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  4. Review: SGLT2 Inhibitors Provide Clear Renal Benefits in Type 2 Diabetes

It is well known that there remains considerable variation in care and outcomes across the NHS, despite evidenced based guidance. It is essential that unwarranted variation is addressed to ensure equity of treatment and efficient resources utilisation. Peer review and learning can be a helpful method to highlight different approaches to care, with learning from each other and mutual support.

An outcome based peer review was therefore performed by all specialised commissioned renal services in the seven West Midlands renal units in October In total this covers over adult patients receiving renal replacement therapy as a transplant or dialysis, plus many more approaching the need for such treatment. A peer review group was established via open invitation from the expert advisory group of the West Midlands Renal Network, this was led by the Renal Clinical Director.

This multi-professional group, including patient representatives, agreed on the structure for review, and data sets to be collected. Full consultation was then taken within the region with establishment of terms of reference via NHS England Specialised Commissioning. Complementary and alternative medicine CAM is a multibillion-dollar industry. Almost half of the American population uses some form of CAM, with many using them in addition to prescription medications.

Most patients fail to inform their health care providers of their CAM use, and physicians rarely inquire. Annually, thousands of dietary supplement—induced adverse events are reported to Poison Control Centers nationwide. CAM manufacturers are not responsible for proving safety and efficacy, because the Food and Drug Administration does not regulate them.

However, concern exists surrounding the safety of CAM. English-language studies and case reports were selected for inclusion but were limited to those that consisted of human subjects, both adult and pediatric. This review provides details on dietary supplements that have been associated with renal dysfunction and focuses on 17 dietary supplements that have been associated with direct renal injury, CAM-induced immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, and hepatorenal syndrome. It is concluded that it is imperative that use of dietary supplements be monitored closely in all patients.

Health care practitioners must take an active role in identifying patients who are using CAM and provide appropriate patient education. In general, most CAM consumers are not dissatisfied with conventional medicine but instead are aiming to complement mainstream medicine 5.

CCRN Renal Review - FULL

This is significant because nearly 15 million dietary supplement users also use prescription medications 2. This dilemma may be attributed to the lack of specific questioning by practitioners or the patient's perception that the medical establishment has a negative attitude toward CAM. Forty-six percent of supplements users consider these products to be safe and effective.


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Unfortunately, most patients likely do not comprehend the potential for adverse events or drug—supplement interactions 2. The prevalence of drug misadventures related to CAM use is high. Also, there are no requirements for product labeling to warn of known or potential adverse reactions 8. As a whole, the lack of enforcement of good manufacturing practices in the dietary supplement industry is evident in reports of impurities and adulteration 9 — However, the availability of dietary supplement—induced adverse reaction data is limited, because reporting of these events is voluntary The majority of available information comes from case reports; therefore, tangible cause-and-effect relationships usually cannot be established.

The objective of this article is to compile and briefly review the available data on CAM-induced nephrotoxicity. We provide detail of the renal injury and postulated mechanism of toxicity but are often limited by the data presented by the authors of the case reports. This review focuses only on supplements that commonly are available in the US market Table 1. A variety of foods that are ingested for medicinal purposes have been associated with nephrotoxicity.

A discussion of these medicinal foodstuffs e. It should be noted that many widely used dietary supplements are not generally taken in pure form but are mixtures of a variety of entities, which may have multiple interactions with each other. This makes it more difficult to identify the offending nephrotoxin in patients who consume CAM.

Review of nephrotoxic dietary supplements a. There are three case reports of renal dysfunction secondary to chromium picolinate CP 15 — Chromium levels were three times normal. An abdominal ultrasound revealed enlarged kidneys, with muddy brown casts and urine microscopy consistent with acute tubular necrosis ATN.

No biopsy was performed.

HIV and renal disease: a contemporary review.

The patient's renal function improved after several days of hemodialysis HD A computed tomography scan and an abdominal ultrasound showed inflammation in the right, sole kidney. A renal biopsy revealed necrotic tubular epithelium with intraluminal debris consistent with ATN. The patient was treated with HD, plasmapheresis, and corticosteroids and ultimately regained normal renal function A renal biopsy revealed severe chronic active interstitial nephritis, consistent with heavy-metal exposure.

Renal function improved with corticosteroid therapy Controversy surrounds the potential of creatine to induce renal failure. Several small-scale trials argued against creatine-induced nephrotoxicity, although creatine has been associated with two cases of renal dysfunction 18 — Koshy et al.

