Renal Function in Type 2 Diabetes Following Gastric Bypass
A Prospective Cohort Study in Mildly Obese Insulin-Dependent Patients
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Background: Metabolic surgery for obese patients with type 2 diabetes (T2D) yields short- and long-term remission rates of 60–90%. Its effects on diabetes-associated complications such as neuropathy and nephropathy have not been well studied to date. Hardly any data are available on this subject with respect to moderately obese patients (body mass index [BMI] 25–35 kg/m2) with insulin-dependent T2D. Our previous studies suggest that, in such patients, treatment with a Roux-en-Y gastric bypass (RYGB) improves diabetic neuropathy. In this pilot study, we investigate the course of diabetic nephropathy after RYGB surgery.
Methods: 20 insulin-dependent patients whose T2D was inadequately controlled with medication, and whose BMI was in the range 25–35 kg/m2, were prospectively included in a pilot study. All patients underwent a standardized RYGB operation. Blood and urine tests for renal function were performed before surgery and 12 and 24 months afterward.
Results: The serum creatinine level fell from 0.82 ± 0.23 to 0.69 ± 0.13 mg/dL (p = 0.0025) in the first 12 months after surgery and was unchanged a further 12 months later. The glomerular filtration rate (eGFR) rose in the first 24 months after surgery from 96.4 ± 28.7 to 111.7 ± 23.3 mL/min/1.73 m2 (p = 0.0093). The urinary albumin/creatinine and high-molecular-weight adiponectin/creatinine ratios fell markedly in the first 24 months after surgery (2.89 ± 3.14 versus 1.00 ± 0.24 mg/mmol [p = 0.0491] and 0.18 ± 0.06 versus 0.04 ± 0.01 μg/g [p = 0.0392]).
Conclusion: RYGB has positive effects on renal function and may therefore be a good treatment option for moderately obese, insulin-dependent patients whose T2D cannot be adequately controlled with medication. These results still need to be confirmed in randomized, controlled trials with longer periods of follow-up.
Diabetic nephropathy is the most common and costly complication of type 2 diabetes (1, 2). Its prevalence is 20–40% in patients with type 2 diabetes, and about 20% of patients with diabetic nephropathy develop terminal renal failure requiring dialysis (1–4). The high prevalence and expensive dialysis treatment place a great burden on the healthcare system (5, 6). Although diabetic nephropathy is the most common reason for dialysis, therapy to date is still based on supportive measures without any causal therapeutic approach. Strict blood glucose control does not lead to any improvements in nephropathy, and the number of patients who would have to be treated in order to prevent the development of terminal renal failure in one patient is about 3300 (7–10). Current therapies are based on renal protection by blocking the renin-angiotensin system, blood pressure control, and a diet low in salt (1, 11).
Metabolic surgery, which comprises bariatric procedures for treating metabolic disorders, has been found to be an effective therapeutic option compared with medication treatment in prospective randomized trials (RCTs) and in a meta-analysis of 7 RCTs and 6 observational studies in patients with type 2 diabetes (12–14). Metabolic surgery results in blood glucose regulation that is superior to medication treatment, to a reduction in the amount of insulin required, and, in many cases, to a situation where oral antidiabetic medication can be stopped altogether (15). 60–90% of obese patients will enter remission of their type 2 diabetes after metabolic procedures in the short to medium term (16, 17).
Despite such positive effects on blood glucose control, few data are available to date on the effects of metabolic procedures on specific complications of type 2 diabetes. The prospective Swedish Obese Subject Study (SOS) showed a reduction in all cause mortality after bariatric surgery as well as a reduction in cardiovascular mortality in obese patients (18, 19). The latest insights from the SOS Study and other studies indicated a reduction in the incidence of microvascular and macrovascular complications after metabolic operations compared with conservative treatment in patients with type 2 diabetes (20, 21). Schauer et al. showed in an RCT a notable improvement in microalbuminuria, three years after sleeve gastrectomy as well as after Roux-en-Y gastric bypass surgery. By comparison, medication treatment alone did not have a correspondingly positive effect on diabetic nephropathy (12).
Few data are currently available on the effects of metabolic surgery on type 2 diabetes and diabetes specific complications in patients who are not morbidly obese (body mass index [BMI] 25–35 kg/m2). Furthermore, uncertainty prevails regarding the mechanisms by means of which metabolic procedures bring about an improvement of diabetic complications.
This study investigated the effects of surgical therapy as a new and experimental approach in patients with poorly controlled type 2 diabetes and a BMI <35 kg/m2 and long term insulin-dependent type 2 diabetes.
