Arya M. Sharma, MD

Prof. Dr. Dr. h.c. mult. Eberhard Ritz, Heidelberg

This annual conference, now in its 35th year, is hosted by Eberhard Ritz, who I have known for most of my professional career. Ritz, is certainly one of Germany’s pre-eminent nephrologists and as an emiritus professor still appears as active as ever, churning out article after article on a remarkably wide range of topics in nephrology and hypertension.

At this year’s Seminar, Ritz also presented an overview of the impact of obesity on kidney function. The summary of this talk was recently published in Current Opinions in Nephrology and Hypertension.

As Ritz points out, obesity has now been show to be a risk factor for chronic kidney disease, independent of its common association with diabetes and/or hypertension.

The earliest record of nephrotic range proteinuria (where patients excrete several grams of protein with their urine every day) in patients with severe obesity, was in 1974 by Weisinger. This report described four patients with severe proteinuria, which decreased with weight loss and reappeared with subsequent weight regain.

Weisinger also described a typical focal segmental glomerulosclerosis (FSGS) on histological exams of kidney biopsies from these patients, findings that appeared quite different from other causes of proteinuria (e.g. diabetic nephropathy).

Subsequent studies have confirmed similar findings in other patients with severe obesity and protienuria and between 1986 and 2000 a more than 10-fold increase in the prevalence of this problem was reported.

Also, more recently, similar (albeit less severe) FSGS has been reported even with moderate obesity as well as in obese children and adolescents.

Although proteinuria is generally reduced with weight loss, few patients manage to keep the weight off, resulting in recurrence of protein excretion and deterioration of renal function.

More recently, bariatric surgery, which generally results in much better long-term weight loss, has been reported to reduce proteinuria and stabilse renal function in obese patients with FSGS.

Of course, although FSGS appears to be the lesion that is most typically associated with obesity, it must be noted that all forms of kidney disease can be worsened by excess weight.

Unfortunately, large prospective trials of weight loss (surgical or non-surgical) to prevent the progressive loss of kidney function in patients with excess weight are lacking.

Such studies may be particularly relevant today, as type 2 diabetes, a condition that often goes into prolonged remission after bariatric surgery, is now emerging as the single most common driver of endstage kidney failure leaving patients with no option other than dialysis or kidney transplantation.

I am sure that many obese patients with progressive renal failure would likely prefer bariatric surgery to a life on dialysis - but whether or not this is indeed the best option will probably first have to be shown in a trial.

Nevertheless, I am sure that some of my readers will probably know of cases where renal function (protein excretion and/or loss of filtration rate) was affected by weight loss - I’d certainly be very interested in hearing about these observations.

AMS
Edmonton, Alberta

Ritz E, Koleganova N, & Piecha G (2011). Is there an obesity-metabolic syndrome related glomerulopathy? Current opinion in nephrology and hypertension, 20 (1), 44-9 PMID: 21088574

Apple Bark

This week, I am attending the 46th European Association for the Study of Diabetes (EASD) Annual Meeting in Stockholm, Sweden, where there is considerable enthusiasm about the many new drugs and drug classes for diabetes treatment, which are likely to hit the market in the next few years.

One such group of novel orally active anti-diabetic agents are the sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), which act by blocking this transporter in the renal proximal tubule.

As reader may know, blood glucose is freely filtered in the kidney and is normally entirely reabsorbed in the renal tubule (which is why there is usually almost no glucose in the urine of non-diabetic individuals).

Experts may care that SGLT2 is a low-affinity high-capacity transporter sodium/glucose co-transporter, in contrast to SGLT1, located later in the tubule, which is a high-affinity low-capacity transporter and normally reabsorbs any remaining glucose missed by SGLT2.

As outlined by Clifford Bailey from Aston University, Birmingham, UK, the history of SGLT2 inhibitors dates as far back as 1835, when phlorizin, a naturally occurring flavonoid, later shown to be a competitive inhibitor of renal glucose transport, was identified in the bark of the apple tree.

Phlorizin’s glycosuric effect was reported in the 1860s, its renal actions in rat kidneys was shown in 1903 and in humans in 1933. Subsequently, it was shown that phlorizin may well have a significant glucose-lowering effects in patients with diabetes.

However, because phlorizin inhibits both SGLT2 and SGLT1 it had to be pharmacologically tweaked to make it specific for SGLT2 but also to make it longer acting. SGLT2 inhibitors that are currently in development, include dapagliflozin (AstraZeneca), canagliflozin (Johnson & Johnson), sergliflozin (GSK), ASP1941 (Astellas), BI 10773 (Boehringer Ingelheim), and LX4211 (Lexicon).

At blood glucose levels of 8 mmol/L, about 260 g (or almost half a pound of glucose) is filtered every day.

SGLT2 inhibitors reduce glucose reabsorption by about 25%, which means that about 70g of glucose or 280 calories are lost in the urine per day; the higher the blood glucose levels, the greater the caloric loss.

To put this in perspective, if the 280 calories lost in the urine are not replaced by dietary energy intake (in any form), weekly caloric deficit would be around 2000 Kcal, theoretically resulting in about 0.75 lbs weight loss.

Thus, although the primary objective of SGLT2 inhibitors is to help improve blood glucose levels in diabetic patients (which they do), an interesting “side effect” of this treatment is modest weight loss (2-3.5%).

The SGLT2 inhibitors appear to be well tolerated with almost no renal side effects but perhaps a minor increase in genital infection in women.

