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Management of diabetes mellitus in patients with chronic kidney disease

Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 DOI 10.1186/s40842-015-0001-9 Management of diabetes mellitus in patients withchronic kidney disease Allison J. Hahr and Mark E. Molitch* Glycemic control is essential to delay or prevent the onset of diabetic kidney disease. There are a number ofglucose-lowering medications available but only a fraction of them can be used safely in chronic kidney diseaseand many of them need an adjustment in dosing. The ideal target hemoglobin A1c is approximately 7 % but thistarget is adjusted based on the needs of the patient. Diabetes control should be optimized for each individualpatient, with measures to reduce diabetes-related complications and minimize adverse events. Overall care ofdiabetes necessitates attention to multiple aspects, including reducing the risk of cardiovascular disease, and often,multidisciplinary care is needed.
Keywords: Diabetes, Chronic kidney disease, Diabetic kidney disease, Nephropathy, Glycemic control, Hemoglobin A1c diagnosis of diabetes since the onset of diabetes itself is Diabetes mellitus is a growing epidemic and is the most usually known. It typically takes about 5 years for micro- common cause of chronic kidney disease (CKD) and vascular complications to develop. In patients with type 2 kidney failure. Diabetic nephropathy affects approxi- diabetes, screening should begin at initial diagnosis since mately 20–40 % of individuals who have diabetes [ the exact onset of diabetes is often unknown .
making it one of the most common complications re- Diabetic nephropathy can be detected by the measure- lated to diabetes. Screening for diabetic nephropathy ment of urine albumin or serum creatinine, and both along with early intervention is fundamental to delaying tests should be performed at minimum annually its progression in conjunction with providing proper those with abnormal levels should have repeat tests done glycemic control. Given the growing population that is sooner. The first stage of nephropathy is usually the on- now affected by diabetes and thus, nephropathy, know- set of elevated urine albumin which predicts the devel- ledge regarding the safe use of various anti-hyperglycemic opment of CKD and a gradual decline in glomerular agents in those with nephropathy is of importance. In filtration rate (GFR). Some individuals with CKD, how- addition, attention to modification of cardiovascular ever, do not develop elevated urine albumin initially. It is disease (CVD) risk factors is essential. Altogether, know- therefore important that individuals have both blood ledge regarding the prevention and management of dia- and urine screening tests performed. Using both modal- betic nephropathy, along with other aspects of diabetes ities allows for identification of more cases of nephropa- care, is part of the comprehensive care of any patient with thy than using either test alone.
The urine albumin to creatinine ratio can be measured on a spot or timed urine collection such as 4 or 24 h.
Microalbuminuria is defined as >30 mg/g creatinine or Recommendations for nephropathy screening in diabetes 30 mg per 24 h. Clinical-or macro-albuminuria is de- Patients with diabetes should be screened on an annual fined as >300 mg/g creatinine or 300 mg per 24 h. An basis for nephropathy. In individuals with type 1 diabetes, abnormal value should be confirmed on at least one screening for nephropathy should start 5 years after additional urine specimen over a 6 month period. Re-cently, the terms "moderately increased" and "severely * Correspondence: Division of Endocrinology, Metabolism, and Molecular Medicine, " albuminuria have been introduced to replace Northwestern University Feinberg School of Medicine, 645 N. Michigan the terms "microalbuminuria" and "macroalbuminuria".
Avenue, Suite 530, 60611 Chicago, Illinois, USA 2015 Hahr and Molitch; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver applies to the data made available in this article,unless otherwise stated.
Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 Increased albumin excretion is not only a marker for whether risk reduction of diabetic nephropathy persists early diabetic kidney disease but also for increased risk long-term, the EDIC Study demonstrated there were for macrovascular disease Other causes of elevated fewer cases of new microalbuminuria and progression to urine protein should be considered and avoided such as albuminuria in the original intensive group. In this long- infection, strenuous exercise, hypertension, heart failure term follow-up study of the original DCCT treatment and hematuria. The serum creatinine should be used to groups, it was shown that intensive treatment did result estimate GFR and thus, the level of CKD.
in a significant decrease in the development of estimated One must also consider that the development of ne- GFR levels of <60 ml/min/1.73 m2 In patients with phropathy may not be related to the diabetes itself. In type 2 diabetes, the Kumamoto study, UKPDS and Vet- patients with type 1 diabetes, the onset of retinopathy erans Affairs Cooperative studies showed reduction of usually precedes the development of nephropathy. An new onset nephropathy and progression of nephropathy individual who present with nephropathy but no retin- with intensive glycemic control –A systematic re- opathy should have an evaluation for other causes. Re- view and meta-analysis of 7 trials evaluating intensive ferral to a nephrologist should be utilized to establish glucose control on kidney-related end points in patients the cause of nephropathy when this is uncertain. Ne- with type 2 diabetes showed lower risk of developing phrologists are also vital to assist management of com- microalbuminuria and macroalbuminuria. The intensive plications of advancing kidney disease, such as difficult control groups had a median A1c ranging from 6.4– to control hypertension, hyperkalemia and rapid pro- 7.4 %. The A1c difference in the intensive groups com- pared to the control groups ranged from 0.6–2.3 %, with4 of the studies demonstrating an A1c difference of Glycemic control in CKD more than 1 %. The analysis also found there was no Glycemic control is essential to delay the onset of com- benefit in regards to doubling of serum creatinine, devel- plications from diabetes, and it can be challenging for opment of ESRD or death related to kidney disease even the most experienced physician. Blood sugar con- trol in those with CKD adds another level of complexity.