Laboratory analysis revealed an elevated serum creatinine SCr. Urinalysis showed proteinuria and hematuria, with urine sediment containing white-cell casts and dysmorphic red cells. A renal biopsy demonstrated acute focal interstitial nephritis, tubular injury, a thickened basement membrane, and effacement of the foot processes.

Renal Failure: Vol 41, No 1

Renal function fully recovered after hydration The second case involved a yr-old man with an 8-yr history of FSGS and frequently relapsing nephrotic syndrome The patient had been in remission for 5 yr. One month after stopping the creatine, the patient's renal function normalized Germanium has been associated with renal dysfunction, and, in all cases, the overall exposure to germanium ranged from 2 to 36 mo and the cumulative dosage of germanium ingested ranged from 15 to g.

In most cases, histologic examination revealed tubular degeneration with minor glomerular abnormalities. Recovery of renal function is often slow and incomplete 23 — Fanconi syndrome is impairment in renal proximal tubular function and may lead to acidosis, dehydration, and electrolyte imbalances. It is often treated supportively until the underlying cause is addressed. Subsequently, the patient progressed to chronic renal failure Chaparral-induced nephrotoxicity is reported in a single case involving a yr-old woman with a 3-mo history of chaparral ingestion 18 mo before diagnosis The patient presented with an elevated SCr and was found to have bilateral renal cystic disease and cystic renal cell carcinoma Meticulous search excluded major causes of cystic renal disease.

The authors concluded that nordihydroguaiaretic acid, in the form of chaparral, was the most likely cause of the carcinoma. Nordihydroguaiaretic acid is a major constituent of chaparral and has been associated with cystic nephropathy in animal studies 35 , Progressive renal failure and proteinuria is reported in a yr-old man who also developed generalized erythrodermic skin eruptions, fever, and pleural and pericardial effusions 1 d after taking yohimbine, a component of yohimbe.

A renal biopsy was not preformed in this case. The patient was treated with corticosteroids and regained normal renal function within 2 wk. The authors concluded that this was yohimbine-induced systemic lupus erythematosus with resultant renal dysfunction The active constituent of willow bark is believed to be salicin.

In vivo , salicin is metabolized to saligenin, which is further metabolized to salicylate 38 , Salicylates are known to cause renal dysfunction, secondary to prostaglandin inhibition and a reduction in renal blood flow Willow bark has been implicated in the renal dysfunction diagnosed on review of the autopsy of Ludwig van Beethoven His kidneys were described as normal size and shape but with calcareous deposits in each calyx.

It is believed that these deposits were necrotic papillae consistent with analgesic nephropathy 40 , A single case report of renal and cardiac toxicity in a yr-old man has been reported Three days after ingesting thunder god vine extract, the patient presented with profuse nausea, vomiting, diarrhea, leukopenia, renal failure, hypotension, and extensive cardiac abnormalities. The patient died 3 d after presentation from intractable shock. The authors could not differentiate the cause of this patient's renal dysfunction, postulating that it could have been supplement-induced nephrotoxicity, in conjunction with prolonged shock A case report of cat's claw—induced renal dysfunction described a patient who had systemic lupus erythematosus and worsening renal function and urinary sediment abnormalities after using cat's claw A biopsy was not done, but a diagnosis of acute allergic interstitial nephritis was made.

Renal function improved 1 mo after discontinuation of the supplement Stone formation within the urinary tract represents a complication of several disease states. Renal stones are generally composed of calcium, oxalate, urate, cystine, or struvite. However, the exact composition of the stones depends on the underlying condition. Kidney stones travel through the collecting system, but many are too large to negotiate the narrow conduits, causing obstruction with resultant renal dysfunction.

Vitamin C is metabolized to several byproducts, including oxalate, before elimination via filtration and tubular reabsorption Multiple episodes of oxalosis from vitamin C supplementation have been reported 45 — Since , the Food and Drug Administration has received nearly reports of ephedra-induced adverse events There have been two reports of nephrolithiasis associated with ephedra.

Analysis of the stones revealed the presence of ephedrine, norephedrine, and pseudoephedrine. The Food and Drug Administration has determined that ephedra presents an unreasonable risk for adverse events, and in April , it prohibited the sale of ephedra-containing dietary supplements in the United States Despite this ban, ephedra is widely available for purchase on the internet. Cranberries contain oxalate, and one concentrated cranberry tablet mg contains approximately mg of oxalate. Terris et al. After presenting with severe right flank pain, hematuria, and an elevated SCr, an abdominal ultrasound revealed left and right ureteral stones.

