Urinary oxalate is derived from endogenous production and absorption from exogenous sources. Hyperoxaluria (urine oxalate above the normal range of 10–35 mg/24 hr) can be primary or secondary. Primary hyperoxaluria results from genetic defects in glyoxylate metabolism, producing nephrolithiasis, nephrocalcinosis, and progressive renal insufficiency [9]. Secondary hyperoxaluria is acquired from enteric causes or ethyl glycol intoxication. Normally, Ca binds most of the intestinal oxalate, with subsequent stool CaOx elimination. Accordingly, only 4 to 12% of enteric oxalate is normally absorbed. After small bowel bypass, Ca complexes with poorly absorbed fatty acids, leaving behind excess unbound oxalate for absorption, 65 to 80% of which occurs in the colon [6, 7]. This mechanism also explains the enteric hyperoxaluria in chronic diarrhea and malabsorption.
Another important but under-appreciated etiology of secondary hyperoxaluria is increased synthesis from vitamin C [1–5]. We previously reported the quantitative dose-response relationship in a patient receiving vitamin C solely from parenteral nutrition [5]. If coexisting, malabsorption and high-dose vitamin C could potentiate the hyperoxaluria induced by each other.
Clinically, hyperoxaluria presents in one of several ways, depending on the severity, chronicity, etiologies and co-factors. First, at one extreme, as in ethylene glycol intoxication, fulminant acute renal failure from intraluminal obstruction can develop, due to excessive oxalate production and profound hyperoxaluria. Second, at the other end, intermittent hyperoxaluria could cause episodic painful renal colic from small punctuate Ca Ox calculi. Despite short-term morbidities, few suffer from serious long-term renal insufficiency. The third mode of clinical presentation is illustrated by primary hyperoxaluria.
Our patient demonstrates the fourth mode of manifestation in that insidious renal failure, easily missed, slowly evolves over weeks to months, unbeknown to patients and physicians until renal function is compromised by >50–70 %. Typically, for diffuse intraluminal crystal deposits and extensive interstitial fibrosis to develop, the course is protracted. While the first three modes (ethylene glycol intoxication, episodic stone attacks, and primary hyperoxaluria) are clinically symptomatic and promptly treated, the 4th mode is generally quiescent, asymptomatic, undiagnosed, and untreated for months, like our patient, unless tests reveal incidental unexpected progressive renal failure.
In our patient, intratubular luminal precipitation of Ca oxalate was promoted by four pathogenic factors (Fig 3): (1) high urine specific gravity (due to diarrhea-induced dehydration), (2) hyperoxaluria from all three potentiating mechanisms (oxalate-rich diet, 680 mg daily vitamin C, and possible malabsorption), (3) relative hypercalciuria (due to furosemide, chronic metabolic acidosis, and hypercalcemia, caused by CaCO3 pills and vitamin A and D), and (4) hypocitraturia (due to metabolic acidosis, initially from chronic diarrhea and later aggravated by progressive renal failure).
The pathophysiology of hyperoxaluria-induced nephropathy is schematized in Fig 3. Tubular fluid supersaturated with Ca oxalate crystals causes luminal obstruction, macrophage recruitment, up-regulated reactive oxygen species, pro-inflammatory & pro-fibrogenic cytokines, creating a vicious cycle of interstitial nephritis, relentless injuries, apoptosis, necrosis, fibrosis, with eventual nephron drop-out and tubular atrophy. Initially, hypocitraturia from stool alkali losses is modest, but with worsening renal failure, metabolic acidosis and hypocitraturia become more severe. Nephron losses further elevate blood and filtered oxalate, raising tubular fluid oxalate concentration in surviving nephrons. These changes exacerbate the risks for luminal crystals precipitation, tubular obstruction, inflammation, and interstitial nephritis. As more tubules die out, the vicious cycle is exaggerated. This could explain the steep increase in serum creatinine from 1.8 to 8.4 mg/dL (representing 44 % loss in creatinine clearance in 5 weeks before admission) vs. the gentle rise from 1.2 to 1.8 mg/dL (representing 28% loss in clearance over the preceding 4 months) (Fig 1b).
Treatment of hyperoxaluria-induced nephropathy depends on interrupting the pathophysiology (Fig 3), specifically, by increased fluids, low oxalate diet, discontinuing vitamins A, C, D, and CaCO3, prescribing thiazide (or metolazone if creatinine is elevated, to reduce urine Ca), and NaHCO3 to increase urine citrate. Metabolic acidosis is known to markedly decrease tubular fluid citrate, the predominant endogenous inhibitor of Ca oxalate precipitation [8]. In patients with malabsorption, underlying etiologies should be addressed, and Na or K alkali salts (citrate or bicarbonate) should minimize metabolic acidosis, increase urine citrate, and reduce urine Ca. (Fig 3). We counseled continued alcohol abstinence in our patient. All identifiable causes of hypercalcemia and hypercalciuria were eliminated, and we empirically added vitamin B6, which promotes conversion of glyoxylate to glycine instead of oxalate.
Unfortunately, vitamin C-induced hyperoxaluria is often missed or diagnosed late in the course of renal failure, and for several reasons. One, increasingly individuals take daily multi-vitamins or high-dose vitamin C on their own. Second, current commercial preparations contain vitamin C typically several-fold over the adult daily requirement of 60 mg. Most juices, soft drinks, and diet supplements contain > 120 mg of vitamin C per 8 oz. These add greatly to food-derived oxalate. Third, self-prescribed medications are not routinely checked or discovered by physicians, as the potential adverse hyperoxaluric consequence is generally unrecognized. Fourth, the causal relationship between hyperoxaluria and renal failure is also under-appreciated. Finally, when advanced renal insufficiency emerges, the focus is shifted to uremia management. Identifying and defining the etiology is seldom exhaustively undertaken or usually unsuccessful.