hypoglycemia and mortality in patients with type 2 dia- It requires detailed knowledge of which medications can betes treated with intensive glucose control (mean A1c be safely used and how kidney disease affects metabol- 6.4 % vs. 7.5 %), without any risk reduction on CVD.
ism of these medications. In addition, the glycemic tar- The increased mortality could not be attributed to get needs to be individualized for each patient, hypoglycemia . In the ADVANCE trial, more inten- acknowledging that our ability to interpret the data can sive glycemic control (A1c 6.5 % vs. 7.3 %) showed no be altered in the setting of kidney disease.
reduction in CVD. However, the intensive group had a21 % reduction in nephropathy The VADT study Glycemic goal to attain A1c 7.0 % (intensive group with A1c 6.9 % vs. 8.4 %) also showed Glycemic control is essential to delay or possibly prevent no benefit on CVD risk with stricter glucose control nephropathy. In general, the recommended target A1c for diabetes control by the ADA has been less than or The data clearly show that lowering A1c leads to bene- around 7 % The ADA advises both higher (<8 %) or fit in regards to nephropathy. Benefits in A1c reduction stricter (<6.5 %) A1c goals for certain populations are also seen on rates of retinopathy and neuropathy.
AACE suggests a goal A1c of ≤6.5 % in healthy patients However, the effect of lowering A1c is much less in who are at low risk for hypoglycemia but also acknowl- regards to macrovascular disease. Thus, it is reasonable edges the goals need to be individualized The 2007 that a target A1c 7.0 % offers an optimal risk to benefit Kidney Disease Outcomes Quality Initiative (KDOQI) ratio rather than a target that is considerably lower.
guidelines for Diabetes and CKD endorse a target A1c of<7.0 % but their updated 2012 guidelines instead rec- Glycemic goal in CKD ommend an A1c of 7.0 % [ Lower A1c levels are associated with higher risk of In type 1 diabetes, a number of studies show the de- hypoglycemia which necessitates tailored A1c targets velopment of microalbuminuria is associated with for different individuals. Consequences of hypoglycemia, poorer glycemic control. In the DCCT, intensive therapy which in turn can cause injury, myocardial infarction, in patients with type 1 diabetes (mean A1c 9.1 % vs.
seizure, stroke or death, are greatest in those who are 7.2 %) reduced the occurrence of microalbuminuria by frail and elderly, with erratic eating habits, on insulin 34 % in the primary prevention group and 43 % in the and sulfonylureas, and with CKD. Higher A1c targets secondary intervention group (who had known early should be considered for those with shortened life ex- complications at baseline); risk reduction in progression pectancies, a known history of severe hypoglycemia or to clinical albuminuria was also seen To assess hypoglycemia unawareness, CKD, as well as in children.
Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 The Controversies Conference on Diabetic Kidney All available insulin preparations can be used in pa- Disease (DKD) held by KDIGO addressed a number of tients with CKD, and there is no specified advised reduc- issues surrounding DKD, including appropriate glycemic tion in dosing for patients on insulin. The insulin type, control targets There are insufficient data and trials dose and administration must be tailored to each patient regarding the ideal glucose target in patients with CKD to achieve goal glycemic levels but limit hypoglycemia.
stage 3 or worse. One study showed that A1c levels An inpatient study randomizing weight-based basal and >9 % and < 6.5 % were associated with increased mortal- bolus insulin in patients with a GFR <45 mL/min/ ity in the presence of non-dialysis dependent CKD stage 1.73 m2 to 0.5 units/kg body weight vs. 0.25 units/kg 3 or worse ESRD patients with diabetes benefit showed similar glycemic control but significantly less from maintaining their A1c between 7–8 %, as A1c hypoglycemia in the group with the lower weight-based levels above 8 % or below 7 % carry increased risks of all-cause and cardiovascular death A recent ob- The rapid-acting insulin analogs aspart, lispro and servational study found patients who started dialysis at a glulisine are the quickest absorbed and are ideal for younger age (<60 years old) had poorer survival with rapid correction of elevated blood sugars or for prandial A1c >8.5 % (HR 1.5 compared to those with A1c 6.5– insulin needs; they most resemble physiologic insulin se- 7.4 %); there was no difference in older patients cretion. They have an onset of action at 5–15 min, peakaction at 30–90 min and an average duration of 5 h.
Some studies have shown glulisine has a slightly longer The hemoglobin A1c can be inaccurate in some patients duration of action than the other two rapid-acting insu- with kidney disease. Contributing factors include anemia lins. These insulins can be given up to 15 min prior to from reduced lifespan of the red blood cell, hemolysis eating. They are used in "basal-bolus therapy", also and iron deficiency; falsely increased levels can occur known as multiple daily injections (MDI), as well as in from carbamylation of hemoglobin and the presence of continuous subcutaneous insulin infusions, also known acidosis. Fructosamine and glycated albumin are alterna- as insulin pumps. The approximate retail cost per vial is tive measures available to estimate glycemic control.
Fructosamine reflects the glycation of multiple serum Patients with Stage 4–5 CKD and those on dialysis proteins whereas glycated albumin reflects glycation of often have some delayed gastric emptying; giving rapid- only albumin; both provide an estimate of control over acting insulin after the meal may be helpful for match- the past 2 weeks. It is unclear if they offer superior mea- ing the insulin peak with the time of the postprandial sures of glucose control compared to A1c in patients blood glucose peak. In patients with nausea who may with CKD. Some studies suggest glycated albumin is su- not know how much they will eat, postprandial rapid- perior to A1c in dialysis patients since A1c tends to acting insulin dosing may be worth trying. Similarly, underestimate glycemic control in those with ESRD, but patients on peritoneal dialysis obtain large amounts of others argue that A1c remains the gold standard in these calories from their dialysis fluid and often eat less than they might expect so that postprandial dosing may behelpful for them also.