In the setting of the prospective DiaSurg-1 pilot study, 20 patients underwent Roux-en-Y gastric bypass surgery outside of the German and international guidelines for obesity surgery. The procedures were undertaken from November 2010 to August 2012. Type 2 diabetes that was poorly controlled by medication was defined as insulin-dependent type 2 diabetes, with insulin treatment for a minimum of 12 months and persistent HbA1c measurements ≥ 7% in spite of the treatment, and/or persistent diabetic microvascular complications. All patients had participated in numerous therapeutic approaches to achieving weight loss and improving their type 2 diabetes in the years preceding their inclusion in the study. The measures comprised increased physical exercise and dietary changes under medical supervision, also accompanied by dieticians and psychosomatic specialists. Insulin treatment was started in accordance with the currently valid German S3 guideline for the treatment of type 2 diabetes once conservative measures had been exhausted and the effects of oral medication therapy had been insufficiently effective, with persisting pathological blood glucose concentrations.
We showed previously for this prospective study including 20 patients—which is unique worldwide—that diabetic nephropathy improved notably within 3 months after Roux-en-Y gastric bypass surgery and that the underlying mechanism seemed to be the reduction in nitrosative stress (22–24). Furthermore, the need for insulin fell drastically, and blood glucose measurements had improved significantly. In actual fact, 90% of patients did not require insulin treatment 12 months after surgery (23).
The study furthermore aimed to find out,
- Whether Roux-en-Y gastric bypass surgery had a similarly positive effect on diabetic nephropathy
- Whether it was possible to confirm in humans the pathophysiological mechanisms of diabetic nephropathy that have been observed in animal experiments.
The study cohort comprised the same group of mildly obese patients (BMI 25–35 kg/m2) with insulin-dependent type 2 diabetes that was not controlled by medication whose data were analyzed in studies published earlier. At that time, we studied the effects of Roux-en-Y gastric bypass surgery on glucose metabolism and diabetic complications (22–24). We defined type 2 diabetes not controllable by medication as poor blood glucose regulation, with HbA1c >7.0% in spite of insulin treatment for a minimum of 12 months and/or persistent microvascular complications.
The present study is a secondary analysis of the effects of Roux-en-Y gastric bypass operations on renal function. Before starting insulin treatment, all patients were instructed in the setting of a multimodal therapeutic concept to increase their physical exercise/activity and modify their diet. Furthermore, they received psychosomatic healthcare. Medication therapy was conducted in accordance with the German S3 guideline for the therapy of type 2 diabetes. Table 1 provides an overview of patient characteristics, duration of diabetes, and insulin treatment. Our inclusion criteria were as follows:
- Age 18–70 years
- Insulin-dependent type 2 diabetes
- BMI 25–35 kg/m2
- Confirmation of sufficient endogenous insulin secretion as measure by a glucagon test (C peptide >1.5 ng/mL)
- Glycated hemoglobin (HbA1c) > 7 %.
Ten men and ten women were recruited consecutively and unselected on the basis of these criteria, with the proviso that they were able to give consent and agreed to have a Roux-en-Y gastric bypass operation. The eBox contains further information on material and methods.
The study cohort consisted of 20 patients (10 men, 10 women) of an average age of 58.6 ± 6.1 years, who have had diabetes for a mean period of 12.2 ± 5.0 years. The mean duration of insulin treatment was 7.7 ± 5.3 years. Table 1 provides an overview of the included patients’ characteristics. Table 2 shows changes in HbA1c measurements, insulin therapy, antihypertensive treatment, and postoperative renal function.
One woman died from intrahepatic cholangiocellular cancer, which was not known, and could not be diagnosed, at the time she was included in the study. This means that a follow-up rate of 95% was achieved.
Postoperatively, all patients had notably reduced HbA1c measurements, reaching the desirable target values, and a notably reduced need for insulin treatment and antihypertensive medication (Table 2). Figure 1a shows preoperative serum creatinine concentrations and their postoperative changes. Figure 1b shows the respective estimated glomerular filtration rate (eGFR), which was calculated by using the “modification of diet in renal disease” (MDRD) formula). Serum creatinine concentrations and the eGFR improved notably within the first 12 months after the operation and then remained stable during the 24-month follow-up period (Table 2).
