Pembrolizumab-induced Acute Tubulointerstitial Nephritis Accompanying Fanconi Syndrome and Type 1 Renal Tubular Acidosis.

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Zonisamide-induced distal renal tubular acidosis and critical hypokalaemia.

A woman in her 20s presented with rapidly progressive muscle weakness and a 1-month preceding history of fatigability, nausea and vomiting. She was found to have critical hypokalaemia (K+ 1.8 mmol/L), a prolonged corrected QT interval (581 ms) and a normal anion gap metabolic acidosis (pH 7.15) due to zonisamide-induced distal (type 1) renal tubular acidosis. She was admitted to the intensive care unit for potassium replacement and alkali therapy. Clinical and biochemical improvement ensued, and she was discharged after a 27-day inpatient stay.

Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103).

BACKGROUND AND OBJECTIVES: ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated. PATIENTS AND METHODS: Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well. RESULTS: After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p=0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005). There was an increase>0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69-86% and 93-96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients. CONCLUSIONS: Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters.

Tenofovir-induced distal renal tubular acidosis: A rare cause of recurrent hypokalaemic paralysis.

Tenofovir disoproxil fumarate was the first nucleotide analogue reverse transcriptase inhibitor to be approved for treatment of human immunodeficiency virus infection. It is a relatively safe drug but can present with nephrotoxicity. We report a case of 36-year-old male who presented with acute onset flaccid paraparesis. He was a diagnosed case of acquired immunodeficiency syndrome for 9 years ago and was on tenofovir-based antiretroviral therapy for last 6 months. As the patient had normal anion gap metabolic acidosis, hypokalaemia and urine pH > 5.5, distal renal tubular acidosis (RTA) was suspected. He improved dramatically within 24 h of hospitalisation after potassium correction to regain normal power. Tenofovir-induced distal RTA presenting as hypokalaemic paralysis is a very rare complication of tenofovir; hence, we are reporting this case. In addition, we suggest regular follow-up of patients taking tenofovir with urine analysis and serum potassium to detect this complication earlier as it is reversible.

Distal renal tubular acidosis and lethargy associated with zonisamide treatment in a dog with idiopathic epilepsy.

A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with hypokalaemia, hyperchloremia, and alkaline urine. The serum zonisamide concentration was close to the upper limit, which raised a suspicion of adverse effects of zonisamide. This is the first report showing that the fractional excretion of bicarbonate after compensation for the plasma bicarbonate concentration by a sodium bicarbonate infusion was approximately 5%, indicating distal renal tubular acidosis (RTA). The serum zonisamide concentration decreased, and adverse effects were abated by reducing the zonisamide dosage. Diagnostic therapy with bicarbonate served as a means of compensating for bicarbonate deficiency and contributed to the clinical diagnosis of the condition in zonisamide-associated RTA in dogs.

Presumptive renal tubular acidosis secondary to topiramate administration in a cat.

OBJECTIVE: To describe renal tubular acidosis (RTA) and secondary acquired hyperaldosteronism in a cat as an adverse effect of topiramate therapy. CASE SUMMARY: An 8-year-old neutered female cat on chronic oral topiramate therapy at a recommended dose (11.9 mg/kg q 8 h) for seizure control was presented with severe metabolic acidosis and hypokalemia. Plasma electrolyte and acid-base analysis identified a severe metabolic acidosis (pH 7.153, reference interval: 7.31-7.46), hypokalemia (2.08 mmol/L [2.08 mEq/L], reference interval: 3.5-4.8 mmol/L [3.5-4.8 mEq/L]), and ionized hypercalcemia (1.85 mmol/L [1.85 mEq/L], reference range: 1.1-1.4 mmol/L [1.1-1.4 mEq/L]). Urinalysis revealed a urine specific gravity of 1.021 and a pH of 7.0. Diagnostic workup suggested distal RTA as a cause of the cat's acid-base and electrolyte disturbances. Aldosterone concentration was moderately increased, suggestive of secondary hyperaldosteronism. The metabolic abnormalities resolved with supportive care and discontinuation of topiramate. NEW OR UNIQUE INFORMATION PROVIDED: Topiramate is suggested to have led to the development severe RTA in a cat.

Paint-thinner-induced Acute Kidney Injury: A Case Series and Review.