The short-acting insulin available is regular crystal- Medical therapy in diabetic nephropathy line insulin, which has an onset of action at 30–60 min, Medical therapy for diabetes is continually changing as peak action at 2–3 h and duration up to 5–8 h. Regular new therapies become available for use and new updates insulin should ideally be given 30 min prior to a meal.
are available that add to our knowledge of the safety The main advantage of regular insulin is its substantially profile of available medications. Please refer to Table lower cost compared to the rapid-acting analogs. Regular for adjustments in dosing for diabetes medications used insulin costs about $90 per vial ].
The available intermediate-acting insulin is isophane, or NPH. It has an onset of action at 2–4 h, peak concen- tration at 4–10 h and duration up to 10–18 h. In order Patients with progression of kidney disease are at in- to achieve adequate basal coverage, it is dosed twice creased risk of hypoglycemia due to decreased clearance daily. Its use can be limited by its highly variable absorp- of insulin and some medications used to treat diabetes tion. Its cost is similar to that of Regular insulin.
as well as impairment of renal gluconeogenesis from The long-acting insulin analogs are glargine and lower kidney mass. The kidney is responsible for about detemir. Glargine has an onset of action at 2–4 h, with 30 to 80 % of insulin removal; reduced kidney function minimal peak and duration of 20–24 h; it is usually is associated with a prolonged insulin half-life and a de- dosed once daily. A unique property of glargine is that it crease in insulin requirements as GFR declines does not have a clear peak. Detemir has an onset of Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 Table 1 Dose adjustment for insulin compounds and Table 1 Dose adjustment for insulin compounds and medications for diabetes in CKD medications for diabetes in CKD (Continued) CKD stages 3 and 4 and predialysis stage 5 eGFR 30–49: 50 mg daily eGFR < 30: 25 mg daily No advised dose adjustment* eGFR > 50: 2.5 or 5 mg daily No advised dose adjustment* GFR ≤ 50: 2.5 mg daily No advised dose adjustment* No dose adjustment No advised dose adjustment* eGFR >60: 25 mg daily No advised dose adjustment* eGFR 30–59: 12.5 mg daily No advised dose adjustment* eGFR <30: 6.25 mg daily No advised dose adjustment* eGFR 45 to < 60: max dose 100 mg once daily eGFR <45, avoid use eGFR < 60, avoid use eGFR 50–80: reduce dose by 50 % eGFR < 45, avoid use eGFR <50: avoid use Dopamine receptor No dose adjustment known but not studied: eGFR <30: use with caution eGFR <60: use with caution No dose adjustment known but limited data eGFR <30: avoid use eGFR 30–50: use caution No dose adjustment eGFR <30: avoid use No dose adjustment but use caution whenstarting or titrating the dose No dose adjustment but may wish to usecaution with eGFR <30 No dose adjustment needed eGFR <60: avoid use (but may consider No dose adjustment needed use if patient is on hemodialysis) No dose adjustment known but not studied Per FDA, do not use if serum Cr ≥ 1.5 mg/dL in men ≥ 1.4 mg/dL in women.
*Adjust dose based on patient response **Not available in the U.S.
***Recommendations are controversial eGFR ≥45-59: use caution with dose and followrenal function closely (every 3–6 months) eGFR ≥30-44: max dose 1000 mg/day or use action at 1–3 h, with a small peak at 6–8 h and duration 50 % dose reduction. Follow renal function of action of 18–22 h. Detemir is dosed twice daily to give every 3 months. Do not start as new therapy.
adequate basal coverage in type 1 diabetes; in type 2 dia- eGFR <30: avoid use betes, once daily dosing sometimes is sufficient. The ap- proximate retail price is $160-190 per vial for determir No dose adjustment and glargine insulins There are various premixed preparation of insulin No dose adjustment that have a fixed percentage of an intermediate-acting and a rapid-or short-acting insulin. Because they containa combination of 2 insulins, they have two separate serum Cr >2 mg/dl: avoid use peaks. One example is "70/30" which is 70 % NPH and eGFR <25 or serum Cr >2 mg/dl: avoid use 30 % regular insulin. These preparations offer conveni- ence for the patient with twice daily dosing but offer less eGFR ≥50: 100 mg daily flexibility and more restrictions in titration of the insu-lin. It must be taken at fixed times and the patient must Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 have consistent meals. 70/30 insulin is sometimes help- metformin but take caution with dosing and follow the ful in patients getting 12-hours cycled tube feeds.
renal function more closely, such as every 3 to 6 months.
All insulin is U-100, which is defined as 100 units of If the eGFR is ≥30–44 ml/min/1.73 m2, again use cau- insulin/ml. The exception is insulin U-500 which is 500 tion with dosing, such as limiting its dose to a maximum units of insulin/ml and is only available as regular insu- of 1000 mg daily or using a 50 % reduction, follow renal lin. The high concentration of U-500 insulin alters the function every 3 months and avoid newly initiating met- properties of regular insulin so its pharmacokinetics are formin in patients with this level of CKD. Metformin different. It has a similar onset of action, near 30 min, should be avoided with eGFR <30 ml/min/1.73 m2. It is but the peak is at 4–8 h and duration is 14–15 h. It can recommended that metformin be stopped in the pres- be given up to 30 min prior to meals and is typically ence of situations that are associated with hypoxia or an given two to three times daily, without the use of a basal acute decline in kidney function such as sepsis/shock, insulin . It is generally used in patients who are se- hypotension, acute myocardial infarction, and use of verely insulin resistant and can be used as a subcutane- radiographic contrast or other nephrotoxic agents [ ous injection or in a pump.