Numerous clinical trials (many presented at this conference) show that the gliflozins can be combined with both oral and injectable anti-diabetic agents and generally result in relevant improvements in glycemic control.

As a nephologist, who now works mainly in the area of obesity and metabolic diseases, I am particularly intrigued by the mode of action of these compounds and the fact that this novel class of agents specifically targets the kidney.

The fact that gliflozins also, albeit modestly, promote weight loss, makes these particularly attractive for my patients, as most other oral agents (except metformin and DPP IV inhibitors) tend to promote clinically significant weight gain.

AMS
Stockholm, Sweden

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Vallon V, & Sharma K (2010). Sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Current opinion in nephrology and hypertension, 19 (5), 425-31 PMID: 20539226

Yesterday, I blogged about the fact that obesity may promote the development of kidney disease by making these organs more sensitive to even a moderate increase in blood pressure.

Today, I cite an article by Sankar Navaneethan and Hans Yehnert published in the latest issue of the Surgery for Obesity and Related Diseases (SOARD) suggesting that bariatric surgery may halt and perhaps even reverse progressive loss of renal function in severely obese patients with stage 3 chronic kidney disease (glomerular filtration rate [GFR] 30–59 mL/min/1.73 m2).

In this retrospective study of 25 patients with average BMI at surgery of around 50 and a mean GFR of 47.9 mL/min/1.73 m2, surgery reduced BMI to 38.4 at the end of 6 months and to 34.5 kg/m2at the end of 12 months. This reduction in body weight was accompanied by a significant reduction in blood pressure and an increase in GFR at 6 months to 56.6 and a further increase at 12 months to to 61.6 mL/min/1.73 m2.

These findings are in line with several previous reports of improvement in renal function with weight loss but systematic prospective intervention studies of weight loss in obese patients with impaired renal function are unfortunately still lacking.

Nevertheless, it appears that kidney function may well improve with weight loss and that this treatment option should be considered in obese patients presenting with chronic kidney disease.

AMS
Edmonton, Alberta

With all the talk about obesity as a risk factor for diabetes and heart disease, we may often forget that excess weight affects all organ systems.

One set of organs that appears particularly sensitive to the ill-effects of excess weight are the kidneys.

This is nicely illustrated in a study just published in the American Journal of Kidney Disease by John Munkhaugen and colleagues from the Norwegian University of Science and Technology, Trondheim, Norway.

The researchers examined the combined effect of blood pressure (BP) and body weight on the risk for end-stage renal disease or chronic kidney disease (CKD)-related death.

Participants included data from 74,986 adults of the first Health Study in Nord-Trøndelag (88% participation rate), which were linked to the Norwegian Renal Registry and Cause of Death Registry.

During a median follow-up of 21 years (1,345,882 person-years), 507 men (1.4%) and 319 women (0.8%) initiated renal replacement therapy (n = 157) or died of CKD (n = 669).

The risk associated with body weight started to increase from a BMI of 25.0, but this increased risk was not seen in participants with BP less than 120/80 mm Hg.

In contrast, in participants with even moderately increased BP (pre-hypertension or hypertension), there was a progressive increase in the risk for kidney disease with increasing BMI suggesting an almost 6-fold increased risk in participants with a BMI greater than 35.

The study strongly suggests that individuals with a BMI greater than 30 are increasingly vulnerable to kidney disease even with a modest increase in blood pressure.

This finding has several important clinical implications:

1) Blood pressure should be carefully monitored in all individuals with BMI greater than 30.

2) Even moderately elevated blood pressure (pre-hypertension) should be addressed with lifestyle and, if necessary, pharmacological treatment in obese individuals.

3) Blood pressure treatment targets in obese patients may need to be similar to targets in patients with diabetes (i.e. below 130/80 mm Hg).

AMS
Edmonton, Alberta

Although most of my practice today is bariatric medicine, as a trained nephrologist, I continue to keep an eye on the nephrology literature. I was therefore interested to note this recent study on the outcomes and safety of bariatric surgery in patients who underwent kidney transplants.

As blogged before, obesity is a significant risk factor for progression of renal failure (not surprising as obesity is a common cause of both hypertension and type 2 diabetes), but obesity also often develops in transplant recipients due to some of the immunosuppressive and other medications that these patients may have to be on.

It is therefore not at all surprising that many transplant recipients have (or develop) severe obesity that may warrant consideration for bariatric surgery, which continues to be the only evidence-based treatment for severe obesity.

In this paper published in the latest issue of OBESITY SURGERY, Samuel Szomstein and colleagues from the Cleveland Clinic Florida, USA, performed a retrospective chart review of prospectively collected data on five severely obese women (age 30-48; BMI 48-69) after kidney transplantation who underwent laparoscopic bariatric surgery. All patients were females, with a mean age of 40.8 years (range 30-48) and mean body mass index (BMI) of 52.2 (range 48-69). Four patients had laparoscopic Roux-en-Y gastric bypass and one had laparoscopic sleeve gastrectomy.

Patient lost an average of 50% of their excess weight at two years post surgery (around the same as in non-transplant patients) and there were no postoperative complications in any patients.

Immunosupressive therapy was unaltered after surgery.

Although this paper certainly suggests that bariatric surgery can safely be performed in kidney transplant recipients, the rather short two-year follow-up period and the small number of patients certainly does not allow hard conclusions regarding wether or not bariatric surgery will indeed improve life of the transplant and patients.

For now, I believe that the decision to perform bariatric patients on recipients of kidney or other transplants will likely remain a case-by-case decision at experienced centres.

AMS
Vienna, Austria