As the serum creatinine clearance changes due to the loss of muscle mass after Roux-en-Y gastric bypass surgery, we additionally measured serum cystatin C concentrations. These also fell 12 months after Roux-en-Y gastric bypass surgery (from 0.93 ± 0.16 mg/L to 0.84 ± 0.11 mg/L; P = 0.0526) (eFigure 1a). Furthermore, the cystatin C clearance improved within 12 months postoperatively (from 86.5 ± 18.3 mL/min to 98.1 ± 14.0 mL/min; P = 0.0273) (eFigure 1b). Friedman et al. showed that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine cystatin C clearance reflects renal function after bariatric surgery even more precisely; we therefore also calculated this equation (25). This also showed improved measurements 12 months postoperatively (from 90.87 ± 15.96 mL/min to 99.1 ± 9.26 mL/min; P = 0.0009) (eFigure 1c). Two patients (10%) with a preoperative eGFR of <60 mL/min/1.73m2 presented with a normalized eGFR within 12 months postoperatively, which remained stable after 24 months, at >100 ml/L/min/1.73m2.
Figure 2a shows the change in preoperative and postoperative urinary albumin excretion (UAE), which was corrected for the creatinine secretion in the urine. Urinary albumin excretion improved continuously over 24 months postoperatively (from 2.89±3.14 mg/mmol to 1.00 ± 0.24 mg/mmol; P = 0.0491) (Table 2).
Excretion of high molecular weight (HMW) adiponectin (also corrected for urinary creatinine secretion) fell over the entire follow-up period (from 0.18 ± 0.06 µg/g to 0.05 ± 0.01 µg/g; P = 0.0392) (Figure 2b). Total serum adiponectin concentrations rose after Roux-en-Y gastric bypass surgery (eFigure 2a), whereas serum HMW adiponectin concentrations did not change postoperatively (eFigure 2b).
Four patients (20%) had preoperative microalbuminuria (> 2.5 mg/mmol); three of these patients developed normoalbuminuria within a year after Roux-en-Y gastric bypass surgery. In the fourth patient, microalbuminuria improved notably after 24 months, from 10.1 mg/mmol to 3.6 mg/mmol. None of the other patients developed microalbuminuria postoperatively.
The present pilot study shows that Roux-en-Y gastric bypass surgery does not only have a positive effect on renal function, but it also seems that existing diabetic nephropathy improves in patients who are not morbidly obese (BMI 25–35 kg/m2) with long term insulin-dependent type 2 diabetes. As the study cohort is a unique group of patients with an exceptionally high risk for the development and progression of diabetic nephropathy, the achieved results are of great clinical importance.
Most patients with type 2 diabetes have a BMI <35 kg/m2 (26, 27). To date, no effective causal therapeutic options exist for this group of patients and for the treatment of microvascular complications (1, 4). Treatment is limited to protecting renal function by regulating blood pressure and blocking the renin-angiotensin system (1, 11). We showed that the creatinine clearance as well as the cystatin C clearance notably improved after surgery, and that albuminuria decreased steadily over 24 months after surgery. The fact that creatinine clearance and cystatin C clearance both improved confirms that renal function at least stabilized postoperatively and in some cases even improved.
Furthermore, we showed that improvements in creatinine clearance were not caused by a loss in muscle mass. Three out of four patients who had microalbuminuria preoperatively had normal urinary albumin concentrations after 24 months, and in the fourth patient the microalbuminuria reduced by 66%.
In addition to parameters for assessing diabetic nephropathy—such as the urine albumin-to-creatinine ratio—we also studied the measurements of more recent parameters with higher sensitivity for diabetic nephropathy. Total adiponectin and high molecular weight adiponectin were identified as better indicators for terminal renal failure than microalbuminuria alone (28, 29). The mechanism by which high molecular weight adiponectin is excreted in urine is still not known, however. The molecular weight of 360 kDa is much too high to pass through the basement membrane of even severely damaged kidneys. Investigating high molecular weight adiponectin in urine as a sensitive parameter for diabetic nephropathy showed a clear improvement after the operation. These results support our assumption that Roux-en-Y gastric bypass surgery has protective effects in patients with insulin-dependent type 2 diabetes. In sum, in mildly obese patients with type 2 diabetes requiring insulin, Roux-en-Y gastric bypass surgery can help improve blood glucose control and have a positive and stabilizing effect on renal function.