This approach has been accepted by various soci-eties including KDIGO and confirmed in additional studies The KDIGO Controversies Conference proposed a change to the FDA guidelines Metformin increases insulin sensitivity and decreaseshepatic gluconeogenesis; it does not cause hypoglycemia and may lead to weight loss in some patients. It reduces Sulfonylureas bind to the sulfonylurea receptor on the A1c by 1.0–2.0 % [The most common side effects pancreatic beta-cells and lead to increased insulin secre- are diarrhea, bloating and cramping. Vitamin B12 defi- tion. They typically lower A1c by 1.5–2 % and can cause ciency has been reported with extended use The hypoglycemia. The first-generation sulfonylureas are estimated cost for metformin is about $50 for one rarely prescribed. The second-generation sulfonylureas, month of the 500 mg dose which include glipizide, glimepiride, glyburide, and gli- The FDA recommends that metformin should not be clazide (the latter is not available in the U.S.), are com- used with serum creatinine ≥ 1.5 mg/dl in men and ≥ monly used. The sulfonylureas will decrease A1c by 1– 1.4 mg/dl in women or with decreased creatinine clear- 2 % The estimated cost for one month of glipizide ance in people over age 80. Because metformin is renally and glyburide (5 mg) and glimepiride (2 mg) ranges cleared, this recommendation is in place to reduce the from $10 to $30 [ risk of lactic acidosis in individuals with even modest Sulfonylureas and their metabolites are renally cleared, renal impairment The overall incidence of lactic leading to an increased risk of hypoglycemia as GFR de- acidosis with metformin use, however, appears to be clines. Hypoglycemia is greatly increased with glimepir- rare. A Cochrane database review of 347 prospective ide and glyburide with GFR <60 ml/min/1.73 m2 due to trials and observational cohort studies showed no cases the presence of two active metabolites cleared in part by of fatal or non fatal lactic acidosis in 70,490 patient- the kidney Glyburide should be avoided with eGFR years of metformin users or in 55,451 patient-years of <60 ml/min/1.73 m2 Glimepiride should be used users of other anti-hyperglycemic agents [In a study with caution if the eGFR is <60 ml/min/1.73 m2 and not evaluating metformin-associated lactic acidosis in 14 be used with eGFR <30 ml/min/1.73 m2 Less than patients, other causes of lactic acidosis (including clinical 10 % of glipizide is cleared renally but it should still be shock or tissue hypoxia) were noted and seemed to be used with caution with an eGFR <30 ml/min/1.73 m2 the driving cause and not specifically metformin; 10 of due to the risk of hypoglycemia these patients did have metformin accumulation relatedto elevated serum creatinine (range 3.05-11.8 mg/dl) whereas 4 patients, all with lower creatinine levels Nateglinide and repaglinide, like sulfonylureas, increase though still reduced GFR, had no evidence of metformin insulin secretion by closing a sulfonylurea receptor/ ATP-dependent potassium channel on the beta-cells of Given the differences in translation of creatinine into the pancreas. They have a shorter half-life compared to creatinine clearance based on age, weight and race, it is the sulfonylureas. They result in a rapid and short dur- reasonable to consider use of a GFR-based guideline ation of insulin release and should be taken prior to such as outlined here rather than one based on creatin- meals. They also can cause hypoglycemia The gli- ine alone. Metformin can be used without dose reduc- nides reduce A1c on average by 0.5–1.5 % ] and have tion with an eGFR >60 ml/min/1.73 m2. If the eGFR is an estimated cost of $90 per month (for repaglinide ≥45–59 ml/min/1.73 m2, it is prudent to continue use of 1 mg, and $60 per month for nateglinide 120 mg) Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 The active metabolite of nateglinide accumulates in medication has been studied long-term in patients with CKD; nateglinide should not be used with an eGFR a creatinine >2 mg/dl, so their use should be avoided in <60 ml/min/1.73 m2. The active metabolite is cleared, these patients.
however, by hemodialysis so nateglinide can be used inthose undergoing dialysis ]. Conversely, repaglinide Dipeptidyl peptidase-4 inhibitors appears safe to use in individuals with CKD How- Dipeptidyl peptidase 4 (DPP 4) inhibitors decrease the ever, it is reasonable to exercise caution in those with breakdown of incretin hormones such as GLP-1 and in- more severe renal dysfunction, such as an eGFR <30 ml/ clude sitagliptin, saxagliptin, linagliptin, and alogliptin.
min/1.73 m2, and start at the lowest dose (0.5 mg) with This class of medication is weight-neutral and decreases slow upwards titration.
A1c by 0.5–0.8 % []. One month of 50 mg sitaglipitinor 5 mg saxagliptin is about $280 Approximately 80 % of sitagliptin is cleared by the Thiazolidinediones (pioglitazone, rosiglitazone) increase kidney; with an eGFR of ≥30 to <50 ml/min/1.73 m2, insulin sensitivity by acting as PPARγ agonists. They do 50 mg once daily should be used and with an eGFR not cause hypoglycaemia and they lead to an A1c de- <30 ml/min/1.73 m2, a dose of 25 mg once daily is- crease of 0.5–1.4 % [They are metabolized by the advised [Saxagliptin also needs a dose reduction liver and can be used in CKD. However, fluid retention with eGFR ≤ 50 ml/min/1.73 m2 to 2.5 mg daily; is a major limiting side effect and they should not be otherwise, the standard dose with eGFR >50 ml/min/ used in advanced heart failure. This also makes their use 1.73 m2 is 2.5 or 5 mg daily. Only a small amount of in CKD, particularly patients on dialysis, limiting. They linagliptin is cleared renally; thus, no dose adjust- have been linked with increased fracture rates and bone ment is indicated with a reduced GFR [Aloglip- loss, thus use in patients with underlying bone disease tin also needs a dose reduction from the baseline (such as renal osteodystrophy) needs to be considered.
dose of 25 mg daily to 12.5 mg daily with an eGFR No dose adjustment is indicated with either in CKD.
