the SPRINT CKD data is its size which is larger than MDRD, AASK and REIN-2 combined and thus represent one of the largest existing evidence to treat high blood pressure in CKD. They support CV benefit of aggressive BP lowering in elderly, nondiabetics with a mild decrease in eGFR. Before you start SPRINTING with your patients, let’s look at the population here. This is not a CKD progression trial. The typical patient here is a nondiabetic, elderly about 72 years old (about 3 yr older than the main SPRINT), with baseline GFR ≥ 45 ml/min per 1.73 m2 (in 66%of the patients), having mean urinary albumin excretion of ~80mg/gm. Very few physician colleagues of ours are obliged to refer us such cases (of CKD3a, A2)-that SPRINT CKD is talking about. We need to choose the right population to use this information. Also if you measure the BP the way SPRINT did and want reduce CVD/ deaths notwithstanding the higher pill burden and side effects, and want to get down to 120 (and diastolic BP remains recordable then) here is advice by Richard Lehman-“If you are consulted by an individual who fits its criteria, you could have an informed conversation about their risk-lowering options, of which tighter BP control might be one.”