An Overlooked Link between IgA Nephropathy and Lithium Toxicity: A Case Report

Lithium is one of the first-line agents for treating bipolar disorder. Although this agent is highly effective in treating mood disorders, renal toxicity is a frequent side effect. Lithium metabolism is affected by sodium-lithium counter-transporter (SLC-T) in erythrocytes. The high activity of SLC-T can result in decreased urinary lithium clearance and may lead to accumulation of lithium in the distal renal tubular cells, causing lithium toxicity. SLC-T is a genetic marker in primary hypertension (HTN), HTN in pregnancy, diabetic nephropathy, and IgA nephropathy (IgA-N) with HTN. Patients with IgA-N have been reported to have enhanced SLC-T activity and are likely to have considerably lower renal fractional clearance of lithium. Therefore, patients taking lithium for bipolar disorder with coexisting IgA-N can have severe lithium-induced nephropathy and nephrotoxicity even at therapeutic serum levels. Serum lithium levels reflect only extracellular lithium concentration. However, lithium exerts its effects once it has moved to the intracellular compartment. This phenomenon illustrates the reason why patients with significantly elevated serum levels might be asymptomatic. Creatinine clearance is inversely related to the duration of lithium therapy. The degree of interstitial fibrosis on renal biopsy has been known to be associated with the duration of lithium therapy and cumulative dose. We present a case with a past medical history of bipolar disorder treated with lithium for almost 20 years. His family history was significant for HTN. The patient was diagnosed with renal insufficiency of unknown causes, for which he underwent renal biopsy. The renal biopsy showed a typical lithium-induced tubulointerstitial nephritis and a coincidental finding of IgA-N. We suspect a high activity of SLC-T seen in IgA-N, and the adverse effects of lithium on SLC-T activity might cause reduction of urinary lithium clearance and accumulation of lithium in distal renal tubular cells, contributing to nephrotoxicity. There is a lack of the literature on the coexistence of IgA-N and lithium nephrotoxicity. We recommend in patients with concomitant IgA-N, taking lithium, more frequent monitoring of renal functions, and dose adjustments may reduce the risk of lithium-induced nephrotoxicity.

Abstract P040: Pressure Natriuresis In Female Sprague Dawley Rats: Characteristics And Mechanisms

Raising blood pressure stimulates pressure natriuresis (P-Nat). In males (M) Sprague Dawley rats (SDR), Na + reabsorption (T Na ) is acutely reduced by retraction of proximal tubule (PT) NHE3 to microvillar base and NaPi2 internalization. In females (F), at baseline PT NHE3 is already at microvillar base and NaPi2 is less abundant than in M. We AIM to determine characteristics and mechanisms of P-Nat in F (vs M) rats. Methods: Inactin anesthetized F and M SDR (n=5/group) were provoked by vasoconstriction (or sham). Mean arterial pressure (MAP) was recorded via carotid artery, urine collected via bladder, Na + transporters’ abundance assessed via immunoblot and localization by immunohistochemistry. Results (Fig 1A): Baseline MAP (mmHg) was lower in F vs. M (91 ± 5 vs.105 ± 3, P =0.04) while urine volume (UV) and electrolyte excretion (UNaV, UKV) were similar. After celiac and mesenteric bed constriction, MAP rose to 128 ± 3 mmHg in both sexes; UNaV, UV and C Na increased 12 to 15-fold in F (all P <0.01) vs 6-fold in M ( P >0.08). Constriction of abdominal aorta further raised UNaV in F with less impact in M. Na + transporters . In F, NHE3 remained at PT microvillar base and NaPi2 was internalized with vasoconstriction. NHE3P (indicating inactivation) abundance increased 29% in F, P =0.058. Lithium clearance, measure of volume flow leaving early nephron, increased 9-fold in F ( P =0.02) vs. 5-fold in M ( P =0.07). F mTAL NHE3, NKCC2p, and SPAKp (co-transporter kinase) abundances were 22, 24, and 43% lower vs shams ( ANOVA P <0.0001). Summary: F vs M SDR exhibit more robust P-Nat associated with less T Na in early nephron and reductions in PT-mTAL Na + transporters, consistent with higher UNaV at any given BP (Fig 1B).

Sex and Body Mass Index Modify the Association Between Leptin and Sodium Excretion: A Cross-sectional Study in an African Population

BACKGROUND Renal sodium handling could be a potential mediator linking adipokines to hypertension. The aim of the study was to assess the relationship of leptin with urinary sodium excretion and proximal sodium reabsorption in humans. METHODS This cross-sectional study was conducted on participants of hypertensive families from the Seychelles Island. A split urine (daytime and nighttime) collection and plasma leptin were measured. Endogenous lithium clearance was used to assess proximal sodium reabsorption. Mixed multiple linear regression tests adjusted for confounding factors were used. RESULTS Three hundred and sixty-five participants (57% women) were included in this analysis. Leptin and adiponectin were higher in women (P < 0.001). Leptin was associated positively with daytime (coefficient [c]: 0.16, standard deviation (SD): 0.03, P < 0.001), nighttime urinary sodium excretion (c: 0.17, SD: 0.04), P < 0.01), daytime lithium clearance (c: 0.40, SD: 0.08, P < 0.001), and nighttime lithium clearance (c: 0.39, SD: 0.10, P < 0.001) after adjusting for sex. The association was lost or mitigated only when BMI was introduced in the model. When BMI was categorized in normal vs. overweight participant, leptin was associated with daytime and nighttime sodium excretion rates (c: 0.14, SD: 0.05, P = 0.011 and c: 0.22, SD: 0.07, P = 0.002, respectively) only in overweight participants. CONCLUSION Leptin is associated positively with daytime and nighttime sodium excretion and lithium clearance suggesting a natriuretic rather than a sodium retaining effect of leptin. Sex and body mass index (BMI) are major confounders in this association. These results highlight the importance of sex and obesity in our understanding of the relationships between leptin, blood pressure, and renal sodium handling.

Lithium Toxicity in the Setting of Nonsteroidal Anti-Inflammatory Medications

Lithium toxicity is known to affect multiple organ systems, including the central nervous system. Lithium levels have been used in the diagnosis of toxicity and in assessing response to management. There is evidence that nonsteroidal anti-inflammatory medications (NSAIDs) can increase lithium levels and decrease renal lithium clearance. We present a case of lithium toxicity, which demonstrates this effect and also highlights the fact that lithium levels do not correlate with clinical improvement, especially the neurological deficit.