< 60 ml/min/1.73 m2 and then to 6.25 mg daily with One month of 15 mg of pioglitazone costs about $260 an eGFR < 30 ml/min/1.73 m2.
and 2 mg of rosiglitazone costs about $100 InSeptember 2010, the FDA restricted use of rosiglitazonebased on studies linking it to increased cardiovascular Sodium-glucose co-transporter 2 (SGLT2) inhibitors events. Upon further review, these restrictions were SGLT2 inhibitors reduce glucose absorption from the lifted in 2014.
kidney, leading to an increase in glucose excretion and An association between pioglitazone and bladder can- a reduction in A1c of about 0.9–1.0 % The in- cer has been raised but further analysis and investigation crease in urine glucose can result in a weight loss of up into the data shows that this association is not clearly to 5 kg in one year. Because of an increase in adverse supported A recent pooled multi-population ana- events related to intravascular volume contraction, no lysis also showed no association between the thiazolidi- more than 100 mg once daily of canagliflozin should nediones and bladder cancer be used in patients with an eGFR of 45 to < 60 ml/min/1.73 m2. Its use should be avoided if the eGFR is <45 ml/min/1.73 m2 because of an increase in adverse Alpha-glucosidase inhibitors (acarbose, miglitol) de- events as well as reduced efficacy. Dapagliflozin is not crease the breakdown of oligo-and disaccharides in the approved for use if the eGFR is < 60 ml/min/1.73 m2 small intestine, slowing ingestion of carbohydrates and but empagliflozin can be used down to an eGFR of delaying absorption of glucose after a meal. The major 45 ml/min/1.73 m2 ml/min/1.73 m2. Costs for 30 days side effects are bloating, flatulence, and abdominal of the lowest doses of these drugs are in the $350–400 cramping. They typically lower A1c by 0.5–0.8 % and usually do not lead to weight gain or loss The ap-proximate cost for one month of 25 mg of either dose is Other oral medications about $30 (acarbose) to $250 (miglitol) Bromocriptine (dopamine receptor agonist) has not been Acarbose is minimally absorbed with <2 % of the drug adequately studied in CKD.
and active metabolites present in the urine. With re- Colesevelam (bile acid sequestrant) shows no differ- duced renal function, serum levels of acarbose and me- ence in efficacy or safety in those with an eGFR <50 ml/ tabolites are significantly higher. Miglitol has greater min/1.73 m2 but data are limited as it has not been ad- systemic absorption with >95 % renal excretion. It is equately studied in more advanced CKD. A one month recommended that use of miglitol be avoided if the supply of the 625 mg tablets (6 tablets per day must be GFR is <25 ml/min/1.73 m2 . Additionally, neither taken) is about $420.
Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 Other subcutaneous medications complications is universal. The medication regimen is Glucagon-like peptide 1 (GLP-1) Receptor Agonists based on the comfort of the patient and physician and Exenatide (regular and extended-release) and liraglutide should be individualized, especially as renal function are injectable medications that mimic gut hormones known as incretins, leading to insulin release, delayed For those who need insulin, MDI with an average of 4 glucagon secretion and delayed gastric emptying. They daily injections is common. The closest approximation are FDA approved for use with metformin and/or sulfo- of physiologic insulin secretion can be achieved with an nylureas although in practice, they are also used with in- insulin pump delivering a continuous subcutaneous in- sulin. They contribute to central satiety leading to a fusion. A single type of insulin is used in the pump such reduction in appetite and often weight loss. The average as a rapid-acting analog that serves as the basal, bolus expected A1c decrease is 0.5–1.0 % [The costs of and correction insulin. Insulin pumps require vigilance exenatide regular-release is about $385 for a 10 mcg pen on the part of the patient and their use should be and $596 for 3 pens of the liraglutide Both agents overseen by endocrinologists and experienced diabetes have been associated with pancreatitis, and nausea is a common side effect that can limit its use. In addition, Continuous Glucose Monitoring Systems (CGMS) are liraglutide has been associated with the development of available that can continually measure glucose levels. A thyroid C-cell tumors in animal studies and thus should small plastic catheter is inserted subcutaneously and not be given to patients with or at risk for medullary measures glucose every 5 min. Patients can view this in thyroid cancer. Exenatide is given twice daily and liraglu- real-time and detect upward and downward trends in tide is given once daily; exenatide extended-release is glucose. The added benefit is that alarms for high and dosed once weekly. Albiglutide and dulaglutide are other low readings can be set.