Occupational health hazards contribute significantly to the morbidity and mortality of workers in factories. Toluene has become a widely abused inhaled volatile drug. The spectrum of toluene-induced renal injury includes rhabdomyolysis, myoglobinemia, distal renal tubular acidosis (RTA), acute tubular necrosis, glomerulonephritis, and interstitial nephritis. We describe two patients with paint-thinner-induced kidney injury who were affected through different routes of exposure and recovered well, with one requiring dialysis support; the second patient, who had developed Type 1 distal RTA and mild kidney injury, was managed with conservative measures. Toluene can cause acute neurological symptoms, accompanied by severe metabolic alterations, as well as organ injury and dysfunction. A common association of the development of hypokalemic paralysis and metabolic acidosis with toluene intoxication was observed. Liver injury and rhabdomyolysis are also common. Vomiting, dehydration, tubular injury, and rhabdomyolysis are all possible additional causes of acute renal failure in toluene intoxication. Type 1 distal RTA, which is characterized by an inability to lower urine pH despite acidemia, results in hyperchloremic metabolic acidosis with hypokalemia. The management of acute toluene toxicity is largely conservative, consisting of correcting the electrolytes and the acid-base balance, fluid alterations, and renal replacement therapy in severe acute kidney injury. A clinical suspicion of organ failure and prompt supportive care leads to encouraging results. Adequate protective steps for workplaces involved in the use of such substances in confined spaces include prior risk assessment, using low-toxicity chemical products, ensuring adequate ventilation, safety training, and using appropriate personal protective equipment.

Omeprazole-induced hypomagnesaemia, causing renal tubular acidosis with hypokalaemia, hypocalcaemia, hyperlactacidaemia and hyperammonaemia.

A 72-year-old Japanese man treated with omeprazole for 11 years was admitted due to loss of consciousness and muscle weakness. Wolff-Parkinson-White syndrome-induced tachycardia was considered as the cause of syncope. His blood examination revealed rhabdomyolysis, hypokalaemia, hypomagnesaemia, hypocalcaemia, hyperlactacidaemia, hyperammonaemia and high-anion-gap metabolic acidosis. Hypomagnesaemia could be caused by magnesium malabsorption due to omeprazole use. Hypocalcaemia might be caused by the inhibitory effect of hypomagnesemia on the parathyroid gland hormone secretion. Hyperammonaemia might be caused by two reasons: (1) renal ammonium production induced by hypokalaemia; (2) inhibition of ammonium secretion by omeprazole. Both hypocalcaemia and hypokalaemia might cause chronic elevation of serum creatinine phosphokinase which ended up with rhabdomyolysis. Correction of serum electrolytes rapidly improved his muscle weakness. Discontinuation of omeprazole no longer caused these abnormalities. A physician should be aware of unexplained signs and symptoms of patients using proton-pump inhibitors to avoid life-threatening electrolyte and physiologic disturbances.

Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry.

Chronic heavy metal exposure and the health hazards that ensue are important public-health problems. We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India. Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. Considering their occupation, their blood samples were screened for heavy metals and were found to have toxic levels of cadmium. They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms. It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences. Moreover, regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure.

Impaired consciousness, hypokalaemia and renal tubular acidosis in sustained Nurofen Plus abuse.

Ibuprofen-induced renal tubular acidosis is a rare but important diagnosis which should be considered in patients presenting with hypokalaemia and metabolic acidosis. This case report details the case of a 33-year-old woman presenting with reduced conscious state, metabolic acidosis and profound hypokalaemia without an obvious cause. With correction of the patient's electrolyte and acid-base disturbance, her conscious state improved allowing disclosure of her use of Nurofen Plus for its euphoric opiate effects. The diagnosis of renal tubular acidosis had been considered and subsequent disclosure of excessive chronic ingestion of ibuprofen suggested this to be the underlying cause. The striking feature of our patient was the insidious development of the problem and delayed accurate drug history. An important safety message arising from our case is the composite risk of dependence on the opiate component of over the counter analgesics, such as Nurofen Plus, and adverse events related to the ibuprofen component.

Gut It Out: Laxative Abuse Mimicking Distal Renal Tubular Acidosis.

BACKGROUND: Distal renal tubular acidosis (dRTA) can be inherited or acquired. CASE PRESENTATION: Here, we describe the case of a 45-year-old female patient with non-anion gap metabolic acidosis, hypokalemia, and alkaline urine. She had a history of rheumatoid arthritis and kidney stones and failed to acidify urine upon the fludrocortisone and furosemide test. Therefore, the diagnosis of dRTA secondary to an autoimmune disease was made. A kidney biopsy was examined for markers of acid-secretory intercalated cells. Surprisingly, no obvious difference in the relative number of acid-secretory intercalated cells or in the distribution of major proteins involved in acid secretion was found. Furthermore, increasing doses of potassium citrate failed to correct the hypokalemia and acidosis. Since these findings were rather atypical for autoimmune dRTA, alternative causes of her hypokalemia and metabolic acidosis were sought. The patient was found to chronically consume laxatives, which can also cause kidney stones and may result in a false-positive urinary acidification test. CONCLUSION: Chronic laxative abuse may mimic dRTA and should therefore be considered in unexplained hypokalemia with non-anion gap metabolic acidosis.