The patient's SCr normalized after stone removal. Calcium oxalate was present in the stones.

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After reviewing this patient's case, the authors conducted an experiment to analyze h urine samples from five healthy volunteers before and after consumption of cranberry. Oxalate excretion increased The authors concluded that concentrated cranberry tablets increase the risk for calcium-oxalate stone formation Rhabdomyolysis may be asymptomatic or present with muscle weakness or myalgias and creatinine phosphokinase CPK elevations.

More severe cases may include electrolyte imbalances and AKI.

Rhabdomyolysis can be caused by trauma, extreme physical exertion, electrolyte imbalances, or certain medications Reports of CAM-induced acute rhabdomyolysis leading to renal dysfunction are reviewed next. Weisbord et al. After consuming 10 ml of oil, the patient developed tonic-clonic seizures.


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  5. The patient reported bilateral muscle soreness in his legs on hospital day 2 and reached his peak SCr on hospital day 3. With supportive care, the patient's renal function normalized 17 d after presentation The authors concluded that wormwood oil was responsible for the patient's seizure, which apparently led to rhabdomyolysis and subsequent AKI. Although this is not a case of direct supplement-induced rhabdomyolysis, it does outline the importance of CAM-induced adverse events.

    Table 2 contains a group of dietary supplements that have been associated with seizures in humans. Dietary supplements common names associated with seizures All patients developed extreme muscle pain after participating in strenuous exercise and developed severe rhabdomyolysis. Three patients required HD, four developed compartment syndrome necessitating fasciotomy, and one died of multisystem organ failure 61 — Licorice is a potent diuretic and has been associated with severe hypokalemia 39 , Renal failure is a rare adverse event associated with licorice, but reports of nephrotoxicity secondary to hypokalemia have been described.

    Journal of Renal Nutrition

    Initial laboratory analysis noted hypokalemia with elevated CPK and myoglobin levels. AKI and profound calcium deposition seen in the muscles were secondary to licorice-induced hypokalemic rhabdomyolysis Another case described a yr-old woman who consumed 30 licorice tablets per day for 4 mo to promote weight loss The patient developed painful muscle weakness and was found to have hypokalemia and an elevated CPK.

    A renal biopsy revealed severely damaged tubular cells with intense vacuolar formations Licorice produces rhabdomyolysis-induced renal dysfunction as a result of potassium diuresis. Several other dietary supplements have been used for their diuretic-like effects, and these agents should be used with caution, especially in patients with underlying renal dysfunction or those who take prescription diuretics A list of these agents can be found in Table 3.

    Dietary supplements common names with known or potential diuretic properties 39 , Hepatorenal syndrome is the development of AKI in patients with liver dysfunction. The development of renal dysfunction is an indicator of clinical deterioration as a result of decreased renal perfusion. Overall, increased perfusion requirements activate the renin-angiotensin-aldosterone system with resultant renal vasoconstriction.

    Treatment is centered on correcting the underlying hepatic dysfunction. Dietary supplements with documented hepatorenal syndrome are discussed next.

    Review: SGLT2 Inhibitors Provide Clear Renal Benefits in Type 2 Diabetes

    However, many CAM are hepatotoxic but have yet to produce published reports of hepatorenal syndrome Table 4 contains those CAM with reported hepatotoxic adverse events. Hepatotoxic dietary supplements common names 39 , Pennyroyal has been associated with renal dysfunction in the setting of hepatotoxicity 68 , Two infants died of combined liver and renal failure after ingestion of preparations that contained pennyroyal 69 , An autopsy in one of the children revealed hepatocellular necrosis, edematous hemorrhagic kidneys with ATN, left adrenal hemorrhage, and bilateral lung consolidation Another report described a young woman who presented with oliguria and died within 48 h of multisystem organ failure and anoxic encephalopathy Postmortem findings revealed acute proximal tubular degeneration.

    Initial laboratory results revealed uremia and elevated liver function tests and prothrombin time. The patient subsequently developed hepatic encephalopathy, coagulopathy, and progressive renal failure, leading to the initiation of HD. Autopsy revealed autolysis of the kidneys. A similar case of multisystem organ failure was reported in a patient who handled hydrazine for industrial applications Four cases of nephrotoxicity were seen in patients who consumed yellow oleander and consequently developed jaundice, oliguria, and fever Serum bilirubin, SCr, and blood urea nitrogen levels all were elevated.