GLP-1 receptor agonists that can also be dosed once In addition to glucose control, a comprehensive ap- proach to care is encouraged. Behavioral modification Clearance of exenatide decreases with declines in GFR and lifestyle changes are important to control weight, Additionally, in a case report of a patient with renal improve nutrition, modify dietary intake and monitor impairment and CKD, use of exenatide led to a rise in glucose levels. Appropriate medication should be used serum creatinine that resolved when the medication was for treatment of nephropathy, in conjunction with a stopped The FDA reported cases of acute renal fail- nephrologist as appropriate. Close attention should also ure associated with exenatide use and recommends it be be paid to blood pressure control. Diabetes in itself is a used with caution in those with a GFR of 30–50 ml/ major cause of cardiovascular disease and individuals min/1.73 m2 and not be used if the GFR is <30 ml/min/ with CKD often die of CVD; it is the major cause of 1.73 m2 Liraglutide is not metabolized primarily by death in this population. The presence of microalbumi- the kidney; no dose adjustment is indicated in those with nuria, albuminuria and declining GFR are all known renal impairment, including ESRD, although data in this predictors of CVD. The combination of diabetes and population are limited No dosage restrictions are CKD is particularly powerful in regards to CVD risk, needed for albiglutide or dulaglutide with decreasing necessitating aggressive control of risk factors [In GFR The manufacturer has reported cases of addition to hypertension, dyslipidemia and weight con- renal failure and worsening of chronic renal impairment trol should be addressed. Nutrition plays an important with its use and advises caution with initiating or in- role in individuals with diabetic kidney disease as a bal- creasing the dose in those with nephropathy.
ance of multiple dietary factors including sodium, po-tassium, phosphorus, and protein intake must be followed as well as intake of carbohydrates and un- Pramlintide is also an injectable medication that is used healthy fats. Reduction in weight in patients who are with meals as an adjunct to insulin therapy in both type 1 overweight or obese and increases in exercise are gener- and type 2 diabetes. Amylin is secreted along with insulin ally recommended, keeping in mind the need for cardiac by pancreatic beta-cells and levels are low in patients with stress testing. It is helpful to use an experienced diet- diabetes. It typically reduces A1c by 0.5–1.0 % [with a ician and certified diabetes educator to safely attain cost of about $400 for two of the 1.5 mL pens (1000 mcg/ dietary, exercise and weight loss goals. The KDIGO mL) []. No dose adjustment appears necessary for CKD; Controversies Conference addresses some of the issues it has not been studied in ESRD.
surrounding diabetic kidney disease management in-cluding management of dyslipidemia and blood pres- Strategy for glycemic control and other risk factors sure control [The American Diabetes Association The primary goal of optimizing glycemic control to reduce also has recommendations on management of blood the development of microvascular and macrovascular pressure and dyslipidemia [ Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 Medical therapy in dialysis and post-transplant patients There are a few oral agents that can be used safely in CKD: Chronic kidney disease; CVD: Cardiovascular disease; GFR: Glomerularfiltration rate; DKD: Diabetic kidney disease; MDI: Multiple daily injections; patients on dialysis, particularly if the diabetes is fairly CSII: Continuous subcutaneous insulin infusion; DPP4: Dipeptidyl peptidase-4 mild. Most others, however, will need insulin for gly- inhibitors; SGLT2: Sodium-glucose co-transporter 2; GLP1: Glucagon-like cemic control.
peptide 1; HD: Hemodialysis; PD: Peritoneal dialysis.
Patients receiving hemodialysis (HD) can have differ- Competing interests ent clearance rates of insulin that may be affected by the The authors declare that they have no competing interests.
timing of dialysis. We have done continuous glucosemonitoring on patients undergoing HD and found that Authors' contributions patients' glycemic responses during HD are quite idio- AH and MM participated in the organization of the manuscript and draftedthe manuscript. Both authors read and approved the final manuscript.
syncratic and their insulin regimens need to be individu-alized to avoid both hyper-and hypoglycemia during and Received: 6 November 2014 Accepted: 3 February 2015 after HD. Patients who are on peritoneal dialysis (PD)have exposure to large amounts of glucose in the dialys- ate that can lead to uncontrolled hyperglycemia. In pa- ADA. Microvascular complications and foot care. Sec. 9. In standards of tients receiving PD continuously, a standard basal/bolus medical care in diabetes - 2015. Diabetes Care. 2015;38:S58–66.
KDOQI (Kidney Disease Outcomes Quality Initiative). Clinical practice insulin regimen is best. However, with overnight PD guidelines and clinical practice recommendations for diabetes and chronic using a cycler, coverage of the increased glucose load kidney disease. Am J Kidney Dis. 2007;49:S12–154.
may best be accomplished using a fixed mixture insulin ADA. Glycemic targets. Sec. 6. In standards of medical care in diabetes - 2015.
Diabetes Care. 2015;38:S33–40.
combination, such as 70/30 or 75/25 insulins, given at Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, the onset of PD. The nephrologist prescribing the PD et al. AACE comprehensive diabetes management algorithm 2013. Endocr will often change the glucose concentration of the KDOQI (Kidney Disease Outcomes Quality Initiative). Clinical Practice Guideline dialysate because of the need for more or less fluid for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012, 60:850–886.
removal and such changes need to be discussed with the DCCT. The effect of intensive treatment of diabetes on the development endocrinologist so that the insulin doses may be appro- and progression of long-term complications in insulin-dependent diabetesmellitus. The Diabetes Control and Complications Trial Research Group.
priately changed.
N Engl J Med. 1993;329:977–86.
In the immediate post-transplant period, glycemic DCCT. Effect of intensive therapy on the development and progression of control can acutely decline. This is due to the diabetic nephropathy in the Diabetes Control and Complications Trial. TheDiabetes Control and Complications (DCCT) Research Group. Kidney Int.
initiation of anti-rejection therapies including gluco- corticoids, calcineurin inhibitors and sirolimus, and EDIC. Sustained effect of intensive treatment of type 1 diabetes mellitus on an increase in insulin resistance. In addition, patients development and progression of diabetic nephropathy: the Epidemiologyof Diabetes Interventions and Complications (EDIC) study. JAMA.
may experience other fluctuations in their daily routines including adjustments in diet, activity and Levin SR, Coburn JW, Abraira C, Henderson WG, Colwell JA, Emanuele NV, medications. Because many variables are present, gly- et al. Effect of intensive glycemic control on microalbuminuria in type 2diabetes. Veterans Affairs Cooperative Study on Glycemic Control and cemic control can fluctuate quite a bit, and close Complications in Type 2 Diabetes Feasibility Trial Investigators. Diabetes monitoring of blood glucose levels and adjustments of medications are needed.
Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensiveinsulin therapy prevents the progression of diabetic microvascular complicationsin Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–17.
The management of patients with diabetes and nephrop- UKPDS. Intensive blood-glucose control with sulphonylureas or insulincompared with conventional treatment and risk of complications in patients athy necessitates attention to several aspects of care.
with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Importantly, glycemic control should be optimized for Group. Lancet. 1998;352:837–53.
the patient, attaining the necessary control to reduce Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensiveglucose control in development of renal end points in type 2 diabetes complications but done in a safe, monitored manner.
mellitus: systematic review and meta-analysis intensive glucose control in Screening for development of nephropathy should be type 2 diabetes. Arch Intern Med. 2012;172:761–9.
performed on a regular basis to identify microalbumi- Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects ofintensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
nuria or reductions in GFR and if identified, the diabetes Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al.
regimen should be tailored accordingly. Prevention and Intensive blood glucose control and vascular outcomes in patients with treatment of diabetic nephropathy and other complica- type 2 diabetes. N Engl J Med. 2008;358:2560–72.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al.
tions necessitates a multifactorial approach through the Glucose control and vascular complications in veterans with type 2 use of a diabetologist, nephrologist, dietician, diabetes diabetes. N Engl J Med. 2009;360:129–39.
educator and additional specialists experienced in the Molitch ME, Adler AI, Flyvbjerg A, Nelson RG, So WY, Wanner C, et al.
Diabetic kidney disease: a clinical update from Kidney Disease: Improving complications of diabetes to provide a multifaceted care Global Outcomes. Kidney Int. 2015;87(1):20-30. doi: 10.1038/ki.2014.128.
program to reduce progression of disease.
Epub 2014 Apr 30.
Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2 Shurraw S, Hemmelgarn B, Lin M, Majumdar SR, Klarenbach S, Manns B, Balant L, Zahnd G, Gorgia A, Schwarz R, Fabre J. Pharmacokinetics of et al. Association between glycemic control and adverse outcomes in glipizide in man: influence of renal insufficiency. Diabetologia. 1973:331–8.
people with diabetes mellitus and chronic kidney disease: a population-based Arjona Ferreira JC, Marre M, Barzilai N, Guo H, Golm GT, Sisk CM, et al.
cohort study. Arch Intern Med. 2011;171:1920–7.
Efficacy and Safety of Sitagliptin Versus Glipizide in Patients With Type 2 Ricks J, Molnar MZ, Kovesdy CP, Shah A, Nissenson AR, Williams M, et al.
Diabetes and Moderate-to-Severe Chronic Renal Insufficiency.
Glycemic control and cardiovascular mortality in hemodialysis patients with Diabetes Care. 2013;36(5):1067-73. doi: 10.2337/dc12-1365. Epub 2012 Dec 17.
diabetes: a 6-year cohort study. Diabetes. 2012;61:708–15.
Melander A. Kinetics-effect relations of insulin-releasing drugs in patients Ramirez SP, McCullough KP, Thumma JR, Nelson RG, Morgenstern H, with type 2 diabetes: brief overview. Diabetes. 2004;53 Suppl 3:S151–5.
Gillespie BW, et al. Hemoglobin A(1c) levels and mortality in the diabetic Inoue T, Shibahara N, Miyagawa K, Itahana R, Izumi M, Nakanishi T, et al.
hemodialysis population: findings from the Dialysis Outcomes and Practice Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 Patterns Study (DOPPS). Diabetes Care. 2012;35:2527–32.
diabetes mellitus and renal failure. Clin Nephrol. 2003;60:90–5.
Adler A, Casula A, Steenkamp R, Fogarty D, Wilkie M, Tomlinson L, et al.
Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic patients Association between glycemia and mortality in diabetic individuals on renal with and without impaired renal function. Diabetes Care. 2003;26:886–91.
replacement therapy in the U.K. Diabetes Care. 2014;37:1304–11.
Ryder RE. Pioglitazone has a dubious bladder cancer risk but an undoubted Freedman BI, Shenoy RN, Planer JA, Clay KD, Shihabi ZK, Burkart JM, et al.
cardiovascular benefit. Diabetic Med. 2015;32(3):305-13. doi: 10.1111/dme.12627.
Comparison of glycated albumin and hemoglobin A1c concentrations in Epub 2014 Dec 3.
diabetic subjects on peritoneal and hemodialysis. Perit Dial Int. 2010;30:72–9.
Levin D, Bell S, Sund R, Hartikainen SA, Tuomilehto J, Pukkala E, et al.
Kalantar-Zadeh K. A critical evaluation of glycated protein parameters in Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative advanced nephropathy: a matter of life or death: A1C remains the gold exposure analysis. Diabetologia. 2015;58(3):493-504. doi: 10.1007/s00125-014-3456-9.
standard outcome predictor in diabetic dialysis patients. Counterpoint.
Epub 2014 Dec 7.
Diabetes Care. 2012;35:1625–8.
Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in Freedman BI. A critical evaluation of glycated protein parameters in patients with diabetes mellitus and advanced kidney disease. Semin Dial.
advanced nephropathy: a matter of life or death: time to dispense with the hemoglobin A1C in end-stage kidney disease. Diabetes Care. 2012;35:1621–4.
Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, et al. Effect of renal Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin.
insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30:1862–4.
Baldwin D, Zander J, Munoz C, Raghu P, DeLange-Hudec S, Lee H, et al.