Cleistanthus collinus poisoning affects mitochondrial respiration and induces oxidative stress in the rat kidney.

Cleistanthus collinus is a poisonous shrub used for deliberate self-harm in rural areas of South India and intake of boiled decoction of leaves is a common method of self-harm. Distal renal tubular acidosis (dRTA) is an important clinical symptom observed in C. collinus poisoning, and renal V-ATPases may be potential targets of damage. However, a lack of understanding of molecular mediators involved hampers medical management, which is mainly supportive. We hypothesized that C. collinus poisoning induces renal oxidative stress; probably by inducing mitochondrial uncoupling, which compromises V-ATPase activity to ultimately produce dRTA. This was tested by exposing renal BBMV, kidney cells in culture, and Wistar rats to C. collinus poisoning. Exposure to C. collinus aqueous extract resulted in significant elevations in the lipid peroxidation marker, conjugated dienes, in cell culture and in vivo. A significant decrease in mitochondrial respiratory control ratio was observed in kidneys from C. collinus-treated animals suggesting that mitochondrial oxidative phosphorylation is uncoupled. This was accompanied by significant increase in ADP levels and a decrease in proton pump activity. Thus, these results demonstrate that C. collinus poisoning induces oxidative stress which influences proton pump activity, probably due to feedback inhibition by elevated ADP levels because of mitochondrial dysfunction in the rat kidney.

Tenofovir and Severe Symptomatic Hypophosphatemia.

Tenofovir is a broadly used drug used for the treatment of human immunodeficiency virus (HIV). Although the initial results of the clinical trials supported the renal safety of Tenofovir, clinical use of it has caused a low, albeit a significant, risk of renal damage either in the form of AKI or CKD. The pathophysiology has been linked to the effect of this medication on the proximal tubular cell. Although the exact mechanism is unknown, studies have suggested that Tenofovir accumulates in proximal tubular cells which are rich in mitochondria. It is both filtered in the glomerulus and actively secreted in the tubules for elimination and is excreted unchanged in the urine. Studies have shown an active transportation of 20-30% of this drug into the renal proximal tubule (PCT) cells via the organic anion transporters in the baso-lateral membrane (primarily hOAT1, and OAT3 to a lesser extent) and ultimate excretion of the drug into the tubular lumen via the transporters in the proximal tubular apical membrane MRP4 and MRP2 (multidrug resistance-associated proteins 2 & 4). Subsequently, the mitochondrial injury caused by Tenofovir can lead to the development of Fanconi's syndrome which causes renal tubular acidosis, phosphaturia, aminoaciduria, glucosuria with normoglycemia, and tubular proteinuria. Here we present a case where Tenofovir treatment resulted in severe hypophosphatemia requiring hospitalization for parentral phosphate repletion.

Complications related to chronic supratherapeutic use of codeine containing compound analgesics in a cohort of patients presenting for codeine withdrawal.

INTRODUCTION AND AIMS: This study aimed to compare complications arising due to the supratherapeutic use of paracetamol/codeine or ibuprofen/codeine containing compound analgesics in primary codeine-dependent patients presenting to a drug and alcohol withdrawal service. Data was compared to determine if there was any difference in the number of complications observed between the two groups. DESIGN AND METHODS: A retrospective case review of patients presenting for primary codeine dependence from 2009 to 2014. Sixty patients (42F, 36 ± 10 years) using ibuprofen/codeine and 46 (26F, 39 ± 10 years) using paracetamol/codeine containing compound analgesics were compared. A P value of <0.05 was considered significant. RESULTS: Patients consumed similar daily doses of codeine (699 ± 45 vs. 636 ± 50 mg) with those consuming ibuprofen/codeine containing compound analgesics ingesting twice as many tablets daily (median 60 vs. 30 tablets; P < 0.0001). Complications related to supratherapeutic use of codeine containing compound analgesics occurred more commonly in patients taking ibuprofen/codeine (52/60; 87%) versus paracetamol/codeine compound analgesics (30/46; 65%) (P < 0.01). Patients taking ibuprofen/codeine containing compound analgesics were more likely to have gastrointestinal bleeding (P < 0.05), anaemia (P < 0.0001) and renal tubular acidosis (P < 0.05). There were two deaths in the group abusing ibuprofen/codeine compound analgesics. DISCUSSION AND CONCLUSIONS: In patients with primary codeine dependence, there were more complications related to the supratherapeutic use of ibuprofen/codeine versus paracetamol/codeine containing compound analgesics. The patients in both groups ingested similar total daily codeine amounts. Increased daily tablet intake in the ibuprofen/codeine group could possibly have been linked to lower codeine content per tablet.