Lifestyle modifications/interventions and weight reduction are the cornerstone of prevention and treatment in type 2 diabetes (30–32). However, these measures are of very limited value in overweight or mildly obese patients. Furthermore, we can assume that the etiology of type 2 diabetes in morbidly obese patients differs from that in less severely obese patients (33). For this reason, the cornerstone of diabetes treatment in mildly obese patients is medication treatment to lower blood glucose concentrations (32). In mildly obese patients with insulin-dependent type 2 diabetes, insulin is therefore the only therapeutic option. The results of this pilot study show, however, that Roux-en-Y gastric bypass surgery represents a new therapeutic option and can be effective even in patients with end organ damage. Surgery should be considered especially in patients with a BMI of 30–35 kg/m2 and type 2 diabetes that is difficult to control by medication; this was the suggestion in a new position paper issued by international diabetes organizations (34). The results so far will, however, have to be confirmed in adequately conducted RCTs (35).
In addition, the follow-up study DiaSurg 2 will specifically investigate possible complications after Roux-en-Y gastric bypass surgery—such as perioperative hemorrhages, anastomotic failure, or late complications such as anastomotic ulcers, stenosis, or internal hernias. Furthermore, the nutritional status of patients after Roux-en-Y gastric bypass surgery should be checked at regular intervals, so as to be able to assess the risk of potential deficiency states. In such patients, iron, selenium, and zinc deficiency has been most commonly observed, which can be remedied by giving oral substitution (24).
In addition to the clinical relevance, these results also allow possible conclusions about the pathogenesis and potential therapeutic options of diabetic renal failure, which are currently the subject of experimental studies. Adiponectin seems to have an essential role in maintaining normal podocyte function and thereby also reduces kidney damage (36, 37). Adiponectin deficiency causes increased glomerular permeability, whereas the external administration of adiponectin has a positive effect on renal function in diabetic adiponectin knockout mice (36). Furthermore, the administration of adiponectin improves podocyte function in mouse models with diabetic renal injury (37).
These experimental results probably reflect the underlying mechanisms of the observed developments after RYMB surgery in the context of the present study. In the patients in this cohort, total adiponectin increased notably after the surgery, which—as shown in experiments by Sharma et al. (36)—may have positively affected podocyte function via the adiponectin receptor 1. The restored podocyte function can be verified on the basis of the urinary excretion of albumin and high molecular weight adiponectin. Especially microalbuminuria, which indicates advanced renal injury, regressed completely in three out of four patients. Although albuminuria did not entirely normalize in the fourth patient, microalbuminuria improved substantially after the operation.
The limitations of this study are its small number of cases—only 20 patients were included—and the lack of a conservatively treated control group. Both issues are, however, the result of this being a pilot study. The small cohort of patients may have resulted in a bias in favor of patients with greater motivation and better compliance, compared with studies including larger numbers of patients. The results of this study are none the less of great clinical relevance. The repeated comparisons of the same patients over a time period of 24 months eliminate interpersonal variance completely. Consequently, clear and meaningful conclusions can be drawn, in spite of the small number of cases. Prospective RCTs and large cohort studies with higher case numbers are urgently needed to confirm the present results. For this reason, we initiated the nationwide, prospective, randomized controlled multicenter DiaSurg 2 study, which investigates the effects of Roux-en-Y gastric bypass surgery on microvascular complications in patients with insulin-dependent type 2 diabetes, and which compares these with patients who receive optimal medication treatment (25).
In addition to a renal protective effect, Roux-en-Y gastric bypass surgery seems to also have the potential to improve already existing diabetic nephropathy. Even in patients with long term insulin-dependent type 2 diabetes, this was shown by the improvements in serum concentrations of creatinine and cystatin C, as well as by the regression of albuminuria and lower urinary excretion of high molecular weight adiponectin. The increase in serum concentrations of adiponectin after Roux-en-Y gastric bypass surgery may be the underlying mechanism by which podocyte function is improved.
This study received funding from the German Research Foundation (DFG) in the context of its special research subject 1118 (spokesman: Prof Dr P Nawroth).
Conflict of interest statement
Prof Müller has received honoraria for advisory board activities from Covidien.
The authors declare that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.
Manuscript received on 1 May 2016, revised version accepted on
21 September 2016.
Translated from the original German by Birte Twisselmann, PhD.
Prof. Dr. med. Beat P. Müller
Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
Im Neuenheimer Feld 110
69120 Heidelberg, Germany
Dr. med. Billeter, PhD; Dr. med. Scheurlen, Prof. Dr. med. Fischer, Dr. med. Schulte, Dr. med. Kenngott, Frau Israel, Herr Knefeli, Prof. Dr. med. Büchler, Prof. Dr. med. Müller
Department of Endocrinology, Metabolism and Clinical Chemistry at Heidelberg University Hospital, Heidelberg: Dr. med. Kopf, Prof. Dr. med. Zeier, Prof. Dr. med. Nawroth
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