Graefe-Mody U, Friedrich C, Port A, Ring A, Retlich S, Heise T, et al. Effect of A randomized trial of two weight-based doses of insulin glargine and renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 glulisine in hospitalized subjects with type 2 diabetes and renal insufficiency.
inhibitor linagliptin(*). Diabetes Obes Metab. 2011;13:939–46.
Diabetes Care. 2012;35:1970–4.
Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Epocrates Online. Their Basic and Clinical Pharmacology. Diabetes Ther. 2014;5:355–66.
de la Pena A, Riddle M, Morrow LA, Jiang HH, Linnebjerg H, Scott A, et al.
Linnebjerg H, Kothare PA, Park S, Mace K, Reddy S, Mitchell M, et al. Effect Pharmacokinetics and pharmacodynamics of high-dose human regular of renal impairment on the pharmacokinetics of exenatide. Br J Clin U-500 insulin versus human regular U-100 insulin in healthy obese subjects.
Diabetes Care. 2011;34:2496–501.
Johansen OE, Whitfield R. Exenatide may aggravate moderate diabetic renal Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al.
impairment: a case report. Br J Clin Pharmacol. 2008;66(4):568-9.
Medical management of hyperglycemia in type 2 diabetes: a consensus doi: 10.1111/j.1365-2125.2008.03221.x. Epub 2008 May 15.
algorithm for the initiation and adjustment of therapy: a consensus statement US Food and Drug Administration. Information for Healthcare Professionals: of the American Diabetes Association and the European Association for the Reports of Altered Kidney Function in patients using Exenatide (Marketed as Study of Diabetes. Diabetes Care. 2009;32:193–203.
Byetta). 2009.
Wile DJ, Toth C. Association of Metformin, Elevated Homocysteine, and Davidson JA, Brett J, Falahati A, Scott D. Mild renal impairment and theefficacy and safety of liraglutide. Endocr Pract. 2011;17:345–55.
Methylmalonic Acid Levels and Clinically Worsened Diabetic PeripheralNeuropathy. Diabetes Care. 2010;33:156–61.
Albiglutide Full Prescribing Information. 2014. Sambol NC, Chiang J, Lin ET, Goodman AM, Liu CY, Benet LZ, et al. Kidney function and age are both predictors of pharmacokinetics of metformin.
Dulaglutide Full Prescribing Information. 2015. J Clin Pharmacol. 1995;35:1094–102.
Chang YT, Wu JL, Hsu CC, Wang JD, Sung JM. Diabetes and end-stage renal Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal disease synergistically contribute to increased incidence of cardiovascular lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane events: a nationwide follow-up study during 1998–2009. Diabetes Care.
Database Syst Rev. 2010;14(4):CD002967.
Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP, Bleichner G, et al.
ADA. Cardiovascular disease and risk management. Sec. 8. In standards of Role of metformin accumulation in metformin-associated lactic acidosis.
medical care in diabetes - 2015. Diabetes Care. 2015;38:S49–57.
Diabetes Care. 1995;18:779–84.
Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patientswith type 2 diabetes and kidney disease: a systematic review. JAMA.
Herrington WG, Levy JB. Metformin: effective and safe in renal disease? IntUrol Nephrol. 2008;40:411–7.
Eppenga WL, Lalmohamed A, Geerts AF, Derijks HJ, Wensing M, Egberts A, Submit your next manuscript to BioMed Central
et al. Risk of lactic acidosis or elevated lactate concentrations in metformin and take full advantage of:
users with renal impairment: a population-based cohort study. DiabetesCare. 2014;37:2218–24.
• Convenient online submission
Richy FF, Sabido-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U.
Incidence of lactic acidosis in patients with type 2 diabetes with and • Thorough peer review
without renal impairment treated with metformin: a retrospective cohort • No space constraints or color figure charges
study. Diabetes Care. 2014;37:2291–5.
Holstein A, Plaschke A, Hammer C, Ptak M, Kuhn J, Kratzsch C, et al.
• Immediate publication on acceptance
Hormonal counterregulation and consecutive glimepiride serum • Inclusion in PubMed, CAS, Scopus and Google Scholar
concentrations during severe hypoglycaemia associated with glimepiride • Research which is freely available for redistribution
therapy. Eur J Clin Pharmacol. 2003;59:747–54.
Holstein A, Beil W. Oral antidiabetic drug metabolism: pharmacogenomicsand drug interactions. Expert Opin Drug Metab Toxicol. 2009;5:225–41.
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Chapter 3 - media components and preparation

Media Components The selection or development of the culture medium is vital to success in tissue culture. No single medium will support the growth of all cells, and changes in the medium are often necessary for different types of growth response from a single explant. A literature search is useful for selecting the appropriate medium.provide a useful guide on examining the effect of plant growth regu-lators, salt composition of the basal medium and a statistical analysis of the results. Likewise,can provide a guide for studying the effects of the MS inorganic salts on explant growth. If literature on the plant is not available, the development of a suitable medium is based on trial and error. The approach to developing the medium will depend on the purpose of the cell culture. Many of the media outlined in this manual can serve as useful starting points in developing a medium for a specific purpose, whether it is callus induction, somatic embryo-genesis, anther culture, or shoot proliferation.

Patient Phone (Day): Physician Signature: q PACSCube CD-Rq CareGate Clinical Information/ Diagnosis: q Send CD by courier q Send CD w/patientq Call physician w/appt time q Fax physician w/appt time Are you aware if the patient has M. Tuberculosis: q YES q NO q Call if patient reschedules Does your patient have a pacemaker: q YES q NOAppointment Date and Time: IV Contrast used at the discretion of the radiologist unless otherwise indicated.